Cutaneous neurofibromas are benign nerve tumours, usually  nodular or pedunculated, that can be found anywhere on the skin.  Isolated neurofibromas are common in normal individuals, but if  multiple lesions are present neurofibromatosis (see Ch. 19) should  be excluded. Plexiform neurofibromas typically present in child¬  hood as a manifestation of neurofibromatosis type 1 with a char¬  acteristic S-shaped deformity of the upper eyelid (Fig. 1.16).  Treatment of solitary lesions involves simple excision but removal  of the more diffuse plexiform lesions may be difficult.    The treatment of malignant eyelid tumours in general is discussed  at the end of this section.   Young patients who suffer from one of the following conditions  may develop eyelid malignancies.   • Xeroderma pigmentosum is characterized by skin damage  on exposure to sunlight, leading to progressive cutaneous  abnormalities (Fig. 1.17A). It is inherited in an autosomal  recessive (AR) fashion. Affected patients have a bird-like  facies and a great propensity to the development of basal  cell carcinoma (BCC), squamous cell carcinoma (SCC)   Fig. 1.14 Port-wine stain. (A) Histopathology shows widely dilated blood-filled spaces separated by fibrous septa; (B) and  (C) clinical appearance; (D-F) progression of port-wine stain over time, with associated underlying soft tissue hypertrophy   (Courtesy of J Krachmer, M Marinis and E Holland, from Cornea, Mosby   and melanoma, which are commonly multiple. Conjunctival  malignancies have also been reported.   • Gorlin-Goltz syndrome (naevoid basal cell carcinoma  syndrome) is a rare autosomal dominant (AD) disorder  characterized by extensive congenital deformities of the eye,  face, bone and central nervous system. Many patients  develop multiple small BCC during the second decade of life  (Fig. 1.17B) and are also predisposed to medulloblastoma,  breast carcinoma and Hodgkin lymphoma.   • Muir-Torre syndrome is a rare AD condition that  predisposes to cutaneous and internal malignancies.  Cutaneous tumours include BCC, sebaceous gland  carcinoma and keratoacanthoma. Colorectal and  genitourinary carcinomas are the most common systemic  tumours.   • Bazex syndrome can be used to describe two distinct  conditions: (i) Bazex-Dupre-Christol syndrome, an    X-linked dominant condition characterized by multiple  BCCs, commonly facial including the eyelids, associated with  skin changes including follicular indentations without hairs  on extensor surfaces (follicular atrophoderma), hypohidrosis  and hypotrichosis; (ii) acrokeratosis paraneoplastica of  Bazex, in which eczema-like and psoriatiform lesions are  associated with an underlying malignancy of the upper  respiratory or digestive tract.   BCC is the most common human malignancy and typically affects  older age groups. The most important risk factors are fair skin,  inability to tan and chronic exposure to sunlight. Ninety per cent  of cases occur in the head and neck and about 10% of these  involve the eyelid. BCC is by far the most common malignant  eyelid tumour, accounting for 90% of all cases. It most frequently  arises from the lower eyelid, followed in relative frequency by  the medial canthus, upper eyelid and lateral canthus. The tumour  is slowly growing and locally invasive but non-metastasizing.  Tumours located near the medial canthus are more prone to  invade the orbit and sinuses, are more difficult to manage than  those arising elsewhere and carry the greatest risk of recurrence.  Tumours that recur following incomplete treatment tend to be  more aggressive.   The tumour arises from the cells that form the basal layer of  the epidermis. The cells proliferate downwards (Fig. 1.18A) and  characteristically exhibit palisading at the periphery of a tumour  lobule of cells (Fig. 1.18B). Squamous differentiation with the  production of keratin results in a hyperkeratotic type of BCC.  There can also be sebaceous and adenoid differentiation while the  growth of elongated strands and islands of cells embedded in a  dense fibrous stroma results in a sclerosing (morphoeic) type of  tumour.   Eyelid BCC generally conforms to one of the morphological  patterns below.   • Nodular BCC is a shiny, firm, pearly nodule with small  overlying dilated blood vessels. Initially, growth is slow and  it may take the tumour 1-2 years to reach a diameter of  0.5 cm (Figs 1.19A and B).   • Noduloulcerative BCC (rodent ulcer) is centrally ulcerated  with pearly raised rolled edges and dilated and irregular  blood vessels (telangiectasis) over its lateral margins (Fig.  1.19C); with time it may erode a large portion of the eyelid  (Fig. 1.19D).   • Sclerosing (morphoeic) BCC is less common and may be  difficult to diagnose because it infiltrates laterally beneath   Fig. 1.18 Histopathology of basal cell carcinoma. (A) Histopathology shows downward proliferation of lobules of basophilic  (purple) cells; (B) palisading of cells at the periphery of a tumour lobule   Fig. 1.19 Clinical appearance of basal cell carcinoma. (A) Early nodular lesion; (B) larger nodular tumour; (C) rodent ulcer;  (D) large rodent ulcer;    the epidermis as an indurated plaque (Figs 1.19E and F). The  margins of the tumour may be impossible to delineate  clinically and the lesion tends to be much more extensive on  palpation than inspection. On cursory examination a  sclerosing BCC may simulate a localized area of chronic  blepharitis.   • Other types not usually found on the lid are cystic, adenoid,  pigmented and multiple superficial.   SCC is a much less common, but typically more aggressive tumour  than BCC with metastasis to regional lymph nodes in about 20%  of cases. Careful surveillance of regional lymph nodes is therefore  an important aspect of initial management. The tumour may also  exhibit perineural spread to the intracranial cavity via the orbit.  SCC accounts for 5-10% of eyelid malignancies and may arise de  novo or from pre-existing actinic keratosis or carcinoma in situ  (Bowen disease, intraepidermal carcinoma - Fig. 1.20). Immuno¬  compromised patients, such as those with acquired immunodefi¬  ciency syndrome (AIDS) or following renal transplantation are at  increased risk, as are those with a predisposing syndrome such as  xeroderma pigmentosum. The tumour has a predilection for the  lower eyelid and the lid margin. It occurs most commonly in older  individuals with a fair complexion and a history of chronic sun  exposure. The diagnosis of SCC may be difficult because certain  ostensibly benign lesions such as keratoacanthoma and cutaneous  horn may reveal histological evidence of invasive SCC at deeper  levels of sectioning.   The tumour arises from the squamous cell layer of the epidermis.  It is composed of variably sized groups of atypical epithelial cells  with prominent nuclei and abundant eosinophilic cytoplasm  within the dermis (Fig. 1.21 A). Well-differentiated tumours may   The clinical types are variable and there are no pathognomonic  characteristics. The tumour may be indistinguishable clinically  from a BCC but surface vascularization is usually absent, growth  is more rapid and hyperkeratosis is more common.   • Nodular SCC is characterized by a hyperkeratotic nodule  that may develop crusting, erosions and fissures   • Ulcerating SCC has a red base and sharply defined,  indurated and everted borders, but pearly margins and  telangiectasia are not usually present (Fig. 1.21C).   Fig. 1.21 Squamous cell carcinoma. (A) Histopathology shows acanthotic squamous epithelium and eosinophilic (pink)  islands of dysplastic squamous epithelium within the dermis; (B) nodular tumour with surface keratosis; (C) ulcerating  tumour; (D) cutaneous horn   (Courtesy of L Horton - fig. A; A Singh, from Clinical Ophthalmic Oncology, Saunders 2007 - fig. B; H Frank - fig. C; S Farley; T Cole and L Rimmer - fig. D)   Keratoacanthoma is a rare, rapidly growing but subsequently  regressing tumour that usually occurs in fair-skinned individuals  with a history of chronic sun exposure. Immunosuppressive  therapy is also a predisposing factor. It is regarded as falling within  the spectrum of SCC, and although invasion and metastasis are  rare, definitive treatment is usually indicated. Histopathologically,  irregular thickened epidermis is surrounded by acanthotic squa¬  mous epithelium; a sharp transition from the thickened involved  area to normal adjacent epidermis is referred to as shoulder for¬  mation (Fig. 1.22A); a keratin-filled crater may be seen.   A pink dome-shaped hyperkeratotic lesion develops, often on the  lower lid (Fig. 1.22B), and may double or treble in size within  weeks (Fig. 1.22C). Growth then ceases for 2-3 months, after which  spontaneous involution occurs, when a keratin-filled crater may  develop (Fig. 1.22D). Complete involution may take up to a year  and usually leaves an unsightly scar.   Treatment generally involves complete surgical excision with a  margin of at least 3 mm, or utilizing Mohs surgery; radiotherapy,  cryotherapy or local chemotherapy are sometimes used. Observa¬  tion is now regarded as inappropriate.   Fig. 1.22 Keratoacanthoma. (A) Histopathology shows irregularly thickened eosinophilic epidermis with a keratin-containing  cup and well-marked shoulder formation; (B) hyperkeratotic nodule; (C) large tumour; (D) keratin-filled crater during involution   Sebaceous gland carcinoma (SGC) is a very rare, slowly growing  tumour that most frequently affects the elderly, with a predisposi¬  tion for females. It usually arises from the meibomian glands,  although on occasion it may arise from the glands of Zeis or else¬  where. The tumour consists histopathologically of lobules of cells  with pale foamy vacuolated lipid-containing cytoplasm and large  hyperchromatic nuclei (Fig. 1.23A). Pagetoid spread refers to  extension of a tumour within the epithelium, and is not uncom¬  mon. Overall mortality is 5-10%; adverse prognostic features  include upper lid involvement, tumour size of 10 mm or more and  duration of symptoms of more than 6 months.   In contrast to BCC and SCC, SGC occurs more commonly on  the upper eyelid where meibomian glands are more numerous;   • Yellowish material within the tumour is highly suggestive of  SGC.   • Nodular SGC presents as a discrete, hard nodule, most  commonly within the upper tarsal plate (Fig. 1.23B), and  may exhibit yellow discoloration due to the presence of  lipid; it can be mistaken for a chalazion.   • Spreading SGC infiltrates into the dermis and causes a  diffuse thickening of the lid margin (Fig. 1.23C) often with  eyelash distortion and loss, and can be mistaken for  blepharitis.   Fig. 1.23 Sebaceous gland carcinoma. (A) Histopathology  shows cells with large hyperchromatic nuclei and  vacuolated cytoplasm; (B) nodular tumour; (C) spreading  tumour   (Courtesy of A Gamer - fig. A; A Singh, from Clinical Ophthalmic Oncology,  Saunders 2007 - fig. B; S Tuft - fig. C)    lid melanomas are non-pigmented and this may give rise to  diagnostic difficulty. Features suggestive of melanoma include  recent onset of a pigmented lesion, change in an existing pig¬  mented lesion, irregular margins, asymmetrical shape, colour  change or presence of multiple colours, and diameter greater than  6 mm.   Lentigo maligna (melanoma in situ , intraepidermal melanoma,  Hutchinson freckle) is an uncommon condition that develops in  sun-damaged skin in elderly individuals. Malignant change may  occur, with infiltration of the dermis. Histopathology shows  intraepidermal proliferation of spindle-shaped atypical melano¬  cytes replacing the basal layer of the epidermis (Fig. 1.24A). Clini¬  cally lentigo maligna presents as a slowly expanding pigmented  macule with an irregular border (Fig. 1.24B). Treatment is usually  by excision. Nodular thickening and areas of irregular pig¬  mentation are highly suggestive of malignant transformation  (Fig. 1.24C).   Histopathology shows large atypical melanocytes invading the  dermis (Fig. 1.25A). Superficial spreading melanoma is character¬  ized by a plaque with an irregular outline and variable pigmenta¬  tion (Fig. 1.25B). Nodular melanoma is typically a blue - black  nodule surrounded by normal skin (Fig. 1.25C). Treatment is  usually by wide excision and may include local lymph node  removal. Radiotherapy, chemotherapy, biological and ‘targeted’  therapy may also be used, generally as adjuvants.   Merkel cells are a form of sensory receptor concerned with light  touch. Merkel cell carcinoma is a rapidly growing, highly malig¬  nant tumour that typically affects older adults. Its rarity may lead  to difficulty in diagnosis and delay in treatment, and 50% of  patients have metastatic spread by presentation. A violaceous,  well-demarcated nodule with intact overlying skin is seen, most  frequently involving the upper eyelid (Fig. 1.26). Treatment is by  excision, often with adjuvant therapy.   Kaposi sarcoma is a vascular tumour that typically affects patients  with AIDS. Many patients have advanced systemic disease although  in some instances the tumour may be the only clinical manifesta¬  tion of human immunodeficiency virus (HIV) infection. Histopa¬  thology shows proliferating spindle cells, vascular channels and  inflammatory cells within the dermis (Fig. 1.27A). Clinically a  pink, red-violet to brown lesion (Fig. 1.27B) develops, which may  be mistaken for a haematoma or naevus. Treatment is by radio¬  therapy or excision, and by optimal control of AIDS where  relevant.   Fig. 1.24 Lentigo maligna of the eyelid. (A) Histopathology  shows melanoma cells proliferating within the basal layers  of the epidermis; (B) early lentigo maligna; (C) melanoma  arising from lentigo maligna   (Courtesy of L Horton - fig. A; S Delva - fig. C)   Fig. 1.25 Melanoma. (A) Histopathology shows melanoma  cells within the dermis; (B) superficial spreading  melanoma; (C) nodular melanoma   Fig. 1.26 Merkel cell carcinoma. (A) Histopathology shows a  sheet of Merkel cells; (B) clinical appearance   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann 2001 - fig. A)   Biopsy can be (i) incisional , using a blade or a biopsy punch, in  which only part of the lesion is removed for histological diagnosis,  or (ii) excisional , in which the entire lesion is removed; the latter  may consist of shave excision using a blade to remove shallow  epithelial tumours, such as papillomas and seborrhoeic keratosis,  or full-thickness skin excision for tumours that are not confined  to the epidermis.   Surgical excision aims to remove the entire tumour with preserva¬  tion of as much normal tissue as possible. Smaller tumours can be  removed via an excision biopsy and the defect closed directly,  whilst awaiting histological confirmation of complete clearance.  Most small BCCs can be cured by excision of the tumour together  with a 2-4 mm margin of clinically normal tissue. More radical  surgical excision is required for large BCCs and aggressive tumours  such as SCC, SGC and melanoma. It may not be possible to close  all defects at the time of initial removal, but it is necessary to  ensure complete clearance of tumour prior to undertaking any    reconstruction. There are several options for the coordination of  histopathological diagnosis and tumour clearance with excision.   • Conventional paraffin-embedded specimen. Rapid  processing can reduce the interval to confirmation of  histological clearance but still requires that reconstruction be  performed as a separate procedure. Faster confirmation can  be achieved using either frozen-section control or  micrographic surgery (see next), and reconstruction can  then take place on the same day.   • Standard frozen section involves histological examination of  the margins of the excised specimen at the time of surgery to  ensure they are tumour-free. If no tumour cells are detected,  the eyelid is reconstructed on the same day; if residual  tumour is present, further excision is performed at the  appropriate edge of the surgical site until no tumour is  detected.   • Mohs micrographic surgery involves layered excision of the  tumour; specimens are usually examined frozen. Processing  of each layer enables a map of the edges of the tumour to be   Fig. 1.27 Kaposi sarcoma. (A) Histopathology shows a  proliferation of predominantly spindle-shaped cells;  vascular channels are evident; (B) clinical appearance   developed. Further tissue is taken in any area where tumour  is still present until clearance is achieved. Although time-  consuming, this technique maximizes the chances of total  tumour excision whilst minimizing sacrifice of normal  tissue. This is a particularly useful technique for tumours  that grow diffusely and have indefinite margins with  finger-like extensions, such as sclerosing BCC, SCC,  recurrent tumours and those involving the medial or lateral  canthi. The irregular contours around the eyelids and  extension of tumours into orbital fat can make  interpretation difficult.   The technique of reconstruction depends on the extent of tissue  removed. It is important to reconstruct both anterior and poste¬  rior lamellae, each of which must be reconstructed with similar  tissue. Anterior lamellar defects may be closed directly or with a  local flap or skin graft. Options for the repair of full-thickness  defects are set out below.   • Small defects involving less than one-third of the eyelid can  usually be closed directly, provided the surrounding tissue is  sufficiently elastic to allow approximation of the cut edges  (Fig. 1.28). If necessary, a lateral cantholysis can be  performed for increased mobilization.   • Moderate size defects involving up to half of the eyelid  may require a flap (e.g. Tenzel semicircular) for closure  (Fig. 1.29).   • Large defects involving over half of the eyelid may be closed  by one of the following techniques:   o Posterior lamellar reconstruction may involve an upper  lid free tarsal graft, buccal mucous membrane or hard  palate graft, or a Hughes tarsoconjunctival flap from the  upper lid, which is left attached for 4-6 weeks before  transection (Fig. 1.30).   O Anterior lamellar reconstruction may involve skin  advancement, a local skin flap or a free skin graft (Fig.  1.31); the patient must be made aware that grafted skin is  unlikely to be a perfect match. At least one reconstructed  lamella requires its own blood supply to maximize the  viability of a free graft component.   Full reconstruction of the defect created by tumour removal may  not always be required. In the laissez-faire approach the wound  edges are approximated as far as possible and the defect is allowed  to granulate and heal by secondary intention. Even large defects  can often achieve a satisfactory outcome with time.   The recurrence rate following irradiation alone is higher than after  surgery, and radiotherapy does not allow histological confirma¬  tion of tumour eradication. Recurrences following radiotherapy  are difficult to treat surgically because of the poor healing proper¬  ties of irradiated tissue. However, it still has utility in some  circumstances.   Fig. 1.28 Direct closure. (A) Preoperative appearance of a  basal cell carcinoma; (B) appearance following excision;   o Patients who are either unsuitable for or refuse surgery,  o Highly radiosensitive tumours, such as Kaposi sarcoma,  o Adjunctive therapy in some cases,  o Palliative treatment.   Fig. 1.29 Tenzel flap. (A) Preoperative appearance; (B)  appearance following excision; (C) appearance following  closure of the flap   Fig. 1.30 Posterior lamellar reconstruction with a Hughes  upper lid flap. (A) Preoperative appearance; (B) appearance  following excision; (C) postoperative appearance with the  flap yet to be divided    Fig. 1.31 Anterior lamellar reconstruction with a free skin  graft. (A) Preoperative appearance; (B) appearance following  excision; (C) skin graft in place   o Medial canthal lesions due to the high probability of  lacrimal canalicular damage,  o Upper eyelid tumours - conjunctival keratinization is  common and difficult to manage.    o Aggressive tumours such as SGC are relatively radio¬  resistant, but higher-dose treatment may be effective.   • Complications. Many of these can be minimized by  appropriate shielding.   o Skin damage and madarosis (eyelash loss),  o Nasolacrimal duct stenosis following irradiation to the  medial canthal area.   Cryotherapy may be considered for small superficial BCCs;  it can be a useful adjunct to surgery in some patients. Complica¬  tions include skin depigmentation, madarosis and conjunctival  overgrowth.   The roots of the eyelashes (cilia) lie against the anterior surface of  the tarsal plate. The cilia pass between the main part of the orbicu¬  laris oculi and its more superficial part (Riolan muscle), exiting the  skin at the anterior lid margin and curving away from the globe. It  is particularly important to be familiar with the normal anatomical  appearance of the lid margin in order to be able to identify the cause  of eyelash misdirection. From anterior to posterior:   • The grey line, by definition the border between the anterior  (lashes, skin and orbicularis) and posterior (tarsal plate and  conjunctiva) lamellae.   • The meibomian gland orifices are located just anterior to  the mucocutaneous junction. The edge of the tarsal plate is  deep to the gland orifices; the glands themselves run  vertically within the plate.   • The mucocutaneous junction is where keratinized  epithelium of the skin merges with conjunctival mucous  membrane.   Trauma to the corneal epithelium may cause punctate epithelial  erosions, with ocular irritation often worsened by blinking.  Corneal ulceration and pannus formation may occur in severe  cases. The clinical appearance varies with the cause.   • Trichiasis refers to misdirection of growth from individual  follicles (Fig. 1.32A), rather than a more extensive inversion  of the lid or lid margin. The follicles are at anatomically  normal sites. It is commonly due to inflammation such as  chronic blepharitis or herpes zoster ophthalmicus, but can    Fig. 1.32 Misdirected lashes. (A) Single trichiatic lash; (B) trichiasis associated with a lid notch following chalazion surgery;  (C) marginal entropion showing rows of misdirected lashes, anterior migration of the mucocutaneous junction, and a  rounded posterior lid margin; (D) acquired distichiasis   (Courtesy of S Chen - fig. A; R Bates - fig. D)    also be caused by trauma, including surgery such as incision  and curettage of a chalazion (Fig. 1.32B).   • Marginal entropion has increasingly been recognized as a  very common cause of eyelash misdirection, the mechanism  of which is thought to be subtle cicatricial posterior lamellar  shortening that rotates a segment of the lid margin towards  the eye. The mucocutaneous junction migrates anteriorly  and the posterior lid margin becomes rounded rather than  physiologically square. Typically, numerous aligned lashes  are involved (Fig. 1.32C).   • Congenital distichiasis is a rare condition that occurs  when a primary epithelial germ cell destined to differentiate  into a meibomian gland develops instead into a complete  pilosebaceous unit. The condition is frequently inherited   in an autosomal dominant manner with high penetrance  but variable expressivity. The majority of patients also  manifest primary lymphoedema of the legs (lymphoedema-  distichiasis syndrome). A partial or complete second row of  lashes is seen to emerge at or slightly behind the meibomian  gland orifices. The aberrant lashes tend to be thinner and    shorter than normal cilia and are often directed posteriorly.  They are usually well tolerated during infancy and may not  become symptomatic until the age of about 5 years.   • Acquired distichiasis is caused by metaplasia of the  meibomian glands into hair follicles such that a variable  number of lashes grow from meibomian gland openings.   The most important cause is intense conjunctival  inflammation (e.g. chemical injury, Stevens-Johnson  syndrome, ocular cicatricial pemphigoid). In contrast to  congenital distichiasis, the cilia tend to be non-pigmented  and stunted (Fig. 1.32D), and are usually symptomatic.   • Entropion. In contrast to marginal entropion, profound  inversion of a substantial width of the lid is readily identified  - see later.   • Epilation with forceps is simple and effective but recurrence  within a few weeks is essentially invariable. It can be used as    a temporizing measure or in the occasional patient who  refuses or cannot tolerate surgery.   • Electrolysis or electrocautery (hyfrecation) are broadly  similar electrosurgical techniques in which, under local  anaesthesia, a fine wire is passed down the hair follicle to  ablate the lash. It is generally useful for a limited number of  lashes; scarring can occur. Frequently multiple treatments  are required to obtain a satisfactory result.   • Laser ablation is also useful for the treatment of limited  aberrant eyelashes, and is performed using a spot size of  50 pan, duration of 0.1-0.2 s and power of 800-1000 mW.  The base of the lash is targeted and shots are applied to  create a crater that follows the axis of the follicle (Fig. 1.33).  Success is broadly comparable to that achieved with  electrosurgery.   o Tarsal facture (transverse tarsotomy) is performed for  marginal entropion. After placing a 4-0 traction suture, a  horizontal incision is made through the tarsal plate via  the conjunctiva, at least halfway down the plate, along the  affected length of the lid and extended to 2-3 mm either  side of the involved region. Depending on the extent of   Fig. 1.33 Laser for trichiasis. (A) Appearance following  ablation of multiple lashes; (B) the eye in Fig. 1 . 32 B 6  weeks after laser ablation    lid involvement, either two or three double-armed  absorbable sutures are passed through the upper edge of  the lower section of the tarsal plate to emerge just  anterior to the lashes, leaving the lid margin very slightly  everted (Fig. 1.34). The sutures are left in place following  the surgery; occasionally short-term use of a bandage  contact lens is required to prevent corneal abrading,  o A full-thickness eyelid pentagon resection can be used for  a focal group of aberrant lashes, typically after trauma, or  for localized marginal entropion,  o Other options include lid splitting (see next) with follicle  excision, and anterior lamellar rotation surgery.   • Cryotherapy applied externally to the skin just inferior to  the base of the abnormal lashes or - especially in distichiasis  - to the internal aspect of the anterior lamella of the lid  following splitting of the margin at the grey line (Fig. 1.35),  can be used for numerous lashes. A double freeze-thaw cycle  at -20 °C is applied under local anaesthesia (including  adrenaline) with a plastic eye protector in place; suturing of  the lid margin is not usually necessary following limited  splitting. The method is effective but carries a high rate of  local adverse effects, and is less commonly performed than  previously.   Eyelash ptosis refers to a downward sagging of the upper lid lashes  (Fig. 1.36A). The condition may be idiopathic or associated with  floppy eyelid syndrome, dermatochalasis with anterior lamellar  slip or long-standing facial palsy.   Trichomegaly is excessive eyelash growth (Fig. 1.36B); the main  causes are listed in Table 1.1.   Madarosis is the term used for the loss of lashes (Fig. 1.36C). The  main causes are shown in Table 1.2.   Poliosis is a premature localized whitening of hair, which may  involve the lashes and eyebrows (Fig. 1.36D); the main causes are  shown in Table 1.3.   Drug-induced - topical prostaglandin analogues,  phenytoin and ciclosporin  Malnutrition  AIDS  Porphyria  Hypothyroidism  Familial   Fig. 1.34 Tarsal fracture for repair of marginal entropion. (A) and (B) insertion of everting sutures following traction suture  emplacement and horizontal tarsal plate incision; (C) and (D) everting sutures in place   (Courtesy of JA Nerad, from Techniques in Ophthalmic Plastic Surgery, Saunders 2010)    Fig. 1.35 Cryotherapy to the eyelid in distichiasis. (A) Separation of the anterior and posterior lamellae; (B) application of  cryoprobe to the posterior lamella   (Courtesy of AG Tyers and JRO Collin, from Colour Atlas of Ophthalmic Plastic Surgery, Butterworth-Heinemann 2001)   Fig. 1.36 Miscellaneous eyelash disorders. (A) Eyelash ptosis; (B) trichomegaly; (C) madarosis; (D) poliosis   (Courtesy of A Pearson - fig. A; L Merin - fig. B; S Tuft - fig. C)   Acute allergic oedema is usually caused by exposure to pollen  or by insect bites, and manifests with the sudden onset of  bilateral boggy periocular oedema (Fig. 1.37A), often accompa¬  nied by conjunctival swelling (chemosis - see Ch. 5). Treatment is  often unnecessary, but systemic antihistamines are sometimes  given.   Contact dermatitis is an inflammatory response that usually  follows exposure to a medication such as eye drops (often  preservative-containing), cosmetics or metals. An irritant can also  cause a non-allergic toxic dermatitis. The individual is sensitized  on first exposure and develops an immune reaction on further  exposure; the mediating reaction is type IV (delayed type) hyper¬  sensitivity. Signs consist of lid skin scaling, angular Assuring,  oedema and tightness (Fig. 1.37B); there maybe chemosis, redness  and papillary conjunctivitis. Corneal involvement is usually  limited to punctate epithelial erosions. Treatment consists  primarily of avoidance of allergen exposure, provided it can be  identified. Cold compresses provide symptomatic relief. Topical    steroids and oral antihistamines can be used, but are rarely  required.   Atopic dermatitis (eczema) is a very common idiopathic condi¬  tion, typically occurring in patients who also suffer from asthma  and hay fever. Eyelid involvement is relatively infrequent but when  present is invariably associated with generalized dermatitis. Thick¬  ening, crusting and Assuring of the lids (Fig. 1.37C) is typical, and  staphylococcal blepharitis, vernal or atopic keratoconjunctivitis  are also commonly present. Herpetic blepharitis and keratocon¬  junctivitis is more common and more severe in patients with  atopy (eczema herpeticum). Treatment of the lid features is with  emollients to hydrate the skin and the judicious use of mild topical  steroid such as hydrocortisone 1%. Uncommon ocular associa¬  tions include keratoconus, cataract and retinal detachment (see  also Ch. 5).   Fig. 1.37 Allergic disorders. (A) Acute allergic oedema; (B)  contact dermatitis; (C) atopic dermatitis   An external hordeolum (stye) is an acute staphylococcal abscess  of a lash follicle and its associated gland of Zeis that is common  in children and young adults. A stye presents as a tender swelling  in the lid margin pointing anteriorly through the skin, usually with  a lash at its apex (Fig. 1.38A). Multiple lesions may be present and  occasionally abscesses may involve the entire lid margin. Treat¬  ment involves topical (occasionally oral) antibiotics, hot com¬  presses and epilation of the associated lash.   Impetigo is an superficial skin infection caused by Staphylococcus  aureus or Streptococcus pyogenes ; it typically affects children.  Involvement of the eyelids is usually associated with infection of    the face. Painful erythematous macules rapidly develop into thin-  walled blisters, which develop golden-yellow crusts on rupturing  (Fig. 1.38B). There maybe fever, malaise and local lymphadenopa-  thy. Treatment is with topical and sometimes oral antibiotics  (beta-lactamase resistant), and preventative measures to reduce  transmission as the condition is highly contagious; it is particularly  dangerous to neonates, contact with whom should be avoided.   Erysipelas (St Anthony’s fire) is an uncommon acute, potentially  severe, dermal and superficial lymphatic infection usually caused  by S. pyogenes. Diabetes, obesity and alcohol abuse are predispos¬  ing. An inflamed erythematous plaque develops (Fig. 1.38C); a  well-defined raised border distinguishes erysipelas from other  forms of cellulitis. Complications such as metastatic infection  are rare. Treatment is with oral antibiotics, but recurrence is  common.   Fig. 1.38 Bacterial infections. (A) External hordeolum (stye); (B) impetigo; (C) erysipelas; (D) necrotizing fasciitis   Necrotizing fasciitis is a rare but commonly very severe infection  involving subcutaneous soft tissue and the skin, with associated  rapidly progressive necrosis. It is usually caused by S. pyogenes and  occasionally S. aureus. The most frequent sites of involvement are  the extremities, trunk and perineum, as well as postoperative  wound sites. Unless early aggressive treatment is instituted, in the  form of surgical debridement and high-dose intravenous antibiot¬  ics, death may result. Periocular infection is rare; redness and  oedema are followed by the formation of large bullae and black  discoloration of the skin due to necrosis (Fig. 1.38D).   Molluscum contagiosum is a skin infection caused by a human-  specific double-stranded DNA poxvirus that typically affects oth¬  erwise healthy children, with a peak incidence between 2 and 4  years of age. Transmission is by contact and subsequently by  autoinoculation. Multiple, and occasionally confluent, lesions  may develop in immunocompromised patients. Histopathology  shows a central pit and lobules of hyperplastic epidermis with  intracytoplasmic (Henderson-Patterson) inclusion bodies that  displace the nuclear remnant to the edge of the cell. The bodies  are small and eosinophilic near the surface, and large and basophilic  deeper down (Fig. 1.39A).   Single or multiple pale, waxy, umbilicated nodules develop (Fig.  1.39B); white cheesy material consisting of infected degenerate cells  can be expressed from the lesion. Lesions on the lid margin (Fig.  1.39C) may shed virus into the tear film and give rise to a secondary  ipsilateral chronic follicular conjunctivitis. Unless the lid margin  is examined carefully the causative molluscum lesion may be  overlooked.   Spontaneous resolution will usually occur within a few months so  treatment may not be necessary, particularly in children, unless  complications such as a significant secondary conjunctivitis are  problematic. Options include shave excision, cauterization, chem¬  ical ablation, cryotherapy and pulsed dye laser.   Herpes zoster ophthalmicus (HZO - Fig. 1.40) is a common, gen¬  erally unilateral infection caused by varicella-zoster virus. It is  discussed in detail in Ch. 6.   Fig. 1.39 Molluscum contagiosum. (A) Histopathology shows  lobules of hyperplastic epidermis and a pit containing  intracytoplasmic inclusion bodies; (B) multiple molluscum  nodules; (C) lid margin nodule   (Courtesy of A Gamer - fig. A; N Rogers - fig. B)   Fig. 1.40 Herpes zoster ophthalmicus - maculopapular  crusting rash with periocular oedema, showing clear  midline delineation   Herpes simplex skin rash results from either primary infection or  reactivation of herpes simplex vims previously dormant in the  trigeminal ganglion. Prodromal facial and lid tingling lasting  about 24 hours is followed by the development of eyelid and peri¬  ocular skin vesicles (Fig. 1.41 A) that break down over 48 hours  (Fig. 1.41B). Although typically still confined to a single dermatome  and with individual lesions that are often similar in appearance,  the distribution of the herpes simplex skin rash contrasts with the  sharply delineated unilateral involvement in HZO (see Fig. 1.40).  There is commonly associated papillary conjunctivitis, discharge  and lid swelling; dendritic corneal ulcers can develop, especially in  atopic patients, in whom skin involvement can be extensive and  very severe (eczema herpeticum - Fig. 1.41C).   In many patients things will gradually settle without treatment  over about a week. If treatment is necessary, a topical (aciclovir  cream five times daily for 5 days) or oral (oral aciclovir, famciclovir  or valaciclovir) antiviral agent can be used. Antibiotics (e.g.  co-amoxiclav, erythromycin) may also be required in patients  with secondary bacterial infection; this is particularly common in  eczema herpeticum.   Fig. 1.41 Herpes simplex. (A) Vesicles; (B) progression to  crusting; (C) eczema herpeticum   Chronic blepharitis (chronic marginal blepharitis) is a very  common cause of ocular discomfort and irritation. The poor cor¬  relation between symptoms and signs, the uncertain aetiology and  mechanisms of the disease process all combine to make manage¬  ment difficult. Blepharitis may be subdivided into anterior and  posterior, although there is considerable overlap and both types  are often present (mixed blepharitis).   • Anterior blepharitis affects the area surrounding the bases of  the eyelashes and may be staphylococcal or seborrhoeic. It is  sometimes regarded as related more to chronic infective  elements and hence more amenable to treatment and  remission than the posterior form. An aetiological factor in  staphylococcal blepharitis may be an abnormal cell-mediated  response to components of the cell wall of S. aureus , which  may also be responsible for the red eyes and peripheral  corneal infiltrates seen in some patients; it is more common  and more marked in patients with atopic dermatitis.  Seborrhoeic blepharitis is strongly associated with  generalized seborrhoeic dermatitis that characteristically  involves the scalp, nasolabial folds, skin behind the ears and  the sternum.   • Posterior blepharitis is caused by meibomian gland  dysfunction and alterations in meibomian gland secretions.  Bacterial lipases may result in the formation of free fatty  acids. This increases the melting point of the meibum,  preventing its expression from the glands, contributing to  ocular surface irritation and possibly enabling growth of S.    aureus. Loss of the tear film phospholipids that act as  surfactants results in increased tear evaporation and  osmolarity, and an unstable tear film. Posterior blepharitis is  commonly thought of as a more persistent and chronic  inflammatory condition than anterior blepharitis; there is an  association with acne rosacea.   • A reaction to the extremely common hair follicle and  sebaceous gland-dwelling mite Demodex and other  microorganisms may play a causative role in some patients  - Demodex folliculorum longus in anterior blepharitis and  Demodex folliculorum brevis in posterior blepharitis - though  the mite can be found normally in a majority of older  patients, most of whom do not develop symptomatic  blepharitis. It has been proposed that circumstances such as  overpopulation or hypersensitivity (perhaps to a bacillus  carried symbiotically by Demodex) may lead to symptoms.  Demodex mites are a major cause of the animal disease  mange.   • Symptoms are caused by disruption of normal ocular  surface function and reduction in tear stability, and are  similar in all forms of blepharitis, though stinging may be  more common in posterior disease. Because of poor  correlation between the severity of symptoms and signs it  can be difficult to objectively assess the benefit of treatment.  Burning, grittiness, mild photophobia, and crusting and  redness of the lid margins with remissions and exacerbations  are characteristic. Symptoms are usually worse in the  mornings although in patients with associated dry eye they   o Hard scales and crusting mainly located around the bases  of the lashes; collarettes are cylindrical collections around  lash bases (Fig. 1.42A).   o Long-standing cases may develop scarring and notching  (tylosis) of the lid margin, madarosis, trichiasis and  poliosis.   o Associated tear film instability and dry eye syndrome are  common.   o Atopic keratoconjunctivitis may be present in patients  with atopic dermatitis.   o Hyperaemic and greasy anterior lid margins with soft  scales and adherence of lashes to each other (Fig. 1.42B).   Fig. 1.42 Chronic anterior blepharitis. (A) Scales and crusting  including collarettes in staphylococcal; (B) greasy lid margin  with sticky lashes in seborrhoeic    • Signs - posterior blepharitis (meibomian gland disease)  o Excessive and abnormal meibomian gland secretion,   manifesting as capping of meibomian gland orifices with  oil globules (Fig. 1.43A).   o Pouting, recession, or plugging of meibomian gland  orifices (Fig. 1.43B).   o Pressure on the lid margin results in expression of  meibomian fluid that may be turbid or toothpaste-like  (Fig. 1.43C); in severe cases the secretions become so  inspissated that expression is impossible,  o Lid transillumination may show gland loss and cystic  dilatation of meibomian ducts,  o The tear film is oily and foamy and often unstable, and  froth may accumulate on the lid margins (Fig. 1.43D) or  inner canthi.   • Demodex infestation may lead to cylindrical dandruff-like  scaling (collarettes) around the base of eyelashes, though this  is not always present. The mites can be demonstrated under  xi6 slit lamp magnification by first manually clearing around  the base of an eyelash then with fine forceps gently rotating  the lash or moving it from side to side for 5-10 seconds,  when if one or more mites (0.2-0.4 mm long - Fig. 1.44)  does not emerge the lash should be gently epilated; slide  microscopy can be performed on the mites or lashes if  necessary.   • Secondary changes include papillary conjunctivitis, inferior  corneal punctate epithelial erosions, corneal scarring and  vascularization including Salzmann nodular degeneration  and advancing wave-like epitheliopathy-type changes, stye  formation, marginal keratitis, and occasionally bacterial  keratitis (especially in contact lens wearers) and  phlyctenulosis.   There is limited evidence to support any particular treatment pro¬  tocol for blepharitis. Patients should be advised that a permanent  cure is unlikely, but control of symptoms is usually possible. The  treatment of anterior and posterior disease is broadly similar for  both types, particular given that they commonly co-exist, but  some treatments are fairly specific for one or the other.   • Lid hygiene can be carried out once or twice daily initially;  compliance and technique is highly variable.   o A warm compress should first be applied for several  minutes to soften crusts at the bases of the lashes,  o Lid cleaning is subsequently performed to mechanically  remove crusts and other debris, scrubbing the lid  margins with a cotton bud or clean facecloth dipped  in a warm dilute solution of baby shampoo or sodium  bicarbonate.   o Commercially produced soap/alcohol impregnated pads  for lid scrubbing are available and are often highly  effective, but care should be taken not to induce  mechanical irritation.   Fig. 1.43 Chronic posterior blepharitis. (A) Capping of meibomian gland orifices by oil globules; (B) hyperaemic, telangiectatic  lid margin; (C) expressed toothpaste-like material; (D) froth on the eyelid margin   (Courtesy of J Silbert, from Anterior Segment Complications of Contact Lens Wear, Butterworth-Heinemarm 1999 - fig. C)   Fig. 1.44 Demodex mite. (A) Mite visible at eyelash base as a whitish lesion (arrow) after lash manipulation following  clearance of collarette; (B) photograph taken two seconds later showing rapid migration    o When substantial meibomian gland disease is present,  the regimen may include expression of accumulated  meibum by rolling the finger anteriorly over the  margin.   o The putative action of lid hygiene against Demodex is via  prevention of reproduction,  o Lid hygiene can be performed less frequently as the  condition is brought under control.   O Topical sodium fusidic acid, erythromycin, bacitracin,  azithromycin or chloramphenicol is used to treat active  folliculitis in anterior disease and is occasionally used for  an extended period. Following lid hygiene the ointment  should be rubbed onto the anterior lid margin with a  cotton bud or clean finger.   o Oral antibiotic regimens include doxycycline (50-100 mg  twice daily for 1 week and then daily for 6-24 weeks),  other tetracyclines, or azithromycin (500 mg daily for  3 days for three cycles at l-week intervals); antibiotics are  thought to reduce bacterial colonization and may also  exert other effects such as a reduction in staphylococcal  lipase production with tetracyclines. Tetracyclines may be  more effective in the treatment of posterior disease, and  azithromycin in anterior. Tetracyclines should not be  used in children under the age of 12 years or in pregnant  or breast-feeding women because they are deposited in  growing bone and teeth; patients should also be aware of  the possibility of increased sun sensitivity. Erythromycin  250 mg once or twice daily is an alternative.   • Plant and fish oil supplements have been shown to be of  substantial benefit in some cases.   • Topical steroid. A low potency preparation such as  fluorometholone 0.1% or loteprednol four times daily for  1 week is useful in patients with substantial active  inflammation, especially papillary conjunctivitis; occasionally  a higher strength preparation is used.   • Tear substitutes and other dry eye treatments are  typically helpful for associated tear insufficiency and  instability.   • Tea tree oil has been suggested as a treatment, based  primarily on its likely activity against Demodex infestation;  the optimal vehicle and regimen has not been established  but lid, eyebrow and periocular skin cleansing once daily  with a 50% scrub and application of 5% ointment has been  described. Topical permethrin and topical (1% cream) or  oral (two doses of 200 fig/kg 1 week apart) ivermectin have  also been used by some practitioners. High temperature  cleaning of bedding, the use of tea tree shampoo and facial  soap, and treating the patient’s partner may all help to  reduce recurrences.   • Novel therapies include topical ciclosporin, pulsed light  application, and purpose-designed devices to probe, heat  and/or express the meibomian glands (e.g. Lipiflow ™) in  posterior disease.   The crab louse Phthirus pubis is adapted to living in pubic hair,  but is also commonly found in other hair-covered body areas such  as the chest, axillae and eyelids (phthiriasis palpebrarum). Symp¬  toms consist of chronic irritation and itching of the lids, but the  lice are often an incidental discovery. Conjunctivitis is uncom¬  mon. The lice are readily visible anchored to lashes (Fig. 1.45A);  lice have six legs rather than the eight possessed by ticks (see next).  Ova and their empty shells appear as oval, brownish, opalescent  pearls adherent to the base of the cilia (Fig. 1.45B). Treatment  consists of mechanical removal of the lice and their attached lashes  with fine forceps. If necessary, topical yellow mercuric oxide 1%  or petroleum jelly can be applied to the lashes and lids twice a day  for 10 days. Delousing of the patient, family members, clothing  and bedding is important to prevent recurrence.   Fig. 1.45 Phthiriasis palpebrarum. (A) Louse anchored to  lashes; (B) louse, ova and shells   Ticks (see Fig. 11.69B) can attach themselves to the eyelid and  should be removed at the earliest opportunity in order to mini¬  mize the risk of contracting a tick-borne zoonosis such as Lyme  disease, Rocky Mountain fever or tularaemia. If the tick is attached  some distance from the eye such that spray can safely be applied,  an insect repellent containing pyrethrin or a pyrethroid should be  sprayed on the tick twice at intervals of a minute; alternatively a  scabies cream containing permethrin can be applied. These have  a toxic effect that prevents the tick from injecting saliva, and after  24 hours it should drop off or can be removed with fine-tipped  forceps at the slit lamp (blunt-tipped needle-holders are an alter¬  native in restrained small children). It is critical that the tick is  detached as close to its skin attachment as possible in order to  remove its head and mouthparts, following which it might be  retained in sealed packaging to permit identification if necessary.  In areas endemic for Lyme disease, some authorities suggest  routine antibiotic prophylaxis with doxycycline (in the absence of  contraindications) following a confirmed deer tick bite, but as a  minimum patients should be told to seek medical advice urgently  at the onset of suspicious symptoms, particularly erythema  migrans, over the subsequent few weeks. Lyme disease transmis¬  sion is thought to require attachment of the tick for at least  36 hours.   The infection is usually caused by Moraxella lacunata or S. aureus  although other bacteria, and rarely herpes simplex, have also been  implicated. Red, scaly, macerated and fissured skin is seen at the  lateral and/or medial canthi of one or both eyes (Fig. 1.46A). Skin  chafing secondary to tear overflow, especially at the lateral canthus,  can cause a similar clinical picture, and may also predispose to  infection (Fig. 1.46B). Associated papillary and follicular conjunc¬  tivitis may occur. Treatment involves topical chloramphenicol,  bacitracin or erythromycin.   Fig. 1.46 (A) Angular blepharitis; (B) tear overflow from a lax   Childhood blepharokeratoconjunctivitis is a poorly defined con¬  dition that tends to be more severe in Asian and Middle Eastern  populations. Presentation is usually at about 6 years of age with  recurrent episodes of anterior or posterior blepharitis, sometimes  associated with recurrent styes or chalazia. Constant eye rubbing  and photophobia may lead to misdiagnosis as allergic eye disease.  Conjunctival changes include diffuse hyperaemia, bulbar phlyctens  and follicular or papillary hyperplasia.   Corneal changes include superficial punctate keratopathy, mar¬  ginal keratitis, peripheral vascularization and axial subepithelial  haze. Treatment is with lid hygiene and topical antibiotic  ointment at bedtime. Topical low-dose steroids (prednisolone  0.1% or fluorometholone 0.1%) and erythromycin syrup 125 mg  daily for 4-6 weeks may also be used.   Ptosis is an abnormally low position of the upper lid; it may be   • Neurogenic ptosis is caused by an innervational defect  such as third nerve paresis and Horner syndrome (see  Ch. 19).   • Myogenic ptosis is caused by a myopathy of the levator  muscle itself, or by impairment of transmission of impulses  at the neuromuscular junction (neuromyopathic). Acquired  myogenic ptosis occurs in myasthenia gravis, myotonic  dystrophy and progressive external ophthalmoplegia (see  Ch. 19).   • Aponeurotic or involutional ptosis is caused by a defect in  the levator aponeurosis.   • Mechanical ptosis is caused by the gravitational effect of a  mass or by scarring.    Fig. 1.47 Causes of pseudoptosis. (A) Right phthisis bulbi; (B) contralateral lid retraction; (C) ipsilateral hypotropia;  (D) bilateral brow ptosis   The age at onset of ptosis and its duration will usually distinguish  congenital from acquired cases. If the history is ambiguous, old  photographs may be helpful. It is also important to enquire about  symptoms of possible underlying systemic disease, such as associ¬  ated diplopia, variability of ptosis during the day and excessive  fatigue.   A false impression of ptosis may be caused by the following:   • Lack of support of the lids by the globe may be due to an  orbital volume deficit associated with an artificial eye,  microphthalmos, phthisis bulbi (Fig. 1.47A), or  enophthalmos.   • Contralateral lid retraction, which is detected by comparing  the levels of the upper lids, remembering that the margin of  the upper lid normally covers the superior 2 mm of the  cornea (Fig. 1.47B).   • Ipsilateral hypotropia causes pseudoptosis because the  upper lid follows the globe downwards (Fig. 1.47C). It  disappears when the hypotropic eye assumes fixation on  covering the normal eye.   • Brow ptosis due to excessive skin on the brow, or seventh  nerve palsy, which is diagnosed by manually elevating the  eyebrow (Fig. 1.47D).    • Dermatochalasis. Overhanging skin on the upper lids  (Fig. 1.48) may be mistaken for ptosis, but may also cause  mechanical ptosis.   • Margin-reflex distance is the distance between the upper lid  margin and the corneal reflection of a pen torch held by the   Fig. 1.49 Margin-reflex distance. (A) Normal; (B) mild ptosis;  (C) moderate ptosis; (D) severe ptosis    examiner on which the patient fixates (Fig. 149); the normal  measurement is 4-5 mm.   • Palpebral fissure height is the distance between the upper  and lower lid margins, measured in the pupillary plane (Fig.  1.50). The upper lid margin normally rests about 2 mm  below the upper limbus and the lower 1 mm above the lower  limbus. This measurement is shorter in males (7-10 mm)  than in females (8-12 mm). Unilateral ptosis can be    quantified by comparison with the contralateral side. Ptosis  may be graded as mild (up to 2 mm), moderate (3 mm) and  severe (4 mm or more).   • Levator function (upper lid excursion) is measured by  placing a thumb firmly against the patient’s brow to negate  the action of the frontalis muscle, with the eyes in downgaze  (Fig. 1.51A). The patient then looks up as far as possible  and the amount of excursion is measured with a rule   (Fig. 1.51B). Levator function is graded as normal (15 mm  or more), good (12-14 mm), fair (5-11 mm) and poor  (4 mm or less).   • Upper lid crease is taken as the vertical distance between the  lid margin and the lid crease in downgaze. In females it  measures about 10 mm and in males 8 mm. Absence of the  crease in a patient with congenital ptosis is evidence of poor  levator function, whereas a high crease suggests an  aponeurotic defect (usually involutional). The skin crease is  also used as a guide to the initial incision in some surgical  procedures.   • Pretarsal show is the distance between the lid margin and  the skin fold with the eyes in the primary position.   • The pupils should be examined to exclude Horner  syndrome and a subtle pupil-involving third nerve palsy -  the latter is an unlikely acute clinical presentation (see Ch. 19).   • Increased innervation may flow to the levator muscle of a  unilateral ptosis, particularly in upgaze. Associated increased  innervation to the contralateral normal levator will result in  lid retraction. The examiner should therefore manually  elevate the ptotic lid and look for drooping of the opposite  lid. If this occurs, the patient should be warned that surgical  correction may induce a lower position in the opposite lid.   • Fatigability is tested by asking the patient to look up  without blinking for 30-60 seconds. Progressive drooping of  one or both lids, or an inability to maintain upgaze, is  suggestive of myasthenia gravis (see Ch. 19). Myasthenic  ptosis may show an overshoot of the upper lid on saccade  from downgaze to the primary position (Cogan twitch sign)  and a ‘hop’ on side-gaze.   • Ocular motility defects, particularly of the superior rectus,  must be evaluated in patients with congenital ptosis.  Correction of an ipsilateral hypotropia may improve the  degree of ptosis. Deficits consistent with a subtle or partial  third nerve paresis should be identified.   • Jaw-winking can be identified by asking the patient to chew  and move the jaws from side to side (see below).   • The Bell phenomenon is tested by manually holding the lids  open, asking the patient to try to shut the eyes and observing  upward and outward rotation of the globe. A weak Bell  phenomenon carries a variable risk of postoperative  exposure keratopathy, particularly following large levator  resections or suspension procedures.   • The tear film should be inspected - a poor volume or  unstable film may be worsened by ptosis surgery and should  be addressed preoperatively as far as possible.   Congenital ptosis probably results from a failure of neuronal  migration or development with muscular sequelae secondary to  this; a minority of patients have a family history.   o In downgaze the ptotic lid is higher than the normal  because of poor relaxation of the levator muscle. This is  in contrast to acquired ptosis, in which the affected lid is  either level with or lower than the normal lid on  downgaze.   o Following surgical correction the lid lag in downgaze may  worsen.   o Superior rectus weakness may be present because of its  close embryological association with the levator.   O Refractive errors are common and more frequently  responsible for amblyopia than the ptosis itself.   Treatment should be carried out during the preschool years once  accurate measurements can be obtained, but may be considered  earlier in severe cases to prevent amblyopia. Levator resection (see  below) is usually required.   About 5% of all cases of congenital ptosis are associated with the  Marcus Gunn jaw-winking phenomenon. The vast majority are  unilateral. Although the exact aetiology is unclear, it has been  postulated that a branch of the mandibular division of the fifth  cranial nerve is misdirected to the levator muscle.   O Retraction of the ptotic lid in conjunction with  stimulation of the ipsilateral pterygoid muscles by  chewing, sucking, opening the mouth (Figs 1.53A and B)  or contralateral jaw movement,  o Less common stimuli to winking include jaw protrusion,  smiling, swallowing and clenching of teeth,  o Jaw-winking does not improve with age (Figs 1.53C and  D), although patients may learn to mask it.   Surgery should be considered if jaw-winking or ptosis represents  a significant functional or cosmetic problem.   • Mild cases with reasonable levator function of 5 mm or  better, and little synkinetic movement may be treated with  unilateral levator advancement.   • Moderate cases. Unilateral levator disinsertion can be  performed to address the synkinetic winking component,  with ipsilateral brow (frontalis) suspension so that lid  elevation is due solely to frontalis muscle elevation.   • Bilateral surgery. Bilateral levator disinsertion with bilateral  brow suspension may be carried out to produce a  symmetrical result.   Third nerve misdirection syndromes may be congenital, but more  frequently follow acquired third nerve palsy. Bizarre movements  of the upper lid accompany various eye movements (Fig. 1.54).  Ptosis may also occur following aberrant facial nerve regeneration.  Treatment is by levator disinsertion and brow suspension.    Fig. 1.52 Congenital ptosis. (A) Mild right ptosis; (B) good levator function; (C) severe left ptosis with absent skin crease;  (D) very poor levator function; (E) severe bilateral ptosis; (F) very poor levator function    Fig. 1.53 Marcus Gunn jaw-winking syndrome. (A) Moderate left ptosis; (B) retraction of the lid on opening the mouth; (C) and  (D) similar phenomenon in an older patient   Fig. 1.54 Third nerve redirection. (A) Moderate right ptosis;  (B) retraction of the lid on right gaze   Involutional (aponeurotic) ptosis is an age-related condition  caused by dehiscence, disinsertion or stretching of the levator  aponeurosis, limiting the transmission of force from a normal  levator muscle to the upper lid. Due to fatigue of the Muller  muscle it frequently worsens towards the end of the day, so that  it can sometimes be confused with myasthenic ptosis. There is a  variable, usually bilateral, ptosis with a high upper lid crease and  good levator function. In severe cases the upper lid crease may be  absent, the eyelid above the tarsal plate very thin and the upper  sulcus deep (Fig. 1.55). Treatment options include levator resec¬  tion, advancement with reinsertion or anterior levator repair.   Mechanical ptosis is the result of impaired mobility of the upper  lid. It may be caused by dermatochalasis, large tumours such as  neurofibromas (Fig. 1.56), heavy scar tissue, severe oedema and  anterior orbital lesions.    Fig. 1.55 Severe bilateral involutional ptosis with absent skin  creases and deep sulci   • The levator aponeurosis fuses with the orbital septum  about 4 mm above the superior border of the tarsal plate  (Fig. 1.57). Its posterior fibres insert into the lower third of  the anterior surface of the tarsal plate. The medial and  lateral horns are expansions that act as check ligaments.  Surgically, the aponeurosis can be approached through the  skin or conjunctiva.   • Muller muscle is inserted into the upper border of the tarsal  plate and can be approached transconjunctivally.   • The inferior tarsal aponeurosis consists of the  capsulopalpebral expansion of the inferior rectus muscle and  is analogous to the levator aponeurosis.    The maximal elevation achievable is 2-3 mm, so it is used in cases  of mild ptosis with good (at least 10 mm) levator function, which  includes most cases of Horner syndrome and mild congenital  ptosis.   In this technique the levator complex is shortened through either  an anterior - skin (Fig. 1.59) - or posterior - conjunctival -  approach. Indications include ptosis of any cause, provided resid¬  ual levator function is at least 5 mm. The extent of resection is  determined by the severity of the ptosis and the amount of levator  function.   Brow (frontalis) suspension is used for severe ptosis (>4 mm) with  very poor levator function (<4 mm) from a variety of causes,  typical indications being ptosis associated with third nerve palsy,  blepharophimosis syndrome and following an unsatisfactory  result from previous levator resection. The tarsal plate is sus¬  pended from the frontalis muscle with a sling consisting of autolo¬  gous fascia lata (Fig. 1.60) or non-absorbable material such as  prolene or silicone.   Involutional (age-related) ectropion affects the lower lid of elderly  patients. It causes epiphora (tear overflow) and may exacerbate  ocular surface disease. The red appearance of the exposed con¬  junctiva is cosmetically poor. In long-standing cases the tarsal  conjunctiva may become chronically inflamed, thickened and  keratinized (Fig. 1.61). Aetiological factors include:   • Horizontal lid laxity can be demonstrated by pulling the  central part of the lid 8 mm or more from the globe, with a  failure to snap back to its normal position on release  without the patient first blinking.   Fig. 1.58 Conjunctiva-Muller resection. (A) Clamping of  conjunctiva and Muller muscle; (B) appearance after  excision and suturing   (Courtesy of AG Tyers and JRO Collin , from Colour Atlas of Ophthalmic Plastic  Surgery, Butterworth-Heinemann 2001)   (B) threading of fascia lata strips; (C) tightening and tying  of strips   (Courtesy of AG Tyers and JRO Collin , from Colour Atlas of Ophthalmic Plastic  Surgery, Butterworth-Heinemann 2001)    Fig. 1.61 Severe long-standing involutional ectropion with  keratinization of the marginal conjunctiva    • Lateral canthal tendon laxity, characterized by a rounded  appearance of the lateral canthus (see Fig. 1.46B) and the  ability to pull the lower lid medially more than 2 mm.   • Medial canthal tendon laxity, demonstrated by pulling the  lower lid laterally and observing the position of the inferior  punctum. If the lid is normal the punctum should not be  displaced more than 1-2 mm. If laxity is mild the punctum  reaches the limbus, and if severe it may reach the pupil.   • Generalized ectropion is treated with repair of horizontal lid  laxity. This is achieved with a lateral tarsal strip procedure,  in which the lower canthal tendon is tightened by shortening  and reattachment to the lateral orbital rim (Fig. 1.62); this is  particularly helpful if the lateral canthus is rounded and lax,  with associated tear overflow. Excision of a tarsoconjunctival  pentagon (Fig. 1.63) is an alternative that can be placed to  excise an area of misdirected lashes or keratinized  conjunctiva.   • Medial ectropion, if mild, may be treated with a medial  conjunctival diamond excision (medial spindle procedure),  though must often be combined with a tarsal strip or lateral  canthal sling (see ‘Treatment’), or pentagon excision as  significant horizontal laxity frequently co-exists.   • Medial canthal tendon laxity, if marked, requires  stabilization prior to horizontal shortening to avoid  excessive dragging of the punctum laterally.   • Punctal ectropion without more extensive lid involvement  is considered in Ch. 2.   skin and underlying tissues, which pulls the eyelid away from the   globe (Fig. 1.64). If the skin is pushed up over the orbital margin    with a finger the ectropion will be relieved. Opening the mouth  tends to accentuate the eversion. Depending on the cause, both  lids may be involved and the defect may be local (e.g. trauma) or  general (e.g. burns, dermatitis, ichthyosis). Mild localized cases are  treated by excision of the offending scar tissue combined with a  procedure that lengthens vertical skin deficiency, such as Z-plasty.  Severe generalized cases require transposition flaps or free skin  grafts; sources of skin include the upper lids, posterior auricular,  preauricular and supraclavicular areas.   Paralytic ectropion is caused by ipsilateral facial nerve palsy (Fig.  1.65) and is associated with retraction of the upper and lower lids  and brow ptosis; the latter may mimic narrowing of the palpebral  aperture.   Complications include exposure keratopathy due to lagophthal¬  mos, and watering caused by malposition of the inferior lacrimal  punctum, failure of the lacrimal pump mechanism and an increase  in tear production resulting from corneal exposure.   • Temporary measures may be instituted to protect the cornea  in anticipation of spontaneous recovery of facial nerve  function.   o Lubrication with higher viscosity tear substitutes during  the day, with instillation of ointment and taping shut of  the lids during sleep, are usually adequate in mild cases.   O Botulinum toxin injection into the levator to induce  temporary ptosis.   o Temporary tarsorrhaphy may be necessary, particularly in  patients with a poor Bell phenomenon with the cornea  remaining exposed when the patient attempts to blink;  the lateral aspects of the upper and lower lids are sutured  together.   • Permanent treatment should be considered when there is  irreversible damage to the facial nerve as may occur  following removal of an acoustic neuroma, or when no  further improvement has occurred for 6-12 months in a Bell  palsy.   o Medial canthoplasty may be performed if the medial  canthal tendon is intact. The eyelids are sutured together  medial to the lacrimal puncta (Fig. 1.66A) so that the  puncta become inverted and the fissure between the inner  canthus and puncta is shortened,  o A lateral canthal sling or tarsal strip may be used to  correct residual ectropion and raise the lateral canthus  (Fig. 1.66B).   Fig. 1.62 Lateral tarsal strip procedure. (A) Lateral canthotomy; (B) cantholysis - the lower limb of the lateral canthal tendon  is cut away from the inferior orbital rim; (C) the anterior and posterior lid lamellae are divided, and a ‘strip’ of tendon/  lateral tarsal plate dissected out; (D) the strip is shortened and then reattached to the inner aspect of the orbital rim  periosteum with 4-0 absorbable suture; (E) excess lid margin is trimmed; (F) the skin incision (canthotomy) is closed   (Courtesy of JA Nerad, from Techniques in Ophthalmic Plastic Surgery, Saunders 2010)   (Courtesy of AG Tyers and JRO Collin, from Colour Atlas of Ophthalmic Plastic  Surgery, Butterworth-Heinemann 2001)   (A) Medial canthoplasty; (B) lateral canthal sling -  refashioned canthal tendon from the lower lid is passed  through a buttonhole in the tendon from the upper lid   (Courtesy of AG Tyers and JRO Collin, from Colour Atlas of Ophthalmic Plastic  Surgery, Butterworth-Heinemann 2001)   Mechanical ectropion is caused by tumours on or near the lid  margin that mechanically evert the lid. Treatment involves removal  of the cause if possible, and correction of significant horizontal lid  laxity.   Involutional (age-related) entropion affects mainly the lower lid.  The constant rubbing of the lashes on the cornea in long-standing  entropion (pseudotrichiasis - Fig. 1.67A) may cause irritation,  corneal punctate epithelial erosions and, in severe cases, pannus  formation and ulceration. Aetiological factors include:   • Horizontal lid laxity caused by stretching of the canthal  tendons and tarsal plate.    • Vertical lid instability caused by attenuation, dehiscence or  disinsertion of the lower lid retractors. Weakness of the  latter is recognized by decreased excursion of the lower lid  in downgaze.   • Over-riding of the pretarsal by the preseptal orbicularis  during lid closure tends to move the lower border of the  tarsal plate anteriorly, away from the globe, and the upper  border towards the globe, thus tipping the lid inwards  (Fig. 1.67B).   • Orbital septum laxity with prolapse of orbital fat into the  lower lid.   Temporary protection must be as short-term as possible; options  include lubricants, taping, soft bandage contact lenses and  orbicularis chemodenervation with botulinum toxin injection.   o Transverse everting sutures prevent over-riding of the  preseptal orbicularis. They are quick and easy to insert  (Fig. 1.68), providing a correction typically lasting several  months, and may be used in circumstances (e.g. a  confused patient) where a more intricate procedure is not  likely to be tolerated.   o The Wies procedure gives a durable correction. It consists  of full-thickness horizontal lid-splitting and insertion of  everting sutures (Fig. 1.69). The scar creates a barrier  between the preseptal and pretarsal orbicularis, and the  everting suture fairly effectively transfers the pull of the  lower lid retractors from the tarsal plate to the skin and  orbicularis.   o Lower lid retractor reinsertion (Fig. 1.70) involves direct  exposure and advancement of the retractors as opposed  to the less precise approach used in the Wies procedure.  The subciliary skin incision used, and its repair, also  create a barrier to over-riding of the preseptal orbicularis  muscle. It can be performed as a primary treatment but  may be reserved for recurrence.   • Horizontal lid laxity is usually present and can be corrected  with a lateral canthal sling (tarsal strip - see Fig. 1.62) or, less  commonly, a full-thickness lateral pentagon excision (see  Fig. 1.63). Tightening serves also to retain the lid in  apposition against the globe, preventing over-correction.   Scarring of the palpebral conjunctiva can rotate the upper or lower  lid margin towards the globe. Causes include cicatrizing conjunc¬  tivitis, trachoma, trauma and chemical injuries. Temporary meas¬  ures are similar to those listed for involutional entropion.  Definitive surgical treatment of mild cases is by tarsal fracture  (transverse tarsotomy) with anterior rotation of the lid margin, as  for marginal entropion of the lower lid. Treatment of severe cases  is difficult and is directed at replacing deficient or keratinized  conjunctiva and replacing the scarred and contracted tarsal plate  with composite grafts.   An eyelid varix (plural - varices) is a common lesion that may be  mistaken for a naevus or haemangioma. A varix is commonly an    Fig. 1.68 Lid-everting sutures for entropion. (A) Three double-  armed sutures are passed as shown; (B) sutures are tied;  (C) schematic   (Courtesy of AG Tyers and JRO Collin, from Colour Atlas of Ophthalmic Plastic  Surgery, Butterworth-Heinemann 2001)   Fig. 1.69 Wies procedure for entropion. (A) Full-thickness incision; (B) sutures are passed through the conjunctiva and lower  lid retractors; (C) sutures are passed anterior to the tarsal plate to exit inferior to the lashes; (D) schematic   (Courtesy of AG Tyers and JRO Collin, from Colour Atlas of Ophthalmic Plastic Surgery, Butterworth-Heinemann 2001 - figs A-C)    isolated lesion, but may be associated with orbital involvement  (see Ch. 3). It appears as a dark red or purple subcutaneous com¬  pressible (unless thrombosed) lesion (Figs 1.71A and B), which in  some cases becomes apparent only with a Valsalva manoeuvre  (Figs 1.71C and D). It is clinically and histologically similar to a  lymphangioma. Simple excision may be performed for diagnostic  or cosmetic reasons; the possibility of orbital communication  should be borne in mind during surgery.   This is described in the discussion of pseudoptosis (above) and  upper lid blepharoplasty (below).   Floppy eyelid syndrome (FES) is an uncommon unilateral or bilat¬  eral condition that is often overlooked as a cause of persistent  ocular surface symptoms. It typically affects obese middle-aged  and older men who sleep with one or both eyelids against the  pillow, leading to pulling of the lid away from the globe; conse¬  quent nocturnal exposure and poor contact with the globe, often  exacerbated by other ocular surface disease such as dry eye and  blepharitis, result in chronic keratoconjunctivitis. Obstructive  sleep apnoea (OSA) is strongly associated; OSA is linked to   Fig. 1.70 Lower retractor reinsertion. (A) Incision to expose the lower border of the tarsal plate; (B) reflection of the orbital  septum and fat pad to expose the lower lid retractors; (C) tightening of retractors by plication; (D) schematic   (Courtesy of AG Tyers and JRO Collin, from Colour Atlas of Ophthalmic Plastic Surgery, Butterworth-Heinemann 2001)    significant morbidity, including cardiopulmonary disease and  subtle but irreversible mental dysfunction.   substantial excess loose upper lid skin (Fig. 1.72A). The tarsal  plate has a rubbery consistency (Fig. 1.72B); the lid is very  easy to evert (Fig. 1.72C), to fold and to pull away from  the eye.    Papillary conjunctivitis of the superior tarsal conjunctiva  may be intense (Fig. 1.72D).   Keratopathy. Punctate keratopathy, filamentary keratitis and  superior superficial vascularization may be present.   Other findings may include eyelash ptosis, lacrimal gland  prolapse, ectropion and aponeurotic ptosis. Patients with  both FES and OSA seem to have a considerably higher than  average prevalence of glaucoma.   Investigation for OSA should be considered in most cases of  FES, particularly if the patient reports substantial snoring  and/or excessive daytime sleepiness.   Fig. 1.71 Eyelid varices. (A) Typical appearance of a commonly seen small varix; (B) magnified view; (C) larger lesion, probably  with orbital involvement, before Valsalva manoeuvre; (D) during Valsalva   Fig. 1.72 Floppy eyelid syndrome. (A) Redundant upper lid skin; (B) loose and rubbery tarsal plates; (C) very easily everted  eyelid; (D) superior tarsal papillary conjunctivitis   • Treatment of associated OSA is likely to be of benefit;  overweight patients should be encouraged to lose weight.   • Mild cases may respond to lubrication together with  nocturnal eye shield wear or taping of the lids.   • Moderate to severe cases require horizontal shortening to  stabilize the lid and ocular surface and prevent nocturnal  lagophthalmos; a pentagonal excision of 10 mm or more is  taken from the junction of the lateral third and medial  two-thirds of the upper lid.   Blepharochalasis is an uncommon condition characterized by  recurrent episodes of painless, non-pitting oedema of both upper  lids which usually resolves spontaneously after a few days. Presen¬  tation is usually around puberty, episodes becoming less frequent  with time. Eyelid skin becomes stretched and atrophic, character¬  istically said to resemble wrinkled cigarette paper; severe cases may  give rise to stretching of the canthal tendons and levator aponeu¬  rosis resulting in ptosis (Fig. 1.73), and lacrimal gland prolapse may  occur. A hypertrophic form with orbital fat herniation and an  atrophic form with absorption of orbital fat have been described.  The differential diagnosis includes similarly episodic conditions,  particularly drug-induced urticaria and angioedema. Treatment  involves blepharoplasty for redundant upper lid skin, and correc¬  tion of ptosis.   Eyelid imbrication syndrome is an uncommon and frequently  unrecognized disorder in which the upper lid overlaps the lower  on closure so that the lower lashes irritate the superior marginal  tarsal conjunctiva.   It may be unilateral or bilateral and the major symptom is  ocular irritation. It can be acquired, commonly associated with  floppy eyelid syndrome, or - very rarely - congenital; occasionally   Fig. 1.73 Blepharochalasis - left aponeurotic ptosis and  thinned upper lid skin   Fig. 1.74 (A) Left lid retraction in thyroid eye disease;  (B) following Muller muscle recession    it may follow lower lid tarsal strip surgery. Associated signs include  superior tarsal papillary conjunctivitis and rose Bengal staining of  the superior marginal conjunctiva. Definitive treatment consists  of upper lid pentagon resection and/or lateral canthal tightening.   Upper lid retraction is suspected when the upper lid margin is  either level with or above the superior limbus (Fig. 1.74A); the  causes are listed in Table 1.5. Where there is no loss or tightness  of the upper eyelid skin, retraction is corrected by surgical release  of the eyelid retractors, usually via a transconjunctival posterior  approach. Mild retraction may be treated with Muller muscle  recession (Fig. 1.74B). Moderate to severe retraction may require  levator aponeurosis recession.   Inferior scleral show may be physiological in patients with large  eyes or shallow orbits, but is commonly involutional or secondary  to some of the conditions in Table 1.5. It may follow lower lid  blepharoplasty, when aggressive upward massage of the lid for 2  or 3 months may be curative for minor degrees. In other cases, a  tarsal strip operation may raise the lid slightly, but when moderate  elevation is required inferior retractor recession with a posterior  lamellar spacer is likely to be necessary; more aggressive proce¬  dures have been described for severe cases.   • Collier sign of the dorsal midbrain (Parinaud  syndrome - Fig. 1.75B)   • Reduction in cutaneous elasticity and thickness results in  loose, wrinkled skin.   • Weakening of the orbital septum may lead to orbital fat  prolapse.   • Thinning and stretching of the canthal tendons, levator  aponeurosis and lower lid retractors may cause eyelid laxity  and ptosis.   • Atrophy of orbital and eyebrow fat pads can give  enophthalmos and eyebrow sagging.   • Weakening of the frontalis muscle and epicranial  aponeurosis may cause descent of the eyebrows and  increasing looseness of upper eyelid skin.   • Thinning and stretching of midfacial support leads to  descent with formation of a tear trough depression and  exacerbation of lower eyelid changes.   • Thinning and resorption of periorbital bone exacerbates the  appearance of surplus overlying tissues.   Botulinum toxin injection can be used to reduce wrinkling, par¬  ticularly for ‘crows’ feet’ at the lateral canthus and for glabellar    frown lines, and ‘brow lift’ by a reduction in the action of brow  depressors. Complications include temporary ptosis, lagophthal¬  mos, ectropion and diplopia.   These are used to address age-related wrinkles, and less commonly  defects from other causes such as trauma. Complications include  hypersensitivity reactions.   • Hyaluronic acid is the most commonly used tissue filler,  and can be used to temporarily fill in hollows and replace  lost volume. They are injected deep to orbicularis and the  effects generally last 3-12 months depending on the agent  used.   • Others include collagen, microspheres of calcium  hydroxyapatite and synthetic fillers.   Removal of the superficial layers of the skin, by chemical peels or  laser, can lead to a reduction in wrinkling, increased evenness of  pigmentation, removal of blemishes and improved texture by gen¬  erating new epidermis and increasing collagen production in the  dermis.   Upper eyelid involutional changes are characterized by surplus  upper eyelid skin (dermatochalasis) that leads to baggy lids with  indistinct creases and pseudo- or mechanical ptosis. It may  cause a heavy sensation around the eyes, brow ache and, in  more advanced cases, obstruction of the superior visual field  (Fig. 1.76A). Upper lid blepharoplasty (Fig. 1.76B) is effective for  the removal of surplus skin and can be combined with reduction  of the superior orbital fat pads. Care must be taken prior to  surgery to look for ptosis of the eyelid or eyebrow and ocular  surface dryness. Complications include removal of excess skin  leading to lagophthalmos and corneal drying, and removal of  excess orbital fat leading to an unattractive hollowed out upper  eyelid sulcus.   Lower lid involutional changes are characterized by excess skin  and/or prolapsed orbital fat (Fig. 1.77A); blepharoplasty can  address these (Fig. 1.77B).   • Anterior approach. Where there is excess skin an anterior  approach is used to raise a skin/muscle flap that can be lifted  and re-draped on the lid with the surplus removed. At the  same time the inferior orbital fat pads can be reduced by a  small incision through the septum.   • Posterior approach. Bulging of the lower eyelid fat pads  without eyelid laxity or surplus skin is best reduced by a   Fig. 1.75 Causes of lid retraction. (A) Unilateral myasthenic ptosis with contralateral lid retraction; (B) Collier sign; (C) ‘setting  sun’ sign in infantile hydrocephalus; (D) parkinsonism    posterior, transconjunctival approach. Complications  include lower eyelid retraction, contour abnormalities  (particularly lateral drooping), and frank ectropion.   Brow ptosis frequently accompanies dermatochalasis (Fig. 1.78A)  and may also follow facial nerve palsy or localized trauma. Lifting  of the brow needs to precede or occasionally be combined with  upper lid blepharoplasty.   • Direct brow lift. An incision is made above the eyebrow  hairs and an ellipse of skin removed (Fig. 1.78B).   • Endoscopic brow lift. Small incisions within the hair-line  enable endoscopic elevation of the whole forehead tissues  and release at the eyebrow periosteum to allow lifting of the  eyebrows through sutures supported on frontal bone  anchors within the hair-line.   Epicanthic folds are bilateral vertical folds of skin that extend from  the upper or lower lids towards the medial canthi. They may give  rise to a pseudoexotropia. The folds may involve the upper or  lower lids or both; lower lid folds extending upwards to the medial  canthal area (epicanthus inversus - Fig. 1.79A) are associated with  the blepharophimosis syndrome. Treatment is by V-Y (Fig. 1.79B)  or Z-plasty.   Telecanthus is an uncommon condition that may occur in isola¬  tion or in association with blepharophimosis and some systemic    Fig. 1.76 (A) Severe dermatochalasis causing reduction of  upper visual field; (B) appearance following surgery   Fig. 1.77 (A) Mild dermatochalasis and excess lower lid skin;  (B) appearance following upper and lower lid blepharoplasty   Fig. 1.78 (A) Right brow ptosis and dermatochalasis; (B)  following direct brow-lift    syndromes. It consists of increased distance between the medial  canthi due to abnormally long medial canthal tendons (Fig. i.8o).  It should not be confused with hypertelorism in which there is  wide bony separation of the orbits. Treatment involves shortening  and refixation of the medial canthal tendons to the anterior lac¬  rimal crest, or insertion of a trans-nasal suture.   Blepharophimosis, ptosis and epicanthus inversus syndrome  (BPES) is a complex of eyelid malformations consisting of moder¬  ate to severe symmetrical ptosis with poor levator function, tele¬  canthus, epicanthus inversus (see Fig. 1.79A), manifesting with  small palpebral fissures (Fig. 1.81). Other minor facial anomalies    are commonly present. Inheritance is usually autosomal domi¬  nant; both BPES type I (with premature ovarian failure) and BPES  type II (without premature ovarian failure) are caused by muta¬  tions in the FOXL2 gene on chromosome 3. Treatment initially  involves correction of epicanthus and telecanthus, followed later  by bilateral frontalis suspension. It is also important to treat  amblyopia, which is present in about 50%.   Epiblepharon comprises an extra horizontal fold of skin stretching  across the anterior lid margin; it is very common in individuals of  Eastern Asian ethnicity. The lashes are directed vertically, espe¬  cially in the medial part of the lid (Figs 1.82A and B). When the  fold of skin is pulled down the lashes turn out and the normal  location of the lid becomes apparent (Fig. 1.82C); it should not be  confused with the much less common congenital entropion (see  next). Treatment is not required in the majority of Caucasians  because spontaneous resolution with age is usual. Persistent cases  may be treated surgically.   Upper lid entropion is usually secondary to the mechanical effects  of microphthalmos, which cause variable degrees of upper lid  inversion. Lower lid entropion (Fig. 1.83) is generally caused by  maldevelopment of the inferior retractor aponeurosis. Treatment  involves the excision of a strip of skin and muscle, and fixation of  the skin crease to the tarsal plate (Hotz procedure).   A congenital coloboma is an uncommon, unilateral or bilateral,  partial- or full-thickness eyelid defect. It occurs when eyelid devel¬  opment is incomplete, due to either failure of migration of lid  ectoderm to fuse the lid folds or to mechanical forces such as  amniotic bands. Colobomata elsewhere in the eye, as well as a  range of other associations, may be present. The treatment of small  defects involves primary closure, while large defects require skin  grafts and rotation flaps.   • Upper lid colobomas occur at the junction of the middle  and inner thirds (Fig. 1.84A); relatively strong associations  include cryptophthalmos (see below), facial abnormalities  and Goldenhar syndrome.   • Lower lid colobomas occur at the junction of the middle  and outer thirds (Fig. 1.84B) and are frequently associated  with systemic conditions.   • Treacher Collins syndrome (mandibulofacial dysostosis) is  a genetically heterogeneous condition characterized by  malformation of derivatives of the first and second branchial  arches, principally mandibular and ear anomalies. Lower  eyelid coloboma is a feature; ocular anomalies also described  include slanted palpebral apertures, cataract,  microphthalmos and lacrimal atresia.   Fig. 1.82 (A) Epiblepharon; (B) lashes pointing upwards; (C)  normal position of lashes following manual correction   1.85A) is covered by a fused layer of skin with no separation  between the lids.   • Incomplete cryptophthalmos is characterized by  rudimentary lids and microphthalmos (Fig. 1.85B).   • Fraser syndrome is a dominantly inherited condition in  which cryptophthalmos is a common finding; other features  can include syndactyly, urogenital and craniofacial anomalies.   Fig. 1.84 (A) Upper lid colobomas; (B) lower lid colobomas in  Treacher Collins syndrome   Euryblepharon refers to horizontal enlargement of the palpebral  fissure with associated lateral canthal malposition and lateral  ectropion (Fig. 1.86); lagophthalmos and exposure keratopathy  may result.   Microblepharon is characterized by small eyelids, often associated  with anophthalmos (Fig. 1.87).   (Courtesy of D Taylor and C Hoyt , from Pediatric Ophthalmology and  Strabismus, Elsevier 2005)   Ablepharon consists of deficiency of the anterior lamellae of the  eyelids (Fig. 1.88A); treatment involves reconstructive skin grafting.  Ablepharon-macrostomia syndrome is characterized by an enlarged  fish-like mouth (Fig. 1.88B), ear, skin and genital anomalies.   Fig. 1.88 (A) Ablepharon; (B) following reconstruction - note  enlarged fish-like mouth   (Courtesy of D Taylor and C Hoyt , from Pediatric Ophthalmology and  Strabismus, Elsevier 2005 - fig. A; H Mroczkowska - fig. B)   Congenital upper lid eversion is a rare condition more frequently  seen in infants of Afro-Caribbean origin, in Down syndrome and  in congenital ichthyosis (collodion skin disease - Fig. 1.89). It is  typically bilateral and symmetrical. It may resolve spontaneously  with conservative treatment or require surgery.    Fig. 1.89 Congenital upper lid eversion in a patient with  ichthyosis   (Courtesy of D Taylor and C Hoyt, from Pediatric Ophthalmology and  Strabismus, Elsevier 2005)   In ankyloblepharon filiforme adnatum the upper and lower  eyelids are joined by thin tags (Fig. 1.90); most cases are sporadic.  Treatment involves transection with scissors; anaesthesia is not  required.    Secondary punctal stenosis 70  Canalicular obstruction 70  Nasolacrimal duct obstruction 71  Dacryolithiasis 72   • The puncta are located at the posterior edge of the lid  margin, at the junction of the lash-bearing lateral five-sixths  (pars ciliaris) and the medial non-ciliated one-sixth (pars  lacrimalis). Normally they face slightly posteriorly and can  be inspected by everting the medial aspect of the lids.  Treatment of watering caused by punctal stenosis or  malposition is relatively straightforward.   • The canaliculi pass vertically from the lid margin for about  2 mm (ampullae). They then turn medially and run  horizontally for about 8 mm to reach the lacrimal sac. The  superior and inferior canaliculi usually (>90%) unite to  form the common canaliculus, which opens into the lateral  wall of the lacrimal sac. Uncommonly, each canaliculus    opens separately into the sac. A small flap of mucosa  (Rosenmuller valve) overhangs the junction of the common  canaliculus and the lacrimal sac (the internal punctum) and  prevents reflux of tears into the canaliculi. Treatment of  canalicular obstruction may be complex.   • The lacrimal sac is 10-12 mm long and lies in the lacrimal  fossa between the anterior and posterior lacrimal crests. The  lacrimal bone and the frontal process of the maxilla separate  the lacrimal sac from the middle meatus of the nasal cavity.  In a dacryocystorhinostomy (DCR) an anastomosis is  created between the sac and the nasal mucosa to bypass an  obstruction in the nasolacrimal duct.   • The nasolacrimal duct is 12-18 mm long and is the inferior  continuation of the lacrimal sac. It descends and angles  slightly laterally and posteriorly to open into the inferior  nasal meatus, lateral to and below the inferior turbinate. The  opening of the duct is partially covered by a mucosal fold  (valve of Hasner).   across the ocular surface. A variable amount of the aqueous com¬  ponent of the tear film is lost by evaporation, with the remainder   • Tears flow along the upper and lower marginal strips (Fig.  2.2A), pooling in the lacus lacrimalis medial to the lower  puncta, then entering the upper and lower canaliculi by a  combination of capillarity and suction.   • With each blink, the pretarsal orbicularis oculi muscle  compresses the ampullae, shortens and compresses the  horizontal canaliculi, and closes and moves the puncta  medially, resisting reflux. Simultaneously, contraction of the  lacrimal part of the orbicularis oculi creates a positive  pressure that forces tears down the nasolacrimal duct and  into the nose, mediated by helically arranged connective  tissue fibres around the lacrimal sac (Fig. 2.2B).   • When the eyes open, the canaliculi and sac expand, creating  negative pressure that draws tears from the canaliculi into  the sac (Fig. 2.2C).   Epiphora is the overflow of tears at the eyelid margin; strictly,  it is a sign rather than a symptom. There are two mechanisms:   • Hypersecretion secondary to anterior segment disease such  as dry eye (‘paradoxical watering’) or inflammation. In these  cases watering is associated with symptoms of the underlying  cause, and treatment is usually medical.   • Defective drainage due to a compromised lacrimal drainage  system; this may be caused by:   o Malposition (e.g. ectropion) of the lacrimal puncta.  o Obstruction at any point along the drainage system, from  the punctal region to the valve of Hasner.  o Lacrimal pump failure, which may occur secondarily to  lower lid laxity or weakness of the orbicularis muscle (e.g.  facial nerve palsy).   Enquiry should be made about ocular discomfort and redness to  aid in excluding hypersecretion. Drainage failure tends to be exac¬  erbated by a cold and windy environment, and to be least evident  in a warm dry room; a complaint of the tears overflowing onto  the cheek is likely to indicate drainage failure rather than  hypersecretion.   Punctal abnormality is the most common cause of lacrimal drain¬  age failure.   • The puncta and eyelids should be examined using a slit  lamp. It is critical that examination of the puncta is performed  prior to cannulation for diagnostic irrigation, which  temporarily dilates the punctal opening and masks stenosis,  o There will often be obvious tear overflow from the medial,  or less commonly the lateral, canthal region; this is more  likely to indicate defective drainage than an irritative cause,  o Visible mucopurulent discharge is more likely to occur  with nasolacrimal duct obstruction than a blockage more  proximally.   o Punctal stenosis (Fig. 2.3A). This is extremely common,  and has been reported as present in up to about half of  the general population; over half of patients with evident  stenosis are asymptomatic, in many cases due to  insufficiency of tear production or increased evaporation,  o Ectropion, either localised to the punctal region or   involving the wider lid, is often associated with secondary  stenosis (Fig. 2.3B).   redundant conjunctiva (conjunctivochalasis - Fig. 2.3C)  is common but underdiagnosed,  o Occasionally an eyelash may lodge in the ampulla  (Fig. 2.3D).   o A large caruncle may displace the punctum away from  the globe (Fig. 2.3E).    o In the presence of substantial lid laxity, the puncta may  rarely over-ride each other.   o A pouting punctum (Fig. 2.3F) is typical of canaliculitis.  o The eyelid skin will often be moderately scaly and  erythematous in chronic epiphora.   • The lacrimal sac should be palpated. Punctal reflux of  mucopurulent material on compression is indicative of  a mucocoele (a dilated mucus-filled sac; US spelling   - mucocele) with a patent canalicular system, but with an  obstruction either at or distal to the lower end of the  lacrimal sac. In acute dacryocystitis palpation is painful and  should be avoided. Rarely, palpation of the sac will reveal a  stone or tumour.   The marginal tear strip of both eyes should be examined on the  slit lamp prior to any manipulation of the eyelids or instillation of  topical medication. Many patients with watering do not have  obvious overflow of tears but merely show a high meniscus (mar¬  ginal tear strip) of 0.6 mm or more (Fig. 2.4) versus o.2-0.4mm  normally. The fluorescein disappearance test is performed by  instilling fluorescein 1 or 2% drops into both conjunctival for-  nices; normally, little or no dye remains after 5-10 minutes. Pro¬  longed retention is indicative of inadequate lacrimal drainage.  This should be distinguished from the ‘fluorescein clearance test’  used to assess tear turnover in dry eye, in which retained stain is  measured in the meniscus 15 minutes after instillation of 5 ql of  fluorescein.   Lacrimal irrigation should be performed only after ascertaining  punctal patency; if absent or severely stenosed, surgical enlarge¬  ment of the punctum may be needed before canalicular and naso¬  lacrimal duct patency can be confirmed. It is contraindicated in  acute infection.   • A punctum dilator is used to enlarge the punctal orifice  (Fig. 2.5A), entering vertically and then tilting the  instrument horizontally whilst exerting lateral tension  on the lid (Fig. 2.5B,C).   • A gently curved, blunt-tipped 26- or 27-gauge lacrimal  cannula on a 3 ml saline-filled syringe is inserted into the  lower punctum and, whilst keeping a gentle stretch laterally  on the eyelid, advanced a few millimetres, following the  contour of the canaliculus (Fig. 2.5D).   • A hard stop occurs if the cannula enters the lacrimal sac,  coming to a stop at the medial wall of the sac, through  which can be felt the rigid lacrimal bone (Fig. 2.6A). This  excludes complete obstruction of the canalicular system.  Gentle saline irrigation is then attempted. If saline passes  into the nose and throat, when it will be tasted by the  patient, a patent lacrimal system is present, although there  may still be stenosis; alternatively, symptoms may be due to  subtle lacrimal pump failure. Failure of saline to reach the  throat is indicative of total obstruction of the nasolacrimal   Fig. 2.3 (A) Marked punctal stenosis; (B) punctal ectropion and stenosis; (C) conjunctivochalasis; (D) punctal obstruction by  an eyelash; (E) large caruncle; (F) pouting punctum    duct. In this situation, the lacrimal sac will distend slightly  during irrigation and there will be reflux, usually through  both the upper and lower puncta. The regurgitated material  may be clear, mucoid or mucopurulent, depending on the  contents of the lacrimal sac.    • A soft stop is experienced if the cannula stops at or proximal  to the junction of the common canaliculus and the lacrimal  sac. The sac is thus not entered - a spongy feeling is  experienced as the cannula presses the soft tissue of the  common canaliculus and the lateral wall against the medial    wall of the sac and the lacrimal bone behind it (Fig. 2.6B).   As a crimped canaliculus with occlusion of the cannula tip  against the canalicular wall can also give this impression, it is  worthwhile slightly retracting the tip, increasing the lateral  tension on the lid, and gently repeating the attempt to  advance the probe. In the case of lower canalicular  obstruction, a soft stop will be associated with reflux of  saline through the lower punctum. Reflux through the upper  punctum indicates patency of both upper and lower  canaliculi, but obstruction of the common canaliculus.   Dye testing is indicated only in patients with suspected partial  obstruction of the drainage system. Epiphora is present, but there  is no punctal abnormality and the patient tastes saline in his or  her throat on irrigation.   obstruction of the lacrimal passages and lacrimal pump  failure from primary hypersecretion of tears. A drop of 2%  fluorescein is instilled into the conjunctival sac of one eye  only. After about 5 minutes, a cotton-tipped bud moistened  in local anaesthetic is inserted under the inferior turbinate at  the nasolacrimal duct opening. The results are interpreted as  follows:   o Positive: fluorescein recovered from the nose indicates  patency of the drainage system. Watering is due to  primary hypersecretion and no further tests are necessary,  o Negative: no dye recovered from the nose indicates a  partial obstruction (site unknown) or failure of the  lacrimal pump mechanism. In this situation the  secondary dye test is performed immediately. There is a  high false-negative rate - that is, dye is commonly not  recovered even in the presence of a functionally patent  drainage system. Modifications involving direct  observation of the oropharynx using cobalt blue light for  up to an hour may reduce the false-negative rate almost  to zero.   Fig. 2.5 (A) Dilatation of the inferior punctum; (B,C) dilatation  technique; (D) irrigation    Fig. 2.6 Possible results of probing. (A) Hard stop; (B) soft  stop    • The secondary (irrigation) test (Fig. 2.7B) identifies lacrimal  pump failure or the probable site of partial obstruction, on  the basis of whether the topical fluorescein instilled for the  primary test entered the lacrimal sac. Topical anaesthetic is  instilled and any residual fluorescein washed out from the  conjunctival fornix. The drainage system is then irrigated  with a cotton bud under the inferior turbinate,  o Positive: fluorescein-stained saline recovered from the  nose indicates that fluorescein entered the lacrimal sac,  thus confirming functional patency of the upper lacrimal  passages. Partial obstruction of the nasolacrimal duct  distal to the sac is inferred.   o Negative: unstained saline recovered from the nose  indicates that fluorescein did not enter the lacrimal sac.  This implies upper lacrimal (punctal or canalicular)  dysfunction, which may be due to partial physical  occlusion and/or pump failure.   Dacryocystography (DCG - Fig. 2.8) involves the injection of  radio-opaque contrast medium (ethiodized oil) into the canaliculi  followed by the capture of magnified images. Indications include  confirmation of the precise site of lacrimal drainage obstruction  to guide surgery, and the diagnosis of diverticuli, fistulae and  filling defects (e.g. stones, tumours). It should not be performed   Fig. 2.8 Dacryocystography (DCG). (A) Conventional DCG  without subtraction shows normal filling on both sides;   (B) normal left filling and obstruction at the junction of the  right sac and nasolacrimal duct; (C) digital subtraction DCG  showing similar findings to (B)    Fig. 2.9 Nuclear lacrimal scintigraphy showing passage of  tracer via the right lacrimal system but obstructed drainage  in the left nasolacrimal duct   in the presence of acute infection. A DCG is unnecessary if the site  of obstruction is obvious (e.g. regurgitating mucocoele). A normal  dacryocystogram in the presence of subjective and objective epi¬  phora suggests failure of the lacrimal pump, though this is more  readily demonstrated by simple irrigation.   Scintigraphy (Fig. 2.9) assesses tear drainage under more physio¬  logical conditions than DCG, by labelling the tears with a radioac¬  tive substance and tracking their progress. Although it does not  provide the same detailed anatomical visualization as DCG, it may  be used to identify the location of a partial or functional block (e.g.  indicating the absence of significant tear entry to the canaliculi,  localizing the site of physiological obstruction to the eyelids), to  confirm functional obstruction, or sometimes to confirm the pres¬  ence of normal drainage such that surgery is not indicated.   Computed tomography (CT) and magnetic resonance imaging  (MRI) are occasionally employed in the assessment of lacrimal  obstruction, for instance in the investigation of paranasal sinus or  suspected lacrimal sac pathology.   Assessment of the nasal cavity, especially with endoscopy, can be  invaluable in the detection of obstructions such as nasal polyps or  a deviated septum.   Conjunctivochalasis is characterized by one or more folds of  redundant conjunctiva prolapsing over the lower eyelid margin    (see Fig. 2.3C). It can exacerbate the symptoms of dry eye and  commonly contributes to epiphora, of which it can be an under¬  recognized cause. It is thought to be predominantly an involu¬  tional process involving the loss of conjunctival adhesion to  underlying Tenon capsule and episclera and may be analogous to  the conjunctival abnormalities leading to superior limbic kerato¬  conjunctivitis (see Ch. 5). Chronic low-grade ocular surface  inflammation (e.g. dry eye, blepharitis) is likely to play a role. If  severe, exposure of a redundant fold can occur (Fig. 2.10).   • Observation or lubricants alone may be appropriate in mild  cases.   • Surgical options include securing the bulbar conjunctiva to  the sclera with three absorbable sutures (e.g. 6-0 polyglactin)  placed 6-8 mm from the limbus, or excision of a crescent¬  shaped area of excess bulbar conjunctiva, with an anterior  limit of around 6 mm from the limbus; suturing the edges of  the excised patch together, or replacement with amniotic  membrane have been described.   Primary stenosis (see Fig. 2.3A) occurs in the absence of punctal  eversion. The most common causes are chronic blepharitis and  idiopathic stenosis; others include herpes simplex and herpes  zoster lid infection, local radiotherapy, cicatrizing conjunctivitis,  chronic topical glaucoma treatment, systemic cytotoxic drugs such  as 5-fluorouracil, and rare systemic conditions such as porphyria  cutanea tarda.   • Dilatation of the punctum alone can be tried but rarely  gives sustained benefit.   • Punctoplasty is usually required. A number of techniques  have been described, including one-, two- (Fig. 2.11) or  three-snip enlargement with removal of the posterior  ampulla wall, and procedures using a mechanical punch,  laser or microsurgery; a temporary stent can be used.   Fig. 2.10 Conjunctivochalasis. Substantial exposed fold with  conjunctival and corneal rose Bengal staining   Secondary stenosis occurs after punctal eversion leads to chronic  failure of tear entry, and punctoplasty is usually performed in  conjunction with correction of the eversion.   • Retropunctal (Ziegler) cautery can be used for pure punctal  eversion. Burns are applied to the palpebral conjunctiva at  approximately 5 mm below the punctum. Subsequent tissue  shrinkage should invert the punctum.   • Medial conjunctivoplasty can be used in medial ectropion  of a larger area of lid if there is no substantial horizontal  laxity. A diamond-shaped piece of tarsoconjunctiva is  excised, about 4 mm high and 8 mm wide, parallel with and  inferolateral to the canaliculus and punctum, followed by  approximation of the superior and inferior wound margins  with sutures (Fig. 2.12). Incorporation of the lower lid  retractors in the sutures further aids repositioning.   • Lower lid tightening , usually with a tarsal strip, is used to  correct lower lid laxity and may be combined with medial  conjunctivoplasty where there is a significant medial  ectropion component.   Causes include congenital, trauma, herpes simplex infection,  drugs and irradiation. Chronic dacryocystitis can cause a mem¬  brane to form in the common canaliculus. The initial surgical  approach has tended over recent years to attempt to preserve the  physiological anatomy.   • Partial obstruction of the common or individual canaliculi,  or anywhere in the lacrimal drainage system, may be treated  by simple intubation of one or both canaliculi with silicone  stents. These are left in situ for 6 weeks to 6 months   o Canalicular trephination using a purpose-made  minitrephine (Sisler), followed by intubation;  trephination has also been described using an intravenous  catheter with a retracted introducer needle used as a stent  and then advanced to overcome the obstruction. Balloon  canaliculoplasty and endoscopic laser techniques are    available. These less invasive options may have lower  success rates than more aggressive surgery.   O With 6-8 mm of patent normal canaliculus between  the punctum and the obstruction, anastomosis  of the patent part of the canaliculus into the  lacrimal sac, with intubation, can be performed  (canaliculodacryocystorhinostomy - CDCR).   o Where obstruction is severe or it is not possible  to anastomose functioning canaliculi to the  lacrimal sac, conventional surgery consists of  conjunctivodacryocystorhinostomy and the insertion of a  toughened glass (Lester Jones) tube (Fig. 2.14); this may  also be used when the lacrimal system is intact but  non-functioning due to failure of the physiological pump  (e.g. facial nerve palsy). The surgery is performed as for  an external approach dacryocystorhinostomy (DCR - see  below) but the caruncle is excised and a track for the  tube created between the lacus lacrimalis and the lacrimal  sac. Patient satisfaction is variable.   o Conventional (external approach) dacryocystorhinostomy  (DCR) is indicated for obstruction distal to the medial  opening of the common canaliculus, and consists of  anastomosis of the lacrimal sac to the mucosa of the  middle nasal meatus. The procedure is usually performed  under hypotensive general anaesthesia. A vertical skin  incision is made 10 mm medial to the inner canthus, the   Fig. 2.14 (A) Lester Jones tube; (B) CT scan 3D  reconstruction of tube in situ    medial canthal tendon and lacrimal sac exposed and  reflected, and after removal of the intervening bone the  sac is incised and attached to an opening created in the  nasal mucosa (Fig. 2.15). The success rate is over 90%;  causes of failure include inadequate size and position of  the ostium, unrecognized common canalicular    obstruction, scarring and the ‘sump syndrome’, in which  the surgical opening in the lacrimal bone is too small and  too high. Complications include cutaneous scarring,  injury to medial canthal structures, haemorrhage,  infection and cerebrospinal fluid rhinorrhoea if the  subarachnoid space is inadvertently entered,  o Endoscopic DCR encompasses several techniques. A light  pipe can be passed through the canalicular system into  the lacrimal sac to guide an endoscopic approach from  within the nose, or a microendoscopic transcanalicular  procedure can be performed using a drill or laser to  establish communication with the nasal cavity.   Advantages over conventional DCR include less marked  systemic disturbance with minimal blood loss and a lower  risk of cerebrospinal fluid leakage, the avoidance of a skin  incision and generally a shorter operating time.  Disadvantages include generally a slightly lower success  rate and visualization difficulties, meaning that additional  procedures are sometimes needed,  o Other procedures, often reserved for partial nasolacrimal  duct obstruction, include probing and intubation, stent  insertion and balloon dacryocystoplasty.   Dacryoliths (lacrimal stones) may occur in any part of the lacrimal  system. They are more common in males. Although the pathogen¬  esis is unclear, it has been proposed that tear stagnation secondary  to inflammatory obstruction may precipitate stone formation,  which tends to be associated with squamous metaplasia of the  lacrimal sac epithelium. Presentation is often in late adulthood;  symptoms may include intermittent epiphora, recurrent attacks of  acute dacryocystitis and lacrimal sac distension.   The lacrimal sac is distended and relatively firm, but is not  inflamed and tender as in acute dacryocystitis.   Mucus reflux on pressure may or may not be present. Treat¬  ment involves a DCR.   The lower end of the nasolacrimal duct, in the region of the valve  of Hasner, is the last portion of the lacrimal drainage system to  canalize, with complete patency most commonly occurring soon  after birth. Epiphora affects at least 20% of neonates, but sponta¬  neous resolution occurs in over 95% within the first year; it has  been suggested that early epiphora with resolution maybe regarded  as a normal variant.   o Epiphora and matting of eyelashes may be constant or  intermittent, and may be particularly noticeable when  the child has an upper respiratory tract infection;  intercurrent frank bacterial conjunctivitis may be treated  with a broad-spectrum topical antibiotic.    o Gentle pressure over the lacrimal sac may cause  mucopurulent reflux,  o Acute dacryocystitis is very rare,  o Normal visual function should be confirmed as far as  possible, and an anterior segment examination with  assessment of the red reflex performed,  o The fluorescein disappearance test (see above) is highly  specific in this setting; only a fine line of dye, at most,  should remain at 5-10 minutes under inspection with a  blue light in a darkened room.   • Differential diagnosis includes other congenital causes of  a watering eye, such as punctal atresia; it is important to  exclude congenital glaucoma, chronic conjunctivitis (e.g.  chlamydial), keratitis and uveitis.   o Massage of the lacrimal sac has been suggested as a  means of rupturing a membranous obstruction by  hydrostatic pressure. The index finger is initially placed  over the common canaliculus to block reflux, and then  rolled over the sac, massaging downwards. The likelihood  of success and the optimal regimen is undetermined,  o Probing. Passage of a fine wire via the canalicular system  and nasolacrimal duct (Fig. 2.16) to disrupt the  obstructive membrane at the valve of Hasner is usually  regarded as the definitive treatment, and may be preceded  and followed by irrigation to confirm the site of  obstruction and subsequent patency respectively. Probing  can be repeated if a first procedure is unsuccessful. Nasal  endoscopic guidance may enhance success, and should be  considered at least for repeat procedures. If symptoms are  mild-moderate, probing may be delayed until the age of  12-18, or even 24, months and is carried out under  general anaesthesia. For more marked symptoms, early  probing may be appropriate and in young children is  sometimes performed under topical anaesthesia in an  outpatient setting. Risks include the induction of  canalicular stenosis due to probe trauma, which may be  relatively common. It should be noted that there is little    evidence of a difference in final outcome at 24 months  conferred by intervention versus non-intervention.   Failure of probing may result from abnormal anatomy,  which can usually be recognized by difficulty in passing  the probe and subsequent non-patency of the drainage  system on irrigation.   o Options after probing failure include intubation with  silastic tubing with or without balloon dilatation of  the nasolacrimal duct, endoscopic procedures, and  dacryocystorhinostomy.   A congenital dacryocoele (amniontocoele) is a collection of amni-  otic fluid or mucus in the lacrimal sac caused by an imperforate  Hasner valve. Presentation is perinatal with a bluish cystic swelling  at or below the medial canthus (Fig. 2.17), accompanied by epi¬  phora. If an intranasal component is large it can cause respiratory  distress. It should not be mistaken for an encephalocoele, the latter  being characterized by a pulsatile swelling above the medial  canthal tendon. Resolution is common with only conservative  treatment, but if this fails, probing is usually adequate.    Chronic canaliculitis is an uncommon condition, frequently  caused by Actinomyces israelii , anaerobic Gram-positive bacteria.  Occasionally scarring and canalicular obstruction may result.  Presentation is with unilateral epiphora associated with chronic  mucopurulent conjunctivitis refractory to conventional treat¬  ment. There is pericanalicular redness and oedema, and mucopu¬  rulent discharge on pressure over the canaliculus (Fig. 2.18A).  A ‘pouting’ punctum (see Fig. 2.3F) may be a diagnostic clue in  mild cases. In contrast to dacryocystitis, there is no lacrimal sac    involvement. Concretions (sulfur granules) are metabolic prod¬  ucts of Actinomyces and other hydrogen sulfide-utilizing bacteria,  and classically are expressed on canalicular compression or follow¬  ing canaliculotomy (Fig. 2.18B). A topical antibiotic such as a  fluoroquinolone four times daily for 10 days may be tried initially  but is rarely curative unless combined with canaliculotomy (a  linear incision into the conjunctival side of the canaliculus) and  curettage of concretions. Giant fornix syndrome (see Ch. 5),  dacryolithiasis and lacrimal diverticulum may give a similar clini¬  cal picture. Herpes simplex is a classic cause of acute - as opposed  to chronic - canaliculitis.    Infection of the lacrimal sac is usually secondary to obstruction of  the nasolacrimal duct. It may be acute or chronic and is most  commonly staphylococcal or streptococcal.   Fig. 2.18 Chronic canaliculitis. (A) Mucopurulent discharge on  pressure over an inflamed upper canaliculus; (B) sulfur  concretions released by canaliculotomy    Fig. 2.19 (A) Acute dacryocystitis; (B) lacrimal abscess and  preseptal cellulitis; (C) lacrimal fistula   Presentation is with the subacute onset of pain in the medial  canthal area, associated with epiphora. A very tender, tense red  swelling develops at the medial canthus (Fig. 2.19A), commonly  progressing to abscess formation (Fig. 2.19B); there maybe associ¬  ated preseptal cellulitis.   o Initial treatment involves the application of warm  compresses and oral antibiotics such as flucloxacillin or  co-amoxiclav; irrigation and probing should not be  performed.   o Incision and drainage may be considered if pus points and  an abscess is about to drain spontaneously. However, this  carries the risk of a persistent sac-skin fistula (Fig. 2.19C).    O Dacryocystorhinostomy is commonly required after the  acute infection has been controlled, and may reduce the  risk of recurrent infection.   Presentation is with chronic epiphora, which may be associated  with a chronic or recurrent unilateral conjunctivitis. A mucocoele  is usually evident as a painless swelling at the inner canthus (Fig.  2.20A), but if an obvious swelling is absent pressure over the sac  commonly still results in mucopurulent canalicular reflux (Fig.  2.20B). Treatment is with a dacryocystorhinostomy; the enlarged  sac often makes this technically easier.   Idiopathic orbital inflammatory  disease 89  Orbital myositis 90  Acute dacryoadenitis 91  Tolosa-Hunt syndrome 92  Wegener granulomatosis 92   Optic nerve glioma 106  Optic nerve sheath meningioma 107  Plexiform neurofibroma 109  Isolated neurofibroma 109   The orbit is a pear-shaped cavity, the stalk of which is the optic   • The roof consists of two bones: the lesser wing of the  sphenoid and the orbital plate of the frontal bone. It is  located subjacent to the anterior cranial fossa and the frontal  sinus. A defect in the orbital roof may cause pulsatile  proptosis due to transmission of cerebrospinal fluid  pulsation to the orbit.   • The lateral wall also consists of two bones: the greater wing  of the sphenoid and the zygomatic. The anterior half of the  globe is vulnerable to lateral trauma since it protrudes  beyond the lateral orbital margin.   • The floor consists of three bones: the zygomatic, maxillary  and palatine. The posteromedial portion of the maxillary  bone is relatively weak and may be involved in a ‘blowout’  fracture (see Ch. 21). The orbital floor also forms the roof of  the maxillary sinus so that maxillary carcinoma invading the  orbit may displace the globe upwards.   • The medial wall consists of four bones: maxillary, lacrimal,  ethmoid and sphenoid. The lamina papyracea, which forms  part of the medial wall, is paper-thin and perforated by  numerous foramina for nerves and blood vessels. Orbital  cellulitis is therefore frequently secondary to ethmoidal  sinusitis.   • The superior orbital fissure is a slit linking the cranium and  the orbit, between the greater and lesser wings of the  sphenoid bone; through it pass numerous important  structures.   O The superior portion contains the lacrimal, frontal  and trochlear nerves, and the superior ophthalmic  vein.    O The inferior portion contains the superior and inferior  divisions of the oculomotor nerve, the abducens and  nasociliary nerves, and sympathetic fibres from the  cavernous plexus.   o Inflammation of the superior orbital fissure and apex  (Tolosa-Hunt syndrome) may therefore result in a  multitude of signs including ophthalmoplegia and venous  outflow obstruction.   • The inferior orbital fissure lies between the greater wing of  the sphenoid and the maxilla, connecting the orbit to the  pterygopalatine and infratemporal fossae. Through it run  the maxillary nerve, the zygomatic nerve and branches  of the pterygopalatine ganglion, as well as the inferior  ophthalmic vein.   Symptoms of orbital disease include eyelid and conjunctival swell¬  ing, redness, watering, pain (sometimes on, or exacerbated by, eye  movement), increasing ocular prominence, displacement or a  sunken impression of the eye, double vision and blurring, and  sometimes a pulsing sensation or audible bruit.   Eyelid and periocular oedema, skin discoloration, ptosis, chemosis  (oedema of the conjunctiva, which may involve the plica and  caruncle) and epibulbar injection (Fig. 3.2) may be seen; causes  include thyroid eye disease, orbital inflammatory diseases and  obstruction to venous drainage.   Proptosis (Fig. 3.3) describes an abnormal protrusion of an organ,  but is generally applied to the eyeball; exophthalmos refers    specifically to the eyeball only. Proptosis may be caused by retro¬  bulbar lesions or, less frequently, a shallow orbit. The intraorbital  portion of the optic nerve is longer (25 mm) than the distance  between the back of the globe and the optic canal (18 mm). This  allows for significant forward displacement of the globe (propto¬  sis) without excessive stretching of the nerve.   • Asymmetrical proptosis is readily detected by looking down  at the patient from above and behind (Fig. 3.4A).   • The direction of proptosis may indicate the likely pathology.  For example, space-occupying lesions within the muscle  cone such as a cavernous haemangioma or optic nerve  tumours cause axial proptosis, whereas extraconal lesions  usually give rise to combined proptosis and dystopia (see  next).   • Dystopia implies displacement of the globe in the coronal  plane, usually due to an extraconal orbital mass such as a  lacrimal gland tumour (Fig. 3.4B). Horizontal displacement  is measured from the midline (nose) to the centre of the  pupil while vertical dystopia is read on a vertical scale  perpendicular to a horizontal rule placed over the bridge of  the nose. The measured eye should fixate straight ahead, if  necessary facilitating this by occluding the fellow eye.   • The severity of proptosis can be measured with a plastic rule  resting on the lateral orbital margin, or with the Luedde™  exophthalmometer using a similar principle. Commonly, a  binocular exophthalmometer (e.g. Hertel) is employed,  using visualization of the corneal apices to determine the   Fig. 3.4 General signs of orbital disease. (A) Left proptosis  visualized from above; (B) right inferior dystopia; (C)  measurement of proptosis with an exophthalmometer    degree of ocular protrusion from a scale (Fig. 3.4C).  Measurements can be taken both relaxed and with the  Valsalva manoeuvre. Readings greater than 20 mm are  indicative of proptosis and a difference of 2-3 mm or more  between the two eyes is suspicious regardless of the absolute  values. The dimensions of the palpebral apertures and any  lagophthalmos should also be noted.    • Pseudoproptosis (the false impression of proptosis) may be  due to facial asymmetry, enlargement of the globe (e.g. high  myopia or buphthalmos), lid retraction or contralateral  enophthalmos.   Enophthalmos implies recession of the globe within the orbit.  Causes include congenital and traumatic orbital wall abnormali¬  ties, atrophy of the orbital contents (e.g. radiotherapy, sclero¬  derma, chronic eye poking in blind infants - the ‘oculodigitaf  sign) or sclerosis (e.g. metastatic scirrhous carcinoma, sclerosing  orbital inflammatory disease). Pseudoenophthalmos may be  caused by a small or shrunken eye (microphthalmos or phthisis  bulbi), by ptosis, or by contralateral proptosis or pseudoproptosis.   Defective ocular motility is very common in orbital disease. Causes  include an orbital mass, restrictive myopathy (e.g. thyroid eye  disease - Fig. 3.5, orbital myositis, tethering of muscles or tissue  after orbital wall fracture), ocular motor nerve involvement  associated with lesions in the cavernous sinus, orbital fissures or  posterior orbit (e.g. carotid-cavernous fistula, Tolosa-Hunt syn¬  drome, malignant lacrimal gland tumours). The following tests  may be used to differentiate a restrictive from a neurological  motility defect:   • Forced duction test. Under topical anaesthesia, the insertion  of the muscle in an involved eye is grasped with forceps and  the globe rotated in the direction of reduced mobility;  checked movement of the globe indicates a restrictive  problem; no resistance will be encountered with a  neurological lesion.   • Differential intraocular pressure (IOP) test involves less  discomfort than forced duction and an objective rather than    subjective endpoint. The IOP is measured in the primary  position of gaze and then with the patient attempting to  look in the direction of limited mobility; an increase of  6 mmHg or more denotes resistance transmitted to the  globe by muscle restriction (the Braley sign).   • Saccadic eye movements in neurological lesions are reduced  in velocity, while restrictive defects manifest normal saccadic  velocity with sudden halting of ocular movement.   • Increasing venous pressure by dependent head position, the  Valsalva manoeuvre or jugular compression may induce or  exacerbate proptosis in patients with orbital venous  anomalies or infants with orbital capillary haemangioma.   • Pulsation is caused either by an arteriovenous  communication or a defect in the orbital roof. In the former,  pulsation may be associated with a bruit depending on the  size of the communication. In the latter the pulsation is  transmitted from the brain by the cerebrospinal fluid and  there is no associated bruit. Mild pulsation is best detected  on the slit lamp, particularly by applanation tonometry.   • A bruit is a sign found with a larger carotid-cavernous  fistula. It is best heard with the bell of the stethoscope and is  lessened or abolished by gently compressing the ipsilateral  carotid artery in the neck.   • Optic disc swelling may be the initial feature of compressive  optic neuropathy (Fig. 3.6A).   • Optic atrophy (Fig. 3.6B), which may be preceded by  swelling, is a feature of severe compressive optic neuropathy.  Important causes include thyroid eye disease and optic nerve  tumours.   Fig. 3.5 Restrictive myopathy and bilateral lid retraction and proptosis in thyroid eye disease - nine positions of gaze    Fig. 3.6 Fundus changes in orbital disease. (A) Disc swelling; (B) optic atrophy; (C) opticociliary vessels on a chronically  swollen disc; (D) choroidal folds    • Opticociliary collaterals consist of enlarged pre-existing  peripapillary capillaries that divert blood from the central  retinal venous circulation to the peripapillary choroidal  circulation when there is obstruction of the normal drainage  channels. On ophthalmoscopy the vessels appear as large  tortuous channels most frequently sited temporally, which  disappear at the disc margin (Fig. 3.6C). The collaterals may  be associated with any orbital or optic nerve tumour that  compresses the intraorbital optic nerve and impairs blood  flow through the central retinal vein. The most common  tumour associated with shunts is an optic nerve sheath  meningioma but they may also occur with optic nerve  glioma, central retinal vein occlusion, idiopathic intracranial  hypertension and glaucoma.    • Choroidal folds (Fig. 3.6D) are discussed in detail in Ch. 14;  they may occur in a wide variety of orbital lesions. Although  tending to be more common with greater amounts of  proptosis and anteriorly located tumours, in some cases  their presence can precede the onset of proptosis.   • Computed tomography (CT) is useful for depicting bony  structures and the location and size of space-occupying  lesions. It is of particular value in patients with orbital  trauma because it can detect small fractures, foreign bodies,  blood, herniation of extraocular muscle and emphysema (see  Ch. 21). It is, however, unable to distinguish different    pathological soft tissue masses that are radiologically  isodense. Confirmation of an orbital abscess in cellulitis is a  relatively common indication.   • Magnetic resonance imaging (MRI) can demonstrate orbital  apex lesions and intracranial extension of orbital tumours,  and is useful for imaging orbital inflammatory disease. Serial  short Ti inversion recovery (STIR) scans are valuable in  assessing inflammatory activity in thyroid eye disease (see  Ch. 19).   • Plain X-rays are little used except for the initial diagnosis of  traumatic bony injury.   • Ultrasonography can provide useful information,  particularly with high-grade apparatus and an experienced  operator, but does not image the orbital apex well.   • Fine needle biopsy is sometimes performed, particularly in  suspected neoplastic disease. Potential problems include  haemorrhage and ocular penetration.   Thyroid eye disease (TED), also known as thyroid-associated orbi-  topathy and Graves ophthalmopathy, is a very common orbital  disorder, and is the most common cause of both bilateral and  unilateral proptosis in an adult.   Thyrotoxicosis (hyperthyroidism) is a condition involving exces¬  sive secretion of thyroid hormones. Graves disease, the most  common form of hyperthyroidism, is an autoimmune disorder in  which IgG antibodies bind to thyroid stimulating hormone (TSH)  receptors in the thyroid gland and stimulate secretion of thyroid  hormones. It is more common in females and may be associated  with other autoimmune disorders. Presentation is often in the  fourth or fifth decades with symptoms including weight loss  despite good appetite, increased bowel frequency, sweating, heat  intolerance, nervousness, irritability, palpitations, weakness and  fatigue. There may be enlargement of the thyroid gland, tremor,  palmar erythema, and warm and sweaty skin. Thyroid acropachy  is a phenomenon similar to clubbing of the fingers, occurring in  1%; pretibial myxoedema (1-5%) is indurated thickening of the  skin of the shins. Cardiac manifestations may include sinus tachy¬  cardia and other arrhythmias. Other autoimmune disorders can  be associated. Thyroid function is commonly tested initially with  a TSH level; if this is low, or normal but thyroid disease is still  suspected, a range of additional investigations can be carried out.  Treatment options include carbimazole, propylthiouracil, pro¬  pranolol, thyroid ablation with radioactive iodine, and partial  thyroidectomy.   Once a patient has Graves disease, the major clinical risk factor for  developing TED is smoking. The greater the number of cigarettes    smoked per day, the greater the risk, and giving up smoking seems  to reduce the risk. Women are five times more likely to be affected  by TED than men, but this largely reflects the increased incidence  of Graves disease in women. Radioactive iodine used to treat  hyperthyroidism can worsen TED. TED can also, though less com¬  monly, occur in euthyroid and hypothyroid (including treated  hyperthyroid) patients. It can sometimes be the presenting mani¬  festation of thyroid-related disease.   Thyroid ophthalmopathy involves an organ-specific autoimmune  reaction in which an antibody that reacts against thyroid gland  cells and orbital fibroblasts leads to inflammation of extraocular  muscles, interstitial tissues, orbital fat and lacrimal glands charac¬  terized by pleomorphic cellular infiltration, associated with  increased secretion of glycosaminoglycans and osmotic imbibition  of water. There is an increase in the volume of the orbital contents,  particularly the muscles, which can swell to eight times their  normal size. There may be a secondary elevation of intraorbital  pressure, and the optic nerve may be compressed. Subsequent  degeneration of muscle fibres eventually leads to fibrosis, which  exerts a tethering effect on the involved muscle, resulting in  restrictive myopathy and diplopia.   TED typically proceeds through a congestive (inflammatory) stage  in which the eyes are red and painful; this tends to remit within  1-3 years and only about 10% of patients develop serious long¬  term ocular problems. A fibrotic (quiescent) stage follows in  which the eyes are white, although a painless motility defect may  be present. Clinical features broadly can be categorized into (i)  soft tissue involvement, (ii) lid retraction, (iii) proptosis, (iv) optic  neuropathy and (v) restrictive myopathy. A commonly used clas¬  sification for the severity of TED has been issued by the European  Group on Graves Orbitopathy (EUGOGO): (i) sight-threatening  due to optic neuropathy or corneal breakdown; (ii) moderate-  severe, with one of moderate-severe soft tissue involvement, lid  retraction of 2 mm or more, diplopia and proptosis of 3 mm or  more; (iii) mild, with only a minor impact on daily life.   • Symptoms. Grittiness, red eyes, lacrimation, photophobia,  puffy lids and retrobulbar discomfort.   o Epibulbar hyperaemia. This is a sensitive sign of  inflammatory activity. Intense focal hyperaemia may  outline the insertions of the horizontal recti (Fig. 3.7A).  o Periorbital swelling is caused by oedema and infiltration  behind the orbital septum; this may be associated with  chemosis and prolapse of retroseptal fat into the eyelids  (Fig. 3.7B).   (A) Epibulbar hyperaemia overlying a horizontal rectus  muscle; (B) periorbital oedema, chemosis and prolapse of  fat into the eyelids; (C) superior limbic keratoconjunctivitis    o Tear insufficiency and instability is common,  o Corneal signs are exacerbated by lid retraction (see next)  and can include punctate epithelial erosions, superior  limbic keratoconjunctivitis (Fig. 3.7C and see Ch. 5), and  occasionally bacterial keratitis, thinning and scarring.    contracture of the levator palpebrae and inferior rectus muscles  associated with adhesion to overlying orbital tissues is another  probable mechanism, together with secondary overaction in  response to hypo- or hypertropia produced by fibrosis.   • Symptoms. Patients may complain of a staring or bulging¬  eyed appearance, difficulty closing the eyes and ocular  surface symptoms.   o The upper lid margin normally rests 2 mm below the  limbus (Fig. 3.8A, right eye). Lid retraction is suspected  when the margin is either level with or above the superior  limbus, allowing sclera to be visible (‘scleral show’; Fig.   o The lower eyelid margin normally rests at the inferior  limbus; retraction is suspected when sclera shows below  the limbus. Lid retraction may occur in isolation or in  association with proptosis, which exaggerates its severity.  O The Dalrymple sign is lid retraction in primary gaze (Fig.  3.8B).   o The Kocher sign describes a staring and frightened  appearance of the eyes which is particularly marked on  attentive fixation (Fig. 3.8C).  o The von Graefe sign signifies retarded descent of the  upper lid on downgaze (lid lag - Fig. 3.8D).   • Signs. Proptosis is axial, unilateral or bilateral, symmetrical  (Fig. 3.9A) or asymmetrical (Fig. 3.9B), and frequently  permanent. Severe proptosis may compromise lid closure  and along with lid retraction and tear dysfunction can lead  to exposure keratopathy, corneal ulceration and infection  (Fig. 3.9C).   Between 30% and 50% of patients with TED develop ophthalmo¬  plegia and this may be permanent. Ocular motility is restricted  initially by inflammatory oedema, and later by fibrosis.   • Symptoms. Double vision, and often discomfort in some  positions of gaze.   contracture of the inferior rectus, may mimic superior  rectus palsy and is the most common motility deficit,  o Abduction defect due to fibrosis of the medial rectus,  which may simulate sixth nerve palsy,  o Depression defect (Fig. 3.10B) secondary to fibrosis of the  superior rectus.   Retraction of upper and lower lids occurs in about 50% of patients  with Graves disease. Humorally induced overaction of Muller  muscle is postulated to occur as a result of sympathetic overstimu¬  lation secondary to high levels of thyroid hormones. Fibrotic   Optic neuropathy is a fairly common (up to 6%) serious compli¬  cation caused by compression of the optic nerve or its blood  supply at the orbital apex by the congested and enlarged recti (Fig.  3.11) and swollen orbital tissue. Such compression, which may   Fig. 3.8 Lid signs in thyroid eye disease. (A) Mild left lid retraction; (B) moderate bilateral symmetrical lid retraction -  Dalrymple sign; (C) severe bilateral lid retraction - Kocher sign; (D) right lid lag on downgaze - von Graefe sign   (Courtesy of G Rose - fig. B; S Chen - fig. C)    occur in the absence of significant proptosis, may lead to severe  visual impairment if adequate and timely treatment is not  instituted.   • Symptoms. Impairment of central vision occurs in  conjunction with other symptoms of TED. In order to detect  early involvement, patients should be advised to monitor  their own visual function by alternately occluding each eye,  reading small print and assessing the intensity of colours, for  example on a television screen.   • Signs. A high index of suspicion should be maintained for  optic neuropathy, and it is important not to mistakenly  attribute disproportionate visual loss to minor disease.   o Visual acuity (VA) is usually reduced, but not invariably,  o Colour desaturation is a sensitive feature,  o There may be diminished light brightness appreciation,  o A relative afferent pupillary defect, if present, should give  cause for marked concern.   o Visual field defects can be central or paracentral and may  be combined with nerve fibre bundle defects. These  findings, in concert with elevated IOP, may be confused  with primary open-angle glaucoma,  o The optic disc may be normal, swollen or, rarely, atrophic.   Investigations other than blood tests for thyroid disease are not  necessary if the diagnosis is evident clinically, but the exclusion of  other conditions is sometimes indicated. Visual field testing is  carried out if there is a suspicion of optic nerve compromise, and    may be performed as part of a baseline evaluation even if there is  no apparent visual impairment. MRI, CT and ultrasonographic  imaging of the orbits are indicated in some circumstances, such as  helping to confirm an equivocal diagnosis by identification of the  typical pattern of extraocular muscle involvement in TED, consist¬  ing of muscle belly enlargement with tendon sparing. Imaging is  also used in the assessment of optic nerve compression and prior  to orbital wall surgery. Visual evoked potentials are sometimes  utilized in optic neuropathy.   Treatment can be classified into that of mild disease (most  patients), moderate to severe active disease, and treatment of post-  inflammatory complications. The first measure taken in all cases  should be the cessation of smoking. Thyroid dysfunction should  also be managed adequately; if radioiodine treatment is adminis¬  tered in patients with pre-existing TED, a short course of oral  steroids should be given in concert.   o Topical anti-inflammatory agents (steroids, non-steroidal  anti-inflammatory drugs (NSAIDs), ciclosporin) are  advocated by some authorities.   o Head elevation with three pillows during sleep to reduce  periorbital oedema.    Fig. 3.9 Proptosis in thyroid eye disease. (A) Symmetrical;  (B) asymmetrical; (C) bacterial keratitis due to severe  exposure   (Courtesy of A Pearson - figs A and B; S Kumar Puri - fig. C)   o Clinical activity score. EUGOGO suggests calculating a  ‘clinical activity score’ to aid in determining a threshold  for the use of immunosuppressives, assigning one point  for each feature present from the following list and  considering treatment for a score of 3 or more out of 7.   3. Eyelid swelling considered to be due to active  (inflammatory phase) TED.   5. Conjunctival redness considered to be due to active  (inflammatory phase) TED.   Fig. 3.10 Restrictive thyroid myopathy. (A) Defective elevation  of the left eye; (B) defective depression of the right eye   During subsequent review, a point is allocated for an increase in  proptosis of 2 mm or more, a decrease in uniocular excursion in  any one direction of 8° or more, or a decrease in Snellen acuity of  one line.   moderate to severe disease. Oral prednisolone 60-80 mg/  day may be given initially, and tapered depending on  response. Intravenous methylprednisolone is often  reserved for acute compressive optic neuropathy (see  below), but tolerability is better and outcomes may be  superior compared with oral treatment; a lower-intensity  regimen in the absence of acute sight-threatening disease  is 0.5 g once weekly for 6 weeks followed by 0.25 g once  weekly for 6 weeks. A reduction in discomfort, chemosis  and periorbital oedema usually occurs within 24 hours,  with a maximal response within 2-8 weeks. Ideally, oral  steroid therapy should be discontinued after several  months, but long-term low-dose maintenance may be  necessary.   o Orbital steroid injections are occasionally used in selected  cases to minimize systemic side effects, but are typically  considerably less effective than systemic treatment.   o Low-dose fractionated radiotherapy may be used in  addition to steroids or when steroids are contraindicated  or ineffective, but because of the delayed effect is not  used as the sole treatment of acute optic nerve  compression. A positive response is usually evident  within 6 weeks, with maximal improvement by 4 months;  around 40% will not respond. Adverse effects include  cataract, radiation retinopathy, optic neuropathy and an  increased risk of local cancer; the threshold for its use  should be higher in younger patients and diabetics, the  latter because of a possibly increased risk of retinopathy.   Fig. 3.11 CT shows muscle enlargement in thyroid eye  disease. (A) Axial view; (B) coronal view - note sparing of  the right lateral rectus muscle; (C) coronal view shows  crowding at the orbital apex   (Courtesy of N Sibtain - figs A and B; J Nerad, K Carter and M Alford, from  ‘Oculoplastic and Reconstructive Surgeryin Rapid Diagnosis in  Ophthalmology Mosby 2008 - fig. C)   o Combined therapy with irradiation, azathioprine and  low-dose prednisolone may be more effective than  steroids or radiotherapy alone,  o Optic neuropathy, and less commonly intractable corneal  exposure, requires aggressive treatment. Pulsed  intravenous methylprednisolone is commonly used,  regimens including 0.5-1 g on three successive days with  conversion to oral treatment (e.g. 40 mg/day  prednisolone) or 0.5-1 g on alternate days, 3-6 times,  keeping the maximum dose below 8 g to reduce the risk  of liver compromise, followed by oral prednisolone;  appropriate monitoring should be instituted, including    liver function tests, as well as gastric protective treatment  and osteoporosis prophylaxis if necessary. Orbital wall  decompression (see below) and/or orbital apex  decompression may be considered if steroids are  ineffective (20% receiving intravenous treatment) or  contraindicated. Orbital radiotherapy may also be  administered, but is generally only used as an adjunct to  other modalities.   o Several drugs targeting specific aspects of the immune  response in TED are under investigation, notably  monoclonal antibody treatment with rituximab.   • Post-inflammatory complications. Eyelid surgery should be  performed only after any necessary orbital and then  strabismus procedures have been undertaken, as orbital  decompression may impact both ocular motility and eyelid  position, and extraocular muscle surgery may affect eyelid  position.   o Proptosis. After active inflammation has remitted, the  patient can be left with cosmetically and functionally  significant proptosis, the treatment of which is essentially  surgical. Surgical decompression increases the volume of  the orbit by removing the bony walls and may be  combined with removal of orbital fat. Most surgery is  undertaken via an external approach, though the medial  wall and the medial part of the floor can be reached  endoscopically. One-wall (deep lateral) decompression is  effective (approximately 4-5 mm reduction in proptosis)  and may reduce the risk of postoperative diplopia;  two-wall (balanced medial and lateral - Fig. 3.12)  decompression provides a greater effect but with a  significant risk of inducing diplopia; three-wall  decompression includes the floor with a reduction in  proptosis of 6-10 mm but may lead to hypoglobus and  carries a higher risk of infraorbital nerve damage and  diplopia; very severe proptosis may require removal of  part of the orbital roof in addition (four-wall  decompression).   O Restrictive myopathy. Surgery is required in most cases  experiencing persistent diplopia in the primary or reading   Fig. 3.12 Axial CT following bilateral lateral and medial wall  decompression   positions of gaze, provided the inflammatory stage has  subsided and the angle of deviation has been stable for at  least 6-12 months. Until these criteria are met, diplopia  may be alleviated, if possible, with prisms or sometimes  botulinum toxin. The goal of operative treatment is to  achieve binocular single vision in the primary and  reading positions; restrictive myopathy often precludes  binocularity in all positions of gaze, though with time the  field of binocular single vision may enlarge as a result of  increasing fusional vergence. Recession of the inferior  and/or medial recti is the most commonly indicated  surgery (a rectus muscle is never resected, only recessed  in TED), generally utilizing adjustable sutures (see Ch.   18). The suture is adjusted later the same day or on the  first postoperative day to achieve optimal alignment, and  the patient is encouraged subsequently to practise  achieving single vision with a consistently accessible  target such as a television.   O Lid retraction. Mild lid retraction frequently improves  spontaneously so does not require treatment. Control of  hyperthyroidism may also be beneficial. Botulinum toxin  injection to the levator aponeurosis and Muller muscle  may be used as a temporary measure in patients awaiting  definitive correction. Mullerotomy (disinsertion of  Muller muscle) is effective for mild lid retraction, but  more severe cases may also require recession/disinsertion  of the levator aponeurosis and the suspensory ligament of  the superior conjunctival fornix. Recession of the lower  lid retractors, with or without a hard palate graft, can be  used when retraction of the lower lid is 2 mm or more  (see also Ch. 1).   Fig. 3.13 Preseptal cellulitis. (A) Left preseptal cellulitis  resulting from an infected eyelid abrasion; (B) axial CT  shows opacification anterior to the orbital septum    orbital cellulitis, proptosis and chemosis are absent, and visual  acuity, pupillary reactions and ocular motility are unimpaired.  The patient is often pyrexial. Imaging with MRI or CT (Fig. 3.13B)  is not indicated unless orbital cellulitis or a lid abscess is suspected,  or there is a failure to respond to therapy.   Preseptal cellulitis is an infection of the subcutaneous tissues ante¬  rior to the orbital septum. It is considerably more common than  orbital cellulitis, and though regarded as less serious, can still be  associated with severe complications such as abscess formation,  meningitis and cavernous sinus thrombosis. Rapid progression to  orbital cellulitis may occasionally occur. Organisms typically  responsible are Staphylococcus aureus and Streptococcus pyogenes ,  with causes including skin trauma such as laceration or insect  bites, spread from focal ocular or periocular infection such as an  acute hordeolum, dacryocystitis, conjunctivitis or sinusitis, and  haematogenous spread from remote infection such as the upper  respiratory tract or middle ear.   The condition manifests with a swollen, often firm, tender red  eyelid that may be very severe (Fig. 3.13A); however, in contrast to    Treatment is with oral antibiotics such as co-amoxiclav  250-500 mg/125 m g 2-3 times daily or 875/125 mg twice daily,  depending on severity. Severe infection may require intravenous  antibiotics. The patient’s tetanus status should be ascertained in  cases following trauma.   Bacterial orbital cellulitis is a serious infection of the soft tissues  behind the orbital septum, which can be sight- and life-threatening.  It can occur at any age but is more common in children. Strepto¬  coccus pneumoniae , Staphylococcus aureus , Streptococcus pyogenes  and Haemophilus influenzae are common causative organisms,  with infection originating typically from the paranasal (especially  ethmoid) sinuses. Infection can also spread from preseptal cellu¬  litis, dacryocystitis, midfacial skin or dental infection, and can    follow trauma, including any form of ocular surgery. Blood-borne  spread from infection elsewhere in the body may occur.   • Symptoms consist of the rapid onset of pain exacerbated by  eye movement, swelling of the eye, malaise, and frequently  visual impairment and double vision. There is commonly a  recent history of nasal, sinus or respiratory symptoms.   o VA may be reduced and colour vision impaired, raising  the possibility of optic nerve compression; the presence  of a relative afferent pupillary defect in a previously  normal eye makes this almost certain,  o Tender, firm, erythematous and warm eyelids, with  periocular and conjunctival (chemosis) oedema,  conjunctival injection and sometimes subconjunctival  haemorrhage; the signs are usually unilateral, though  oedema may spread to the contralateral eyelids,  o Proptosis is common in established infection, but is often  obscured by lid swelling; it may be non-axial (dystopia),  particularly if an abscess is present,  o Painful ophthalmoplegia (Fig. 3.14A).   • Other neoplasm, e.g. metastatic lesion with  inflammation, lymphoma, Waldenstrom  macroglobulinaemia    o Choroidal folds and optic disc swelling may be present  on fundus examination.   • Differential diagnosis. Major diagnostic alternatives are  listed in Table 3.1.   o Ocular complications include optic neuropathy, exposure  keratopathy, raised IOP, endophthalmitis and occlusion  of the central retinal artery or vein,  o Subperiosteal abscess, most frequently located along the  medial orbital wall.   O Intracranial complications, which are uncommon (3-4%)  but extremely serious, include meningitis, brain abscess  and cavernous sinus thrombosis.   (Fig. 3.14B) is vital to confirm the diagnosis and exclude a   • Hospital admission is mandatory, with urgent  otolaryngological assessment and frequent ophthalmic  review. Paediatric specialist advice should be sought in the  management of a child, and a low threshold should be  adopted for infectious disease specialist consultation.   • Delineation of the extent of erythema on the skin using a  surgical marker may help in judging progress.   • Antibiotics are given intravenously, with the specific drug  depending on local sensitivities; ceftazidime is a typical  choice, supplemented by oral metronidazole to cover  anaerobes. Intravenous antibiotics should be continued until  the patient has been apyrexial for 4 days, followed by 1-3  weeks of oral treatment.   • Monitoring of optic nerve function is performed at least  every 4 hours initially by testing VA, colour vision, light  brightness appreciation and pupillary reactions.   • Surgery. Drainage of an orbital abscess should be considered  at an early stage; drainage of infected sinuses should be  considered if there is a lack of response to antibiotics, or if  there is very severe sinus disease. Biopsy of inflammatory  tissue may be performed for an atypical clinical picture.  Severe optic nerve compression may warrant an emergency  canthotomy/cantholysis (see Ch. 21).   Mucormycosis is a rare aggressive and often fatal infection caused  by fungi of the family Mucoraceae. It typically affects patients with  diabetic ketoacidosis or immunosuppression and is extremely rare  in the immunocompetent. Infection is acquired by the inhalation  of spores, which give rise to an upper respiratory infection. Spread  then occurs to the contiguous sinuses and subsequently to the  orbit and brain. Invasion of blood vessels by the hyphae results in  occlusive vasculitis with infarction of orbital tissues.   • Symptoms. Gradual onset facial and periorbital swelling,  diplopia and visual loss.   • Signs are similar to bacterial orbital cellulitis, but tend to be  less acute and with slower progression. Infarction  superimposed on septic necrosis is responsible for the classic  black eschar that may develop on the palate, turbinates,  nasal septum, skin and eyelids (Fig. 3.15).   • Complications include retinal vascular occlusion, multiple  cranial nerve palsies and cerebrovascular occlusion.    • Investigation is much the same as for bacterial orbital  cellulitis.   • Correction of the underlying metabolic defect should be  instituted if possible.   • Daily packing and irrigation of the involved areas with  antifungal agent.   • Wide excision of devitalized and necrotic tissues;  exenteration may be required in unresponsive cases in order  to reduce the risk of death.   Idiopathic orbital inflammatory disease (IOID; also non-specific  orbital inflammation or orbital pseudotumour) is an uncommon  disorder characterized by non-neoplastic, non-infective, space-  occupying orbital infiltration with inflammatory features. The  process may preferentially involve any or all of the orbital soft  tissues. Histopathological analysis reveals pleomorphic inflamma¬  tory cellular infiltration followed by reactive fibrosis. Unilateral  disease is typical in adults, although in children bilateral involve¬  ment may occur. Intracranial extension is rare; simultaneous  orbital and sinus involvement is also rare, and may be a distinct  entity.   • Symptoms typically consist of acute or subacute ocular and  periocular redness, swelling and pain (Fig. 3.16A). systemic  symptoms are common in children.   (Courtesy of R Bates - fig. A; A Pearson - figs B and C)   o Pyrexia is present in up to 50% of children, but is rare in  adults.   o Features of optic nerve dysfunction, particularly if the  inflammation involves the posterior orbit; there may be  optic disc swelling.   o Choroidal folds, if present, may be associated with  reduced vision but optic neuropathy must always be  suspected.    • Course. The natural history of the inflammatory process is  very variable.   o Severe prolonged inflammation eventually leading to  progressive fibrosis of orbital tissues, resulting in a  ‘frozen orbit’ characterized by ophthalmoplegia, which  may be associated with ptosis and visual impairment  caused by optic nerve involvement.   o CT shows ill-defined orbital opacification and loss of  definition of contents (Figs 3.16B and C).  o Biopsy is generally required in persistent cases to confirm  the diagnosis, and particularly to rule out neoplasia and  systemic inflammatory conditions,  o A wide range of other investigations may be considered  to aid in the exclusion of alternative diagnoses,  particularly infection, lymphoma and non-neoplastic  infiltrative disorders such as sarcoidosis and Wegener  granulomatosis.   • Observation, for relatively mild disease, in anticipation of  spontaneous remission.   • NSAIDs alone (e.g. ibuprofen) are often effective and may  be tried in mild disease prior to steroid therapy.  Co-prescription of a proton pump inhibitor should be  considered.   • Systemic steroids should be administered only after the  diagnosis has been confirmed, as they may mask other  pathology such as infection and Wegener granulomatosis.  Oral prednisolone is initially given at a dose of 1.0-1.5 mg/  kg/day, subsequently being tapered and discontinued over a  number of weeks depending on clinical response; further  treatment may be needed in the event of recurrence.   • Orbital depot steroid injection may be useful in some cases.   • Radiotherapy may be considered if there has been no  improvement after 2 weeks of adequate steroid therapy. Even  low-dose treatment (e.g. 10 Gy) may produce remission,  though much higher total doses may be necessary.   • Other options, usually as supplementary treatments or in  resistant cases, include cytotoxic drugs (e.g. methotrexate,  azathioprine), calcineurin inhibitors (e.g. ciclosporin,  tacrolimus) and biological blockers.   • Surgical resection of an inflammatory focus may be  contemplated in highly resistant cases.   one or more extraocular muscles and is considered a subtype of   IOID. Histology shows a chronic inflammatory cellular infiltrate  associated with the muscle fibres (Fig. 3.17A).   • Symptoms. Acute pain, exacerbated by eye movement, and  diplopia; onset is usually in early adulthood.   • Signs are generally more subtle than IOID.  o Lid oedema, ptosis and chemosis.   o Pain and diplopia associated with eye movements,  o Vascular injection over the involved muscle (Fig. 3.17B).  o In chronic cases the affected muscle may become  fibrosed, with permanent restrictive myopathy.   o Acute non-recurrent involvement that resolves  spontaneously within 6 weeks,  o Chronic disease characterized by either a single episode  persisting for longer than 2 months (often for years) or  recurrent attacks.   • Investigation consists primarily of MRI or CT, which show  enlargement of the affected muscles (Fig. 3.17C), with or  without involvement of the tendons of insertion; this is in  contrast to TED-related muscle enlargement, in which the  tendon is always spared. Additional investigations may be  required in some cases.   Treatment is aimed at relieving discomfort and dysfunction,  shortening the course and preventing recurrences. NSAIDs may  be adequate in mild disease, but systemic steroids are generally  required and usually produce dramatic improvement, although  recurrence is seen in 50%. Radiotherapy is also effective, particu¬  larly in limiting recurrence.   Acute dacryoadenitis may be idiopathic or due to viral (e.g.  mumps, Epstein-Barr, cytomegalovirus) or - rarely - bacterial  infection; the lacrimal gland is often involved in IOID. Chronic  conditions such as sarcoidosis, Sjogren syndrome, thyroid disease  and some chronic infections usually give a less acute onset, and  involvement can be bilateral. Presentation in acute disease is with  the rapid onset of discomfort in the region of the gland. Lacrimal  secretion may be reduced or increased, and discharge may be  reported. Swelling of the lateral aspect of the eyelid overlying the  palpebral lobe leads to a characteristic S-shaped ptosis, and  enlargement of the orbital lobe may give a slight downward and  inward dystopia (Fig. 3.18A) and occasionally proptosis and other  signs of orbital disease. There is tenderness over the lacrimal gland,  and injection of the conjunctiva overlying the palpebral lobe may  be seen on upper lid eversion (Fig. 3.18B). Chemosis may be  present. There may be local (e.g. pre-auricular) lymph node  enlargement. CT shows enlargement of the gland and involvement  of adjacent tissues (Fig. 3.18C) without bony erosion; the latter  suggests a tumour. Biopsy is sometimes indicated, particularly to   Fig. 3.17 Orbital myositis. (A) Histology shows a chronic  inflammatory cellular infiltrate in relation to muscle fibres;  (B) vascular injection over the insertion of the right medial  rectus; (C) coronal CT shows enlargement of the right  medial rectus   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann 2001 - fig. A; J Nerad, K Carter and M Alford , from  ‘Oculoplastic and Reconstructive Surgeryin Rapid Diagnosis in  Ophthalmology, Mosby 2008 - figs B and C)   Fig. 3.18 Left acute dacryoadenitis. (A) Swelling on the  lateral aspect of the eyelid and an S-shaped ptosis;   (B) injection of the palpebral portion of the lacrimal gland  and adjacent conjunctiva; (C) axial CT shows enlargement  of the gland and opacification of adjacent tissues   (Courtesy of R Bates - fig. B; A Pearson - fig. C)    exclude a tumour. Treatment varies according to the cause, but in  many cases is not required.   Tolosa-Hunt syndrome is a rare idiopathic condition caused  by non-specific granulomatous inflammation of the cavernous  sinus, superior orbital fissure and/or orbital apex. It is a diagnosis  of exclusion and should be investigated fully. Presentation is  with ipsilateral periorbital or hemicranial pain, and diplopia due  to one or more ocular motor pareses, with pupillary and eyelid  involvement in many cases. Proptosis, if present, is usually  mild. Sensory loss along the distribution of the first and second  divisions of the trigeminal nerve is common. The patient may be  pyrexial. Diagnosis is with imaging, together with other investiga¬  tions to rule out identifiable causes, including neoplasia. Treat¬  ment is with systemic steroids and other immunosuppressants as  necessary; the clinical course is characterized by remissions and  recurrences.   Wegener granulomatosis (see Ch. 8), an idiopathic multisystem  granulomatous disorder that may involve the orbit, often bilater¬  ally, usually by contiguous spread from the paranasal sinuses or  nasopharynx. Primary orbital involvement is less common. The  possibility of Wegener granulomatosis should be considered in  any patient with bilateral orbital inflammation, particularly if  associated with sinus pathology. Antineutrophilic cytoplasmic  antibody (cANCA variant) is a useful serological test. Other ocular  features include scleritis, peripheral ulcerative keratitis, intraocu¬  lar inflammation and retinal vascular occlusions. Treatment is  with cyclophosphamide and steroids, which are usually effective.  In resistant cases ciclosporin, azathioprine, antithymocyte globu¬  lin or plasmapheresis may be useful. Surgical decompression may  be required for severe orbital involvement.   This refers to clotting within the cavernous sinus, usually resulting  from infection such as sinusitis, orbital or preseptal cellulitis or  otitis. There is a high mortality rate: 20% treated and up to 100%  untreated. Features are of rapid onset and may include severe  headache, malaise, nausea and vomiting, unilateral or often bilat¬  eral proptosis, chemosis, congestion of the facial, conjunctival and  retinal veins, reduced vision, and signs resulting from compro¬  mised function of the third to sixth cranial nerves, which run  through the cavernous sinus. Diagnosis is with imaging, especially  MRI and MRI venography; systemic investigation for infection is  also performed, including lumbar puncture. Treatment consists of  intravenous antibiotics and sometimes surgical drainage.   A carotid-cavernous fistula involves the development of an arte¬  riovenous fistula between the carotid artery and the venous cav¬  ernous sinus (see Fig. 19.60) with a rise in venous pressure in the  sinus and structures draining to it. Ocular manifestations occur  because of venous and arterial stasis around the eye and orbit,  increased episcleral venous pressure and a decrease in arterial  blood flow to the cranial nerves within the cavernous sinus.  Carotid-cavernous fistulae are classified into ‘direct’ and ‘indirect’  forms.   • Direct fistulae are high-flow shunts in which carotid artery  blood passes directly into the cavernous sinus through a  defect in the wall of the intracavernous portion of the  internal carotid artery as a result of trauma (75%), including  surgery, spontaneous rupture of an intracavernous carotid  aneurysm or an atherosclerotic artery, the latter frequently  in a middle-aged hypertensive woman; spontaneous fistulae  usually have lower flow.   • In an indirect fistula (‘dural shunt’), the intracavernous  portion of the internal carotid artery remains intact. Arterial  blood flows through the meningeal branches of the external  or internal carotid arteries indirectly into the cavernous  sinus, and the clinical features are more subtle than in a  direct fistula such that the condition may be overlooked.  Spontaneous rupture of an atherosclerotic artery or of a  congenital malformation is the usual cause, and may be  precipitated by minor trauma or straining. Connective tissue  and collagen vascular disorders can be associated.   • Symptoms - direct. Presentation may be days or weeks after  head injury with a classic triad of pulsatile proptosis,  conjunctival chemosis and a whooshing noise in the head.   • Symptoms - indirect. Gradual onset of redness of one or  both eyes is a typical presentation, caused by conjunctival  vascular engorgement.   o Immediate visual loss may be due to ocular or optic  nerve damage at the time of head trauma,  o Delayed visual loss may occur as a result of exposure  keratopathy, secondary glaucoma, central retinal vein  occlusion, anterior segment ischaemia or ischaemic optic  neuropathy.   o Signs are usually ipsilateral to the fistula but may be  bilateral, or even contralateral, because of midline  connections between the two cavernous sinuses,  o Marked epibulbar vascular dilatation (Fig. 3.19A).   O Chemosis, commonly haemorrhagic, particularly in the  early stages (Fig. 3.19B).   o Pulsatile proptosis associated with a bruit and a thrill,  both of which can be abolished by ipsilateral carotid  compression in the neck.    o Increased IOP due to elevated episcleral venous pressure  and orbital congestion, and sometimes angle-closure  glaucoma.   o Anterior segment ischaemia, characterized by corneal  epithelial oedema, aqueous cells and flare, and in severe  cases iris atrophy, cataract and rubeosis iridis.  o Ptosis due to third nerve involvement,  o Ophthalmoplegia (60-70%) due to the ocular motor nerve  damage from initial trauma, an intracavernous aneurysm  or the fistula itself. The sixth cranial nerve is most  frequently affected because of its free-floating location  within the cavernous sinus. The third and fourth nerves,  situated in the lateral wall of the sinus, are less frequently  involved. Engorgement and swelling of extraocular muscles  may also contribute to defective ocular motility,  o Fundus examination may show optic disc swelling,  venous dilatation and intraretinal haemorrhages (Fig.  3.19C) from venous stasis and impaired retinal blood  flow. Vitreous haemorrhage is rare.   o Milder epibulbar vascular dilatation than with a direct  fistula (Fig. 3.19D).   o Exaggerated ocular pulsation; this is readily detected on  slit lamp applanation tonometry,  o The presence of ‘corkscrew’ epibulbar vessels (Fig. 3.19E)  is a common subtle later sign; these are not  pathognomonic and can be found in normal eyes,  o Raised IOP, often bilateral but higher on the side of the  fistula.   o Proptosis and bruit are mild if present,  o Ophthalmoplegia caused by sixth nerve palsy or swelling  of extraocular muscles in marked cases,  o Fundus may be normal or manifest moderate venous  dilatation, with later tortuosity (Fig. 3.19F); as with  corkscrew conjunctival vessels, this is not pathognomonic  (see Ch. 13).   • Investigation. CT and MRI may demonstrate prominence of  the superior ophthalmic vein (Fig. 3.20A) and diffuse  enlargement of extraocular muscles (Fig. 3.20B), though  these may only be visible with a direct fistula. Orbital  Doppler imaging may show abnormal flow patterns,  particularly in the superior orbital vein. Definitive diagnosis  may involve selective catheter digital subtraction  angiography, especially in mild dural fistulae, though CT  and MRI angiography can be useful.   Ocular complications may require specific measures in addition  to treatment of the fistula itself. Neurological subspecialist opinion  should be sought at an early stage, even if features are mild, as  some fistula patterns (e.g. cortical venous drainage) carry a high  risk of stroke.   • Direct. Most carotid-cavernous fistulae are not life-  threatening; the organ at major risk is the eye. Surgery  is indicated if spontaneous closure does not occur. A   Fig. 3.19 Carotid-cavernous fistula. (A) Marked epibulbar vascular dilatation in an established direct fistula; (B) haemorrhagic  chemosis in an acute direct fistula; (C) acute fundus appearance in a moderate direct fistula; (D) mild epibulbar vascular  dilatation in an indirect fistula; (E) corkscrew conjunctival vessel; (F) retinal venous tortuosity   (Courtesy of S Chen - figs A and F; C Barry - figs C and D)   Fig. 3.20 CT in direct carotid-cavernous fistula. (A) Axial  image shows enlargement of the right superior ophthalmic  vein; (B) coronal view shows enlargement of extraocular  muscles on the right   post-traumatic fistula is much less likely to close on its own  than a spontaneous fistula because of higher blood flow.  Treatment is likely to consist of a transarterial approach to  repair the artery (e.g. coil - Fig. 3.21, other) or occlude the  involved sinus (e.g. coil, balloon, other). Craniotomy for  arterial repair is occasionally needed.   • Indirect. If required, treatment usually involves transvenous  occlusion of the involved sinus. Spontaneous closure or  occluding thrombosis sometimes (up to 50%) occurs;  intermittent carotid compression under specialist  supervision has been reported to increase the likelihood that  this will take place.   A dacryops is a frequently bilateral cyst of the lacrimal gland that  is thought to develop from a dilated obstructed duct. A round  cystic lesion protrudes into the superior fornix from the palpebral  lobe of the gland (Fig. 3.22), and may present with inflammation.  The possibility of a malignant tumour should always be consid¬  ered. Treatment involves excision or marsupialization, with his-  topathological analysis.   An orbital dermoid cyst is a choristoma (a mass of histologically  normal tissue in an abnormal location) derived from displacement  of ectoderm to a subcutaneous location along embryonic lines of  closure. Dermoids are lined by keratinized stratified squamous  epithelium (like skin), have a fibrous wall and contain dermal   Fig. 3.21 Coil embolization of a direct carotid-cavernous  fistula. (A) Early arterial phase catheter angiogram shows  filling of the cavernous sinus (arrow) and superior  ophthalmic vein (arrowhead); (B) following deposition of  coils in the cavernous sinus - the fistula is closed and  there is no retrograde flow in the superior ophthalmic vein   (Courtesy of J Trobe, from 1 Neuro-ophthalmologyin Rapid Diagnosis in  Ophthalmology, Mosby 2008)    appendages such as sweat glands, sebaceous glands and hair fol¬  licles; epidermoid cysts do not contain adnexal structures. Der¬  moids may be ‘superficial’ or ‘deep’, located anterior or posterior  to the orbital septum respectively. Epibulbar dermoids and der-  molipomas are related lesions (see Ch. 12).   Dermoid cysts are one of the most frequently encountered orbital  tumours in children.   o A superficial orbital dermoid cyst presents in infancy with  a painless nodule, most commonly located in the  superotemporal and occasionally the superonasal part of  the orbit.   o A deep dermoid cyst presents in adolescence or adult life  with a gradually increasingly protruding eye, or acutely  with an inflamed orbit due to rupture.   o Superficial: a firm round smooth non-tender mass 1-2 cm  in diameter (Fig. 3.23A), mobile under the skin but  usually tethered to the adjacent periosteum. The posterior  margins are easily palpable, denoting a lack of deeper  origin or extension.   o Deep: proptosis, dystopia or a mass lesion with indistinct  posterior margins (Fig. 3.23B).   o Superficial: imaging shows a well-circumscribed  heterogeneous cystic lesion (Fig. 3.24A).   o Deep: imaging again shows a well-circumscribed lesion  (Fig. 3.24B). Some deep dermoids, associated with bony  defects, may extend into the inferotemporal fossa or  intracranially.   Small lesions may be observed, bearing in mind the possibility of  rupture, particularly from trauma; the inflammation can be  addressed with oral steroids.    • Superficial dermoid. Treatment is by excision in toto (Fig.  3.25), taking care not to rupture the lesion, since leaking of  keratin into the surrounding tissue typically results in severe  granulomatous inflammation.   • Deep dermoid. Excision in toto is advisable because deep  dermoids enlarge and may leak into adjacent tissues  inducing inflammation, often followed by fibrosis. If  incompletely excised, dermoids may recur with persistent  low-grade inflammation.   A mucocoele (US spelling - mucocele) develops when the drain¬  age of normal paranasal sinus secretions is obstructed due to infec¬  tion, allergy, trauma, tumour or congenital narrowing. A slowly  expanding cystic accumulation of mucoid secretions and epithelial  debris develops and gradually erodes the bony walls of the sinus,  causing symptoms by encroachment upon surrounding tissues.  Orbital invasion occurs usually from a frontal or ethmoidal   Fig. 3.23 Orbital dermoid cysts. (A) Superficial cyst left eye;  (B) left deep cyst causing mild dystopia    Fig. 3.24 Orbital dermoid cysts - imaging. (A) Axial CT image  showing a well-circumscribed heterogeneous superficial  lesion; (B) deep dermoid - CT showing a well-circumscribed  cystic lesion and bone remodelling   (Courtesy of K Nischal - fig. A; A Pearson - fig. B)   Fig. 3.25 Superficial orbital dermoid cyst - appearance at  surgery (orbitotomy)   Fig. 3.26 (A) Left ethmoidal sinus mucocoele causing  dystopia; (B) coronal CT shows orbital involvement and  indentation of the medial rectus    mucocoele, but rarely from those arising in the maxillary sinus.  Presentation is in adult life with proptosis or dystopia (Fig. 3.26A),  diplopia or epiphora. Pain is uncommon unless secondary infec¬  tion develops (mucopyocoele). CT shows a soft tissue mass with  thinning or erosion of the bony walls of the sinus (Fig. 3.26B).  Treatment involves complete excision.   An encephalocoele (US spelling - encephalocele) is formed by  herniation of intracranial contents through a congenital defect of  the base of the skull, and can be located at the front or back of the  head. A meningocoele contains only dura whilst a meningo-  encephalocoele also contains brain tissue. Presentation is usually  during infancy. Anterior orbital encephalocoeles involve the  superomedial part of the orbit and displace the globe forwards and  laterally (Fig. 3.27A), whereas posterior orbital encephalocoeles  (frequently associated with neurofibromatosis type I) displace the  globe forwards and downwards (Fig. 3.27B). The displacement  increases on straining or crying and may be reduced by manual  pressure. Pulsating proptosis may occur due to communication  with the subarachnoid space but, because the communication is  not vascular, there is neither a thrill nor a bruit. CT shows the  bony defect responsible for the herniation (Fig. 3.27C). The dif¬  ferential diagnosis of anterior encephalocoele includes other  causes of medial canthal swelling such as dermoid cyst and amni-  ontocoele, and of posterior encephalocoele includes other orbital  lesions that present during early life such as capillary haemangi¬  oma, juvenile xanthogranuloma, teratoma and microphthalmos  with cyst.   Fig. 3.27 Encephalocoele. (A) Anterior superomedial  encephalocoele causing proptosis and down and out  dystopia; (B) posterior encephalocoele causing proptosis  and inferior dystopia; (C) coronal CT of posterior  encephalocoele showing a large bony defect   Primary orbital varices (combined venous-lymphatic malforma¬  tions of the orbit - see also next topic) consist of a plexus of thin-  walled distensible low-flow vein-like vessels that are commonly,  though not always, intrinsic to the normal circulation. They are  probably hamartomatous (hamartoma - a disorganized over¬  growth of mature tissues normally present in the involved area).  Associations include varices of the eyelids (Fig. 3.28A and see    Fig. 1.71) and conjunctiva (Fig. 3.28B). They commonly present at  any time from early childhood to late middle age, but occasionally  can be acquired later secondary to a local high-flow vascular lesion  or trauma.   Most cases are unilateral and the most frequent site is upper nasal.  Intermittent non-pulsatile proptosis without a bruit is reported.  If there is free communication with the normal circulation, revers¬  ible proptosis may be precipitated or accentuated by increasing  venous pressure through coughing, straining, the Valsalva  manoeuvre (Figs 3.28C and D), assuming a head-down position  or external compression of the jugular veins. Imaging (e.g. MRI  and magnetic resonance venography (MRV), CT, ultrasound,  venography) shows a lobulated mass with variable contrast  enhancement, and may demonstrate phleboliths (Fig. 3.28E) and  sometimes orbital expansion (particularly in childhood) or an  associated orbital wall defect. Complications include acute orbital  haemorrhage, thrombosis (pain, proptosis, decreased vision) and  optic nerve compression. Patients with long-standing lesions may  develop atrophy of surrounding fat, giving enophthalmos with a  deepened superior sulcus (Fig. 3.28F).   Small lesions generally do not require treatment. Surgical excision  is technically difficult and often incomplete because the lesions are  friable and bleed easily; it can be complicated by severe orbital  haemorrhage and vascular optic nerve compromise. Specialized  techniques such as embolization and carbon dioxide laser surgery  may be helpful adjuncts. Indications include recurrent thrombo¬  sis, pain, severe proptosis and optic nerve compression.   Lymphangioma is a rare hamartomatous vascular tumour that  tends to enlarge and infiltrate diffusely with time. Some authori¬  ties believe lymphangiomas to be a variant of venous orbital  anomaly (varices) across a single spectrum, and the term com¬  bined venous-lymphatic malformations of the orbit has been sug¬  gested. Although usually isolated from the main circulation,  bleeding into the lumen may occur with subsequent formation  of blood-filled ‘chocolate cysts’ that may regress spontaneously  with time. Presentation is usually in early childhood. Differential  diagnosis is principally from orbital venous anomalies and haem¬  angiomas. Intracranial vascular malformations can be present in  association.   Anterior lesions typically manifest as several soft bluish masses in  the upper nasal quadrant (Fig. 3.29).   Posterior lesions may cause slowly progressive proptosis, or  initially may lie dormant and later present with the sudden onset    Fig. 3.28 (A) Substantial eyelid varices; (B) conjunctival varices; (C) orbital varices before Valsalva and (D) with Valsalva;   (E) axial CT shows medial opacification and phleboliths; (F) left fat atrophy resulting in enophthalmos and deep superior  sulcus   (Courtesy of G Rose - figs C and D; A Pearson - figs E and F)    of painful proptosis (Figs 3.30A and B) secondary to spontaneous  haemorrhage, which may be associated with optic nerve compres¬  sion. Involvement of the lids, conjunctiva (Fig. 3.30C) and  oropharynx (Fig. 3.30D) maybe seen; intracranial lesions may also  be present.   In many cases the visual prognosis is good without treatment.  Surgical excision is difficult because lesions are unencapsulated,  friable, bleed easily and commonly infiltrate normal orbital tissues;  repeated subtotal excision may be necessary. Persistent sight-  threatening chocolate cysts can be drained or removed sub-totally  by controlled vaporization using a carbon dioxide laser.   Capillary haemangioma is the most common tumour of the orbit  and periorbital area in childhood. Girls are affected more com¬  monly than boys (3:1). It may present as a small isolated lesion of   Fig. 3.30 (A) Severe proptosis due to bleeding from a posterior lymphangioma; (B) axial CT shows proptosis and orbital  opacification; (C) conjunctival involvement; (D) oral lesions   (Courtesy of A Pearson - figs A and B; C Barry - fig. C)   minimal clinical significance, or as a large disfiguring mass that  can cause visual impairment and systemic complications. An  established tumour is composed of anastomosing small vascular  channels without true encapsulation (see Fig. 1.13C); it is a hamar¬  toma - a disorganized overgrowth of mature tissues normally  present in the involved area - and believed to be due principally  to endothelial cell proliferation. Large or multiple lesions may  have associated visceral involvement, which can lead to serious  complications such as thrombocytopenia (Kasabach-Merritt syn¬  drome, with up to 50% mortality) and high-output cardiac failure,  and systemic investigation should be considered. The incidence of  infantile haemangioma in the general population is around 5%,  and a small proportion of these, especially if a large facial haeman¬  gioma is present, will have PH ACE (PH ACES) syndrome, which  includes a range of possible systemic features including eye  involvement.   • Symptoms. The lesion is usually noticed by the parent,  usually in the first few months of life; approximately 30%  are present at birth.   bright red (Fig. 3.31A and see Fig. 1.13A).  o Preseptal (deeper) tumours appear dark blue or purple  through the overlying skin (Fig. 3.31B and see Fig. 3.31A)  and are most frequently located superiorly,  o A large tumour may enlarge and change in colour to a  deep blue during crying or straining, but both pulsation  and a bruit are absent.   o Deep orbital tumours give rise to unilateral proptosis  without skin discoloration.   o Haemangiomatous involvement of the palpebral or  forniceal conjunctiva is common (Fig. 3.31C).  o Additional haemangiomas on the eyelids (see Ch. 1) or  elsewhere are common.   • Investigation. Imaging is generally performed for other than  very small lesions, mainly to rule out more extensive orbital  disease. Ultrasound shows medium internal reflectivity  (Fig. 3.32A), and on MRI or CT the lesion appears as a soft  tissue mass in the anterior orbit or as an extraconal mass  with finger-like posterior expansions (Fig. 3.32B). The  orbital cavity may show enlargement but there is no bony  erosion.   The natural course is characterized by rapid growth 3-6 months  after diagnosis (Fig. 3.33), followed by a slower phase of natural  resolution in which 30% of lesions resolve by the age of 3 years  and about 75% by the age of 7. Treatment is indicated principally  for amblyopia secondary to induced astigmatism, anisometropia,  occlusion or strabismus, and less commonly for cosmesis, optic  nerve compression or exposure keratopathy.   Fig. 3.31 Capillary haemangioma. (A) Large preseptal tumour  causing ptosis and purple cutaneous discoloration -- there  is a superficial component (strawberry naevus); (B) inferior  preseptal tumour; (C) involvement of forniceal conjunctiva   • Beta-blockers. Oral propranolol is now widely used, and  seems most effective in the proliferative stage; prescription  and monitoring should generally be carried out by a  paediatrician. Topical preparations including timolol are  also under investigation, with initially favourable results.   Fig. 3.32 Imaging of capillary haemangioma. (A) Ultrasound  of a preseptal lesion with an intraorbital component;   (B) axial enhanced CT shows a homogeneous intraconal  orbital soft tissue mass   (Courtesy of K Nischal - fig. A; A Pearson - fig. B)   o Injection of triamcinolone acetonide (1-2 ml total of  40 mg/ml over several injection sites) or betamethasone  (4 mg/ml) into a cutaneous or preseptal tumour is  usually effective in early lesions. Regression usually begins  within 2 weeks but, if necessary, second and third  injections can be given after about 2 months. It is  advisable not to inject deeply into the orbit for fear of  causing occlusion of the central retinal artery due to  retrograde introduction of the suspension. Other  complications include skin depigmentation and necrosis,  fat atrophy and systemic effects such as adrenal  suppression.   o Topical high-potency steroids (e.g. clobetasol propionate  cream) are sometimes appropriate but are slow to exert  their effect.   o Systemic steroids administered daily over several weeks  may be used, particularly if there is a large orbital  component or a rapid onset of action is required.    • Laser may be used to close blood vessels in superficial skin  lesions less than 2 mm in thickness.   • Interferon alfa-2a and vincristine may be used for some  steroid-resistant sight-threatening lesions.   • Local resection with cutting cautery or carbon dioxide laser  may reduce the bulk of an anterior circumscribed tumour,  but is usually reserved for the late inactive stage unless a  resistant tumour is sight- or life-threatening.   Cavernous haemangioma occurs in middle-aged adults, with a  female preponderance of 70%; growth may be accelerated by preg¬  nancy. It is the most common orbital tumour in adults, and is  probably a vascular malformation rather than a neoplastic lesion.  Although it may develop anywhere in the orbit, it most frequently  occurs within the lateral part of the muscle cone just behind the  globe, and behaves like a low-flow arteriovenous malformation.   Fig. 3.33 Growth of capillary haemangioma. (A) At  presentation; (B) several months later    Fig. 3.34 Cavernous haemangioma. (A) Histology shows congested variably sized endothelial-lined vascular channels  separated by fibrous septa; (B) right axial proptosis; (C) axial CT shows a well-circumscribed retrobulbar oval lesion and  proptosis; (D) the tumour is encapsulated and relatively easy to remove   • Symptoms. Slowly progressive unilateral proptosis; bilateral  cases are very rare.   o Axial proptosis (Fig. 3.34B), which may be associated with  optic disc oedema and choroidal folds,  o A lesion at the orbital apex may compress the optic nerve  without causing significant proptosis; gaze-evoked  transient blurring of vision may occur,  o There may be impairment of extraocular muscle  excursion.   • Investigation. CT (Fig. 3.34C) and MRI show a well-  circumscribed oval lesion, usually within the muscle cone.  There is only slow contrast enhancement. Ultrasound is also  useful.   Many cavernous haemangiomas are detected by chance on scans  performed for unrelated reasons and observation alone is often  appropriate. Symptomatic lesions require surgical excision in  most cases because they gradually enlarge. The cavernous  haemangioma, unlike its capillary counterpart, is usually well-  encapsulated and relatively easy to remove (Fig. 3.34D).   Pleomorphic adenoma (benign mixed-cell tumour) is the most  common epithelial tumour of the lacrimal gland and is derived    Fig. 3.35 Pleomorphic lacrimal gland adenoma. (A) Histology  shows glandular tissue and squamous differentiation with  keratin formation; (B) inferonasal dystopia due to a tumour  arising from the orbital lobe; (C) eyelid swelling without  dystopia; (D) eversion of the upper eyelid reveals the  tumour; (E) coronal CT showing an orbital lobe lesion   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann 2001 - fig. A; A Pearson - figs B and E)    from the ducts and secretory elements including myoepithelial  cells. On histopathology, the inner layer of cells forms glandular  tissue that may be associated with squamous differentiation and  keratin production (Fig. 3.35 A); the outer cells undergo metaplas¬  tic change leading to the formation of myxoid tissue. Young to  middle-aged adults are the predominantly affected group.   • Symptoms. Painless slowly progressive proptosis or swelling  in the superolateral eyelid, usually of more than a year’s  duration. Old photographs may reveal an abnormality many  years prior to presentation.   o Orbital lobe tumour presents as a smooth, firm, non¬  tender mass in the lacrimal gland fossa with inferonasal    dystopia (Fig. 3.35B); posterior extension may cause  proptosis, ophthalmoplegia and choroidal folds,  o Palpebral lobe tumour is less common and tends to grow  anteriorly causing upper lid swelling without dystopia  (Fig. 3.35C); it may be visible to inspection (Fig. 3.35D).   • Investigation. CT shows a round or oval mass, with a  smooth outline and indentation but not destruction of the  lacrimal gland fossa (Fig. 3.35E). The lesion may indent the  globe, and calcification may be shown.   Treatment involves surgical excision. If the diagnosis is strongly  suspected, it is wise to avoid prior biopsy to prevent tumour  seeding into adjacent orbital tissue, although this may not always   Fig. 3.36 Lateral orbitotomy. (A) Incision of temporalis muscle; (B) drilling of underlying bone for subsequent wiring;  (C) removal of the lateral orbital wall and the tumour; (D) repair of the lateral orbital wall    be possible in the context of diagnostic uncertainty. Tumours of the  palpebral lobe are usually resected, along with a margin of normal  tissue, through an anterior (trans-septal) orbitotomy. Those of the  orbital portion are excised through a lateral orbitotomy:   2. The underlying bone is drilled for subsequent wiring (Fig. 3.36B).   3. The lateral orbital wall is removed and the tumour excised  including a margin of adjacent tissue and periorbita (Fig. 3.36C).   4. The lateral orbital wall (Fig. 3.36D) and temporalis are repaired.  The prognosis is excellent provided excision is complete and  without disruption of the capsule. Incomplete excision or prelimi¬  nary incisional biopsy may result in seeding of the tumour into  adjacent tissues, with recurrence and occasionally malignant  change.   Lacrimal gland carcinoma is a rare tumour that carries a high  morbidity and mortality. In order of frequency the main histologi¬  cal types are adenoid cystic (50%), pleomorphic adenocarcinoma,  mucoepidermoid and squamous cell. Histopathology shows nests  of basaloid cells with numerous mitoses (Fig. 3.37A). The peak  incidence is in middle-aged adults.   • Symptoms. A malignant mixed-cell tumour presents in  three main clinical settings:    o After incomplete or piecemeal excision of a benign  pleomorphic adenoma, followed by one or more  recurrences over a period of several years with eventual  malignant transformation.   o As a long-standing proptosis or swollen upper lid that  suddenly starts to increase.   o Without a previous history of a pleomorphic adenoma as  a rapidly growing lacrimal gland mass, usually of several  months’ duration.   O The history is shorter than that of a benign tumour.   o Pain is a frequent feature of malignancy but may also  occur with inflammatory lesions.   O Posterior extension, with involvement of the superior  orbital fissure, may give rise to epibulbar congestion,  proptosis, periorbital oedema and ophthalmoplegia  (Fig. 3.37B).   o CT shows a globular lesion with irregular serrated edges,  often with contiguous erosion or invasion of bone  (Fig. 3.37C). Calcification is commonly seen within the  tumour.   Fig. 3.37 Lacrimal gland carcinoma. (A) Histology of adenoid  cystic carcinoma shows nests of basaloid cells with solid  and cribriform areas; (B) dystopia, proptosis, periorbital  oedema and epibulbar congestion due to extension  involving the superior orbital fissure; (C) coronal CT shows  contiguous erosion of bone and spotty calcification in the  tumour   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann 2001 - fig. A; A Pearson - fig. C)   o Biopsy is necessary to establish the histological diagnosis.  Subsequent management depends on the extent of tumour  invasion of adjacent structures as seen on imaging,  o Neurological assessment is mandatory because adenoid-  cystic carcinoma exhibits perineural spread and may  extend into the cavernous sinus.   Treatment involves excision of the tumour and adjacent tissues.  Extensive tumours may require orbital exenteration or  midfacial resection, but the prognosis for life is frequently poor.  Radiotherapy combined with local resection may prolong life and  reduce pain. Adjuvant intra-arterial chemotherapy and/or brachy-  therapy may be utilized in some cases.   Optic nerve glioma is a slowly growing, pilocytic astrocytoma that  typically affects children (median age 6.5 years); histopathology  shows spindle-shaped pilocytic (hair-like) astrocytes and glial fila¬  ments (Fig. 3.38A). The prognosis is variable; some have an indo¬  lent course with little growth, while others may extend intracranially  and threaten life. Approximately 30% of patients have associated  neurofibromatosis type I (NFi - see Ch. 19) and in these patients  the prognosis is generally superior. Malignant glioma (glioblast¬  oma) is rare, has a very poor prognosis, and usually occurs in adult  males.   o Slowly progressive visual loss, followed later by proptosis,  although this sequence may occasionally be reversed.   o Acute loss of vision due to haemorrhage into the tumour  can occur, but is uncommon.   O Proptosis is often non-axial, with temporal or inferior  dystopia (Fig. 3.38B).   o Opticociliary collaterals (see Fig. 3.6C) and other fundus  signs such as central retinal vein occlusion are  occasionally seen.   o MRI effectively demonstrates the tumour, and may show  intracranial extension if present.   o CT in patients with associated NFi shows a fusiform  enlargement of the optic nerve with a clear-cut margin  produced by the intact dural sheath (Fig. 3.38C). In  patients without NFi the nerve is more irregular and  shows low-density areas.   As the tumour is intrinsic to the optic nerve, resection means that  all vision will be lost in the operated eye.    Fig. 3.38 Optic nerve glioma. (A) Histopathology - spindle-  shaped pilocytic astrocytes and glial filaments; (B)  proptosis with inferior dystopia; (C) axial CT showing  fusiform optic nerve enlargement   (Courtesy of J Harry - fig. A; K Nischal - fig. B; A Pearson - fig. C)    • Observation may be considered in patients with a typical  pilocytic astrocytoma on imaging in whom the tumour is  confined to the orbit, especially if there is good vision and  no significant cosmetic impairment; serial MRI is important  if this option is chosen. Spontaneous regression has been  reported, usually in NFi, but is very rare.   • Surgical excision with preservation of the globe is indicated  in those with large or growing tumours where complete  resection of the tumour can be achieved, particularly if  vision is poor and proptosis significant. A key goal is to  prevent chiasmal involvement, and an intracranial approach  may be necessary to achieve adequate resection.   • Radiotherapy may be combined with chemotherapy for  tumours with extension that precludes complete surgical  excision.   Optic nerve sheath meningioma is a benign tumour arising from  meningothelial cells of the arachnoid villi surrounding the intraor¬  bital, or less commonly the intracanalicular, portion of the optic  nerve. In some cases the tumour merely encircles the optic nerve  whilst in others it invades the nerve, growing along the fibrovas-  cular pial septa. However, about two-thirds of all meningiomas  affecting the optic nerve arise from extension of primarily intra¬  cranial lesions. Primary optic nerve sheath meningiomas are less  common than optic nerve gliomas and, as with other meningi¬  omas, typically affect middle-aged women. Histopathologically,  meningothelial (irregular lobules of meningothelial cells separated  by fibrovascular strands - Fig. 3.39A) and psammomatous (psam¬  moma bodies among proliferating meningothelial cells - Fig.  3.39B) types are distinguished. The prognosis for life is good in  adults, although the tumour may be more aggressive in children,  in whom 25% occur. They are more common in neurofibromatosis  type II (NF2).   • Symptoms typically consist of gradual visual impairment in  one eye. Transient obscurations of vision may occur.   • Signs. The classic (Hoyt-Spencer) triad consists of  progressive visual loss, optic atrophy and opticociliary shunt  vessels, although the simultaneous occurrence of all three  signs in one individual is actually uncommon. The usual  sequence of involvement is the opposite of that seen in  tumours that develop outside the dural sheath:   1. Optic nerve dysfunction and chronic disc swelling followed  by atrophy.   Fig. 3.39 Optic nerve meningioma. (A) Meningothelial histopathology; (B) psammomatous histopathology; (C) defective  elevation of the right eye; (D) MRI showing lesion associated with left optic nerve; (E) axial CT of a small tumour showing  calcification   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 - figs A and B; A Pearson - fig. E)   o MRI is the investigation of choice (Fig. 3.39D).  o CT shows thickening and calcification of the optic nerve  (Fig. 3.39E).   Treatment may not be indicated in a middle-aged patient with a  slowly growing lesion, but excision is required for an aggressive  tumour, particularly if the eye is blind or there is a risk of    intracranial extension. Attempts at optic nerve-sparing surgery  commonly fail but may be considered on a case basis. Fractionated  stereotactic radiotherapy may be appropriate as a vision-sparing  approach, or as adjunctive treatment following surgery.   Plexiform neurofibroma is the most common peripheral neural  tumour of the orbit. It occurs almost exclusively in association  with NFi. Presentation is in early childhood with periorbital swell¬  ing; classically, involvement of the eyelids causes mechanical ptosis  with a characteristic S-shaped deformity (see Fig. 1.16), but diffuse  involvement of the orbit with disfiguring hypertrophy of periocu¬  lar tissues may occur. On palpation the involved tissues are said  to resemble a ‘bag of worms’. Malignant change can occur, and  should be suspected if there is rapid change; radiotherapy may  promote this. Treatment is often unsatisfactory and complete sur¬  gical removal is extremely difficult. Orbital surgery should be  avoided when possible because of the intricate relationship  between the tumour and important structures.   Isolated (localized) neurofibroma is less common than plexiform  neurofibroma; about 10% of patients have NFi. Presentation is in  the third or fourth decades with insidious mildly painful propto¬  sis, usually not associated with visual impairment or ocular motil¬  ity dysfunction. Excision is commonly straightforward because the  tumour is well-circumscribed and relatively avascular.   Lymphomas of the ocular adnexa constitute approximately 8% of  all extranodal lymphomas. The majority of orbital lymphomas are  non-Hodgkin, and most of these (80%) are of B-cell origin. Those  affected are typically older individuals. The condition may be  primary, involving one or both orbits only, or secondary if there  are one or more identical foci elsewhere in the body; a substantial  proportion of apparently primary lesions will develop disease else¬  where within a few years. The course is variable and relatively  unpredictable. In some patients histological features raise suspi¬  cion of malignancy and yet the lesion resolves spontaneously or  with steroid treatment. Conversely, what appears to be reactive  lymphoid hyperplasia may be followed by the development of  lymphoma. Small lesions and those involving only the conjunctiva  have the best prognosis. Conjunctival and intraocular lymphomas  are discussed in Chapter 12.   • Symptoms. An absence of symptoms is common, but may  include discomfort, double vision, a bulging eye or a visible  mass.   o Any part of the orbit may be affected (Fig. 3.40A);  anterior lesions may be palpated, and generally have a  rubbery consistency (Fig. 3.40B).  o Occasionally the lymphoma may be confined to the  conjunctiva or lacrimal glands, sparing the orbit,  o Local lymph nodes should be palpated, but systemic  evaluation by an appropriate specialist is required.   o Orbital imaging, usually with MRI (Fig. 3.40C).  o Biopsy is usually performed to establish the diagnosis,  o Systemic investigation to establish the extent of  disease.   Radiotherapy is used for localized lesions, and chemotherapy for  disseminated disease and some subtypes. Immunotherapy (e.g.  rituximab) is a newer modality that may assume a dominant role  in the future. Occasionally a well-defined orbital lesion may be  resected.   Rhabdomyosarcoma (RMS) is the most common soft tissue  sarcoma of childhood: 40% develop in the head and neck, and it  is the most common primary orbital malignancy in children but  is still a rare condition; 90% occur in children under 16 and the  average age of onset is 7 years. The tumour is derived from undif¬  ferentiated mesenchymal cells that have the potential to differenti¬  ate into striated muscle. Various genetic predispositions have been  identified, including variants of the RBi gene responsible for retin¬  oblastoma. Four subtypes are recognized:   • Embryonal constitutes the majority (85%) of orbital lesions.  Cells may show light microscopic features of striated muscle  differentiation. Embryonal usually carries a good prognosis.   • Alveolar makes up most of the balance of orbital RMS.   Fewer cells show skeletal muscle differentiation than  embryonal, and the prognosis is worse. Particular  chromosomal translocations are characteristic on cytogenetic  analysis of biopsy material.   • Botyroid (4%) and pleomorphic RMS are much less  common in the orbit.   • Symptoms. Rapidly progressive unilateral proptosis is usual,  and may mimic an inflammatory condition such as orbital  cellulitis.   O The tumour is most commonly superonasal or superior,  but may arise anywhere in the orbit, including inferiorly  (Figs 3.41A and B). It can also arise in other tissues, such  as conjunctiva and uvea.   Fig. 3.40 Orbital lymphoma. (A) Involvement of the superior  orbit causing proptosis and inferior dystopia; (B) anterior  lesion; (C) axial Tl-weighted MR of the patient in (A) shows  a large orbital soft tissue mass and proptosis    o Swelling and redness of overlying skin develop but the  skin is not warm (see Fig. 3.41A).   o MRI shows a poorly defined mass (Fig. 3.41C).  o CT shows a poorly defined mass of homogeneous   density, often with adjacent bony destruction (Fig. 3.41D).  o Incisional biopsy is performed to confirm the diagnosis  and establish the histopathological subtype and  cytogenetic characteristics,  o Systemic investigation for metastasis should be   Commonly used guidelines for staging and a corresponding treat¬  ment protocol were produced by the Intergroup Rhabdomyosar¬  coma Study Group (IRSG); treatment encompasses a combination  of radiotherapy, chemotherapy and sometimes surgical debulking.  The prognosis for patients with disease confined to the orbit is  good.   Orbital metastases are an infrequent cause of proptosis, and are  much less common than metastases to the choroid. If the orbit is  the site of initial manifestation of the tumour, the ophthalmologist  may be the first specialist to see the patient. In approximate order  of frequency the most common primary sites are breast (up to  70%), bronchus, prostate, skin (melanoma), gastrointestinal tract  and kidney.   • Signs. Associated with the range of tumours that can spread   o Dystopia and proptosis (Fig. 3.42A) are the most  common features.   o Infiltration of orbital tissues characterized by ptosis,  diplopia, brawny indurated periorbital skin and a firm  orbit, with resistance to manual retropulsion of the globe.   O Primarily with cranial nerve involvement (II, III, IV, V,  VI) and only mild proptosis with orbital apex lesions.   o Imaging: CT (Fig. 3.42B) and MRI typically show a  non-encapsulated mass.   o Fine needle biopsy is useful for histological confirmation.  If this fails, open biopsy may be required.   o A search for a primary must be carried out if the patient  was not previously known to have cancer.    Fig. 3.41 Rhabdomyosarcoma. (A) Superiorly and (B) anteroinferiorly located lesions; (C) axial T2-weighted MR showing a large  retrobulbar mass with indentation of the globe and proptosis; (D) CT showing bony destruction and intracranial spread   (Courtesy of M Szreter - fig. A; A Pearson - fig. B; S Chen - fig. D)   Treatment is aimed at preserving vision and relieving pain, because  most patients die within a year (average 4 months). Radiotherapy  is the mainstay of local treatment, but systemic therapy may also  be of benefit. Surgical excision of the focus is occasionally carried  out. Orbital exenteration is usually only performed if other modal¬  ities fail to control intolerable symptoms.   Neuroblastoma is one of the most common childhood malignan¬  cies. It arises from neural crest-derived tissue of the sympathetic  nervous system, most commonly in the abdomen (Fig. 3.43A).  Presentation is usually in early childhood; in almost half of all  cases the tumour is disseminated at diagnosis, when it carries a  very poor prognosis. Orbital metastases may be bilateral and    typically present with the abrupt onset of proptosis accompanied  by a superior orbital mass and lid ecchymosis (Fig. 3.43B).   Myeloid sarcoma (granulocytic sarcoma) is a solid tumour com¬  posed of malignant cells of myeloid origin. Because the tumour  may exhibit a characteristic green colour it was formerly referred  to as chloroma. Myeloid sarcoma may occur as a manifestation of  established myeloid leukaemia, or it may precede the disease.  Orbital involvement usually presents at about age 7 years with the  rapid onset of proptosis, sometimes bilateral, and can be associ¬  ated with ecchymosis and lid oedema. When orbital involvement  precedes systemic leukaemia, the diagnosis may be difficult.   Langerhans cell histiocytosis is a rare group of disorders due to  clonal proliferations of histiocytes. Presentation ranges from local¬  ized disease, usually with bone destruction (eosinophilic granu¬  loma), through multifocal bone involvement to a fulminant   Fig. 3.42 Metastatic renal carcinoma. (A) Proptosis; (B) axial  CT showing a non-encapsulated retrobulbar mass    systemic disease. Soft tissues are less commonly involved, but  cutaneous and visceral lesions may occur. Orbital involvement  consists of unilateral or bilateral osteolytic lesions and soft tissue  involvement, typically in the superotemporal quadrant (Fig. 3.44).  Patients with solitary lesions tend to have a more benign course,  and respond well to treatment with local curettage and intrale-  sional steroid injection or radiotherapy. Systemic disease has a  worse prognosis.   Malignant tumours of the paranasal sinuses, although rare, may  invade the orbit and carry a poor prognosis unless diagnosed early.  It is therefore important to be aware of both their otorhinolaryn-  gological and ophthalmic features.   • Maxillary carcinoma is by far the most common sinus  tumour to invade the orbit (Fig. 3.45).  o Otorhinolaryngological manifestations include facial pain  and swelling, epistaxis and nasal discharge,  o Ophthalmic features include upward dystopia, diplopia  and epiphora.   Fig. 3.43 Neuroblastoma. (A) Axial CT shows a tumour  adjacent to the kidney; (B) bilateral orbital metastases   (Courtesy of B Zitelli and H Davis, from Atlas of Pediatric Physical Diagnosis,  Mosby 2002)   • Nasopharyngeal carcinoma may spread to the orbit through  the inferior orbital fissure; proptosis is a late finding.   • Intracranial meningioma arising from the sphenoid ridge  may invade the orbit by direct spread and cause proptosis  (see Fig. 19.54). Occasionally tumours arising from the  tuberculum sellae or olfactory groove may invade the orbit  through the superior orbital fissure or optic canal.   • Fibrous dysplasia is a disorder in which fibrous tissue  develops instead of normal bone, leading to weakening and  a mass effect (Fig. 3.46 A), usually in childhood or early  adulthood. Within the orbital region this may cause facial  asymmetry, proptosis, dystopia (Fig. 3.46B) and visual loss.  Most orbital disease is due to the monostotic form;  polyostotic disease is associated with endocrine disorders  and cutaneous pigmentation (McCune-Albright syndrome  -10% of cases).   • Orbital invasion may occur from eyelid malignancies such as  basal cell carcinoma, squamous cell carcinoma or sebaceous  gland carcinoma, from conjunctival tumours (e.g. melanoma  - Fig. 3.47A), and from intraocular tumours such as  choroidal melanoma or retinoblastoma (Fig. 3.47B).   Removal of an eye or the contents of the orbit may be indicated  for intraocular or orbital malignancy or where the eye is blind and    painful or unsightly. A number of different surgical and rehabilita¬  tion techniques are available.   Enucleation (removal of the globe) is indicated in the following  circumstances:   • Primary intraocular malignancies where other treatment  modalities are not appropriate. The tumour is left intact  within the eye for histopathological examination.   • After severe trauma where the risk of sympathetic  ophthalmitis may outweigh any prospect of visual recovery;  a rare indication (see Ch. 21).   • Blind painful or unsightly eyes can also be managed by  enucleation, although evisceration is generally considered  the procedure of choice.   Evisceration refers to removal of the entire contents of the globe,  whilst the sclera and extraocular muscles remain intact. Generally  the cornea is removed (Fig. 3.48) to provide access to the ocular  contents. Retention of the sclera and lack of disruption of the   Fig. 3.46 Fibrous dysplasia of the orbit. (A) Coronal CT scan  showing involvement of the floor and medial wall of the  right orbit; (B) upward dystopia of the right eye   Fig. 3.47 (A) Orbital invasion by conjunctival melanoma; (B)  orbital invasion by retinoblastoma    extraocular muscles is considered to provide somewhat better  motility than is achieved after enucleation. Evisceration provides  disrupted and incomplete material for histology and should not  be undertaken in the presence of suspected intraocular  malignancy.   • Orbital malignancy, either primary or where a tumour has  invaded the orbit from the eyelids, conjunctiva, globe or  adnexa, when other forms of treatment have a very poor  chance of success. Anteriorly sited tumours may allow  relative sparing of posterior orbital tissue, and posterior  tumours may allow sparing of eyelid skin to line the socket  (Fig. 3.49C). Following exenteration, prostheses can be  attached to the surrounding skin with adhesive, mounted on  glasses (Fig. 3.50), or secured with osseo-integrated magnets  mounted on the orbital rim bones. The socket may be lined  with skin or a split-skin graft, or left to heal by secondary  intention.   • Non-malignant disease such as orbital mucormycosis is a  rare indication.   A cosmetic shell is an ocular prosthesis that is used to cover a  phthisical or unsightly eye. The shell can restore volume, and often  provides a good cosmetic appearance, with reasonable motility as  a result of transmitted movements from the globe.   Enucleation or evisceration leads to a reduction in volume of the  orbital contents. A large prosthetic eye without an underlying  orbital implant does not provide a satisfactory solution, due to  stretching of the lower lid under its weight and to poor motility.  An implant is usually inserted during the surgery at which the eye  is removed, though secondary placement can be performed later  or a previously inserted implant exchanged. Implant materials  may be solid (‘non-integrated’, e.g. silicone, acrylic) or porous  (‘integrated’, e.g. polyethylene, hydroxyapatite). Fibrovascular  ingrowth into the latter facilitates motility of an overlying pros¬  thesis; a peg can also be inserted into porous implants to improve  later motility, though the peg must be covered in situ by socket  tissue and cannot attach directly to the overlying prosthesis. The  motility of unpegged implants is also usually good, particularly if  donor sclera or a mesh wrap is used and the extraocular muscles  secured to the surface.   • Post-enucleation socket syndrome (PESS) is caused by  failure to correct the volume deficit adequately. It is  characterized by a deep upper lid sulcus, ptosis,  enophthalmos (Fig. 3.51) and backwards rotation of the top  of the prosthesis.   • Extrusion (Fig. 3.52) is a significant concern with all  implants. Careful placement of an implant, ensuring it is  sufficiently deep and is well covered with vascularized  tissue, is more important than the choice of implant  material.    Fig.3.49 Exenteration. (A) Including eyelid removal, 2 days  postoperatively; (B) patient in (A) 6 months later; (C) with  sparing of the eyelids   (Courtesy of S Chen - figs A and B; A Pearson - fig. C)   Fig. 3.56 Crouzon syndrome. (A) Proptosis, midfacial  hypoplasia and mandibular prognathism; (B) proptosis and  hypertelorism - a ‘V’ exotropia is also shown   Fig. 3.57 Apert syndrome. (A) Mild shallow orbits, midfacial  hypoplasia and ‘parrot-beak’ nose; (B) syndactyly   After enucleation or evisceration a conformer (Fig. 3.53) made of  silicone or acrylic material is placed to support the conjunctival  fornices and remains in place until the socket is fitted with an    artificial eye (Fig. 3.54). Initial socket impression moulds can  usually be taken at around 6-8 weeks postoperatively and a tem¬  porary artificial eye placed whilst waiting for manufacture of a  prosthesis shaped to fit the individual socket and matched to the  fellow eye (Fig. 3.55).    The craniosynostoses are a group of rare congenital conditions in  which an abnormally shaped skull results from premature closure  of skull sutures.   • Crouzon syndrome features a short anteroposterior skull  diameter, with midfacial hypoplasia giving a prominent  lower jaw (Fig. 3.56A); proptosis due to shallow orbits and  hypertelorism (wide orbital separation) are the most  conspicuous ocular features (Fig. 3.56B). Vision-threatening  complications include exposure keratopathy and optic  atrophy, mechanisms including chronic papilloedema and  cerebral hypoperfusion secondary to sleep apnoea.   Strabismus ( C V’ exotropia - see Fig. 3.56B), ametropia and  amblyopia can occur, and other ocular associations have  been reported. Inheritance is usually autosomal dominant  (AD); allelic variants in the gene FGFR2 are responsible.   • Apert syndrome is the most severe of the craniosynostoses.  Oxycephaly (conical skull), midfacial hypoplasia with a  beaked nose and low-set ears (Fig. 3.57A), syndactyly   (Fig. 3.57B) and developmental delay (30%) may be present.  Shallow orbits, proptosis and hypertelorism are generally  less pronounced than in Crouzon syndrome, but the same  vision-threatening complications occur. Inheritance can  be AD, but in the majority of cases the condition is  sporadic and associated with older parental age. As with  Crouzon syndrome, it is frequently the result of mutations  in FGFR2.   • Pfeiffer syndrome features midfacial hypoplasia and  down-slanting palpebral fissures. Ocular features are similar  to Apert syndrome. Inheritance is AD with genetic  heterogeneity.   Dry eye occurs when there is inadequate tear volume or function,  resulting in an unstable tear film and ocular surface disease. It is  an extremely common condition, particularly in postmenopausal  women and the elderly.   • Keratoconjunctivitis sicca (KCS) refers to any eye with  some degree of dryness.   • Xerophthalmia describes a dry eye associated with vitamin  A deficiency.   • Xerosis refers to the extreme ocular dryness and  keratinization that occurs in eyes with severe conjunctival  cicatrization.   • Sjogren syndrome is an autoimmune inflammatory disease  of which dry eyes is a feature.   The constituents are complex, with as many as a hundred distinct  proteins identified.   The tear film is mechanically distributed over the ocular surface  through a neuronally controlled blinking mechanism. Three  factors are required for effective resurfacing of the tear film:   o The outer lipid layer is composed of a polar phase   containing phospholipids adjacent to the aqueous-mucin  phase and a non-polar phase containing waxes,  cholesterol esters and triglycerides,  o The polar lipids are bound to lipocalins within the   aqueous layer. These are small secreted proteins that have  the ability to bind hydrophobic molecules and may also  contribute to tear viscosity.   O Lid movement during blinking is important in releasing  lipids from glands. The thickness of the layer can be  increased by forced blinking, and conversely reduced by  infrequent blinking.   o To prevent evaporation of the aqueous layer and  maintain tear film thickness,  o To act as a surfactant allowing spread of the tear film,  o Deficiency results in evaporative dry eye.   o The main lacrimal glands produce about 95% of the  aqueous component of tears and the accessory lacrimal  glands of Krause and Wolfring produce the remainder,  o Secretion of tears has basic (resting) and much greater  reflex components. The latter occurs in response to  corneal and conjunctival sensory stimulation, tear  break-up and ocular inflammation, and is mediated via  the fifth cranial nerve. It is reduced by topical anaesthesia  and falls during sleep. Secretion can increase 500% in  response to injury.   o Water, electrolytes, dissolved mucins and proteins,  o Growth factors derived from the lacrimal gland, the  production of which increases in response to injury.    o Pro-inflammatory interleukin cytokines that accumulate  during sleep when tear production is reduced.   o Antibacterial activity due to proteins such as IgA,  lysozyme and lactoferrin.   o To wash away debris and noxious stimuli and facilitate  the transport of leukocytes after injury,  o To optically enhance the corneal surface by abolishing  minute irregularities.   o Mucins are high molecular weight glycoproteins that may  be transmembrane or secretory in type,  o Secretory mucins are further classified as gel-forming or  soluble. They are produced mainly by conjunctival goblet  cells but also by the lacrimal glands,  o The superficial epithelial cells of the cornea and   conjunctiva produce transmembrane mucins that form  their glycocalyx (extracellular coating),  o Staining of diseased epithelium with rose Bengal indicates  that the transmembrane and gel mucous layers are absent  and the cell surface exposed. Damage to the epithelial  cells will prevent normal tear film adherence.   o To permit wetting by converting the corneal epithelium  from a hydrophobic to a hydrophilic surface,  o Lubrication.   o Deficiency of the mucous layer may be a feature of  both aqueous deficiency and evaporative states. Goblet  cell loss occurs with cicatrizing conjunctivitis, vitamin A  deficiency, chemical burns and toxicity from  medications.   O Androgens are the prime hormones responsible for  regulation of lipid production,  o Oestrogens and progesterone receptors in the conjunctiva  and the lacrimal glands are essential for the normal  function of these tissues.   • Neural via fibres adjacent to the lacrimal glands and goblet  cells that stimulate aqueous and mucus secretion.   The four core inter-related mechanisms thought to be responsible  for the manifestations of dry eye are tear instability, tear hyperos-  molarity, inflammation and ocular surface damage. Inflammation  in the conjunctiva and accessory glands as well as the ocular  surface is present in 80% of patients with KCS and may be both a  cause and consequence of dry eye, amplifying and perpetuating  disease; the presence of inflammation is the rationale for specific  anti-inflammatory measures such as steroid therapy.   The classification of dry eye usually applied is that of the 2007  International Dry Eye Workshop (DEWS), with a basic division  into aqueous-deficient and evaporative types. Most individuals  have considerable overlap between mechanisms, and it is impor¬  tant to be aware during patient assessment of the likely presence  of multiple contributory factors.   o Lacrimal deficiency: primary (e.g. age-related dry eye,  congenital alacrima, familial dysautonomia) or secondary  (e.g. inflammatory and neoplastic lacrimal gland  infiltration, acquired immunodeficiency syndrome  (AIDS), graft-versus-host disease, lacrimal gland or nerve  ablation).   o Lacrimal gland duct obstruction, e.g. trachoma, cicatricial  pemphigoid, chemical injury, Stevens-Johnson syndrome.   o Reflex hyposecretion: sensory (e.g. contact lens wear,  diabetes, refractive surgery, neurotrophic keratitis) or motor  block (e.g. seventh cranial nerve damage, systemic drugs).   o Disorders of lid aperture, e.g. excessive scleral show, lid  retraction, proptosis, facial nerve palsy.   o Low blink rate, e.g. Parkinson disease, prolonged  computer monitor use, reading, watching television.   As well as the basic classification, DEWS draws attention to the  effect of the environment on the type of dry eye with which a  patient presents. These can be both internal, such as age, hormonal  status and behaviour patterns, and external, such as the exacerba¬  tion of evaporative factors in an atmosphere with low relative  humidity.    Sjogren syndrome (SS) is an autoimmune disorder characterized  by lymphocytic inflammation and destruction of lacrimal and  salivary glands (Fig. 4.2A) and other exocrine organs. The classic  clinical triad consists of dry eyes, dry mouth (Fig. 4.2B) and  parotid gland enlargement (Fig. 4.2C), but other features are   Fig. 4.2 Sjogren syndrome. (A) Histology of the lacrimal gland  shows lymphocytic infiltration; (B) dry fissured tongue;   (Courtesy of MA Mir ; from Atlas of Clinical Diagnosis, Saunders 2003 -  fig.C)    common and can affect all organ systems. The condition is classi¬  fied as primary when it exists in isolation, and secondary when  associated with another disease, commonly rheumatoid arthritis  or systemic lupus erythematosus. Primary SS affects females more  frequently than males. Although in clinical practice the diagnosis  may be made on less stringent grounds, the American College of  Rheumatology (ACR) criteria for diagnosis specify, in patients  with a clinical picture suggestive of SS:   • Positivity for anti-SSA or anti-SSB antibodies, or positive  rheumatoid factor together with significantly positive  antinuclear antibody.   • Focal lymphocytic sialadenitis to a specified extent on  salivary gland biopsy (see Fig. 4.2A).   Widely used but older American-European Consensus Group cri¬  teria are more extensive and include more clinical findings, but  give results substantially consistent with the ACR criteria.   Treatment options for SS include a range of symptomatic  treatments for dry eye, as discussed below, dry mouth and other  manifestations, salivary stimulants (e.g. oral pilocarpine) and in  some cases immunosuppression and biological blockers such as  rituximab.   The most common ocular symptoms are feelings of dryness,  grittiness and burning that characteristically worsen over the  course of the day. Stringy discharge, transient blurring of vision,  redness and crusting of the lids are also common. Lack of emo¬  tional or reflex tearing is unusual. The symptoms of KCS are  frequently exacerbated on exposure to conditions associated with  increased tear evaporation (e.g. air-conditioning, wind and central  heating) or prolonged reading or video display unit use, when  blink frequency is reduced.   • Posterior (seborrhoeic) blepharitis with meibomian gland  dysfunction is often present (Figs 4.3A and B).   o Staining with fluorescein (Fig. 4.4A) and rose Bengal  (Fig. 4.4B).  o Keratinization.   o Conjunctivochalasis is a common response to, and  exacerbating factor for, the chronic irritation of dry eye,  such that a self-sustaining cycle is maintained. It also  commonly occurs in other ocular surface disease (see Ch. 5).   o In the normal eye, as the tear film breaks down the mucin  layer becomes contaminated with lipid but is washed away,  o In the dry eye, the lipid-contaminated mucin accumulates  in the tear film as particles and debris that move with  each blink (Fig. 4.5A).   Fig. 4.3 Posterior blepharitis in dry eye. (A) Oil globules at meibomian gland orifices; (B) lid notching   Fig. 4.5 Tear film abnormalities in dry eye. (A) Mucous debris; (B) thin marginal tear meniscus    o The marginal tear meniscus (strip) is a crude measure of  the volume of aqueous in the tear film. In the normal eye  the meniscus is 0.2-0.4mm in height, but in dry eye  becomes thin or absent (Fig. 4.5B).   o Punctate epithelial erosions that stain well with  fluorescein (Figs 4.6A and B).   o Filaments consist of strands of mucus and debris such as  shed epithelial cells, and are typically attached at one end  to the corneal surface (Fig. 4.6C); they stain well with  rose Bengal but less so with fluorescein.   O Mucous plaques with similar constituents may occur in  severe dry eye. They consist of semi-transparent,  white-to-grey, often slightly elevated lesions of varying  size (Figs 4.6D and E).   • Complications can be vision-threatening and include  epithelial breakdown, melting (Fig. 4.7A), perforation  (Fig. 4.7B) and bacterial keratitis (Fig. 4.7C).    The aim of investigation is to confirm and quantify a clinical  diagnosis of dry eye. Unfortunately, although the repeatability of  symptoms is good, that of clinical tests is poor, as is the correlation  between symptoms and tests. The reliability of tests improves as  the severity of dry eye increases. The tests measure the following  parameters:   • Stability of the tear film as related to its break-up time  (BUT).   There is no clinical test to confirm the diagnosis of evaporative  dry eye. It is therefore a presumptive diagnosis based on the pres¬  ence of associated clinical findings. It is suggested the tests are  performed in the following order because the Schirmer strip paper  can damage the ocular surface and cause staining.   The tear film BUT is abnormal in aqueous tear deficiency and  meibomian gland disorders. It is measured as follows:   • Fluorescein 2% or an impregnated fluorescein strip  moistened with non-preserved saline is instilled into the  lower fornix.   • The tear film is examined at the slit lamp with a broad beam  using the cobalt blue filter. After an interval, black spots or  lines appear in the fluorescein-stained film (Fig. 4.8A),  indicating the formation of dry areas.   • The BUT is the interval between the last blink and the  appearance of the first randomly distributed dry spot. A  BUT of less than 10 seconds is suspicious.   The development of dry spots always in the same location  may indicate a local corneal surface abnormality (e.g. epithelial    basement membrane disease) rather than an intrinsic instability  of the tear film.   The Schirmer test is a useful assessment of aqueous tear produc¬  tion. The test involves measuring the amount of wetting of a  special (no. 41 Whatman) filter paper, 5 mm wide and 35 mm long.  The test can be performed with or without topical anaesthesia. In  theory, when performed with an anaesthetic (Schirmer 2) basic  secretion is measured and without anaesthetic (Schirmer 1) it  measures maximum basic plus reflex secretion. In practice,  however, topical anaesthesia cannot abolish all sensory and psy¬  chological stimuli for reflex secretion. The test is performed as  follows:   • Excess tears are delicately dried. If topical anaesthesia is  applied the excess should be removed from the inferior  fornix with filter paper.   • The filter paper is folded 5 mm from one end and inserted at  the junction of the middle and outer third of the lower lid,  taking care not to touch the cornea or lashes (Fig. 4.8B).   • The patient is asked to keep the eyes gently closed.   • After 5 minutes the filter paper is removed and the amount  of wetting from the fold measured.   • Less than 10 mm of wetting after 5 minutes without  anaesthesia or less than 6 mm with anaesthesia is considered  abnormal.   Results can be variable and a single Schirmer test should not be  used as the sole criterion for diagnosing dry eye, but repeatedly  abnormal tests are highly supportive.   • Fluorescein stains corneal and conjunctival epithelium (see  Figs 4.4 and 4.6) where there is sufficient damage to allow  the dye to enter the tissues.   • Rose Bengal is a dye that has an affinity for dead or  devitalized epithelial cells that have a lost or altered mucous  layer (Fig. 4.8C). Corneal filaments and plaques (see Fig.  4.6B) are also shown up more clearly by the dye and the use  of a red-free filter may help visualization. A 1% solution of  rose Bengal or a moistened impregnated strip can be used.  The dye may cause intense stinging that can last for up to a  day, particularly in patients with severe KCS; to minimize  irritation a very small drop should be used, immediately  preceded by a drop of topical anaesthetic, and the excess  washed out with saline.   • Lissamine green stains in a similar fashion to rose Bengal  but causes less irritation and may be preferred.   o Interpalpebral staining of the cornea and conjunctiva  (see Fig. 4.4B) is common in aqueous tear deficiency,  o Superior conjunctival stain may indicate superior limbic  keratoconjunctivitis.   O Inferior corneal and conjunctival stain is often present in  patients with blepharitis or exposure.    Fig. 4.6 Corneal signs in dry eye. (A) and (B) Punctate  erosions stained with fluorescein; (C) corneal filaments;   (D) mild (rose Bengal stain) and (E) severe mucous plaque  formation   (Courtesy of S Tuft - fig. C; R Bates - fig. E)   Fig. 4.7 Severe corneal complications of dry eye. (A) Melting;  (B) perforation with iris plugging; (C) bacterial infection    Fig. 4.8 Diagnostic tests in dry eye. (A) Tear film break-up  time - numerous dry spots are present in a fluorescein-  stained tear film; (B) Schirmer test; (C) corneal and  conjunctival staining with rose Bengal   • Fluorescein clearance test and the tear function index may  be assessed by placing 5 pi of fluorescein on the ocular  surface and measuring the residual dye in a Schirmer strip  placed on the lower lateral lid margin at set intervals.   • Tear film osmolarity measurement techniques are available;  this may be a particularly accurate means of diagnosis.   • Tear constituent measurement. Tear samples can be assayed  for the presence of markers known to be elevated (e.g.  matrix metalloproteinase-9) or decreased (e.g. lactoferrin) in  dry eye.   • Phenol red thread test uses a thread impregnated with a  pH-sensitive dye. The end of the thread is placed over the  lower lid and the length wetted (the dye changes from yellow  to red in tears) is measured after 15 seconds. A value of   6 mm is abnormal. It is comparable to the Schirmer test but  takes less time to perform.   • Tear meniscometry is a technique to quantify the height  and thus the volume of the lower lid meniscus.   The underlying causative processes of dry eye are generally not  reversible and management is therefore structured around the  control of symptoms and the prevention of surface damage.  DEWS have produced guidelines based on earlier International  Taskforce Guidelines for Dry Eye, in which suggested treatment  options depend on the level of severity of disease graded from 1 to  4. The DEWS guidelines can also be applied in a graded approach,  proceeding to the next level if the preceding measures are  inadequate.   o Establishment of realistic expectations and emphasis on  the importance of compliance.   o Lifestyle review including the importance of blinking  whilst reading, watching television or using a computer  screen (which should be orientated below eye level to  minimize palpebral aperture size), and the management  of contact lens wear.   o Instillation aids for eye drops (manufacturer-supplied or  makeshift, such as nut-crackers to hold plastic bottles)  should be advocated for patients with reduced dexterity  (e.g. rheumatoid arthritis).   o Caution the patient that laser refractive surgery can  exacerbate dry eye.    • Systemic medication review to exclude contributory effects  and eliminate offending agents. Discontinuation of toxic/  preserved topical medication if possible.   - see below; some authorities advocate that use of preserved  drops should fall within level 1, and categorize non-  preserved drops as a level 2 measure. Mucolytic agents may  be specifically indicated for some patients.   • Eyelid therapy. Basic measures such as warm compresses  and lid hygiene for blepharitis; reparative lid surgery (e.g.  entropion, ectropion, excessive lid laxity or scleral show)  may be considered as an early measure. Nocturnal  lagophthalmos can be addressed by taping the lids closed at  bedtime, wearing swimming goggles during sleep, or in  extreme cases by lateral tarsorrhaphy.   • Non-preserved tear substitutes are categorized as level 2  treatment by some authorities.   • Anti-inflammatory agents such as topical steroids, oral  omega fatty acids and other agents such as topical  ciclosporin.   o Eyelid surgery, such as tarsorrhaphy,  o Salivary gland autotransplantation,  o Mucous membrane or amniotic membrane  transplantation for corneal complications.   Tear substitutes have a relatively simple formulation that cannot  approximate the complex components and structure of the normal  tear film. Their delivery is also periodic rather than continuous.  Almost all are based on replacement of the aqueous phase of the  tear film. There are no mucus substitutes, and paraffin is only an  approximation to the action of tear lipids. The optimal frequency  of instillation varies with agent and with severity   • Drops and gels. A large range of preparations is available;  one agent or category of preparation has not demonstrated  superiority, and particular agents are often preferred by  individual patients with limited rationale.   o Cellulose derivatives (e.g. hypromellose, methylcellulose)  are appropriate for mild cases.   o Carbomer gels adhere to the ocular surface and so are  longer-lasting, but some patients are troubled by slight  blurring.   o Other agents include polyvinyl alcohol (PVA), which  increases the persistence of the tear film and is useful in  mucin deficiency, sodium hyaluronate, povidone,  glycerine, propylene glycol, polysorbate and others,  o Diquafosol is a newer agent that works as a topical  secretagogue.   • Ointments containing petrolatum (paraffin) mineral oil can  be used at bedtime to supplement daytime drops or gel  instillation; daytime use is precluded by marked blurring.  Some practitioners do not prescribe these for long-term use.   • Eyelid sprays are applied to the closed eye and typically  contain a liposome-based agent that may stabilize the tear  film and reduce evaporation.   • Artificial tear inserts emplaced once or twice daily offer  extended duration treatment and are preferred by some  patients.   • Mucolytic agents. Acetylcysteine 5% drops may be useful in  patients with corneal filaments and mucous plaques, which  acetylcysteine dissolves; it may cause stinging on instillation.  Acetylcysteine is malodorous and has a limited shelf life.  Manual debridement of filaments may also be useful.   • Preservatives can be a potent source of toxicity, especially  after punctal occlusion. Numerous non-preserved drops are  now available, including some multi-dose products, and in  general should be used in preference to preservative-  containing preparations in any more than mild disease or  with instillation more than three or four times daily. If  possible, preservative-free formulations should also be used  for dry eye patients when other topical medication is  required, for example in the treatment of glaucoma. Newer  preservatives such as Polyquad and Purite seem to exhibit  lower ocular surface toxicity than older agents such as  benzalkonium chloride.   tears and prolongs the effect of artificial tears. It is of greatest value   in patients with moderate to severe KCS who have not responded   • Temporary occlusion can be achieved by inserting collagen  plugs into the canaliculi; these dissolve over a number of  weeks. The main aim is to ensure that epiphora does not  occur following permanent occlusion.   o Initially the inferior puncta are occluded and the patient  is reviewed after 1 or 2 weeks.   o If the patient is now asymptomatic and without epiphora,  the plugs can be removed and the inferior canaliculi  permanently occluded (see below),  o In severe KCS both the inferior and superior canaliculi  can be plugged.   • Reversible prolonged occlusion can be achieved with silicone  (Fig. 4.9) or long-acting (2-6 months) collagen plugs.   Fig. 4.9 (A) Insertion of a silicone plug; (B) plug in place   o Plugs that pass into the horizontal portion of the  canaliculus cannot be visualized and although they can  usually be flushed out with saline, if they cause epiphora  this is not always possible and surgical retrieval may be  needed.   • Permanent occlusion should be undertaken only in patients  with severe dry eye who have had a positive response to  temporary plugs without epiphora. It should be avoided in  patients, especially if young, who may have reversible  pathology. All four puncta should not be occluded at the  same time.   o Permanent occlusion is performed following punctal  dilatation by coagulating the proximal canaliculus with  cautery; following successful occlusion, it is important to  watch for signs of recanalization,  o Laser cautery seems to be less consistently effective than  surgical thermal coagulation.   • Topical steroids, generally low-intensity preparations such  as fluorometholone, are effective supplementary treatment  for acute exacerbations. The risks of longer-term treatment  must be balanced against the potential benefits in each case.   • Omega fatty acid supplements (e.g. omega-3 fish oil, flax  seed oil) can have a dramatic effect on symptoms and may  facilitate the reduction of topical medication.   • Oral tetracyclines for an extended course, often 3 months at  a relatively low dose, may control associated blepharitis,  especially meibomianitis, and reduce tear levels of  inflammatory mediators. Doxycycline may be preferred to  minocycline on the grounds of adverse effect profile.   • Topical ciclosporin (usually 0.05%) reduces T-cell mediated  inflammation of lacrimal tissue, resulting in an increase in  the number of goblet cells and reversal of squamous  metaplasia of the conjunctiva.   Although contact lens wear can exacerbate dry eye, particularly  due to inflammatory, sensory and evaporative effects, these can be  outweighed by the reservoir effect of fluid trapped behind the lens,  and they are effective at relieving symptoms from secondary  corneal changes. Patients should be cautioned regarding the pos¬  sibility of bacterial keratitis.   • Low water content HEMA lenses may be successfully fitted  to moderately dry eyes.   • Silicone rubber lenses that contain no water and readily  transmit oxygen are effective in protecting the cornea in  extreme tear film deficiency, although deposition of debris  on the surface of the lens can blur vision and be  problematic. The continued availability of these lenses is in  doubt.    • Occlusive gas permeable scleral contact lenses provide a  reservoir of saline over the cornea. They can be worn on an  extremely dry eye with exposure.   • Room humidifiers may be tried but are frequently  disappointing because much apparatus is incapable of  significantly increasing the relative humidity of an average¬  sized room. A temporary local increase in humidity can be  achieved with moist chamber goggles or side shields to  glasses but may be cosmetically unacceptable.   • Botulinum toxin injection to the orbicularis muscle may  help control the blepharospasm that often occurs in severe  dry eye. Injected at the medial canthus it can also reduce  tear drainage, presumably by limiting lid movement.   • Oral cholinergic agonists such as pilocarpine (5 mg four  times daily) and cevilemine may reduce the symptoms of dry  eye and dry mouth in patients with Sjogren syndrome.  Adverse effects including blurred vision and sweating may  be less marked with cevilemine.   • Submandibular gland transplantation for extreme dry eye  requires extensive surgery and may produce excessive levels  of mucus in the tear film.   • Serum eye drops. Autologous or umbilical cord serum  (20-100%), the blood component remaining after clotting,  has produced subjective and objective improvements in  studies in patients with dry eye; they may aid the healing of  persistent epithelial defects. Their production and storage  carries practical challenges.   ALLERGIC CONJUNCTIVITIS 144  Acute allergic conjunctivitis 144  Seasonal and perennial allergic  conjunctivitis 144  Vernal keratoconjunctivitis 145    Atopic keratoconjunctivitis 148  Treatment of VKC and AKC 150  Non-allergic eosinophilic  conjunctivitis 151  Contact allergic  blepharoconjunctivitis 151  Giant (mechanically induced) papillary  conjunctivitis 151   Mucous membrane pemphigoid 152  Stevens-Johnson syndrome/toxic  epidermal necrolysis (Lyell  syndrome) 155   DEGENERATIONS 162  Pinguecula 162  Pterygium 162  Concretions 164  Conjunctivochalasis 165  Retention (primary epithelial inclusion)  cyst 165   The conjunctiva is a transparent mucous membrane that lines the  inner surface of the eyelids and the anterior surface of the globe,  terminating at the corneoscleral limbus. It is richly vascular, sup¬  plied by the anterior ciliary and palpebral arteries. There is a dense  lymphatic network, with drainage to the preauricular and sub¬  mandibular nodes corresponding to that of the eyelids. It has a  key protective role, mediating both passive and active immunity.  Anatomically, it is divided into the following:   • The palpebral conjunctiva starts at the mucocutaneous  junction of the lid margins and is firmly attached to the  posterior tarsal plates. The tarsal blood vessels are vertically  orientated.   • The bulbar conjunctiva covers the anterior sclera and is  continuous with the corneal epithelium at the limbus. Radial  ridges at the limbus form the palisades of Vogt, the likely  reservoir of corneal stem cells. The stroma is loosely  attached to the underlying Tenon capsule, except at the  limbus, where the two layers fuse. The plica semilunaris  (semilunar fold) is present nasally, medial to which lies a  fleshy nodule (caruncle) consisting of modified cutaneous  tissue.   • The epithelium is non-keratinizing and around five cell  layers deep (Fig. 5.1). Basal cuboidal cells evolve into  flattened polyhedral cells, subsequently being shed from the  surface. Mucus-secreting goblet cells are located within the  epithelium, being most dense inferonasally and in the  fornices.   • The stroma (substantia propria) consists of richly  vascularized loose connective tissue. The accessory lacrimal  glands of Krause and Wolfring are located deep within the  stroma. Secretions from the accessory lacrimal glands are  essential components of the tear film.    • Conjunctiva-associated lymphoid tissue (CALT) is critical  in the initiation and regulation of ocular surface immune  responses. It consists of lymphocytes within the epithelial  layers, lymphatics and associated blood vessels, with a  stromal component of lymphocytes and plasma cells,  including follicular aggregates.   it may also occur to a lesser extent in blepharitis and dry eye.   • Watery discharge is composed of a serous exudate and  tears, and occurs in acute viral or acute allergic  conjunctivitis.   • Mucoid discharge is typical of chronic allergic conjunctivitis  and dry eye.   • Mucopurulent discharge typically occurs in chlamydial or  acute bacterial infection.   • Hyperaemia that is diffuse, beefy-red and more intense away  from the limbus is usual in bacterial infection (Fig. 5.2A).  This ‘conjunctival injection’ should be distinguished from  the ciliary injection of iridocyclitis (see Ch. 11).   • Haemorrhages may occur in viral conjunctivitis, when  they are often multiple, small and discrete (‘petechial’ -  Fig. 5.2B), and severe bacterial conjunctivitis, when they are  larger and diffuse.   • Chemosis (conjunctival oedema) is seen as a translucent  swelling (Fig. 5.2C), which when severe may protrude  through the eyelids. Acute chemosis usually indicates a  hypersensitivity response (e.g. pollen), but can also occur in  severe infective conjunctivitis. Subacute or chronic chemosis  has numerous causes:   o Local, e.g. thyroid eye disease, chronic allergic  conjunctivitis, ocular or eyelid surgery, trauma,  o Increased systemic vascular permeability, e.g. allergic  conditions, infections including meningitis, vasculitis,  o Increased venous pressure, e.g. superior vena cava  syndrome, right-sided heart failure,  o Decreased plasma oncotic pressure, e.g. nephrotic  syndrome.   Fig. 5.2 Signs of conjunctival inflammation. (A) Hyperaemia (conjunctival injection); (B) petechial haemorrhages; (C) chemosis;  (D) pseudomembrane; (E) infiltration; (F) scarring   (Courtesy of P Saine -fig. A; S Tuft - fig. B; C Barry - fig. F)   o Pseudomembranes (Fig. 5.2D) consist of coagulated  exudate adherent to the inflamed conjunctival  epithelium. They can be peeled away leaving the  underlying epithelium intact,  o True membranes involve the superficial layers of the  conjunctival epithelium so that attempted removal leads  to tearing. The distinction between a true membrane and  a pseudomembrane is rarely clinically helpful and both  can leave scarring following resolution.    o Causes include severe adenoviral conjunctivitis,  gonococcal and some other bacterial conjunctivitides  (Streptococcus spp., Cory neb acterium diphtheriae),  ligneous conjunctivitis and Stevens-Johnson syndrome.   • Infiltration represents cellular recruitment to the site of  chronic inflammation and typically accompanies a papillary  response. It is recognized by loss of detail of the normal tarsal  conjunctival vessels, especially on the upper lid (Fig. 5.2E).   • Subconjunctival cicatrization (scarring) may occur in  trachoma and other severe conjunctivitides (Fig. 5.2F).    Severe scarring is associated with loss of goblet cells and  accessory lacrimal glands, and can lead to cicatricial  entropion.   resembling translucent grains of rice, most prominent in  the fornices (Fig. 5.3A). Blood vessels run around or  across rather than within the lesions,  o Histology shows a subepithelial lymphoid germinal centre  with central immature lymphocytes and mature cells  peripherally (Fig. 5.3B).   o Causes include viral and chlamydial conjunctivitis,  Parinaud oculoglandular syndrome and hypersensitivity  to topical medications. Small follicles are a normal  finding in childhood (folliculosis), as are follicles in  the fornices and at the margin of the upper tarsal  plate in adults.   • Papillae can develop only in the palpebral conjunctiva and  in the limbal bulbar conjunctiva where it is attached to the  deeper fibrous layer.   o Signs. In contrast to follicles, a vascular core is present.  Micropapillae form a mosaic-like pattern of elevated red  dots as a result of the central vascular channel,    macropapillae (<1 mm - Fig. 5.3C) and giant papillae  (>1 mm) develop with prolonged inflammation. Apical  infiltrate or staining with fluorescein or the presence of  mucus can be present with marked activity. Limbal  papillae have a gelatinous appearance,  o Histology shows folds of hyperplastic conjunctival  epithelium with a fibrovascular core and subepithelial  stromal infiltration with inflammatory cells (Fig. 5.3D).  Late changes include superficial stromal hyalinization,  scarring and the formation of crypts containing goblet  cells.   conjunctivitis, chronic blepharitis, contact lens wear,  superior limbic keratoconjunctivitis and floppy eyelid  syndrome.   The most common cause of lymphadenopathy associated with  conjunctivitis is viral infection. It may also occur in chlamydial  and severe bacterial conjunctivitis (especially gonococcal), and  Parinaud oculoglandular syndrome. The preauricular site is typi¬  cally affected.   Fig. 5.3 (A) Conjunctival follicles; (B) histology of a follicle showing two subepithelial germinal centres with immature  lymphocytes centrally and mature cells peripherally; (C) conjunctival macropapillae; (D) histology of a papilla showing folds  of hyperplastic conjunctival epithelium with a fibrovascular core and subepithelial stromal infiltration with inflammatory  cells   Acute bacterial conjunctivitis is a common and usually self-  limiting condition caused by direct contact with infected secre¬  tions. The most common isolates are Streptococcus pneumoniae ,  Staphylococcus aureus , Haemophilus influenzae and Moraxella  catarrhalis. A minority of cases, usually severe, are caused by the  sexually transmitted organism Neisseria gonorrhoeae , which can  readily invade the intact corneal epithelium. Meningococcal  (.Neisseria meningitidis ) conjunctivitis is rare, and usually affects  children.   o Acute onset of redness, grittiness, burning and discharge,  o Involvement is usually bilateral although one eye may  become affected 1-2 days before the other,  o On waking, the eyelids are frequently stuck together and  may be difficult to open.   o Systemic symptoms may occur in patients with severe  conjunctivitis associated with gonococcus,  meningococcus, Chlamydia and H. influenzae. In  children, the possibility of progression to systemic  involvement should always be borne in mind.   • Signs are variable and depend on the severity of infection,  o Eyelid oedema and erythema (Fig. 5.4A) may occur in  severe infection, particularly gonococcal,  o Conjunctival injection as previously described (Fig. 5.4B  and see Fig. 5.2A).   o The discharge can initially be watery, mimicking viral  conjunctivitis, but rapidly becomes mucopurulent  (Fig. 5.4C).   o Hyperacute purulent discharge (Fig. 5.4D) may signify  gonococcal or meningococcal conjunctivitis,  o Superficial corneal punctate epithelial erosions are  common.   o Peripheral corneal ulceration may occur in gonococcal  and meningococcal infection, and may rapidly progress  to perforation.   o Fymphadenopathy is usually absent except in severe  gonococcal and meningococcal infection.    Fig. 5.4 Bacterial conjunctivitis. (A) Eyelid oedema and erythema in severe infection; (B) diffuse tarsal and forniceal  conjunctival hyperaemia (injection); (C) mucopurulent discharge; (D) profuse purulent discharge    • Investigations are not performed routinely but may be  indicated in the following situations:   o In severe cases, binocular conjunctival swabs and  scrapings should be taken for urgent Gram staining,  particularly to exclude gonococcal and meningococcal  infection (Gram-negative kidney-shaped intracellular  diplococci).   o Culture should include enriched media such as chocolate  agar or Thayer-Martin for N. gonorrhoeae.  o Polymerase chain reaction (PCR) may be required for  less severe cases that fail to respond to treatment,  particularly to rule out the possibility of chlamydial and  viral infection.   • Topical antibiotics, usually four times daily for up to a week  but sometimes more intensively, are frequently administered  to speed recovery and prevent re-infection and transmission.  There is no evidence that any particular antibiotic is more  effective. Ointments and gels provide a higher concentration  for longer periods than drops but daytime use is limited  because of blurred vision. The following antibiotics are  available:   o Chloramphenicol, aminoglycosides (gentamicin,  neomycin, tobramycin), quinolones (ciprofloxacin,  ofloxacin, levofloxacin, lomefloxacin, gatifloxacin,  moxifloxacin, besifloxacin), macrolides (erythromycin,  azithromycin) polymyxin B, fusidic acid and bacitracin,  o Some practitioners, particularly in the United States,  believe that chloramphenicol should not be used for  routine treatment because of a possible link with aplastic  anaemia.   o Gonococcal and meningococcal conjunctivitis should be  treated with a quinolone, gentamicin, chloramphenicol or  bacitracin 1-2 hourly as well as systemic therapy (see below).   o Gonococcal infection is usually treated with a third-  generation cephalosporin such as ceftriaxone; quinolones  and some macrolides are alternatives. It is essential to  seek advice from a microbiologist and/or genitourinary  specialist.   treated with oral amoxicillin with clavulanic acid; there is  a 25% risk of developing otitis and other systemic  problems.   O Meningococcal conjunctivitis, also particularly in  children, in whom early systemic prophylaxis may be  life-saving as up to 30% develop invasive systemic disease.  The advice of paediatric and infectious disease specialists  must be sought but if in doubt treatment with  intramuscular benzylpenicillin, ceftriaxone or cefotaxime,  or oral ciprofloxacin should not be delayed,  o Preseptal or orbital cellulitis (see Ch. 3).    • Topical steroids may reduce scarring in membranous and  pseudomembranous conjunctivitis, although evidence for  their use is unclear.   • Irrigation to remove excessive discharge may be useful in  hyperpurulent cases.   • Contact lens wear should be discontinued until at least 48  hours after complete resolution of symptoms. Contact lenses  should not be worn whilst topical antibiotic treatment  continues.   • Risk of transmission should be reduced by hand-washing  and the avoidance of towel sharing.   • Review is unnecessary for most mild/moderate adult cases,  although patients should be cautioned to seek further advice  in the event of deterioration.   Giant fornix syndrome is an uncommon entity causing chronic  relapsing pseudomembranous purulent conjunctivitis. It is believed  to be due to retained debris in a voluminous upper fornix acting  as a focus for persistent bacterial colonization (usually S. aureus)  in an elderly patient with levator disinsertion. Large protein aggre¬  gations may be visualized in the upper fornix, though double  eversion with a retractor may be necessary to identify these. Sec¬  ondary corneal vascularization and lacrimal obstruction are  common. It is frequently unilateral. Treatment involves repeated  sweeping of the fornix with a cotton-tipped applicator and topical  and systemic antibiotics; intensive topical steroid may be helpful.  Surgical forniceal reconstruction may be necessary in recalcitrant  cases.   Chlamydia trachomatis (Fig. 5.5) is a species of Chlamydiae, a  phylum of bacteria that cannot replicate extracellularly and hence  depends on host cells. They exist in two principal forms: (a) a  robust infective extracellular ‘elementary body’ and (b) a fragile  intracellular replicating ‘reticular body’. Adult chlamydial (inclu¬  sion) conjunctivitis is an oculogenital infection usually caused by  serovars (serological variants) D-K of C. trachomatis , and affects  5-20% of sexually active young adults in Western countries.  Transmission is by autoinoculation from genital secretions,  although eye-to-eye spread probably accounts for about 10%. The  incubation period is about a week.   • In males chlamydial infection is the most common cause of  non-gonococcal urethritis (NGU), also termed non-specific  urethritis (NSU). It should be noted that the latter term is  also sometimes used to mean urethritis in which both  gonococcal and chlamydial infection have been ruled out.   C. trachomatis may also cause epididymitis, and can act as a  trigger for Reiter syndrome.   • In females chlamydial urethritis typically causes dysuria and  discharge. It may progress to pelvic inflammatory disease  (PID), carrying a risk of infertility; 5-10% of women with  PID develop perihepatitis (Fitz-Hugh-Curtis syndrome).   • Symptoms consist of the subacute onset of unilateral or  bilateral redness, watering and discharge. Untreated, the  conjunctivitis becomes chronic, and though self-limiting  may persist for several months. It is important to enquire  about sexual exposure if chlamydial conjunctivitis is  suspected.   o Watery or mucopurulent discharge,  o Tender preauricular lymphadenopathy.  o Large follicles are often most prominent in the inferior  fornix (Fig. 5.6A) and may also involve the upper tarsal  conjunctiva (Fig. 5.6B).  o Superficial punctate keratitis is common,  o Perilimbal subepithelial corneal infiltrates (Fig. 5.6C) may  appear after 2-3 weeks.   O Mild conjunctival scarring and superior corneal pannus  (Fig. 5.6D) are not uncommon.   • Investigations. Tarsal conjunctival scrapings are obtained  using a spatula or the blunt side of a scalpel blade.   o Nucleic acid amplification tests such as PCR are likely to  be the investigation of choice in time but validation for  ocular specimens is limited at present,  o Giemsa staining for basophilic intracytoplasmic bodies is  performed by applying scrapings onto a glass slide.    o Direct immunofluorescence detects free elementary  bodies with about 90% sensitivity and specificity,  o Enzyme immunoassay for direct antigen detection is also  useful.   o McCoy cell culture is highly specific,  o Swabs can be taken for bacterial culture, and serology  may be helpful in selected cases.   Empirical treatment may be given if the clinical picture is convinc¬  ing pending investigation results, or if investigations are negative.   • Referral to a genitourinary specialist is mandatory in  confirmed cases, particularly for the exclusion of other  sexually transmitted infections, contact tracing and  pregnancy testing.   o Azithromycin 1 g repeated after 1 week is generally the  treatment of choice, although a second or a third course  is required in up to 30% of cases. Some guidelines  advocate only a single 1 g dose,  o Doxycycline 100 mg twice daily for 10 days (tetracyclines  are relatively contraindicated in pregnancy/breastfeeding  and in children under 12 years of age).   • Topical antibiotics such as erythromycin or tetracycline  ointment are sometimes used to achieve rapid relief of  ocular symptoms, but are insufficient alone.   • Reduction of transmission risk involves abstinence from  sexual contact until completion of treatment (1 week after  azithromycin), together with other precautions as for any  infectious conjunctivitis.   • Re-testing for persistent infection should take place 6-12  weeks after treatment.   It is important to be aware that symptoms commonly take weeks  to settle, and that follicles and corneal infiltrates can take months  to resolve due to a prolonged hypersensitivity response to chlamy¬  dial antigen.   Trachoma is the leading cause of preventable irreversible blind¬  ness in the world. It is related to poverty, overcrowding and poor  hygiene, the morbidity being a consequence of the establishment  of re-infection cycles within communities. Whereas an isolated  episode of trachomatous conjunctivitis may be relatively innocu¬  ous, recurrent infection elicits a chronic immune response con¬  sisting of a cell-mediated delayed hypersensitivity (Type IV)  reaction to the intermittent presence of chlamydial antigen and  can lead to loss of sight. Prior contact with the organism confers  short-term partial immunity but also leads to a heightened inflam¬  matory reaction upon reinfection. Vaccination has an effect  similar to primary infection in sensitizing the individual, and so   Fig. 5.6 Adult chlamydial conjunctivitis. (A) Large forniceal follicles; (B) superior tarsal follicles; (C) peripheral corneal  infiltrates; (D) superior pannus    is not helpful. The family childcare group is the most important  re-infection reservoir, and consequently young children are par¬  ticularly vulnerable. The fly is an important vector, but there may  be direct transmission from eye or nasal discharge. Trachoma is  associated principally with infection by serovars A, B, Ba and C of  Chlamydia trachomatis , but the serovars D-K conventionally asso¬  ciated with adult inclusion conjunctivitis, and other species of the  Chlamydiaceae family such as Chlamydophila psittaci and Chlamy-  dophila pneumoniae have also been implicated.   Features of trachoma are divided into an ‘active’ inflammatory  stage and a ‘cicatricial’ chronic stage, with considerable overlap. A  World Health Organization (WHO) grading system is in use  (Table 5.1).   • Active trachoma is most common in pre-school children  and is characterized by the following:  o Mixed follicular/papillary conjunctivitis (Fig. 5.7A)  associated with a mucopurulent discharge. In children  under the age of 2 years the papillary component may  predominate.   TF = trachomatous inflammation ( follicular ): five or more  follicles (>0.5 mm) on the superior tarsal plate   Tl = trachomatous inflammation (intense): diffuse  involvement of the tarsal conjunctiva, obscuring 50% or  more of the normal deep tarsal vessels; papillae are  present   TT = trachomatous trichiasis: at least one lash touching  the globe _   CO = corneal opacity sufficient to blur details of at least  part of the pupillary margin   o Linear or stellate (Fig. 5.7C) conjunctival scars in mild  cases, or broad confluent scars (Arlt line - Fig. 5.7D) in  severe disease.   Fig. 5.7 Trachoma. (A) Typical white subtarsal follicles; (B) marked pannus; (C) stellate conjunctival scarring; (D) Arlt’s line and  conjunctival follicles; (E) Herbert pits; (F) cicatricial entropion    o Although the entire conjunctiva is involved, the effects  are most prominent on the upper tarsal plate,  o Superior limbal follicles may resolve to leave a row of  shallow depressions (Herbert pits - Fig. 5.7E).  o Trichiasis, distichiasis, corneal vascularization and  cicatricial entropion (Fig. 5.7F).  o Severe corneal opacification.    o Dry eye caused by destruction of goblet cells and the  ductules of the lacrimal gland.   • Investigations are rarely used in the affected areas, diagnosis  being made on clinical features in most cases. Various field  techniques (e.g. dipstick enzyme immunoassay) are available  and investigations otherwise are similar to those for adult  inclusion conjunctivitis.   The SAFE strategy for trachoma management supported by the  WHO and other agencies encompasses Surgery for trichiasis, Anti¬  biotics for active disease, Facial hygiene and Environmental  improvement.   • Antibiotics should be administered to those affected and to  all family members. A single antibiotic course is not always  effective in eliminating infection in an individual, and  communities may need to receive annual treatment to  suppress infection.   o A single dose of azithromycin (20 mg/kg up to 1 g) is the  treatment of choice.   doxycycline 100 mg twice daily for 10 days (tetracyclines  are relatively contraindicated in pregnancy/breastfeeding  and in children under 12).   o Topical 1% tetracycline ointment is less effective than oral  treatment.   • Environmental improvement, such as access to adequate  water and sanitation, as well as control of flies, is important.   • Surgery is aimed at relieving entropion and trichiasis and  maintaining complete lid closure, principally with bilamellar  tarsal rotation.   Neonatal conjunctivitis (ophthalmia neonatorum) is defined as  conjunctival inflammation developing within the first month of  life. It is the most common infection of any kind in neonates,  occurring in up to 10%. It is identified as a specific entity distinct  from conjunctivitis in older infants because of its potentially  serious nature (both ocular and systemic complications) and  because it is often the result of infection transmitted from mother  to infant during delivery.   C. trachomatis , N. gonorrhoeae (now rare in wealthier  countries, but previously responsible for 25% of childhood  blindness) and herpes simplex virus (HSV, typically HSV-2).  With all of these, conjunctivitis is not uncommonly  associated with severe ocular or systemic complications.   C. trachomatis is the most common cause in cases involving  moderate to severe conjunctival inflammation.   • Staphylococci are usually responsible for mild  conjunctivitis; other bacterial causes include streptococci,   • Topical preparations used as prophylaxis against infection  (see below), may themselves cause conjunctival irritation  (chemical conjunctivitis).   • Congenital nasolacrimal obstruction. Despite poor  neonatal tear production, a persistently mildly watery eye  with recurrent mild bacterial conjunctivitis may be  secondary to an as yet uncanalized tear duct.   o Staphylococci and other bacteria: end of the first week,  o HSV: 1-2 weeks,  o Chlamydia : 1-3 weeks.   o Instillation of a prophylactic chemical preparation,  o Parental symptoms of sexually transmitted infection  (STI).   o Recent conjunctivitis in close contacts,  o Features of systemic illness in the child: pneumonitis,  rhinitis and otitis in chlamydial infection, skin vesicles  and features of encephalitis in HSV; disseminated  gonococcal infection is relatively rare.   o A mildly sticky eye may occur in staphylococcal infection,  or with delayed nasolacrimal duct canalization  (mucopurulent reflux on pressure over the lacrimal sac),  o Discharge is characteristically watery in chemical and  HSV infection, mucopurulent in chlamydial infection,  purulent (Fig. 5.8) in bacterial infection, and  hyperpurulent in gonococcal conjunctivitis,  o Severe eyelid oedema occurs in gonococcal infection; it  may be difficult to distinguish severe conjunctivitis from  preseptal or orbital infection. Signs of dacrocystitis  should be excluded.   o Eyelid and periocular vesicles may occur in HSV  infection, and can critically aid early diagnosis and  treatment.    O Corneal examination is mandatory, and is particularly  important if gonococcal infection is suspected, as  ulceration with rapid progression is common. Use of a  pen torch, insertion of an eyelid speculum and  fluorescein drops may be helpful; the latter may facilitate  identification of a dendritic or geographic epithelial  lesion that may be present in HSV infection (in contrast  to the punctate epitheliopathy seen in older children with  primary herpetic conjunctivitis).   o Congenital glaucoma may masquerade as neonatal  conjunctivitis and should always be considered,  particularly in monocular cases.   o The results of any parental prenatal testing for STI should  be obtained.   o Conjunctival scrapings are taken for nucleic acid  amplification (PCR), particularly for Chlamydia  and HSV.   o Separate conjunctival scrapings are applied to a glass  slide for Gram and Giemsa staining. Multinucleated  giant cells may be present on Gram stain in HSV  infection.   o Conjunctival swabs are taken with a calcium alginate  swab or a sterile cotton-tipped applicator, for standard  bacterial culture and chocolate agar or Thayer-Martin  (for N. gonorrhoeae).   o Epithelial cells infected with HSV may show eosinophilic  intranuclear inclusions on Papanicolaou smear,  o Conjunctival scrapings or fluid from skin vesicles can be  sent for viral culture for HSV.  o Specimens should be taken prior to fluorescein  instillation if immunofluorescent testing is planned.   • Prophylaxis is routinely performed but there is no standard  protocol.   o A single instillation of povidone-iodine 2.5% solution is  effective against common pathogens,  o Erythromycin 0.5% or tetracycline 1% ointment,  o Silver nitrate 1% solution agglutinates gonococci and is  still utilized in areas where gonococcal infection is  common. It should be administered in conjunction with  a single intramuscular dose of benzylpenicillin when  maternal infection is present.   • Chemical conjunctivitis does not require treatment apart  from artificial tears.   • Mild conjunctivitis. A mildly sticky eye is extremely  common in neonates. Investigation is often unnecessary and  a low-intensity regimen with a broad-spectrum topical  antibiotic such as chloramphenicol, erythromycin or fusidic  acid ointment is adequate in most cases. Further  investigation and treatment can be instituted if the condition  fails to settle.    • Moderate to severe cases should be investigated as above;  microscopy with Gram staining alone is highly sensitive and  will often provide a working diagnosis.   o If the diagnosis is uncertain but chlamydial infection is a  reasonable possibility, oral erythromycin can be  commenced on an empirical basis after samples have  been collected.   o If bacteria are evident on Gram stain, a broad-spectrum  topical antibiotic (e.g. chloramphenicol, erythromycin  or bacitracin for Gram-positive organisms, neomycin,  ofloxacin or gentamicin for Gram-negatives) should be  used until sensitivities are available; additional systemic  treatment should be considered in more severe cases.   • Severe conjunctivitis, or when systemic illness is suspected,  requires hospital admission. Samples should be taken for a  range of investigations, including urgent microscopy, and a  broad-spectrum topical antibiotic, such as erythromycin,  commenced. The ocular risk is usually most acute from  gonococcal infection, so empirical topical treatment should  cover this, and in most cases consideration given to systemic  treatment such as parenteral ceftriaxone.   • Chlamydial infection is treated with oral erythromycin for 2  weeks; a longer or supplementary course may be needed.  Erythromycin or tetracycline ointment can be used in  addition, but is probably unnecessary.   • Gonococcal conjunctivitis is treated systemically with a  third-generation cephalosporin and often with  supplementary topical treatment. Co-treatment for  Chlamydia is prudent. Saline irrigation to remove excessive  discharge should be considered.   • Herpes simplex infection should always be regarded  as a systemic condition and is treated with high-dose  intravenous aciclovir under paediatric specialist care. Early  diagnosis and treatment of encephalitis (PCR of  cerebrospinal fluid (CSF) is positive in 95%) may be  life-saving or prevent serious neurological disability. Topical  aciclovir may be considered in addition.   • Microbiological advice should be sought in severe cases,  especially regarding local antibiotic sensitivities.   • Paediatric specialist involvement is mandatory when  systemic disease may be present.   • Genitourinary referral for the mother and her sexual  contacts is important when an STI is diagnosed. The neonate  should be screened for other STIs.   • Notification of a case of neonatal conjunctivitis to the local  public health authority is a statutory requirement in many  countries.   Viral conjunctivitis is a common external ocular infection, adeno¬  virus (a non-enveloped double-stranded DNA virus) being the  most frequent (90%) causative agent. It may be sporadic, or  occur in epidemics in environments such as workplaces (including    hospitals), schools and swimming pools. The spread of this  highly contagious infection is facilitated by the ability of viral  particles to survive on dry surfaces for weeks, and by the fact that  viral shedding may occur for many days before clinical features  are apparent. Transmission is generally by contact with respiratory  or ocular secretions, including via fomites such as contaminated  towels.   The spectrum of viral conjunctivitis varies from mild subclinical  disease to severe inflammation with significant morbidity.  There will often be a history of a close contact with acute  conjunctivitis.   • Non-specific acute follicular conjunctivitis is the most  common clinical form of viral conjunctivitis, and is typically  due to adenoviral infection by a range of serological variants.  Unilateral watering, redness, irritation and/or itching, and  mild photophobia occur, the contralateral eye generally  being affected 1-2 days later, often less severely. The  condition is usually milder than the other clinical forms of  adenoviral conjunctivitis; patients may have accompanying  (usually mild) systemic symptoms, such as a sore throat   • Pharyngoconjunctival fever (PCF) is caused mainly by  adenovirus serovars 3, 4 and 7. It is spread by droplets  within families with upper respiratory tract infection.  Keratitis develops in about 30% of cases but is seldom  severe. Symptoms are essentially as above, though sore  throat is typically prominent.   • Epidemic keratoconjunctivitis (EKC) is caused mainly by  adenovirus serovars 8,19 and 37, and is the most severe  ocular adenoviral infection. Keratitis, which may be marked,  develops in about 80%; photophobia may be  correspondingly prominent.   • Acute haemorrhagic conjunctivitis usually occurs in  tropical areas. It is typically caused by enterovirus and  coxsackievirus, though other microorganisms may present  similarly. It has a rapid onset, and resolves within 1-2 weeks.  Conjunctival haemorrhage is generally marked.   • Chronic/relapsing adenoviral conjunctivitis giving a  chronic non-specific follicular/papillary clinical picture can  persist over years, but is rare and eventually self-limiting.   • Herpes simplex virus (HSV) can cause a follicular  conjunctivitis, particularly in primary infection; this is  usually unilateral and there are often associated skin vesicles.   • Systemic viral infections such as those common in  childhood, e.g. varicella, measles and mumps, can feature an  associated follicular conjunctivitis; varicella-zoster virus  secondary infection commonly causes a conjunctivitis as  part of ophthalmic shingles. An HIV conjunctivitis is  recognized.   • Molluscum contagiosum is a skin infection caused by a  human specific double-stranded DNA poxvirus that typically  affects otherwise healthy children, with a peak incidence  between the ages of 2 and 4 years. Transmission is by    contact, with subsequent autoinoculation. A chronic  follicular conjunctivitis can be associated, and is due to skin  lesion shedding of viral particles. Chronic unilateral ocular  irritation and mild discharge is typical. The eyelash line  should be examined carefully in patients with chronic  conjunctivitis so as not to overlook a molluscum lesion.   • Conjunctival hyperaemia and follicles (Fig. 5.9A) are  typically prominent; papillae may also be seen, particularly  in the superior tarsal conjunctiva.   • Severe inflammation may be associated with conjunctival  haemorrhages (usually petechial in adenoviral infection - see  Fig. 5.2B), chemosis, membranes (rare) and  pseudomembranes (Fig. 5.9B), sometimes with conjunctival  scarring after resolution (Fig. 5.9C).   o Punctate epithelial keratitis (staining) may occur, usually  within 7-10 days of the onset of symptoms, typically  resolving within 2 weeks.   o Focal white subepithelial/anterior stromal infiltrates  (Fig. 5.9D) often develop beneath the fading epithelial  lesions, probably as an immune response to the virus;  they may persist or recur over months or years,  o Small pseudodendritic epithelial formations sometimes  occur.   o A pale, waxy, umbilicated nodule on the lid margin  (Fig. 5.10A) associated with follicular conjunctivitis  (Fig. 5.10B) and mild watery and mucoid discharge,  o Bulbar nodules and confluent cutaneous lesions may  occur in immunocompromised patients.   the diagnosis is in doubt or there is failure of resolution.   • Giemsa stain shows predominantly mononuclear cells in  adenoviral conjunctivitis and multinucleated giant cells in  herpetic infection.   • Nucleic acid amplification techniques such as PCR are  sensitive and specific for viral DNA.   • Viral culture with isolation is the reference standard but is  expensive and fairly slow (days to weeks), and requires  specific transport media. Sensitivity is variable but specificity  is around 100%.   • A ‘point-of-care’ immunochromatography test takes 10  minutes to detect adenoviral antigen in tears; sensitivity and  specificity are excellent.   • Serology for IgM or rising IgG antibody titres to adenovirus  has limitations and is rarely used.   Fig. 5.9 Adenoviral keratoconjunctivitis. (A) Follicular conjunctivitis; (B) pseudomembrane; (C) residual scarring;  (D) subepithelial infiltrates    • Investigation for other causes such as chlamydial infection  may be indicated in non-resolving cases.   The treatment of herpetic ocular surface disease is addressed in  Chapter 6.   • Spontaneous resolution of adenoviral infection usually  occurs within 2-3 weeks, so specific treatment is typically    unnecessary. No antiviral agent with clinically useful activity  against adenovirus has yet been produced.   • Reduction of transmission risk by meticulous hand hygiene,  avoiding eye rubbing and towel sharing. There should be  scrupulous disinfection of instruments and clinical surfaces  after examination of an infected patient (e.g. sodium  hypochlorite, povidone-iodine).   • Molluscum contagiosum. Although lesions are self-limiting  in immunocompetent patients, removal is often necessary to    address secondary conjunctivitis or for cosmetic reasons.  Expression is facilitated by making a small nick in the skin at  the margin of the lesion with the tip of a needle.   • Topical steroids such as prednisolone 0.5% four times daily  may be required for severe membranous or  pseudomembranous adenoviral conjunctivitis. Symptomatic  keratitis may require weak topical steroids but these should  be used with caution as they do not speed resolution but  only suppress inflammation, and lesions commonly recur  after premature discontinuation. Steroids may enhance viral  replication and extend the period during which the patient  remains infectious. Intraocular pressure should be  monitored if treatment is prolonged.   symptomatic relief. Preservative-free preparations may  give superior comfort, and if supplied in single-dose units  may reduce transmission risk,  o Cold (or warm) compresses for symptomatic relief,  o Topical antihistamines and vasoconstrictors may improve  symptoms, particularly itching,  o The place of non-steroidal anti-inflammatory drops is  not well established, but may be effective in some  circumstances such as steroid weaning. They are not  thought to promote viral replication,  o Removal of symptomatic pseudomembranes or  membranes.   o Povidone-iodine is very effective against free (although  less so against intracellular) adenovirus, and has been  proposed as a means of decreasing infectivity.    Atopy is a genetically determined predisposition to hypersensitiv¬  ity reactions upon exposure to specific environmental antigens.  Clinical manifestations include the various forms of allergic con¬  junctivitis, as well as hay fever (seasonal allergic rhinitis), asthma  and eczema. Allergic conjunctivitis is a Type I (immediate) hyper¬  sensitivity reaction, mediated by degranulation of mast cells in  response to the action of IgE; there is evidence of an element of  Type IV hypersensitivity in at least some forms.   Acute allergic conjunctivitis is a common condition caused by  an acute conjunctival reaction to an environmental allergen,  usually pollen. It is typically seen in younger children after playing  outside in spring or summer. Acute itching and watering are  common, but the hallmark is chemosis (Figs 5.11A and B), which  is frequently dramatic and worrying to the child and parents.  Treatment is not usually required and the conjunctival swelling    settles within hours as the acute increase in vascular permeability  resolves. Cool compresses can be used and a single drop of adrena¬  line 0.1% may reduce extreme chemosis.   These common subacute conditions are distinguished from each  other by the timing of exacerbations, thought to relate principally  to differing stimulating allergens in each.   • Seasonal allergic conjunctivitis (‘hay fever eyes’), worse  during the spring and summer, is the more common. The  most frequent allergens are tree and grass pollens, although  the specific allergen varies with geographic location.   • Perennial allergic conjunctivitis causes symptoms  throughout the year, generally worse in the autumn when  exposure to house dust mites, animal dander and fungal   Fig. 5.11 (A) Mild and (B) severe chemosis in acute allergic  conjunctivitis    allergens is greatest. It is less common and tends to be  milder than the seasonal form.   • Symptoms. Transient acute or subacute attacks of redness,  watering and itching, associated with sneezing and nasal  discharge.   • Signs. Conjunctival hyperaemia with a relatively mild  papillary reaction, variable chemosis and lid oedema.   • Investigations are generally not performed although  conjunctival scraping in more active cases may demonstrate  the presence of eosinophils. Skin testing for particular  allergens is rarely required.   • Mast cell stabilizers (e.g. sodium cromoglicate, nedocromil  sodium, lodoxamide) must be used for a few days before  exerting maximal effect, but are suitable (except  lodoxamide) for long-term use if required.   • Antihistamines (e.g. emedastine, epinastine, levocabastine,  bepotastine) can be used for symptomatic exacerbations and  are as effective as mast cell stabilizers.   • Dual action antihistamine and mast cell stabilizers (e.g.  azelastine, ketotifen, olopatadine) act rapidly and are often  very effective for exacerbations.   • Combined preparation of an antihistamine and a  vasoconstrictor (e.g. antazoline with xylometazoline).   • Non-steroidal anti-inflammatory preparations (e.g.  diclofenac) can provide symptomatic relief but are rarely  used.   • Oral antihistamines may be indicated for severe symptoms.  Some, such as diphenhydramine, cause significant  drowsiness and may be useful in aiding sleep; others, such as  loratadine, have a far less marked sedative action.   Vernal keratoconjunctivitis (VKC) is a recurrent bilateral disorder  in which both IgE- and cell-mediated immune mechanisms play  important roles. It primarily affects boys and onset is generally  from about the age of 5 years onwards. There is remission by the  late teens in 95% of cases, although many of the remainder develop  atopic keratoconjunctivitis. VKC is rare in temperate regions but  relatively common in warm dry climates such as the Mediter¬  ranean, sub-Saharan Africa and the Middle East. In temperate  regions over 90% of patients have other atopic conditions such as  asthma and eczema and two-thirds have a family history of atopy.  VKC often occurs on a seasonal basis, with a peak incidence over  late spring and summer, although there may be mild perennial  symptoms.   • Palpebral VKC primarily involves the upper tarsal  conjunctiva. It may be associated with significant corneal  disease as a result of the close apposition between the  inflamed conjunctiva and the corneal epithelium.   • Mixed VKC has features of both palpebral and limbal  disease.   • Symptoms consist of intense itching, which may be  associated with lacrimation, photophobia, a foreign body  sensation, burning and thick mucoid discharge. Increased  blinking is common.   hyperaemia and diffuse velvety papillary hypertrophy on  the superior tarsal plate (Fig. 5.12A).  o Macropapillae (<1 mm) have a flat-topped polygonal  appearance reminiscent of cobblestones; focal (Fig. 5.12B)  or diffuse (Fig. 5.12C) whitish inflammatory infiltrates  may be seen in intense disease,  o Progression to giant papillae (>1 mm) can occur, as  adjacent smaller lesions amalgamate when dividing septa  rupture (Fig. 5.12D).   o Mucus deposition between giant papillae (Fig. 5.12E).  o Decreased disease activity is characterized by milder  conjunctival injection and decreased mucus production  (Fig. 5.12F).   o Gelatinous limbal conjunctival papillae that may be  associated with transient apically located white cellular  collections (Horner-Trantas dots - Fig. 5.13A-C).  o In tropical regions, limbal disease may be severe  (Fig. 5.13D).   • Keratopathy is more frequent in palpebral disease and may  take the following forms:   o Superior punctate epithelial erosions associated  with layers of mucus on the superior cornea  (Fig. 5.14A).   o Epithelial macroerosions caused by a combination of  epithelial toxicity from inflammatory mediators and a  direct mechanical effect from papillae (Fig. 5.14B-D).  o Plaques and ‘shield’ ulcers (Fig. 5.15A and B) may develop  in palpebral or mixed disease when the exposed Bowman  membrane becomes coated with mucus and calcium  phosphate, leading to inadequate wetting and delayed  re-epithelialization. This development is serious and  warrants urgent attention to prevent secondary bacterial  infection.   o Subepithelial scars that are typically grey and oval  (Fig. 5.15C), and may affect vision.   Fig. 5.12 Palpebral vernal disease. (A) Diffuse fine papillary hypertrophy; (B) macropapillae with focal inflammatory infiltrates;  (C) macropapillae with diffuse infiltrate; (D) giant papillae; (E) intense disease with mucus; (F) milder disease; note mucous  discharge   Fig. 5.13 Limbal vernal disease. (A) Sparse limbal papillae; (B) papillae with Horner-Trantas dots; (C) extensive papillae;  (D) severe features   Fig. 5.14 Keratopathy in vernal disease. (A) Superior punctate erosions and mucus stained with rose Bengal; (B-D) gradual  resolution of a macroerosion over months of treatment   Fig. 5.15 Keratopathy in vernal disease. (A) Early plaque; (B) plaque and shield ulcer; (C) subepithelial scarring following  ulceration; (D) pseudogerontoxon and limbal papillae    o Pseudogerontoxon can develop in recurrent limbal  disease. It is characterized by a paralimbal band of  superficial scarring resembling arcus senilis (Fig. 5.15D),  adjacent to a previously inflamed segment of the limbus,  o Vascularization does not tend to be prominent, though  some peripheral superficial vessel ingrowth is common,  especially superiorly.   o Keratoconus and other forms of corneal ectasia are more  common in VKC and are thought to be at least partly  due to persistent eye rubbing,  o Herpes simplex keratitis is more common than average,  though less so than in atopic keratoconjunctivitis. It can  be aggressive and is occasionally bilateral.   • Eyelid disease is usually mild, in contrast to atopic  keratoconjunctivitis.   Atopic keratoconjunctivitis (AKC) is a rare bilateral disease that  typically develops in adulthood (peak incidence 30-50 years) fol¬  lowing a long history of atopic dermatitis (eczema); asthma is also  extremely common in these patients. About 5% have suffered  from childhood VKC. There is little or no gender preponderance.  AKC tends to be chronic and unremitting, with a relatively low  expectation of eventual resolution, and is associated with signifi¬  cant visual morbidity. Whereas VKC is more frequently seasonal  and generally worse in the spring, AKC tends to be perennial and  is often worse in the winter. Patients are sensitive to a wide range  of airborne environmental allergens.   Fig. 5.16 Atopic disease. (A) Severe eyelid involvement; (B) infiltration and scarring of the tarsal conjunctiva; (C) forniceal  shortening; (D) keratinization of the caruncle; (E) dense punctate epithelial erosions; (F) persistent epithelial defect and  peripheral corneal vascularization; a penetrating keratoplasty interface can be seen   The distinction between AKC and VKC is essentially clinical; eosi¬  nophils tend to be less common in conjunctival scrapings than  with VKC.   • Symptoms are similar to those of VKC, but are frequently  more severe and unremitting.   o Skin changes (Fig. 5.16A) are more prominent than in  VKC, and are typically eczematoid: erythema, dryness,    scaliness and thickening, sometimes with disruption to  epidermal integrity such as Assuring and scratches  (excoriation), the latter due to intense itching,  o Associated chronic staphylococcal blepharitis and  madarosis are common.   o There may be keratinization of the lid margin,  o Hertoghe sign: absence of the lateral portion of the  eyebrows.    o Tightening of the facial skin may cause lower lid  ectropion and epiphora.   • Conjunctival involvement is preferentially inferior  palpebral, whereas in VKC it is worse superiorly.   o Discharge is generally more watery than the stringy  mucoid discharge in VKC.   o Papillae are initially smaller than in VKC although larger  lesions may develop later.   o Diffuse conjunctival infiltration and scarring may give a  whitish, featureless appearance (Fig. 5.16B).  o Cicatricial changes can lead to moderate symblepharon  formation, forniceal shortening (Fig. 5.16C) and  keratinization of the caruncle (Fig. 5.16D).  o Limbal involvement similar to that of limbal VKC can be  seen, including Horner-Trantas dots.   o Punctate epithelial erosions over the inferior third of the  cornea are common and can be marked (Fig. 5.16E).  o Persistent epithelial defects (Fig. 5.16F), sometimes with  associated focal thinning, can occasionally progress to  perforation with descemetocoele (US spelling -  descemetocele) formation.   o Plaque formation may occur (see Figs 5.15A and B).  o Peripheral vascularization and stromal scarring are more  common than in VKC.   o Predisposition to secondary bacterial and fungal  infection, and to aggressive herpes simplex keratitis,  o Keratoconus is common (about 15%) and as with VKC  may be secondary to chronic ocular rubbing.   o Presenile shield-like anterior or posterior subcapsular  cataracts are common and may be exacerbated by  long-term steroid therapy.   o Because of the high lid margin carriage of S. aureus ,  cataract surgery carries an increased risk of  endophthalmitis.   • Retinal detachment is more common than in the general  population, and is a particular risk following cataract surgery.   of AKC, although the latter is generally less responsive and requires   • Allergen avoidance, if possible. An allergy specialist opinion  may be requested; allergen (e.g. patch) testing is sometimes  useful, but often gives non-specific results.   • Lid hygiene should be used for associated staphylococcal  blepharitis. Moisturizing cream such as E45 can be applied  to dry, fissured skin.    • Bandage contact lens wear to aid healing of persistent  epithelial defects.   • Mast cell stabilizers (e.g. sodium cromoglicate, nedocromil  sodium, lodoxamide) reduce the frequency of acute  exacerbations and the need for steroids and so form the  basis of many regimens, but are seldom effective in isolation.  Several days to weeks of treatment are needed for a  reasonable response and long-term therapy may be needed  (lodoxamide is not licensed for long-term use).   • Topical antihistamines (e.g. emedastine, epinastine,  levocabastine, bepotastine) when used in isolation are about  as effective as mast cell stabilizers. They are suitable for acute  exacerbations but generally not for continuous long-term  use, and courses of several preparations are licensed for use  only in courses of limited duration. A trial of several  different agents may be worthwhile.   • Combined antihistamine and vasoconstrictor (e.g.  antazoline with xylometazoline) may offer relief in some  cases.   • Combined action antihistamine/mast cell stabilizers (e.g.  azelastine, ketotifen, olopatadine) are helpful in many  patients and have a relatively rapid onset of action.   • Non-steroidal anti-inflammatory preparations (e.g.  ketorolac, diclofenac) may improve comfort by blocking  non-histamine mediators. Combining one of these with  a mast cell stabilizer is an effective regimen in some  patients.   • Topical steroids (e.g. fluorometholone 0.1%, rimexolone  1%, prednisolone 0.5%, loteprednol etabonate 0.2% or 0.5%)  are used for (a) severe exacerbations of conjunctivitis and  (b) significant keratopathy; reducing conjunctival activity  generally leads to corneal improvement. They are usually  prescribed in short but intensive (e.g. 2-hourly initially)  courses, aiming for very prompt tapering. Although the risk  of elevation of intraocular pressure is low, monitoring is  advisable if long-term treatment is necessary. Stronger  preparations such as prednisolone 1% can be used but carry  a higher risk of steroid-induced glaucoma.   • Steroid ointment (e.g. hydrocortisone 0.5%) may be used to  treat the eyelids in AKC, though as with eye drops, the  duration of treatment should be minimized and the  intraocular pressure (IOP) monitored.   • Antibiotics may be used in conjunction with steroids in  severe keratopathy to prevent or treat bacterial infection.   • Acetylcysteine is a mucolytic agent that is useful in VKC for  dissolving mucus filaments and deposits, and addressing  early plaque formation.   o Ciclosporin (0.05-2% between two and six times daily)  may be indicated if steroids are ineffective, inadequate or  poorly tolerated, or as a steroid-sparing agent in patients  with severe disease. The effects typically take some weeks  to be exerted, and relapses may occur if treatment is   O Calcineurin inhibitors show increasing promise as an  alternative to steroids in the treatment of allergic eye  disease. Tacrolimus 0.03% ointment can be effective in  AKC for severe eyelid disease. Instillation into the  fornices has been effective in modulating conjunctival  inflammation in refractory cases.   • Supratarsal steroid injection may be considered in severe  palpebral disease or for non-compliant patients. The  injection is given into the conjunctival surface of the  anaesthetized everted upper eyelid; 0.1 ml of betamethasone  sodium phosphate 4 mg/ml, dexamethasone 4 mg/ml or  triamcinolone 40 mg/ml is given.   • Oral antihistamines help itching, promote sleep and reduce  nocturnal eye rubbing. Because other inflammatory  mediators are involved besides histamines, effectiveness is  not assured. Some antihistamines (e.g. loratadine) cause  relatively little drowsiness.   • Antibiotics (e.g. doxycycline 50-100 mg daily for 6 weeks,  azithromycin 500 mg once daily for 3 days) may be given to  reduce blepharitis-aggravated inflammation, usually in AKC.   • Immunosuppressive agents (e.g. steroids, ciclosporin,  tacrolimus, azathioprine) may be effective at relatively low  doses in AKC unresponsive to other measures. Short courses  of high-dose steroids may be necessary to achieve rapid  control in severe disease. Monoclonal antibodies against T  cells have shown some promise in refractory cases.   • Other treatments that may be effective in some patients  include aspirin in VKC (avoided in children and adolescents  due to Reye syndrome risk), allergen desensitization, and  plasmapheresis in patients with high serum IgE levels.   • Superficial keratectomy may be required to remove plaques  or debride shield ulcers and allow epithelialization. Medical  treatment must be maintained until the cornea has  re-epithelialized in order to prevent recurrences. Excimer  laser phototherapeutic keratectomy is an alternative.   • Surface maintenance/restoration surgery such as  amniotic membrane overlay grafting or lamellar  keratoplasty, or eyelid procedures such as botulinum  toxin-induced ptosis or lateral tarsorrhaphy, may be  required for severe persistent epithelial defects or ulceration.  Gluing may be appropriate for focal (‘punched-out’) corneal  perforations.   Non-allergic eosinophilic conjunctivitis (NAEC) is a recently pro¬  posed chronic non-atopic condition said to occur predominantly   in middle-aged women in whom dry eye is also commonly present;   it has been suggested that it is relatively common but under¬    diagnosed. It is thought to be of similar pathogenesis to non-  allergic eosinophilic rhinitis; conjunctival eosinophilia is present  without significant IgE levels in the serum or tear film. Symptoms  are similar to those of allergic conjunctivitis - itching, redness,  foreign body sensation and mild watery discharge. Treatment is  with a 1-2 week course of topical steroid for exacerbations fol¬  lowed by maintenance with topical mast cell stabilizers, non¬  steroidal anti-inflammatory agents or antihistamines.   Analogous to contact dermatitis, this refers to the acute or sub¬  acute T-cell-mediated delayed hypersensitivity reaction seen most  commonly by ophthalmologists as a reaction to eye drop constitu¬  ents and by optometrists as a reaction to contact lens solutions.  Mascara is a less common cause. There may be a conjunctival  reaction, but signs predominantly involve the eyelid skin: ery¬  thema, thickening, induration and sometimes Assuring occur (Fig.  5.17). Treatment is by removal or discontinuation of the precipi¬  tant, sometimes with a mild topical steroid ointment.   Mechanically induced papillary conjunctivitis, the severe form of  which is known as giant papillary conjunctivitis (GPC), can occur  secondary to a variety of mechanical stimuli of the tarsal conjunc¬  tiva. It is most frequently encountered with contact lens (CL)  wear, when it is termed contact lens-associated papillary conjunc¬  tivitis (CLPC). The risk is increased by the build-up of proteina¬  ceous deposits and cellular debris on the contact lens surface.  Ocular prostheses (Fig. 5.18), exposed sutures and scleral buckles,  corneal surface irregularity and filtering blebs can all be responsi¬  ble. A related phenomenon is the so-called ‘mucus fishing syn¬  drome’, when, in a variety of underlying anterior segment  disorders, patients develop or exacerbate a chronic papillary    reaction due to repetitive manual removal of mucus. Giant papil¬  lae can also be seen in other conditions such as VKC and AKC.   • Symptoms consist of a foreign body sensation, redness,  itching, increased mucus production, blurring and loss of  CL tolerance. Symptoms may be worse after lens removal.  Patients should be questioned about CL cleaning and  maintenance.   o Variable mucous discharge,  o Substantial CL protein deposits may be present,  o Excessive CL mobility due to upper lid capture,  o Superior tarsal hyperaemia and papillae; by definition,  ‘giant’ papillae are >1.0 mm in diameter, but the clinical  syndrome of mechanically induced papillary  conjunctivitis commonly features only fine/medium  papillae, particularly in early or mild disease,  o Focal apical ulceration and whitish scarring may develop  on larger papillae.   o Keratopathy is rare because of the relatively subdued  secretion of inflammatory cytokines,  o Ptosis may occur, mainly as a result of irritative spasm  and tissue laxity secondary to chronic inflammation.   Other causes of conjunctival papillae should be excluded, as well  as CL intolerance due to other causes, such as a reaction to lens  cleaning solutions and dry eyes.   o CL wear should be discontinued for several weeks and  the current lenses replaced. For mild-moderate disease,  this may be adequate for resolution, sometimes in  conjunction with reduced wearing time. In severe CLPC  a longer interval without lens wear may be needed.    o Removal of other underlying causes, such as exposed  sutures or a scleral buckle.   o Assessment of the status and fit of an ocular prosthesis.   O Filtering bleb: partial excision, revision with non¬  penetrating drainage surgery or glaucoma drainage device  implantation.   o Switching to monthly then daily disposable CL if the  condition persists after renewing non-disposable lenses.   o Rigid lenses carry a lesser risk of CLPC (5%), probably  because they are easier to clean effectively.   o Cessation of contact lens wear, substituting spectacles or  refractive surgery, may be necessary for severe or  refractory disease.   o Regular (at least weekly) use of contact lens protein  removal tablets.   o Mast cell stabilizers should be non-preserved in patients  wearing soft contact lenses, or can be instilled when the  lenses are not in the eye, with a delay of perhaps half an  hour after drop instillation prior to lens insertion. Most  can be continued long-term if necessary.   O Antihistamines, non-steroidal anti-inflammatory agents  and combined antihistamines/mast cell stabilizers may  each be of benefit.   o Topical steroids can be used for the acute phase of   resistant cases, particularly those where effective removal  of the stimulus is difficult, as in bleb-related disease.   Mucous membrane pemphigoid (MMP), also known as cicatricial  pemphigoid (CP), comprises a group of chronic autoimmune  mucocutaneous blistering diseases. An unknown trigger leads to  a Type II (cytotoxic) hypersensitivity response resulting in anti¬  bodies binding at the basement membrane zone (BMZ), the acti¬  vation of complement and the recruitment of inflammatory cells,  with localized separation of the epidermis from the dermis at the  BMZ and subsequent progression to scarring.   A wide range of epithelial tissues can be involved, including  the skin and various mucous membranes. Particular clinical  forms of MMP tend to involve specific target tissues: bullous pem¬  phigoid (BP) shows a predilection for skin, and ocular mucous  membrane pemphigoid (OMMP, also known as ocular cicatricial  pemphigoid - OCP) involves the conjunctiva in the majority of  cases and causes progressive scarring (cicatrization). The disease    typically presents in old age and affects females more commonly  than males by a 2:1 ratio. Other causes of cicatrizing conjunctivitis  include Stevens-Johnson syndrome, trachoma, drug-induced,  trauma and severe or chronic conjunctivitis of many types. MMP  should not be confused with pemphigus, a distinct group of  disorders.   Diagnosis is principally clinical, but biopsy of involved mucous  membrane often shows supportive changes (linear antibody and  complement BMZ deposition). Progression has been divided into  stages, from stage I (chronic conjunctivitis) to stage IV (immobile  globe with a keratinized cornea).   • Symptoms. Insidious or relapsing-remitting non-specific  bilateral conjunctivitis; misdiagnosis (e.g. dry eye) is  common.   o Papillary conjunctivitis, diffuse hyperaemia, oedema and  subtle fibrosis (Fig. 5.19A).    o Fine lines of subconjunctival fibrosis and shortening of  the inferior fornices; symblepharon (plural symblephara)  formation refers to adhesion between the bulbar and  palpebral conjunctiva (Fig. 5.19B).   o Flattening of the plica and keratinization of the caruncle  (Fig. 5.19C).   o Dry eye due to destruction of goblet cells and accessory  lacrimal glands, and occlusion of the main lacrimal  ductules.   o Monitoring should include the measurement of forniceal  depth and noting the position of adhesions.   o Aberrant (trichiatic) lashes, chronic blepharitis and  keratinization of the lid margin.   o Ankyloblepharon is an adhesion at the outer canthus  between the upper and lower lids (Fig. 5.19D).   Fig. 5.19 Conjunctivitis in ocular cicatricial pemphigoid. (A) Subtle disease with hyperaemia and early conjunctival fibrosis;  (B) moderate fibrosis with forniceal shortening and symblepharon formation; (C) flat plica and keratinized caruncle;   Fig. 5.20 Keratopathy in ocular cicatricial pemphigoid. (A) Epithelial defect; (B) peripheral vascularization and infiltration;  (C) keratinization with ankyloblepharon; (D) end-stage disease    o Keratinization and conjunctivalization of the corneal  surface (Fig. 5.20C) due to epithelial stem cell failure,  o End-stage disease is characterized by total symblepharon  and corneal opacification (Fig. 5.20D).   • Mucosal involvement is very common and is characterized  by subepidermal blisters, most frequently oral (Fig. 5.21A).  Severe manifestations include oesophageal and laryngeal  strictures.   • Skin lesions are less common (25%) and present as tense  blisters and erosions of the head and neck, groin and  extremities (Fig. 5.21B).   • Dapsone (diaminodiphenylsulfone) is a useful first-line  treatment in patients with mild-moderate disease;  approximately 70% of patients respond. It is contraindicated  in glucose-6-phosphate dehydrogenase deficiency.  Sulfasalazine is sometimes better tolerated.    • Antimetabolites (e.g. azathioprine, methotrexate,  mycophenolate mofetil) are alternatives for mild-moderate  disease if dapsone is contraindicated, ineffective or poorly  tolerated, and are suitable for long-term therapy. Dapsone  can be used in conjunction if necessary. Cyclophosphamide  may be reserved for severe or refractory disease.   • Steroids (prednisolone 1-1.5 mg/kg) are effective for rapid  disease control, but adverse effects limit long-term use. IOP  should be monitored.   • Other measures include intravenous immunoglobulin  therapy and rituximab; remission has been reported with a  combination regimen.   o Artificial tears are an integral part of most regimens,  o Topical steroids, ciclosporin or tacrolimus may be used  as an adjunct to systemic immunosuppressive treatment,  o Retinoic acid may reduce keratinization.  o Antibiotics when indicated,  o Lid hygiene and low-dose oral tetracycline for  blepharitis.   Fig. 5.21 Mucous membrane pemphigoid. (A) Oral blisters; (B) severe skin blistering    • Subconjunctival mitomycin C and/or steroid injection may  be used as a temporizing aid or if systemic  immunosuppression is not possible.   • Contact lenses may be used with caution to protect the  cornea from aberrant lashes and from dehydration.   Reconstructive surgery, preferably under systemic steroid cover,  should be considered when active disease is controlled.   • Lateral tarsorrhaphy or botulinum toxin-induced ptosis may  be used to promote healing of corneal epithelial defects.   • Mucous membrane autografting or amniotic membrane  transplantation for conjunctival resurfacing and forniceal  restoration.   • Limbal stem cell transfer may be attempted for corneal  re - epithelialization.   • Keratoplasty carries a high risk of failure; lamellar grafts may  be effective for perforation.   • Keratoprosthesis (Fig. 5.22) may be the only option in  end-stage disease.   The terms ‘Stevens-Johnson syndrome (SJS)’ and ‘erythema  multiforme major’ have historically been used synonymously.    However, it is now believed that erythema multiforme (without  the ‘major’) is a distinct disease, milder and recurrent, with some¬  what dissimilar clinical features. Toxic epidermal necrolysis (TEN  - Lyell syndrome) is a severe variant of SJS. SJS/TEN patients tend  to be young adults, though other groups may be affected. The  condition involves a cell-mediated delayed hypersensitivity reac¬  tion, usually related to drug exposure. A wide range of medica¬  tions have been incriminated, including antibiotics (especially  sulfonamides and trimethoprim), analgesics including paraceta¬  mol (acetaminophen), cold remedies and anticonvulsants. Infec¬  tions due to microorganisms such as Mycoplasma pneumoniae and  herpes simplex virus, and some cancers have also been implicated.  Because symptoms often take weeks to develop, in many cases the  precipitant cannot be identified. Mortality overall is around 5% in  SJS (death is commonly due to infection), but is considerably  higher in TEN.   In the acute stage there are often practical obstacles to standard   slit lamp examination; the patient may be bedridden and undergo¬  ing barrier nursing; a portable slit lamp may be helpful.   • Symptoms. Acute ocular symptoms may include redness,  mild-severe grittiness, photophobia, watering and blurring.   O Haemorrhagic crusting of the lid margins (Fig. 5.23A) is  characteristic; skin lesions may be confluent and it is  often difficult for an examiner to open the eyes without  causing marked discomfort.   O Papillary conjunctivitis, which can range from mild,  transient and self-limiting to severe (Fig. 5.23B).  o Conjunctival membranes and pseudomembranes  (Fig. 5.23C), severe hyperaemia, haemorrhages, blisters  and patchy infarction.   o Keratopathy: a spectrum of lesions from punctate  erosions to large epithelial defects, secondary bacterial  keratitis and occasionally perforation.   o Conjunctival cicatrization (Fig. 5.23D) with forniceal  shortening and symblepharon formation.   (Fig. 5.23E), sometimes with abrasive plaque formation,  o Eyelid complications include cicatricial entropion and  ectropion, trichiasis, metaplastic lashes and  ankyloblepharon.   o Keratopathy including scarring, vascularization and  keratinization (Fig. 5.23F) as a result of the primary  inflammation and/or infection, as well as cicatricial  entropion and aberrant lashes,  o Watery eyes due to fibrosis of the lacrimal puncta. Dry  eyes may also occur as a result of fibrosis of lacrimal  gland ductules and conjunctival metaplasia with loss of  goblet cells.   Skin biopsy may help to establish the diagnosis but is rarely   • Symptoms. Flu-like symptoms, which can be severe, may  last up to 14 days before the appearance of lesions. In many  cases the patient is very ill and hospitalization is required.  Symptoms of systemic mucosal involvement include nasal  pain and discharge, pain on micturition, diarrhoea, cough,  shortness of breath, and pain on eating and drinking.   o Mucosal involvement is characterized by blistering and  haemorrhagic crusting of the lips (Fig. 5.24A). The  blisters may also involve the tongue, oropharynx, nasal  mucosa and occasionally the genitalia.   O Small purpuric, vesicular, haemorrhagic or necrotic  skin lesions involving the extremities, face and trunk    (Fig. 5.24B). These are usually transient but may be  widespread. Healing usually occurs within 1-4 weeks,  leaving a pigmented scar.   o Widespread sloughing of the epidermis is uncommon,  o ‘Target’ lesions showing the classic three zones are now  viewed as characteristic of erythema multiforme rather  than SJS/TEN.   • Removal of the precipitant if possible, such as  discontinuation of drugs and treatment of suspected  infection.   • General supportive measures such as maintenance of  adequate hydration, electrolyte balance and nutrition  (especially protein replacement) are critical. Management in  a specialist burns unit should reduce the chance of infection  when the extent of skin involvement is substantial.   • Systemic steroids remain controversial. There are reports of  increased mortality in older papers, but later research has  raised the possibility that early short-term high-dose  intravenous treatment may improve outcomes.   • Other immunosuppressants including ciclosporin,  azathioprine, cyclophosphamide and intravenous  immunoglobulin may be considered in selected cases, but  are controversial and controlled trials are lacking.   • Systemic antibiotics may be given as prophylaxis against  skin or other systemic infection, avoiding those known to be  at higher risk of precipitating SJS/TEN.   • Acute disease. Daily review is advisable initially in most  patients to check the corneas and exclude symblepharon  formation.   o Topical lubricants are used as frequently as necessary, e.g.  hypromellose 0.3% preservative-free up to hourly,  high-viscosity ointment during sleep,  o Prevention of corneal exposure, e.g. moisture chambers,  gel pads if mechanically ventilated,  o Topical steroids may be used for iritis and for   conjunctival inflammation, though a benefit for the latter  has not been demonstrated conclusively,  o Topical cycloplegia (e.g. atropine 1% once or twice daily)  may improve comfort.   o Lysis of developing symblephara with a sterile glass rod  or damp cotton bud.   o A scleral ring, consisting of a large haptic lens, may help  to prevent symblepharon formation (Fig. 5.25).  o Pseudomembrane/membrane peeling can be considered,  although the benefit is unproven,  o Treatment of acute corneal problems such as bacterial  keratitis; the use of prophylactic topical antibiotics is  common, but as there may be a propensity to adverse  drug reactions a decision should be made on a case basis,  o Conjunctival swabs should be considered for prophylactic  culture.   Fig. 5.23 Ocular features of Stevens-Johnson syndrome. (A) Haemorrhagic lid crusting; (B) severe acute conjunctivitis;  (C) pseudomembrane; (D) conjunctival scarring; (E) keratinization with severe lid margin involvement; (F) corneal  keratinization   (Courtesy of R Bates - fig. A; S Tuft - figs D, E and F)   Fig. 5.24 Systemic features in Stevens-Johnson syndrome.  (A) Haemorrhagic lip crusting; (B) extensive purpuric  lesions   o IOP monitoring may be prudent, using portable  tonometry if necessary.   o Bandage contact lenses (typically gas permeable scleral  lenses) to maintain surface moisture, protect the cornea  from aberrant lashes and address irregular astigmatism.   o Mucous membrane grafting (e.g. buccal mucosa  autograft) for forniceal reconstruction.   keratectomy for keratinization, lamellar corneal grafting  for superficial scarring (preferred to penetrating  keratoplasty), amniotic membrane grafting, limbal stem  cell transplantation, and keratoprosthesis implantation in  end-stage disease.   Superior limbic keratoconjunctivitis (SLK) is a relatively uncom¬  mon chronic disease of the superior limbus and the superior  bulbar and tarsal conjunctiva. It affects one or both eyes of middle-  aged women, approximately 50% of whom have abnormal thyroid  function (usually hyperthyroidism); approximately 3% of patients  with thyroid eye disease have SLK. The condition is probably  under-diagnosed because symptoms are typically more severe  than signs. The course can be prolonged over years although  remission eventually occurs spontaneously. There are similarities  to mechanically induced papillary conjunctivitis, and a compara¬  ble clinical picture has been described with contact lens wear and  following upper lid surgery or trauma. The condition is believed  to be the result of blink-related trauma between the upper lid and  the superior bulbar conjunctiva, precipitated in many cases by tear  him insufficiency and an excess of lax conjunctival tissue. With  increased conjunctival movement there is mechanical damage to  the tarsal and bulbar conjunctival surfaces, the resultant inflam¬  matory response leading to increasing conjunctival oedema and  redundancy, with the creation of a self-perpetuating cycle. It may  be analogous to conjunctivochalasis affecting the lower bulbar  conjunctiva (see Ch. 2).   Enquiry should be made about contact lens wear, and previous  eyelid surgery or trauma.   • Symptoms include a foreign body sensation, burning, mild  photophobia, mucoid discharge and frequent blinking, and  are often intermittent.   Fig. 5.25 Scleral ring used to prevent symblepharon  formation in Steve ns-J oh nson syndrome   o Papillary hypertrophy of the superior tarsal plate, often  having a diffuse velvety appearance (Fig. 5.26A).   o Hyperaemia of a radial band of the superior bulbar  conjunctiva (Fig. 5.26B) that stains with rose Bengal and  may be best seen macroscopically.   O Limbal papillary hypertrophy (also Fig. 5.26B); limbal  palisades may be lost superiorly.   o Light downward pressure on the upper lid results in a  fold of redundant conjunctiva crossing the upper limbus  (Fig. 5.26C).   o Superior punctate corneal epithelial erosions are common  and are often separated from the limbus by a zone of  normal epithelium.   o Superior filamentary keratitis (Fig. 5.26D) develops in  about one-third of cases.   o Mild superior pannus resembling arcus senilis may be  seen in long-standing disease.   o Thyroid function testing should be performed if the  patient is not known to have thyroid disease,  o Biopsy or impression cytology may reveal keratinization  of the superior bulbar conjunctiva.   o Lubricants (preservative-free may be preferred) to reduce  friction between the tarsal and bulbar conjunctiva should  be used regularly and frequently,  o Acetylcysteine 5% or 10% four times daily to break down  filaments and provide lubrication,  o Mast cell stabilizers and steroids to address any   inflammatory component; steroids may be best used in  short intensive courses with rapid tapering, and should  be reserved for severe cases,  o Promising results have been reported with topical  rebamipide.   o Ciclosporin 0.05% twice daily as primary or adjunctive  therapy, particularly in the presence of coexisting  keratoconjunctivitis sicca.   Fig. 5.26 Superior limbic keratoconjunctivitis. (A) Diffuse velvety papillary hypertrophy; (B) hyperaemic band of superior bulbar  conjunctiva with limbal papillae, stained with rose Bengal; (C) fold of redundant conjunctiva; (D) superior corneal filaments    o Retinoic acid to retard keratinization.  o Autologous serum 20% drops can be beneficial but may  require instillation up to 10 times a day.   • Soft contact lenses, which intervene between the lid  and the superior conjunctiva, are effective in some cases.  Interestingly, a unilateral lens may provide bilateral  relief.   • Supratarsal steroid injection. 0.1 ml of triamcinolone  40 mg/ml may break the inflammatory cycle.   • Resection of the superior limbal conjunctiva, either in a  zone extending 2 mm from the superior limbus or of the  area staining with rose Bengal, is often effective in resistant  disease. Lax conjunctiva is removed, with regrowth tending  to be firmly anchored. There is no consensus as to whether  underlying Tenon capsule should be excised.   • Conjunctival ablation by applying silver nitrate 0.5% (not  cautery sticks) or thermocautery to the affected area.   Ligneous conjunctivitis is a very rare potentially sight- and even  life-threatening disorder characterized by recurrent, often bilateral  fibrin-rich pseudomembranous lesions of wood-like consistency  that develop mainly on the tarsal conjunctiva. It is generally a  systemic condition and may involve the periodontal tissue, the  upper and lower respiratory tract, kidneys, middle ear and female  genitalia; death can occasionally occur from pulmonary involve¬  ment. It is thought that in susceptible patients patterns of damage  repair are abnormal, notably a failure of normal clearance of prod¬  ucts of the acute stages of the healing process. This is manifested  predominantly in mucosal tissue. A deficiency in plasmin-mediated  fibrinolysis may be a key common factor in many patients.  Episodes may be triggered by relatively minor trauma, or by sys¬  temic events such as fever and antifibrinolytic therapy.   • Presentation is with nonspecific conjunctivitis, usually in  childhood (median age 5 years), although onset may be at  any age. A conjunctival lesion is commonly noted by  parents.   o Gradually enlarging red-white lobular conjunctival  masses (Fig. 5.27A and B); may be covered by a thick  yellow-white mucoid discharge.   • Histopathology shows amorphous subepithelial deposits of  eosinophilic material consisting predominantly of fibrin   Treatment tends to be unsatisfactory and spontaneous resolution  is rare. It is important to discontinue any antifibrinolytic drugs.   steroids are commenced immediately and continued until  the wound has re-epithelialized, with subsequent tapering  over several weeks until all signs of inflammation have  disappeared.   o Recurrence may be retarded by long-term ciclosporin and  steroid instillation.   o Prophylactic heparin treatment may be of benefit prior to  ocular surgery in at-risk patients.   Parinaud oculoglandular syndrome is a rare condition consisting  of chronic low-grade fever, unilateral granulomatous conjunctivi¬  tis (Fig. 5.28) with surrounding follicles, and ipsilateral regional  (preauricular) lymphadenopathy. It is virtually synonymous with  cat scratch disease (caused by Bartonella henselae - see Ch. 11),  although several other causes have been implicated, including  tularaemia, insect hairs (ophthalmia nodosum), Treponema pal¬  lidum , sporotrichosis, tuberculosis, and acute C. trachomatis  infection.   Self-injury (factitious keratoconjunctivitis) is most often inten¬  tional, but can also occur inadvertently, as in mucus fishing syn¬  drome and removal of contact lenses. Damage may be the result  of either mechanical trauma or of the instillation of irritant but  readily accessible household substances, such as soap.  Occasionally over-instillation of prescribed ocular medication is  responsible.   • Symptoms. Reported symptoms may seem disproportionate  to signs; the patient may have sought multiple medical  opinions over an extended period, often from a range of  specialists for different complaints.   O Inferior conjunctival injection and staining with rose  Bengal (Fig. 5.29), with quiet superior bulbar conjunctiva,  o Linear corneal abrasions, persistent epithelial defects and  occasionally focal corneal perforation.   Fig. 5.27 Ligneous conjunctivitis. (A) and (B) Multiple ligneous lesions; (C) histology shows eosinophilic fibrinous coagulum on  the conjunctival surface; (D) lesion removal   (Courtesy of JH Krachmer ; MJ Mannis and EJ Holland, from Cornea, Mosby 2005 - fig. B; J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-  Heinemann 2001 - fig. C; J Dart - fig. D)   Fig. 5.28 Granulomatous conjunctivitis in Parinaud syndrome Fig. 5.29 Inferior conjunctival injection and staining with rose   A pinguecula (plural pingueculae) is an innocuous but extremely  common asymptomatic elastotic degeneration of the conjunctival  stroma. A yellow-white mound or aggregation of smaller mounds  is seen on the bulbar conjunctiva adjacent to the limbus (Fig.  5.30A). It is more frequently located at the nasal than the temporal  limbus, but is frequently present at both. Calcification (Fig. 5.30B)  is occasionally present. The cause is believed to be actinic damage,  similar to the aetiology of pterygium (see below), which pinguec¬  ula resembles histologically; the distinction is that the limbal  barrier to extension has remained intact with a pinguecula, though  transformation can occur. Occasionally a pingueculum may  become acutely inflamed (pingueculitis - Fig. 5.30C), often if the  lesion is prominent or overlying calcification leads to epithelial  breakdown.   Treatment is usually unnecessary because growth is absent or very  slow.   • Pingueculitis can be treated with lubrication if mild or with  a short course of topical steroid.   • Excision may be indicated for cosmetic reasons or for  significant irritation; in contrast to pterygium (see next), the  recurrence rate is very low and simple excision is usually  adequate.   • Thermal laser ablation can be effective; gentian violet  marking may be necessary to ensure adequate absorption in  lighter-skinned individuals.   A pterygium (plural pterygia) is a triangular fibrovascular subepi-  thelial ingrowth of degenerative bulbar conjunctival tissue over  the limbus onto the cornea. It typically develops in patients who  have been living in hot climates and, as with pinguecula, may  represent a response to ultraviolet exposure and to other factors    such as chronic surface dryness. A pterygium is histologically  similar to a pinguecula and shows elastotic degenerative changes  in vascularized subepithelial stromal collagen (Fig. 5.31A). In con¬  trast to pingueculae, pterygia encroach onto the cornea, invading  the Bowman layer. Pseudopterygium appears similar clinically but  is caused by a band of conjunctiva adhering to an area of compro¬  mised cornea at its apex. It forms as a response to an acute    Fig. 5.31 Pterygium. (A) Histology shows collagenous  degenerative changes in vascularized subepithelial stroma;  (B) pterygium showing cap, head and body; (C) Stocker line;   • Symptoms. Patients who present with a history of recent  enlargement are more likely to require early excision for  subsequent aggressive growth. Aggressive growth or an  atypical appearance should prompt excision biopsy.   o Most small lesions are asymptomatic,  o Irritation and grittiness are caused by a dellen - localized  drying - effect at the advancing edge due to interference  with the precorneal tear film (more likely if the head of  the pterygium is especially elevated),  o Patients who wear contact lenses may develop symptoms  of irritation at an earlier stage due to edge lift,  o Lesions may interfere with vision by obscuring the visual  axis or inducing astigmatism,  o There may be intermittent inflammation similar to  pingueculitis.   o Cosmesis may be a significant problem,  o Extensive lesions, particularly if recurrent, may be   associated with subconjunctival fibrosis extending to the  fornices that may cause restricted ocular excursion,  o If pseudopterygium is suspected, there may be a history  of a causative episode.   o A pterygium is made up of three parts: a ‘cap’ (an  avascular halo-like zone at the advancing edge), a head  and a body (Fig. 5.31B).   o Linear epithelial iron deposition (Stocker line) may be  seen in the corneal epithelium anterior to the head of the  pterygium (Fig. 5.31C).   o Fuchs islets (Fig. 5.31D) are small discrete whitish flecks  consisting of clusters of pterygial epithelial cells often  present at the advancing edge.   o A pseudopterygium (Fig. 5.31E) is classically distinguished  by both location away from the horizontal (though this  may also be seen with true pterygia) and firm attachment  to the cornea only at its apex (head).   • Medical treatment of symptomatic patients is as for  pinguecula. The patient may be advised to wear sunglasses  to reduce ultraviolet exposure in order to decrease the  growth stimulus.   • Surgery. Simple excision (‘bare sclera’ technique) is  associated with a high rate of recurrence (around 80%),  often with more aggressive behaviour than the original  lesion.   conjunctival patch is usually harvested from the superior  or superotemporal paralimbal region (Fig. 5.32B) the site  generally heals rapidly, even without suturing. Amniotic  membrane patch grafting is an alternative. Both   Fig. 5.32 Surgical treatment of pterygium. (A) Excision site  one week postoperatively showing sutured conjunctival  autograft; (B) autograft donor site at superior limbus    conjunctival grafts and amniotic membranes can be  secured with tissue glue rather than sutured, shortening  operating time and reducing postoperative irritation.   O Adjunctive treatment with mitomycin C or beta-  irradiation are sometimes used in place of patching  techniques.   Concretions are extremely common and are usually associated  with ageing, although they can also form in patients with chronic  conjunctival inflammation such as trachoma. They appear as  multiple tiny cysts containing yellowish-white deposits of epithe¬  lial debris including keratin, commonly located subepithelially in  the inferior tarsal and forniceal conjunctiva (Fig. 5.33A). They can  become calcified and, particularly if large, may erode the overlying  epithelium (Fig. 5.33B) and cause marked irritation. Treatment if  symptomatic involves removal at the slit lamp with a needle under  topical anaesthesia.   Fig. 5.33 (A) Multiple small concretions; (B) large concretion  eroding through the conjunctival surface   Conjunctivochalasis usually appears as a fold of redundant con¬  junctiva interposed between the globe and lower eyelid, protrud¬  ing over the lid margin (Fig. 5.34). It is probably a normal ageing  change that may be exacerbated by inflammation and mechanical  stress related to dry eye and lid margin disease. Symptoms include  watering of the eye due to obstruction of the inferior punctum and  interference with the marginal tear meniscus. Treatment consists  of topical lubricants and treatment of any blepharitis. A short    course of topical steroids or other anti-inflammatory agent may  be helpful. Conjunctival resection can be performed in severe  cases (see also Ch. 2).   Conjunctival retention cysts are thin-walled lesions on the bulbar  conjunctiva containing clear (Fig. 5.35) or occasionally turbid  fluid. They do not usually cause discomfort but may be a mild  cosmetic blemish. Histology shows a fluid-filled internal cavity  lined by a double epithelial layer. Treatment, if required, is initially  by simple puncture with a needle under topical anaesthesia, but  recurrence is common. Bleeding should be encouraged within the  ruptured cyst as it may promote adhesion of the walls and reduce  the chance of recurrence. Cyst wall excision under topical anaes¬  thesia can be carried out for recurrences. The differential diagnosis  includes secondary inclusion cysts following conjunctival surgery,  and lymphangiectasia. The latter is characterized by strings of  cystic or sausage-shaped clear-walled channels, which may become  filled with blood (haemorrhagic lymphangiectasia - Fig. 5.36).    Subconjunctival haemorrhage (Fig. 5.37) is a very common phe¬  nomenon that may result from surgery, conjunctivitis and trauma  (from minor unnoticed to severe skull base), but is often idio¬  pathic and apparently spontaneous, particularly in older patients.  The bleed is usually asymptomatic until noticed by the patient or  others; a momentary sharp pain or a snapping or popping sensa¬  tion is sometimes felt. Coughing, sneezing and vomiting are  common precipitants. In younger people contact lens wear is a  common association, and in older individuals systemic vascular  disease is prevalent, especially hypertension, and blood pressure  should be checked. A local ocular cause should be ruled out by slit  lamp examination. Bleeding diatheses are a very rare association,  but vitamin C deficiency and abusive trauma should always be  considered in infants. The vision is usually unaffected unless a  substantially elevated haemorrhage leads to a large localized  corneal wetting deficit (dellen), which is often uncomfortable. A  large bleed can track into the eyelids. Spontaneous resolution over  a week or two is typical, but two or three narrowly spaced episodes  are not uncommon.   Anatomy and physiology 168  Signs of corneal disease 169  Documentation of clinical signs 172  Specular microscopy 172  Corneal topography 173  Principles of treatment 173   Introduction 183  Epithelial keratitis 184  Disciform keratitis 186  Necrotizing stromal keratitis 187  Neurotrophic ulceration 188  Iridocyclitis 188  Other considerations 188   Epithelial dystrophies 216  Bowman layer/anterior stromal  dystrophies 217  Stromal dystrophies 217  Descemet membrane and endothelial  dystrophies 223   Microcornea 233  Microphthalmos 235  Anophthalmos 235  Nanophthalmos 235  Megalocornea 235  Sclerocornea 237  Cornea plana 237  Keratectasia 237  Posterior keratoconus 237   The cornea is a complex structure which, as well as having a pro¬  tective role, is responsible for about three-quarters of the optical  power of the eye. The normal cornea is free of blood vessels;  nutrients are supplied and metabolic products removed mainly via  the aqueous humour posteriorly and the tears anteriorly. The  cornea is the most densely innervated tissue in the body, and  conditions such as abrasions and bullous keratopathy are associ¬  ated with marked pain, photophobia and reflex lacrimation; a  subepithelial and a deeper stromal nerve plexus are both supplied  by the first division of the trigeminal nerve.   The average corneal diameter is 11.5 mm vertically and 12 mm  horizontally. It is 540 pm thick centrally on average, and thicker  towards the periphery. Central corneal thickness varies between  individuals and is a key determinant of the intraocular pressure  (IOP) measured with conventional techniques.   • The epithelium is stratified squamous and non-keratinized,  and is composed of:   o A single layer of columnar basal cells attached by  hemidesmosomes to an underlying basement  membrane.   o Two to three strata of ‘wing’ cells,  o Two layers of squamous surface cells,  o The surface area of the outermost cells is increased by  microplicae and microvilli that facilitate the attachment  of the tear film and mucin. After a lifespan of a few days  superficial cells are shed into the tear film,  o Corneal stem cells are located at the corneoscleral limbus,  possibly in the palisades of Vogt. Deficiency may result in  chronic epithelial defects and ‘conjunctivalization’  (epithelial instability, vascularization and the appearance  of goblet cells). They are thought to be critical in the  maintenance of a physiological barrier, preventing  conjunctival tissue from growing onto the cornea (e.g.  pterygium). Deficiency may be addressed by stem cell  auto- or allotransplantation.   • The Bowman layer is the acellular superficial layer of the  stroma, and is formed from collagen fibres.   • The stroma makes up 90% of corneal thickness. It is  arranged in regularly orientated layers of collagen fibrils  whose spacing is maintained by proteoglycan ground  substance (chondroitin sulphate and keratan sulphate) with  interspersed modified fibroblasts (keratocytes). Maintenance   of the regular arrangement and spacing of the collagen is  critical to optical clarity. The stroma can scar, but cannot  regenerate following damage.   • Descemet membrane is a discrete sheet composed of a fine  latticework of collagen fibrils that are distinct from the  collagen of the stroma. The membrane consists of an  anterior banded zone that is deposited in utero and a  posterior non-banded zone laid down throughout life by the  endothelium, for which it serves as a modified basement  membrane. It has regenerative potential.   • The endothelium consists of a monolayer of polygonal cells.  Endothelial cells maintain corneal deturgescence throughout  life by pumping excess fluid out of the stroma. The young  adult cell density is about 3000 cells/mm 2 . The number of  cells decreases at about 0.6% per year and neighbouring cells  enlarge to fill the space; the cells cannot regenerate. At a  density of about 500 cells/mm 2 corneal oedema develops and  transparency is impaired.   • The existence of a sixth corneal layer between the stroma  and Descemet membrane has recently been proposed,  though some authorities believe this to be a previously  described continuation of the posterior stroma.   • Punctate epithelial erosions (PEE), tiny epithelial defects  that stain with fluorescein (Figs 6.2A and B) and rose  Bengal, are generally an early sign of epithelial compromise.  Causes include a variety of stimuli; the location of the  lesions may give an indication of aetiology:  o Superior - vernal disease, chlamydial conjunctivitis,  superior limbic keratoconjunctivitis, floppy eyelid  syndrome and mechanically induced keratoconjunctivitis,  o Interpalpebral - dry eye (can also be inferior), reduced  corneal sensation and ultraviolet keratopathy,  o Inferior - chronic blepharitis, lagophthalmos, eye drop  toxicity, self-induced, aberrant eyelashes and entropion,  o Diffuse - some cases of viral and bacterial conjunctivitis,  and toxicity to drops,  o Central - prolonged contact lens wear.    Punctate epithelial keratitis (PEK) appears as granular,  opalescent, swollen epithelial cells, with focal intraepithelial  infiltrates (Fig. 6.2C). They are visible unstained but stain  well with rose Bengal and variably with fluorescein. Causes  include:   contagiosum, early herpes simplex and herpes zoster,  microsporidial and systemic viral infections (e.g. measles,  varicella, rubella).   Subepithelial infiltrates. Tiny subsurface foci of non¬  staining inflammatory infiltrates. Causes include severe or  prolonged adenoviral keratoconjunctivitis, herpes zoster  keratitis, adult inclusion conjunctivitis, marginal keratitis,  rosacea and Thygeson superficial punctate keratitis.  Superficial punctate keratitis is a non-specific term  describing any corneal epithelial disturbance of dot-like  morphology.   Fig. 6.2 Superficial corneal lesions. (A) Punctate epithelial erosions stained with fluorescein in dry eye; (B) high-magnification  view of punctate epithelial erosions; (C) punctate epithelial keratitis; (D) filaments stained with rose Bengal;    Fig. 6.2, Continued (E) loss of lustre in mild corneal oedema; (F) corneal oedema with bullae; (G) superficial vascularization;  (H) pannus    • Filaments. Strands of mucus admixed with epithelium,  attached at one end to the corneal surface, that stain well  with rose Bengal (Fig. 6.2D). The unattached end moves  with each blink. Grey subepithelial opacities may be seen at  the site of attachment. Dry eye is by far the most common  cause; others include superior limbic keratoconjunctivitis,  neurotrophic keratopathy, long-term ocular patching and  essential blepharospasm.   • Epithelial oedema. Subtle oedema may manifest with loss of  normal corneal lustre (Fig. 6.2E), but more commonly,  abundant tiny epithelial vesicles are seen; bullae form in  moderate-severe cases (Fig. 6.2F). The cause is endothelial  decompensation, including that due to severe acute elevation  oflOP.   • Superficial neovascularization (Fig. 6.2G) is a feature of  chronic ocular surface irritation or hypoxia, as in contact  lens wear.   • Infiltrates are yellow- or grey-white opacities located initially  within the anterior stroma (Fig. 6.3A), usually associated with  limbal or conjunctival hyperaemia. They are stromal foci of  acute inflammation composed of inflammatory cells, cellular  and extracellular debris including necrosis. The key  distinction is between sterile and infective lesions (Table 6.1);  ‘PEDAL’ mnemonic: Pain, Epithelial defects, Discharge,  Anterior chamber reaction, Location. Suppurative keratitis is  caused by active infection with bacteria, fungi, protozoa and  occasionally viruses. Non-infectious ‘sterile keratitis’ is due to  an immune hypersensitivity response to antigen as in  marginal keratitis and with contact lens wear.    Fig. 6.3 Deeper corneal lesions. (A) Infiltration; (B) ulceration; (C) lipid deposition with vascularization; (D) folds in Descemet  membrane; (E) descemetocoele; (F) traumatic breaks in Descemet membrane   (Courtesy of C Barry - figs C-D; R Curtis - fig. F)    • Ulceration refers to tissue excavation associated with an  epithelial defect (Fig. 6.3B), usually with infiltration and  necrosis.   • Vascularization occurs in response to a wide variety of  stimuli. Venous channels are easily seen, whereas arterial  feeding vessels are smaller and require higher magnification.  Non-perfused deep vessels appear as ‘ghost vessels’, best  detected by retroillumination.   • Lipid deposition (Fig. 6.3C) may follow chronic  inflammation with leakage from corneal new vessels.   • Folds in Descemet membrane, also known as striate  keratopathy (Fig. 6.3D), may result from corneal oedema  exceeding the capacity of the endothelium to maintain  normal turgescence. Causes include inflammation, trauma  (including surgery) and ocular hypotony.   • Descemetocoele (US spelling - descemetocele) is a bubble¬  like herniation of Descemet membrane into the cornea (Fig.  6.3E), plugging a defect that would otherwise be full-thickness.   • Breaks in Descemet membrane (Fig. 6.3F) may be due to  corneal enlargement (Haab striae in infantile glaucoma) or  deformation such as keratoconus and birth trauma. Acute  influx of aqueous into the corneal stroma (acute hydrops)  can occur.   • The Seidel test demonstrates aqueous leakage. A drop of 1%  or 2% fluorescein is applied and the slit lamp with cobalt  blue filter is used to detect the change from dark orange to  bright yellow-green occurring with localized dilution at a  site of leakage.   Clinical signs should be illustrated with a colour-coded labelled  diagram; including lesion dimensions is particularly useful to  facilitate monitoring (Fig. 6.4). Slit lamp photography is an  increasingly used supplement or alternative, but must be of high  quality.   • Opacities such as scars and degenerations are drawn in  black.   • Epithelial oedema is represented by fine blue circles, stromal  oedema as blue shading and folds in Descemet membrane as  wavy blue lines.   • Blood vessels are added in red. Superficial vessels are wavy  lines that begin outside the limbus and deep vessels are  straight lines that begin at the limbus.   • Pigmented lesions such as iron lines and Krukenberg  spindles are shown in brown.   Specular microscopy is the study of corneal layers under very high  magnification (100 times greater than slit lamp biomicroscopy). It  is mainly used to assess the endothelium, which can be analysed  for cellular size, shape, density and distribution. The healthy  endothelial cell is a regular hexagon (Fig. 6.5A) and the normal  cell density in a young adult is about 3000 cells/mm 2 .   • Physics. When a light beam of the specular  photomicroscope passes through the cornea it encounters a  series of interfaces between optically distinct regions. Some  light is reflected specularly (i.e. like a mirror) back towards  the photomicroscope and forms an image that can be  photographed and analysed.   o Evaluation of the functional reserve of the corneal  endothelium prior to intraocular surgery is the most  common indication. A clear cornea with normal  thickness on pachymetry is not necessarily associated  with normal endothelial morphology or cell density.   Fig. 6.5 Specular micrograph. (A) Normal corneal  endothelium; (B) cornea guttata with marked loss of  endothelial mosaic   (Courtesy of T Casey and K Sharif\ from A Colour Atlas of Corneal  Dystrophies and Degenerations, Wolfe 1991 - fig. B)    Corneal oedema is considerably more likely to occur with  a cell density below 700 cells/mm 2 but unlikely above  1000 cells/mm 2 ,  o Donor cornea evaluation.   o To demonstrate pathology, particularly cornea guttata  (Fig. 6.5B), Descemet membrane irregularities and  posterior polymorphous dystrophy.   Corneal topography is used to image the cornea by projecting a  series of concentric rings of light on the anterior surface, constitut¬  ing a Placido image. The reflected light is analysed using computer    software to produce a detailed surface map. A major application  is the detection and management of corneal ectasia, principally  keratoconus; screening for corneal ectasia is especially important  prior to refractive surgery. It is used in the management of refrac¬  tive error, again in relation to refractive surgery as well as some¬  times for contact lens fitting, and can be used to measure corneal  thickness. Scheimpflug imaging is a newer technology that may  offer advantages in topographic imaging. Anterior segment optical  coherence tomography (OCT) and ultrasound biomicroscopy can  also be used to image the cornea.   • Antimicrobial agents should be started as soon as  preliminary investigations have been performed. The choice  of agent is determined by the likely aetiology according to  clinical findings. Broad-spectrum treatment is generally used  initially, with more selective agents introduced if necessary  when the results of investigation are available.   • Topical steroids should always be used with caution as they  may promote replication of some microorganisms, notably  herpes simplex virus and fungi, and retard reparative  processes such as re-epithelialization. Nevertheless, they are  vital in a range of conditions for the suppression of  destructive vision-compromising inflammation.   • Systemic immunosuppressive agents are useful in some  conditions, particularly autoimmune disease.   • Reduction of exposure to toxic medications and  preservatives wherever possible.   • Lubrication with artificial tears (unpreserved if possible)  and ointment. Taping the lids closed temporarily (Fig. 6.6A)  is often used as a nocturnal adjunct.   • Bandage soft contact lenses should be carefully supervised  to exclude superinfection, and duration kept to a minimum.  Indications include:   o Promotion of healing by mechanically protecting  regenerating corneal epithelium from the constant  rubbing of the eyelids.   o To improve comfort, particularly in the presence of a  large corneal abrasion,  o To seal a small perforation (Fig. 6.6B).   • Surgical eyelid closure is particularly useful in exposure and  neurotrophic keratopathies as well as in persistent epithelial  defects. Lid closure may be used as a conservative method to  heal an infective ulcer in selected cases, such as an eye with  no visual potential in a patient with severe dementia.   O Botulinum toxin injection into the levator muscle to  induce a temporary (2-3 months) ptosis.    Fig. 6.6 Methods of promoting epithelial healing. (A) Taping  the lids temporarily; (B) bandage contact lens in an eye with  a small perforation; (C) central tarsorrhaphy; (D) amniotic  membrane graft over a persistent epithelial defect;   (E) tissue glue under a bandage contact lens in an  eye with severe thinning   (Courtesy of S Tuft - figs A, B, D and E; S Chen - fig. C)    O Temporary or permanent lateral tarsorrhaphy or medial  canthoplasty, and occasionally central tarsorrhaphy (Fig.  6.6C).   • Conjunctival (Gundersen) flap will protect and tend to heal  a corneal epithelial defect and is particularly suitable for  chronic unilateral disease in which the prognosis for  restoration of useful vision is poor. Buccal mucous  membrane is an alternative.   • Amnio tic membrane patch grafting (Fig. 6.6D) for  persistent unresponsive epithelial defects.   • Tissue adhesive (cyanoacrylate glue) to seal small  perforations. The glue can be applied to one side of a  bespoke trimmed patch of sterile plastic drape, which is  pressed over the defect after the edges are dried with a  cellulose sponge. The patch remains in place to seal the  defect, and a bandage contact lens is inserted for comfort  and to aid retention of the patch (Fig. 6.6E).   • Limbal stem cell transplantation may be used if there is  stem cell deficiency as in chemical burns and cicatrizing  conjunctivitis. The source of the donor tissue may be the  fellow eye (autograft) in unilateral disease or a living or  cadaver donor (allograft) when both eyes are affected. A  newer technique involves the in vitro replication of the  patient’s own stem cells with subsequent re-implantation of  the enhanced cell population.   Bacterial keratitis usually develops only when ocular defences have  been compromised (see below). However, some bacteria, includ¬  ing Neisseria gonorrhoeae , Neisseria meningitidis , Corynebacterium  diphtheriae and Haemophilus influenzae are able to penetrate  a healthy corneal epithelium, usually in association with severe  conjunctivitis. It is important to remember that infections may  be polymicrobial, including bacterial and fungal co-infection.  Common pathogens include:   • Pseudomonas aeruginosa is a ubiquitous Gram-negative  bacillus (rod) commensal of the gastrointestinal tract. The  infection is typically aggressive and is responsible for over  60% of contact lens-related keratitis.   • Staphylococcus aureus is a common Gram-positive and  coagulase-positive commensal of the nares, skin and  conjunctiva. Keratitis tends to present with a focal and fairly  well-defined white or yellow-white infiltrate.   • Streptococci. S. pyogenes is a common Gram-positive  commensal of the throat and vagina. S. pneumoniae  (pneumococcus) is a Gram-positive commensal of the upper  respiratory tract. Infections with streptococci are often  aggressive.   • Contact lens wear, particularly if extended, is the most  important risk factor. Corneal epithelial compromise  secondary to hypoxia and minor trauma is thought to be  important, as is bacterial adherence to the lens surface.  Wearers of soft lenses are at higher risk than those of rigid  gas permeable and other types. Infection is more likely if  there is poor lens hygiene but it can also occur even with  apparently meticulous lens care, and with daily disposable  lenses.   • Trauma, including refractive surgery (particularly LASIK  - laser-assisted in situ keratomileusis), has been linked to  bacterial infection, including with atypical mycobacteria. In  developing countries agricultural injury is the major risk  factor, when fungal infection should be considered.   • Ocular surface disease such as herpetic keratitis, bullous  keratopathy, dry eye, chronic blepharitis, trichiasis and  entropion, exposure, severe allergic eye disease and corneal  anaesthesia.   • Other factors include local or systemic immunosuppression,  diabetes and vitamin A deficiency.   • Presentation is with pain, photophobia, blurred vision and  mucopurulent or purulent discharge.   o An epithelial defect with infiltrate involving a larger  area, and significant circumcorneal injection (Fig. 6.7A  and B).   o Stromal oedema, folds in Descemet membrane and  anterior uveitis, commonly with a hypopyon (Fig. 6.7C)  and posterior synechiae in moderate-severe keratitis.  Plaque-like keratic precipitates can form on the  endothelium contiguous with the affected stroma,  o Chemosis and eyelid swelling in moderate-severe cases,  o Severe ulceration may lead to descemetocoele formation  and perforation, particularly in Pseudomonas infection  (Fig. 6.7D).   o Endophthalmitis is rare in the absence of perforation,  o Improvement is usually heralded by a reduction in eyelid  oedema and chemosis, shrinking of the epithelial defect,  decreasing infiltrate density and a reduction in anterior  chamber signs.   • Reduced corneal sensation may suggest associated  neurotrophic keratopathy, particularly where there is no  other major risk factor. Sensation may also be reduced in  chronic surface disease, herpetic keratitis and long-term  contact lens wear.    Fig. 6.7 Bacterial keratitis. (A) Early ulcer; (B) large ulcer; (C) advanced disease with hypopyon; (D) perforation associated with  Pseudomonas infection   (Courtesy of C Barry - fig. B; S Tuft - fig. D)    • Differential diagnosis includes keratitis due to other  microorganisms (fungi, acanthamoeba, stromal herpes  simplex keratitis and mycobacteria), marginal keratitis, sterile  inflammatory corneal infiltrates associated with contact lens  wear, peripheral ulcerative keratitis and toxic keratitis.   • Corneal scraping. This may not be required for a small  infiltrate, particularly one without an epithelial defect and  away from the visual axis.   (preservatives may lower bacterial viability for culture);  one drop of proxymetacaine 0.5% is usually sufficient;  tetracaine may have a greater bacteriostatic effect,  o Scrapings are taken either with a disposable scalpel blade  (e.g. No. 11 or Bard Parker), the bent tip of a larger    diameter (e.g. 20- or 21-gauge) hypodermic needle, or a  sterile spatula (e.g. Kimura).   o The easiest way to ‘plate’ scrapings without breaking the  gel surface is with a spatula. If a fresh spatula is not  available for each sample a single instrument should be  flame-sterilized between scrapes (heat for 5 seconds, cool  for 20-30 seconds). Alternatively, a fresh scalpel blade or  needle can be used for each pass. Calcium alginate swabs  may also be satisfactory.   o Loose mucus and necrotic tissue should be removed from  the surface of the ulcer prior to scraping.   o The margins and base (except if very thin) of the lesion  are scraped (Fig. 6.8A).   o A thin smear is placed on one or two glass slides for  microscopy, including Gram stain (see below). A surface  is provided on one side of one end of the slide  (conventionally ‘up’) for pencil labelling. The sample is    Fig. 6.8 Bacteriology. (A) Corneal scraping; (B) culture media; (C) S. aureus grown on blood agar forming golden colonies with  a shiny surface; (D) N. gonorrhoeae grown on chocolate agar   (Courtesy of J Harry - fig. A; R Emond, P Welsby and H Rowland, from Colour Atlas of Infectious Diseases, Mosby 2003 - figs B-D)    allowed to dry in air at room temperature for several  minutes then placed in a slide carrier,  o Re-scraping is performed for each medium and samples  are plated onto culture media (Table 6.2), taking care not  to break the surface of the gel.  o Routinely, blood, chocolate and Sabouraud media (Fig.   6.8B-D) are used initially and the samples are placed in  an incubator until transported to the laboratory.  Refrigerated media should be gently warmed to room  temperature prior to sample application,  o A blade or needle can be placed directly into bottled  media such as brain-heart infusion (BHI). There is  evidence that a single scrape, sent in BHI to the  laboratory where it is homogenized and plated, provides  similar results to the traditional multi-scrape method,  o Scraping may be delayed without treatment for 12 hours  if antibiotics have previously been commenced.    • Conjunctival swabs may be worthwhile in addition to  corneal scraping, particularly in severe cases, as occasionally  an organism may be cultured when a corneal scrape is  negative. Cotton wool, calcium alginate and synthetic swabs  have all been found to have some bacteriostatic effect;  calcium alginate may be the best option.   • Contact lens cases, as well as bottles of solution and lenses  themselves, should be obtained when possible and sent to  the laboratory for culture. The case should not be cleaned by  the patient first!   o Differentiates bacterial species into ‘Gram-positive’ and  ‘Gram-negative’ based on the ability of the dye (crystal  violet) to penetrate the cell wall,  o Bacteria that take up crystal violet are Gram-positive  and those that allow the dye to wash off are  Gram-negative.   Blood agar in which the cells have been  lysed by heating. Does not contain  chocolate!   Developed during the First World War for the  growth of battlefield anaerobes    o Other stains, generally not requested at initial  investigation, are listed in Table 6.3.   • Culture and sensitivity reports should be obtained as soon  as possible. The type of bacteria alone will generally provide  an indication of the antibiotic category to be used. An  indication of resistance on standard sensitivity testing does  not necessarily extrapolate to topical antibiotic instillation,  where very high tissue levels can be achieved.    treatment. It should also be considered for aggressive  disease, particularly if involving an only eye.   • A clear plastic eye shield should be worn between eye drop  instillation if significant thinning (or perforation) is present.   infiltrates that are clinically sterile and may be treated by  lower-frequency topical antibiotic and/or steroid, and by  temporary cessation of contact lens wear,  o It is important to note that the causative organism cannot  be defined reliably from the ulcer’s appearance,  o Empirical broad-spectrum treatment is usually initiated  before microscopy results are available.   Topical therapy (Table 6.4) can achieve high tissue concentration  and initially should consist of broad-spectrum antibiotics that  cover most common pathogens. Initially instillation is at hourly  intervals day and night for 24-48 hours, and then is tapered  according to clinical progress.   • Antibiotic monotherapy has the major advantage over  duotherapy of lower surface toxicity, as well as greater  convenience.   o A commercially available fluoroquinolone is the usual  choice for empirical monotherapy and appears to be  about as effective as duotherapy.  o Ciprofloxacin or ofloxacin are used in countries where  widespread resistance to earlier-generation  fluoroquinolones has not been identified. Activity against  some Gram-positive organisms, particularly some  streptococci, may be limited.    o Resistance to fluoroquinolones has been reported in some  areas (e.g. Staphylococcus spp. in the USA and  Pseudomonas in India). Moxifloxacin, gatifloxacin and  besifloxacin are new generation fluoroquinolones that  largely address this, and also have better activity against  Gram-positive pathogens. Moxifloxacin has superior  ocular penetration. Novel drug preparations, with higher  concentrations or modified vehicles, have been  introduced to enhance antibacterial activity,  o Ciprofloxacin instillation is associated with white corneal  precipitates (Fig. 6.9) that may delay epithelial healing.   • Antibiotic duotherapy may be preferred as first-line empirical  treatment in aggressive disease or if microscopy suggests  streptococci or a specific microorganism that may be more  effectively treated by a tailored regimen (see Table 6.4).  o Empirical duotherapy usually involves a combination of  two fortified antibiotics, typically a cephalosporin and an  aminoglycoside, in order to cover common Gram¬  positive and Gram-negative pathogens,  o The antibiotics are not commercially available and must  be specially prepared (Table 6.5). A standard parenteral  or lyophilized antibiotic preparation is combined with a  compatible vehicle such that the antibiotic does not  precipitate. Optimally, constitution should take place in  the sterile preparation area of a pharmaceutical  dispensary.    o Disadvantages of fortified antibiotics include high cost,  limited availability, contamination risk, short shelf-life  and the need for refrigeration.   • Subconjunctival antibiotics are usually only indicated if  there is poor compliance with topical treatment.   • Mydriatics (cyclopentolate 1%, homatropine 2% or atropine  1%) are used to prevent the formation of posterior synechiae  and to reduce pain.   o Steroids reduce host inflammation, improve comfort, and  minimize corneal scarring. However, they promote  replication of some microorganisms, particularly fungi,  herpes simplex and mycobacteria and are contraindicated  if a fungal or mycobacterial agent is suspected (beware  prior refractive surgery and trauma involving vegetation).  By suppressing inflammation, they also retard the eye’s  response to bacteria and this can be clinically significant,  particularly if an antibiotic is of limited effect or  bacteriostatic rather than bactericidal,  o Evidence that they improve the final visual outcome is  mainly empirical, but the recent Steroids for Corneal  Ulcers Trial (SCUT) found no eventual benefit in most   500 mg parenteral antibiotic is diluted with  2.5 ml sterile water and added to 7.5 ml  of preservative-free artificial tears   2 ml parenteral antibiotic (40 mg/ml) is  added to 5 ml commercially available  gentamicin ophthalmic solution (0.3%)    cases, though severe cases (counting fingers vision or  large ulcers involving the central 4 mm of the cornea)  tended to do better; a positive culture result was an  inclusion criterion, and steroids were introduced after 48  hours of moxifloxacin.   o Epithelialization may be retarded by steroids and they  should be avoided if there is significant thinning or  delayed epithelial healing; corneal melting can  occasionally be precipitated or worsened.   o Many authorities do not commence topical steroids until  evidence of clinical improvement is seen with antibiotics  alone, typically 24-48 hours after starting treatment.  Others delay their use at least until the sensitivity of the  isolate to antibiotics has been demonstrated, or do not  use them at all.   O Regimens vary from minimal strength preparations at  low frequency to dexamethasone 0.1% every 2 hours; a    reviewed, including contact with the microbiology  laboratory to obtain the latest report.   • There is no need to change the initial therapy if this has  induced a favourable response, even if cultures show a  resistant organism.   • If there is still no improvement after a further 48 hours,  suspension of treatment should be considered for 24 hours  then re-scraping performed with inoculation on a broader  range of media (see Table 6.2) and additional staining  techniques requested (see Table 6.3). Consideration should  be given to the possibility of a non-bacterial causative  microorganism.   • If cultures remain negative, it may be necessary to perform a  corneal biopsy for histology and culture.   • Excisional keratoplasty, penetrating or deep lamellar, may be  considered in cases resistant to medical therapy, or for  incipient or actual perforation (see below).   o Early discontinuation may lead to a rebound recurrence  of sterile inflammation.   o The threshold for topical steroid use may be lower in  cases of corneal graft infection, as they may reduce the  risk of rejection.   Systemic antibiotics are not usually given, but may be appropriate  in the following circumstances:   • Potential for systemic involvement, when microbiological/  infectious disease specialist advice should optimally be  sought but should not delay treatment:   o N. meningitidis , in which early systemic prophylaxis may  be life-saving. Treatment is usually with intramuscular  benzylpenicillin, ceftriaxone or cefotaxime, or oral  ciprofloxacin.   o H. influenzae infection should be treated with oral  amoxicillin with clavulanic acid,  o N. gonorrhoeae requires a third-generation cephalosporin  such as ceftriaxone.   o Ciprofloxacin for its antibacterial activity,  o A tetracycline (e.g. doxycycline 100 mg twice daily) for its  anticollagenase effect.   It is important not to confuse ongoing failure of re-epithelialization  with continued infection. Drug toxicity, particularly following fre¬  quent instillation of fortified aminoglycosides, may give increasing  discomfort, redness and discharge despite the eradication of  infection.   • If no improvement is evident following 24-48 hours of  intensive treatment, the antibiotic regimen should be   A small perforation in which infection is controlled may be man¬  ageable with a bandage contact lens; tissue glue is often adequate  for slightly larger dehiscences. A penetrating keratoplasty or  corneal patch graft may be necessary for larger perforations, or in  those where infection is extensive or inadequately controlled.  Occlusive surface repair techniques may be appropriate in some  circumstances, such as an eye with no useful visual potential.   No clear protocol exists for the management of this rare complica¬  tion, but a similar approach to postoperative endophthalmitis  should be considered, whilst continuing specific management of  the corneal infection. Secondary sterile intraocular inflammation  should not be mistaken for intraocular infection.   • Keratoplasty (lamellar may be adequate) may be required for  residual dense corneal scarring.   • Rigid contact lenses may be required for irregular  astigmatism but are generally only introduced at least 3  months after re-epithelialization.   • Cataract surgery may be required because secondary lens  opacities are common following severe inflammation. Even  in the absence of severe corneal opacification, surgery may  be hampered by corneal haze, posterior synechiae and  zonular fragility.   Fungi are a group of microorganisms that have rigid walls and a  distinct nucleus with multiple chromosomes containing both   DNA and RNA. Fungal keratitis is rare in temperate countries but  is a major cause of visual loss in tropical and developing countries.  Though often evolving insidiously, fungal keratitis can elicit a  severe inflammatory response - corneal perforation is common,  and the outlook for vision is frequently poor. Two main types of  fungi cause keratitis:   • Yeasts (e.g. genus Candida ), ovoid unicellular organisms  that reproduce by budding, are responsible for most cases of  fungal keratitis in temperate climates.   • Filamentous fungi (e.g. genera Fusarium and Aspergillus ),  multicellular organisms that produce tubular projections  known as hyphae. They are the most common pathogens in  tropical climates, but are not uncommon in cooler regions;  the keratitis frequently follows an aggressive course.   Common predisposing factors include chronic ocular surface  disease, the long-term use of topical steroids (often in conjunction  with prior corneal transplantation), contact lens wear, systemic  immunosuppression and diabetes. Filamentary keratitis may be  associated with trauma, often relatively minor, involving plant  matter or gardening/agricultural tools.   The diagnosis is frequently delayed unless there is a high index of  suspicion, and often bacterial infection will initially have been  presumed. Clinical signs are not a definitive means of distinguish¬  ing bacterial and fungal corneal infection; signs such as satellite  infiltrates (see below) can be caused by other microorganisms.   • Symptoms. Gradual onset of pain, grittiness, photophobia,  blurred vision and watery or mucopurulent discharge.   O Grey or yellow-white stromal infiltrate with indistinct  fluffy margins (Fig. 6.10B).  o Progressive infiltration, often with satellite lesions  (Fig. 6.10C and D).   o Feathery branch-like extensions or a ring-shaped infiltrate  (Fig. 6.10E) may develop.   O Rapid progression with necrosis and thinning can occur,  o Penetration of an intact Descemet membrane may occur  and lead to endophthalmitis without evident perforation.   • An epithelial defect is not invariable and is sometimes small  when present.   • Other features include anterior uveitis, hypopyon,  endothelial plaque, raised IOP, scleritis and sterile or  infective endophthalmitis.   • Differential diagnosis includes bacterial, herpetic and  acanthamoebal keratitis. Bacterial infection may sometimes  present subacutely, particularly when atypical organisms are    responsible. It is important to beware of co-infection,  including with an additional fungal species.   o Potassium hydroxide (KOH) preparation with direct  microscopic evaluation is a rapid diagnostic tool that can  be highly sensitive.   o Gram and Giemsa staining are both about 50% sensitive,  o Other stains include periodic acid-Schiff, calcofluor white  and methenamine silver.   • Culture. Corneal scrapes should be plated on Sabouraud  dextrose agar, although most fungi will also grow on blood  agar or in enrichment media. It is important to obtain an  effective scrape from the ulcer base. Sensitivity testing for  antifungal agents can be performed in reference laboratories  but the relevance of these results to clinical effectiveness is  uncertain. If applicable, contact lenses and cases should be  sent for culture.   • Polymerase chain reaction (PCR) analysis of specimens is  rapid and highly sensitive (up to 90%) and may be the  current investigation of choice. Calcium-containing swabs  can inhibit polymerase activity and local collection protocols  should be ascertained prior to specimen collection.   • Corneal biopsy is indicated in suspected fungal keratitis in  the absence of clinical improvement after 3-4 days and if no  growth develops from scrapings after a week. A 2-3 mm  block should be taken, similar to scleral block excision  during trabeculectomy; filamentous fungi tend to proliferate  just anterior to Descemet membrane and a deep stromal  specimen may be required. The excised block is sent for  culture and histopathological analysis.   • Anterior chamber tap has been advocated in resistant cases  with endothelial exudate, because organisms may penetrate  the endothelium.   • Confocal microscopy frequently permits identification of  organisms in vivo , but is not widely available outside tertiary  centres.   • General measures are as for bacterial keratitis although  hospital admission is usually required.   • Removal of the epithelium over the lesion may enhance  penetration of antifungal agents. It may also be helpful to  regularly remove mucus and necrotic tissue with a spatula.   • Topical antifungals should initially be given hourly for 48  hours and then reduced as signs permit. Because most  antifungals are only fungistatic, treatment should be  continued for at least 12 weeks.   o Candida infection is treated with amphotericin B 0.15%  or econazole 1%; alternatives include natamycin 5%,  fluconazole 2%, clotrimazole 1% and voriconazole 1 or 2%.   (B) filamentous keratitis with fluffy edges - there is a large  epithelial defect, and folds in Descemet membrane; (C) and  (D) satellite lesions; (E) ring infiltrate, with satellite lesions  and a hypopyon   (Courtesy of S Tuft - figs B and E; R Fogla - fig. D)    o Filamentous infection is treated with natamycin 5% or  econazole 1%; alternatives are amphotericin B 0.15%,  miconazole 1% and voriconazole 1 or 2%.  o Several others are available.   A broad-spectrum antibiotic might also be considered to  address or prevent bacterial co-infection.    • Systemic antifungals may be given in severe cases, when  lesions are near the limbus, and for suspected  endophthalmitis. Options include voriconazole 400 mg twice  daily for one day then 200 mg twice daily, itraconazole   200 mg once daily, reduced to 100 mg once daily, or  fluconazole 200 mg twice daily.   • Tetracycline (e.g. doxycycline 100 mg twice daily) may be  given for its anticollagenase effect when there is significant  thinning.   • Perforation - actual or impending - is managed as for  bacterial keratitis.   • Therapeutic keratoplasty (penetrating or deep anterior  lamellar) is considered when medical therapy is ineffective  or following perforation.   • Anterior chamber washout with intracameral antifungal  injection may be considered for unresponsive cases in which  there is a stable corneal infiltrate but enlarging endothelial  exudation.   Microsporidia (phylum Microspora) are obligate intracellular  single-celled parasites previously thought to be protozoa but now  reclassified as fungi. They rarely cause disease in the immuno¬  competent and until the advent of acquired immunodeficiency  syndrome (AIDS) were rarely pathogenic for humans. The most  common general infection is enteritis and the most common  ocular manifestation is keratoconjunctivitis.   (Fig. 6.11B) may rarely affect immunocompetent patients,  o Sclerokeratitis and endophthalmitis are rare.   • Medical therapy of epithelial disease is with topical  fumagillin. Highly active antiretroviral therapy (HAART) for  associated AIDS may also help resolution. Stromal disease is  treated with a combination of topical fumagillin and oral  albendazole 400 mg once daily for 2 weeks, repeated 2 weeks  later with a second course. Patients should be closely  monitored for hepatic toxicity. Long-term fumagillin  treatment may be required and it is difficult to eradicate the  parasites in immunocompromised patients.   • Keratoplasty may be indicated although recurrence of  disease can occur in the graft periphery; cryotherapy to the  residual tissue may reduce this risk.   Herpetic eye disease is the most common infectious cause of  corneal blindness in developed countries. As many as 60% of   Fig. 6.11 Microsporidial keratitis. (A) Diffuse punctate  epithelial keratitis; (B) deep stromal infiltrates    corneal ulcers in developing countries may be the result of herpes  simplex virus and 10 million people worldwide may have herpetic  eye disease.   HSV is enveloped with a cuboidal capsule and has a linear double-  stranded DNA genome. The two subtypes are HSV-i and HSV-2 ,  and these reside in almost all neuronal ganglia. HSV-i causes  infection above the waist (principally the face, lips and eyes),  whereas HSV-2 causes venereally acquired infection (genital  herpes). Rarely HSV-2 may be transmitted to the eye through  infected secretions, either venereally or at birth (neonatal conjunc¬  tivitis). HSV transmission is facilitated in conditions of crowding  and poor hygiene.   Primary infection, without previous viral exposure, usually occurs  in childhood and is spread by droplet transmission, or less fre¬  quently by direct inoculation. Due to protection by maternal anti¬  bodies, it is uncommon during the first 6 months of life, though  occasionally severe neonatal systemic disease may occur in which  early diagnosis and intravenous antiviral treatment are critical to  reduce mortality and disability; the presence of maternal antibod¬  ies means that dendritic corneal ulcers may be seen. Most primary  infections with HSV are subclinical or cause only mild fever,  malaise and upper respiratory tract symptoms. Blepharitis and  follicular conjunctivitis may develop but are usually mild and self¬  limited. Treatment, if necessary, involves topical aciclovir oint¬  ment for the eye and/or cream for skin lesions, and occasionally  oral antivirals. There is unfortunately no evidence that antiviral  treatment at this stage reduces the likelihood of recurrent disease.   Recurrent disease (reactivation in the presence of cellular and  humoral immunity) occurs as follows:   • After primary infection the virus is carried to the sensory  ganglion for that dermatome (e.g. trigeminal ganglion)  where latent infection is established. Latent virus is  incorporated in host DNA and cannot be eradicated with  presently available treatment.   • Subclinical reactivation can periodically occur, during  which HSV is shed and patients are contagious.   • Clinical reactivation. A variety of stressors such as fever,  hormonal change, ultraviolet radiation, trauma, or  trigeminal injury may cause clinical reactivation, when the  virus replicates and is transported in the sensory axons to  the periphery.   • The pattern of disease depends on the site of reactivation,  which may be remote from the site of primary disease.  Hundreds of reactivations can occur during a lifetime.   • The rate of ocular recurrence after one episode is about  10% at 1 year and 50% at 10 years. The higher the number of  previous attacks the greater the risk of recurrence.   • Risk factors for severe disease, which may be frequently  recurrent, include atopic eye disease, childhood,  immunodeficiency or suppression, malnutrition, measles  and malaria. Inappropriate use of topical steroids may  enhance the development of geographic ulceration (see  below).   Epithelial (dendritic or geographic) keratitis is associated with  active virus replication.   o Swollen opaque epithelial cells arranged in a coarse  punctate or stellate (Fig. 6.12A) pattern.   O Central desquamation results in a linear-branching  (dendritic) ulcer (Fig. 6.12B), most frequent located  centrally; the branches of the ulcer have characteristic  terminal buds and its bed stains well with fluorescein,  o The virus-laden cells at the margin of the ulcer stain with  rose Bengal (Fig. 6.12C), and this may help distinction  from alternative diagnoses, particularly an atypical  recurrent corneal abrasion,  o Corneal sensation is reduced,  o Inadvertent topical steroid treatment may promote  progressive enlargement of the ulcer to a geographical or  ‘amoeboid’ configuration (Fig. 6.12D).  o Mild associated subepithelial haze is typical,  o Anterior chamber activity may be present, but is usually  mild.   o Follicular conjunctivitis may be associated; topical  antivirals can also cause this,  o Vesicular eyelid lesions may coincide with epithelial  ulceration.   o Elevated IOP is not uncommon (tonometry should be  performed on the unaffected eye first; a disposable prism  should be used, or a re-usable tonometer prism carefully  disinfected after use).   o Following healing, there may be persistent punctate  epithelial erosions and irregular epithelium (Fig. 6.12E)  which settle spontaneously and should not be mistaken  for persistent active infection. A whorled epithelial  appearance commonly results from assiduous, especially  prolonged, topical antiviral instillation,  o Mild subepithelial haze (Fig. 6.12F) may persist for weeks  after the epithelium heals; in some cases mild scarring  may develop, which tends to become more evident after  each recurrence and may eventually substantially threaten  vision.   • Investigation is generally unnecessary as the diagnosis is  principally clinical, but pre-treatment scrapings can be sent  in viral transport medium for culture. PCR and  immunocytochemistry are also available. Giemsa staining  shows multinucleated giant cells. HSV serological titres rise  only on primary infection, but can be used to confirm  previous viral exposure, usually in cases of stromal disease  when the diagnosis is in doubt.   • Differential diagnosis of dendritic ulceration includes  herpes zoster keratitis, healing corneal abrasion  (pseudodendrite), acanthamoeba keratitis, epithelial  rejection in a corneal graft, tyrosinaemia type 2, the  epithelial effects of soft contact lenses, and toxic keratopathy  secondary to topical medication.    Fig. 6.12 Epithelial herpes simplex keratitis. (A) Stellate lesions; (B) bed of a dendritic ulcer stained with fluorescein;   (C) margins of a dendritic ulcer stained with rose Bengal; (D) geographic ulcer; (E) persistent epithelial changes following  resolution of active infection; (F) residual subepithelial haze   (Courtesy of C Barry - fig. B; S Tuft - fig. C)   • Topical. The most frequently used drugs are aciclovir 3%  ointment and ganciclovir 0.15% gel, each administered five  times daily. Trifluridine is an alternative but requires  instillation up to nine times a day. The drugs are relatively  non-toxic, even when given for up to 60 days. They have  approximately equivalent effect, acting preferentially on  virus-laden epithelial cells, and penetrating effectively into  the stroma; 99% of ulcers heal within two weeks.   Idoxuridine and vidarabine are older drugs that are probably  less effective and more toxic.   • Debridement may be used for resistant cases. The corneal  surface is wiped with a sterile cellulose sponge or cotton-  tipped applicator (cotton bud). Epithelium should be  removed 2 mm beyond the edge of the ulcer, since  involvement extends beyond the visible dendrite. The  removal of the virus-containing cells protects adjacent  healthy epithelium from infection and eliminates the  antigenic stimulus to stromal inflammation. A topical  antiviral agent should be used in conjunction.   • Signs of treatment toxicity include superficial punctate  erosions, waves of whorled epithelium, follicular  conjunctivitis and, rarely, punctal occlusion. Absence of  epithelial whorling with a persistent epithelial lesion raises  the possibility of poor or non-compliance.   • Oral antiviral therapy (e.g. aciclovir 200-400 mg five times  a day for 5-10 days, famciclovir or valaciclovir) is indicated  in most immunodeficient patients, in children and patients  with marked ocular surface disease. It is an effective  alternative to topical treatment when the latter is poorly  tolerated, or in resistant cases. The newer oral agents may be  better tolerated than aciclovir, and require less frequent  dosing, but optimal regimens are not yet defined.   • Interferon monotherapy does not seem to be more effective  than antivirals, but the combination of a nucleoside antiviral  with either interferon or debridement seems to speed  healing.   • Skin lesions (see Ch. 1) may be treated with aciclovir cream  five times daily, as for cold sores, and if extensive an oral  antiviral may be given.   • Cycloplegia, e.g. homatropine 1% once or twice daily can be  given to improve comfort if necessary.   • IOP control. If glaucoma treatment is necessary,  prostaglandin derivatives should probably be avoided as they  may promote herpes virus activity and inflammation  generally.   • Topical steroids are not used unless significant disciform  keratitis is also present (see below).   • Slow healing or frequent recurrence may indicate the  presence of a resistant viral strain, and an alternative topical  agent or debridement may be tried. In especially refractory  cases, a combination of two topical agents with oral    valaciclovir or famciclovir may be effective. A significant  minority of resistant cases are due to varicella-zoster virus.   The aetiopathogenesis of disciform keratitis (endotheliitis) is con¬  troversial. It may be the result of active HSV infection of kerato-  cytes or endothelium, or a hypersensitivity reaction to viral antigen  in the cornea.   • Symptoms. Blurred vision of gradual onset, which may be  associated with haloes around lights. Discomfort and redness  are common, but tend to be milder than in purely epithelial  disease. A clear past history of epithelial ulceration is not  always present, and the possibility of a mimicking infection  such as acanthamoeba or fungal keratitis should be borne in  mind.   o A central zone of stromal oedema, often with overlying  epithelial oedema (Fig. 6.13A); occasionally the lesion is  eccentric.   o Folds in Descemet membrane in severe cases,  o A surrounding (Wessely) immune ring of deep stromal  haze (Fig. 6.13C) signifies deposition of viral antigen and  host antibody complexes,  o The IOP may be elevated.   o Reduced corneal sensation; this may aid in distinguishing  other forms of infection.   o Healed lesions often have a faint ring of stromal or  subepithelial opacification and thinning,  o Consecutive episodes may be associated with gradually  worsening subepithelial and/or stromal scarring and  superficial or deep vascularization (Fig. 6.13D).  o Mid-stromal scarring from disciform keratitis is a cause  of interstitial keratitis.   A broad approach to management is set out below, but in practice  regimens should be tailored individually. Careful monitoring and  adequate treatment, dependent on severity of inflammation, is  critical to minimize progression of scarring. Patients should be  cautioned to seek treatment at the first suggestion of recurrence,  though some authorities feel that minimal inflammation may not  warrant treatment or can be addressed with cycloplegia alone.   • Initial treatment is with topical steroids (prednisolone 1% or  dexamethasone 0.1%) with antiviral cover, both four times  daily. As improvement occurs, the frequency of  administration of both is reduced in parallel over not less  than 4 weeks. It is prudent to keep steroid intensity and  duration to the minimum required for effective control of  inflammation. IOP should be monitored. Cycloplegia can be  used to improve comfort if necessary, and some  practitioners recommend topical antibacterial prophylaxis.    Fig. 6.13 Disciform herpes simplex keratitis. (A) Epithelial and stromal oedema, with Descemet membrane folds;  (B) underlying keratic precipitates; (C) Wessely ring; (D) scarring from recurrent disease    • Subsequently prednisolone 0.5% once daily is usually a safe  dose at which to stop topical antiviral cover. Some patients  require a weaker steroid such as fluorometholone 0.1% or  loteprednol 0.2% on alternate days for many months.  Periodic attempts should be made to stop the steroid  altogether.   • With active epithelial ulceration it is reasonable to try to  keep the steroid intensity as low as possible for adequate  effect, with a more frequent antiviral regimen, e.g. initially  topical antiviral five times daily, with steroid two or three  times daily, titrated according to the signs of activity of both;  oral antiviral treatment may be helpful but its efficacy in this  situation has not been established.   • Oral steroids are sometimes used in severe stromal  inflammation as an adjunct, or to reduce steroid-induced  IOP elevation, and/or to avoid viral promotion in infectious  viral keratitis.   • Topical ciclosporin 0.05% may be useful, particularly in  the presence of epithelial ulceration and to facilitate  tapering of topical steroids such as in steroid-related IOP  elevation.    • Fine needle diathermy and laser techniques have been  reported as successfully addressing established corneal  neovascularization and improving vision.   This rare condition is thought to result from active viral replica¬  tion within the stroma, though immune-mediated inflammation  is likely to play a significant role. It may be difficult to distinguish  from severe disciform keratitis and there may be a spectrum of  disease, including overlap with neurotrophic keratopathy. As with  disciform keratitis, a similar clinical picture may be caused by  other infections.   O Stromal necrosis and melting, often with profound  interstitial opacification (Fig. 6.14).  o Anterior uveitis with keratic precipitates underlying the  area of active stromal infiltration,  o An epithelial defect may be present.   • Long-term oral aciclovir reduces the rate of recurrence of  epithelial and stromal keratitis by about 50% and is usually  tolerated well. Prophylaxis should be considered in patients  with frequent debilitating recurrences, particularly if bilateral  or involving an only eye. The standard daily dose of aciclovir  is 400 mg twice daily but if necessary a higher dose can be  tried, based on practice in the management of systemic  herpes simplex infection; continual use for many years has  been documented for systemic indications. The prophylactic  effect decreases or disappears when the drug is stopped.  Excretion is via the kidney, so renal function should be  checked periodically during long-term treatment.    • Treatment is broadly similar to that of aggressive disciform  keratitis, but oral antiviral supplementation, initially at the  upper end of the dose range, is commonly used. The  restoration of epithelial integrity is critical.   Neurotrophic keratopathy (see also separate topic) is caused by  failure of re-epithelialization resulting from corneal anaesthesia,  often exacerbated by other factors such as drug toxicity.   o A non-healing epithelial defect (Fig. 6.15), sometimes  after prolonged topical treatment, is an early sign,  o The stroma beneath the defect is grey and opaque and  may become thin.   • Treatment is that of persistent epithelial defects; topical  steroids to control any inflammatory component should be  kept to a minimum.   Herpetic iridocyclitis can occur without signs of active corneal  inflammation, and may be associated with direct viral activity. IOP  elevation is common and is often presumed to be due to trabecu¬  litis; steroid-induced IOP elevation may also be relatively common  in herpetic iritis. The aetiology may be missed unless there is a  history of previous herpes simplex keratitis; patchy iris atrophy  (Fig. 6.16A) may provide a clue; transillumination (Fig. 6.16B) may  demonstrate subtle lesions. Aqueous sampling for PCR may be  diagnostic. Treatment is primarily with topical steroids, but  adjunctive oral aciclovir may be given.    alternatives that are probably as effective as aciclovir, require  less frequent dosing and may be better tolerated.   • Topical. Oral prophylaxis tends to be preferred to long-term  topical administration. Epithelial toxicity may be  problematic, with mild blurring and persistent discomfort;  allergy and punctal stenosis are also potential problems.   • Secondary infection. Herpetic eye disease is a major  predisposing factor for microbial keratitis.   • Glaucoma secondary to inflammation or chronic steroid use  may progress undetected, particularly if there is a poor view  of the optic disc. Corneal thinning and distortion may give  rise to an inaccurate reading on applanation and alternative  forms of tonometry may be superior in these cases.   A trial of a rigid contact lens is often worthwhile prior to commit¬  ting to surgery. Recurrence of herpetic eye disease and rejection   • Topical antivirals given during a rejection episode may  reduce epithelial viral reactivation but toxicity may delay  re- epithelialization.   • Prophylactic oral aciclovir (400 mg twice daily) improves  graft survival and should be given to patients undergoing  penetrating keratoplasty for herpetic eye disease; it should  also be considered in patients with severe atopic eye disease  but no history of ocular HSV involvement. The duration of  treatment and the optimum dose has not been established.  Immunohistochemistry should be performed on the excised  tissue to confirm the presence of herpes antigen.   Herpes zoster ophthalmicus (HZO) is the term used for shingles  involving the dermatome supplied by the ophthalmic division of  the fifth cranial (trigeminal) nerve. The globe is commonly af¬  fected in HZO; ocular involvement can also occur (though is  rarely clinically significant) when the disease affects the maxillary  division alone. Varicella-zoster virus (VZV) causes both chicken-  pox (varicella) and shingles (herpes zoster); VZV belongs to the  same subfamily of the herpes virus group as HSV - the viruses are  morphologically identical but antigenically distinct. After an  episode of chickenpox the virus travels in a retrograde manner to  the dorsal root and cranial nerve sensory ganglia, where it may  remain dormant for decades, with reactivation thought to occur  after VZV-specific cell-mediated immunity has faded. Re-exposure    to VZV via contact with chickenpox, or by vaccination, may re¬  inforce immunity and protect against the development of   • Direct viral invasion may lead to conjunctivitis and  epithelial keratitis.   • Secondary inflammation and occlusive vasculitis may cause  episcleritis, scleritis, keratitis, uveitis (including segmental  iris infarction), optic neuritis and cranial nerve palsies.  Inflammation and destruction of the peripheral nerves or  central ganglia, or altered signal processing in the central  nervous system (CNS) may be responsible for post-herpetic  neuralgia. Cicatrizing complications may arise following  severe eyelid, periocular skin and conjunctival involvement.   • Reactivation causes necrosis and inflammation in the  affected sensory ganglia, causing corneal anaesthesia that  may result in neurotrophic keratopathy.   • The Hutchinson sign describes involvement of the skin  supplied by the external nasal nerve, a branch of the  nasociliary nerve supplying the tip, side and root of the nose  (Fig. 6.17A). The sign correlates strongly with ocular  involvement, but there is no apparent correlation between  the severity of the nasal rash and that of ocular  complications.   • Age. HZO occurs most frequently in the sixth and seventh  decades. In the elderly, signs and symptoms tend to be more  severe and of longer duration.   • AIDS patients tend to have more severe disease, and shingles  can be an early indicator of human immunodeficiency virus  (HIV) infection; a lower threshold for HIV testing should be  adopted in populations at particular risk. The development  of shingles in children or young adults classically has  prompted a search for immunodeficiency or malignancy,  though the requirement for this has been questioned as an  abnormality will be found in only a small minority.   Fig. 6.17 Herpes zoster ophthalmicus. (A) Hutchinson sign - rash involving the side of the nose; (B) early erythema and  oedema; (C) vesicular stage; (D) mixed vesicular and pustular rash beginning to show crusting - note the boggy oedema  affecting the medial part of both upper lids; (E) severe rash in a patient with AIDS; (F) typical healed appearance with mild  to moderate scarring and depigmentation   • A prodromal phase precedes the appearance of the rash. It  lasts 3-5 days and is characterized by tiredness, fever, malaise  and headache. Symptoms involving the affected dermatome  vary from a superficial itching, tingling or burning sensation  to a severe boring or lancing pain that is either constant or  intermittent. Older patients with early severe pain and a  larger area of involvement are at particular risk of post¬  herpetic neuralgia.   o Painful erythematous areas with a maculopapular rash  develop (Fig. 6.17B), and may be confused with cellulitis  or contact dermatitis.   distinguishing shingles from HSV skin infection; pain is  also markedly worse in shingles. Bilateral disease is very  rare.   o Within 24 hours, groups of vesicles (Fig. 6.17C) appear  and these become confluent over 2-4 days,  o Although the rash itself does not affect the lower eyelid in  HZO, boggy oedema of the upper and lower lids is  common (see Fig. 6.17B) and often spreads to the  contralateral side of the face.   o The vesicles often pass through a pustular phase before  they crust (Fig. 6.17D) and dry after 2-3 weeks,  o Large, deep haemorrhagic lesions are more common in  immunodeficient patients (Fig. 6.17E).  o The lesions heal to leave residual skin destruction and  depigmented scars (Fig. 6.17F).  o Zoster sine herpete is shingles without a rash; this may be  more common than previously realized.   • Disseminated zoster involving multiple dermatomes and  organ systems may develop in immunodeficiency or  malignancy, and with the advent of PCR testing  complications such as meningoencephalitis have increasingly  been identified in immunocompetent individuals.   • Investigation. In the event that clinical diagnosis is  uncertain, typically in immunodeficiency, vesicular fluid can  be sent for PCR, immunomicroscopy or (now rarely)  culture. A viraemia lasting a few days occurs in acute  shingles; PCR of plasma for VZV DNA may be positive  (40%), especially in immunosuppressed patients and can be  particularly useful if zoster sine herpete is suspected. IgM  antibodies to VZV are found in only a minority of early  stage and convalescent patients.   • Oral antiviral treatment, optimally given within 72 hours of  rash onset, reduces the severity and duration of the acute  episode and the risk of post-herpetic neuralgia. The  incidence of late ophthalmic complications is also reduced  by about 50%. Patients presenting later than 72 hours but    still at the vesicular stage also derive benefit from treatment.  Aciclovir (800 mg five times daily for 7-10 days) has been  the mainstay of treatment, but newer agents such as  valaciclovir 1 g three times daily or famciclovir 250-500 mg  three times daily have more convenient regimens, are better  tolerated and are at least as effective as aciclovir. Brivudine is  available in some countries; fatal interactions with  5-fluoropyrimidines have been reported and it should not be  used in combination with even regional 5-fluorouracil.   • Intravenous aciclovir 5-10 mg/kg three times daily is  generally indicated only for severe disease, particularly  encephalitis, and for moderate-severe immunocompromise.   • Systemic steroids (e.g. prednisolone 60 mg daily for 4 days,  then 40 mg for 4 days, then 20 mg for 4 days) remain  somewhat controversial but are commonly used in  moderate-severe disease, particularly for neurological  complications. They should be given only in conjunction  with a systemic antiviral, the course of which will typically  require extension. They should probably be avoided in  immunodeficiency. A moderate reduction in acute pain and  accelerated skin healing is conferred, but steroids have no  effect on the incidence or severity of post-herpetic neuralgia.   • Immunocompromised patients require the input of an  infectious diseases specialist. Antiviral treatment should be  extended and intravenous treatment may be optimal.  Systemic steroids should probably be avoided.   • Symptomatic treatment of skin lesions is by drying,  antisepsis and cold compresses. The benefit of topical  antibiotic-steroid combinations is uncertain.   • Patients with shingles can transmit chickenpox so that  contact with people not known to be immune (particularly  pregnant women) and immunodeficient individuals should  be avoided at least until crusting is complete.   • Acute epithelial keratitis develops in over 50% of patients  within 2 days of the onset of the rash and usually resolves  spontaneously within a few days. It is characterized by  dendritic lesions that are smaller and finer than herpes  simplex dendrites, and have tapered ends without terminal  bulbs (Figs 6.18A and B). The lesions stain better with rose  Bengal than with fluorescein. Treatment, if required, is with  a topical antiviral.   • Conjunctivitis (follicular and/or papillary) is common; it  often occurs in conjunction with lid margin vesicles.  Treatment is not required in the absence of corneal disease,  though some practitioners give topical antibiotic and/or  antiviral prophylaxis.   • Episcleritis occurs at the onset of the rash and usually  resolves spontaneously. A mild non-steroidal anti¬  inflammatory may be used if necessary.   Fig. 6.18 Acute lesions in herpes zoster ophthalmicus. (A) and (B) Dendritic epithelial lesions with tapered ends;  (C) nummular keratitis; (D) stromal keratitis   (Courtesy of J Krachmer, M Mannis and E Holland, from Cornea, Elsevier 2005 - fig. B; C Barry - fig. D)    • Scleritis and sclerokeratitis are uncommon but may develop  at the end of the first week. Treatment of indolent lesions   is with oral flurbiprofen 100 mg three times daily. Oral  steroids with antiviral cover may be required for severe  involvement.   • Nummular keratitis usually develops at the site of epithelial  lesions about 10 days after the onset of the rash. It is  characterized by fine granular subepithelial deposits  surrounded by a halo of stromal haze (Fig. 6.18C). The  lesions fade in response to topical steroids but recur if  treatment is discontinued prematurely.   • Stromal (interstitial) keratitis (Fig. 6.18D) develops in  about 5% 3 weeks after the onset of the rash; significant  scarring can occur (Fig. 6.19A). It usually responds to topical   • Disciform keratitis (immune-mediated endotheliitis) is less  common than with herpes simplex infection but may lead to  corneal decompensation. Treatment is with topical steroids.   • Anterior uveitis affects at least a third of patients and can be  associated with sectoral iris ischaemia and atrophy (Figs  6.19B and C).   • Posterior uveitis (see Ch. 11). Progressive retinal necrosis is  an aggressive retinitis usually occurring in immunodeficient  individuals. Acute retinal necrosis can also be caused by  VZV. Posterior segment examination should always be  performed in patients with HZO; retinal vasculitis has also  been reported.   Fig. 6.19 Chronic lesions in herpes zoster ophthalmicus. (A) Scarring following stromal keratitis, with crystalline lipid  degeneration; (B) iris atrophy in a typical sectoral pattern; (C) more severe sectoral iris atrophy on transillumination; (D) and  (E) scleral atrophy; (F) mucous plaque keratitis    • IOP should be monitored as elevation is common, including  steroid-induced. Prostaglandin derivatives should be avoided  if treatment is necessary.   o Cranial nerve palsies affecting the third (most common),  fourth and sixth nerves usually recover within 6 months,  o Optic neuritis is rare.   o CNS manifestations are rare but include encephalitis,  cranial arteritis, and Guillain-Barre syndrome.   • Neurotrophic keratopathy similar to that seen in HSV  infection develops in up to about 50%, but is usually  relatively mild and settles over several months. Prolonged  severe disease occurs in a minority (see also separate topic).   • Scleritis may become chronic and lead to patchy scleral  atrophy (Figs 6.19D and E).   • Mucous plaque keratitis develops in about 5%, most  commonly between the third and sixth months. It is  characterized by elevated mucous plaques staining with rose  Bengal (Fig. 6.19F). Treatment involves a combination of  topical steroid and acetylcysteine. Untreated, plaques resolve  after a few months, leaving a faint diffuse corneal haze.   • Lipid degeneration may develop in eyes with persistent  severe nummular or disciform keratitis (see Fig. 6.19A).   • Lipid-filled granulomata similar to those resulting from  chronic irritation may develop in the tarsal conjunctiva, and  may progress to erosive calcified concretions.   • Eyelid scarring may result in ptosis, cicatricial entropion  and occasionally ectropion, trichiasis, lid notching and  madarosis.   In the relapsing phase lesions may reappear years after an acute  episode, which may have been forgotten; eyelid scarring may be  the only diagnostic clue. Reactivation of keratitis, episcleritis,  scleritis or iritis can occur.   Post-herpetic neuralgia is defined as pain that persists for more  than one month after the rash has healed. It develops in up to 75%  of patients over 70 years of age. Pain may be constant or intermit¬  tent, worse at night and aggravated by minor stimuli (allodynia),  touch and heat. It generally improves slowly over time, with only  2% of patients affected after 5 years. Neuralgia can impair the  quality of life, and may lead to depression of sufficient severity to  present a danger of suicide. Patients severely affected should be  referred to a specialist pain clinic. Treatment may involve the  following:   o Simple analgesics such as paracetamol,  o Stronger analgesics such as codeine,  o Tricyclic antidepressants, e.g. nortriptyline, amitriptyline,  initially 25 mg nightly adjusted up to 75 mg for several  weeks if necessary.   o Carbamazepine 400 mg daily for lancinating pain,  o Gabapentin (300-600 mg up to three times daily),  sustained-release oxycodone (10-30 mg twice daily), or  both.   Interstitial keratitis (IK) is an inflammation of the corneal stroma  without primary involvement of the epithelium or endothelium.  In most cases, the inflammation is thought to be an immune-  mediated process triggered by an appropriate antigen. The term is  most commonly used to refer to the late appearance of feathery  mid-stromal scarring with ghost vessels rather than the acute pres¬  entation; the former is typically an incidental finding. Syphilitic  IK is the archetype, but the relative frequency of causes varies  markedly by geographic region. There is a wide range of aetiology;  herpetic keratitis (including chickenpox) and other viral infec¬  tions, tuberculosis, Lyme disease and numerous other infections  (parasitic diseases are an important cause in areas where these are  endemic), sarcoidosis, Cogan syndrome and other non-infectious  inflammatory conditions. Patients should be thoroughly investi¬  gated, in particular to exclude a cause with the potential for severe  systemic involvement.   IK of syphilitic origin is usually the result of congenital infection,  though acquired syphilis can also be responsible. All patients with  acute IK, or with the incidental discovery of its chronic appear¬  ance, should be investigated to exclude congenital (and acquired)  syphilis, irrespective of the presence of systemic clinical signs;  there are numerous reported cases of congenital syphilis being  identified for the first time in later life on this basis, averting life-  threatening complications such as neurosyphilis.   Infection of the fetus can occur transplacentally, leading to still¬  birth, subclinical infection, or a range of clinical features.   • Early systemic features include failure to thrive, a  maculopapular rash, mucosal ulcers, characteristic fissures  around the lips (rhagades) and a range of organ involvement.   • Late systemic signs include sensorineural deafness, saddle-  shaped nasal deformity (Fig. 6.20A), sabre tibiae (Fig.   6.20B), bulldog jaw (mandibular prominence due to  maxillary underdevelopment), Hutchinson teeth (notched,  small, widely spaced teeth - Fig. 6.20C), and Clutton joints  (painless effusions in large joints, especially the knees).   Fig. 6.20 Systemic signs of congenital syphilis. (A) Saddle-  shaped nasal deformity; (B) sabre tibiae; (C) Hutchinson  teeth    • Ocular features include anterior uveitis, IK (see below),  dislocated/subluxated lens, cataract, optic atrophy, salt and  pepper pigmentary retinopathy (Fig. 6.21) and Argyll  Robertson pupils.   • Symptoms. The presentation of IK following congenital  syphilitic infection is usually between the ages of 5 and 25  years. The initial symptoms are those of acute anterior  uveitis with severe blurring. Involvement is bilateral in 80%,  although usually not simultaneous. In acquired disease IK is  less common and usually unilateral, typically occurring years  after the age at which the disease was contracted, although it  can occur as part of the syndrome of primary infection.   o Profoundly decreased visual acuity is typical in the active  stage.   o After several months the cornea begins to clear and the  vessels become non-perfused (‘ghost vessels’ - Fig. 6.22B).  o If the cornea later becomes inflamed, the vessels may  re-fill with blood and, rarely, bleed into the stroma  (Fig. 6.22C).   o The healed stage is characterized by ghost vessels, feathery  deep stromal scarring (Fig. 6.22D), and sometimes  thinning, astigmatism and band keratopathy.   Fig. 6.22 Syphilitic interstitial keratitis. (A) Salmon patch; (B) ghost vessels; (C) intrastromal corneal haemorrhage from  re-perfused vessels; (D) typical feathery scarring - the tracks of ghost vessels are clearly seen   (Courtesy of J Krachmer ; M Mannis and E Holland from Cornea, Mosby 2005 - fig. A)    • Treatment of active syphilitic IK is with topical steroids and  cycloplegics, as well as immediate systemic therapy under  the care of a genitourinary or infectious diseases specialist.   Cogan syndrome is a rare systemic autoimmune vasculitis charac¬  terized by intraocular inflammation and vestibuloauditory dys¬  function (particularly neurosensory) developing within months of  each other. The disease primarily occurs in young adults, with  both sexes affected equally; children can also be affected. Systemic  features occur in 30% and may include multisystem vasculitis that  can be life-threatening; multispecialty management is vital.   Ocular and inner ear symptoms are often separated by a substan¬  tial period; the acute phase may last from months to years. Susac  syndrome (retinocochleocerebral vasculopathy) should be consid¬  ered in the differential diagnosis.   • Ocular signs. Corneal involvement commences with faint  bilateral peripheral anterior stromal opacities; deeper  opacities and corneal neovascularization (mid-stromal  vascular loops) then ensue (Fig. 6.23 A), often with central  progression (Fig. 6.23B). Uveitis, scleritis and retinal  vasculitis may develop.    Fig. 6.23 Old interstitial keratitis in Cogan syndrome. (A) Peripheral; (B) more central scarring   o Erythrocyte sedimentation rate (ESR) and C-reactive  protein (CRP) may be elevated; elevated white cell count,  o Antibodies to inner ear antigens may be detectable,  o MRI may show inner ear and other abnormalities.   • Systemic steroids. Vestibuloauditory symptoms require  immediate treatment with 1-2 g/kg prednisolone to prevent  hearing loss; immunosuppressive therapy may also be  required. Systemic steroids may also be required for scleritis  or retinal vasculitis.   Acanthamoeba spp. are ubiquitous free-living protozoa commonly  found in soil, fresh or brackish water and the upper respiratory  tract. The cystic form (Fig. 6.24A) is highly resilient. Under appro¬  priate environmental conditions, the cysts turn into trophozoites,  with tissue penetration and destruction. In developed countries  acanthamoeba keratitis is most frequently associated with contact  lens wear, especially if tap water is used for rinsing.   Early misdiagnosis as herpes simplex keratitis is relatively common,  and with more advanced signs the possibility of fungal keratitis  should be remembered.   o In early disease the epithelial surface is irregular and  greyish (Fig. 6.24B).   o Characteristic perineural infiltrates (radial keratoneuritis)  are seen during the first few weeks and are virtually  pathognomonic (Fig. 6.24D).   infiltrates to form a ring abscess (Figs 6.25A and B) is  typical.   o Scleritis may develop and is generally reactive rather than  an extension of infection.   o Corneal melting may occur at any stage when there is  stromal disease. The melt often develops at the periphery  of the area of infiltrate (Fig. 6.25C).   o Staining of corneal scrapings using periodic  acid-Schiff or calcofluor white (a fluorescent dye  with an affinity for amoebic cysts and fungi).   o Culture. Non-nutrient agar seeded with dead E. coli ,  which trophozoites consume.   O Other investigations include immunohistochemistry, PCR  and in vivo confocal microscopy. Corneal biopsy may be  necessary for diagnosis.   Fig. 6.24 Initial signs of acanthamoeba keratitis. (A) Cysts in a corneal biopsy; (B) greyish early epithelial involvement;  (C) focal anterior stromal infiltrates; (D) radial perineuritis   It is important to maintain a high index of suspicion for Acanth¬  amoeba in any patient with a limited response to antibacterial  therapy. The outcome is very much better if treatment is started  early.   • Debridement of involved epithelium is believed to be  helpful; it may facilitate eye drop penetration.   • Topical amoebicides. Acanthamoeba cysts are resistant to  most antimicrobial agents, and although successful  outcomes have been reported using a variety of topical  preparations, it is likely that some of these are active only  against the trophozoite stage.    o Hexamidine or propamidine (Brolene); the former  probably has greater activity,  o Voriconazole and other azole antifungals may be  effective.   o An optimal regimen has not been established. Examples  include PHMB as duotherapy with chlorhexidine, or  either of these in combination with hexamidine or  propamidine. Instillation is hourly at first, and gradually  reduced; a clear response may take 2 weeks,  o Simultaneous antibacterial treatment for co-infection  may be considered if the clinical picture suggests this,  o Relapses are common as treatment is tapered, and it  may be necessary to continue treatment for many  months.    Fig. 6.25 Advanced acanthamoeba keratitis. (A) Progression  of infiltration, with incipient formation of a ring abscess  and early melting; (B) ring abscess; (C) melting    • Topical steroids should be avoided if possible although  low-dose therapy delayed for at least 2 weeks after starting  anti-amoebic treatment may be useful for persistent  inflammation. Amoebicidal treatment should be continued  in concert with and for several weeks after steroids.   • Therapeutic keratoplasty may be necessary for resistant  cases, including perforation. Late scarring may also require  penetrating keratoplasty.   Marginal keratitis is believed to be caused by a hypersensitivity  reaction against staphylococcal exotoxins and cell wall proteins  with deposition of antigen-antibody complexes in the peripheral  cornea (antigen diffusing from the tear film, antibody from the  blood vessels) with a secondary lymphocytic infiltration. The  lesions are culture-negative but S. aureus can frequently be isolated  from the lid margins.   o Inferior punctate epitheliopathy is an early manifestation,  o Subepithelial marginal infiltrates separated from the  limbus by a clear zone, often associated with an adjacent  area of conjunctival hyperaemia (Fig. 6.26A).  o Characteristically, any epithelial defect will be  considerably smaller than the area of infiltrate  (Fig. 6.26B).   Fig. 6.26 Marginal keratitis. (A) Marginal infiltrates; (B) fluorescein staining characteristically demonstrates a smaller  epithelial defect than infiltrate area; (C) substantial marginal infiltrate - note the relatively quiet eye despite the area of  involvement; (D) mild scarring and pannus    presumed delayed hypersensitivity reaction to staphylococcal  antigen, sometimes associated with rosacea. In developing coun¬  tries the majority are associated with tuberculosis or helminthic  infestation, but causation may be uncertain and a range of other  agents has been implicated.   • Symptoms. Photophobia, lacrimation and blepharospasm,  often in a child or young adult.   o A small white limbal (Fig. 6.27A) or conjunctival nodule  associated with intense local hyperaemia.  o A limbal phlycten may extend onto the cornea (Fig. 6.27B).  o Spontaneous resolution usually occurs within 2-3 weeks;  a healed lesion often leaves a triangular limbal-based scar  associated with superficial vascularization and thinning  (Fig. 6.27C) but occasionally severe thinning and even  perforation can ensue.   • Investigation for tuberculosis is generally indicated only in  endemic areas or in the presence of specific risk factors.    o Usually little or no anterior chamber reaction, even with  large infiltrates.   o Without treatment, resolution generally occurs in 1-4  weeks, depending on severity. Occasionally there is  residual superficial scarring and slight thinning with mild  pannus (Fig. 6.26D). Iris new vessels may develop in the  presence of persistent large lesions, but resolve when  inflammation settles.   A weak topical steroid such as fluorometholone or prednisolone  0.5% is instilled four times daily for 1-2 weeks, sometimes com¬  bined with a topical antibiotic. An oral tetracycline course (eryth¬  romycin in children, breastfeeding and pregnancy) may be  required for recurrent disease. Blepharitis is treated as necessary.   Phlyctenulosis is usually a self-limiting disease but may rarely be  severe. Most cases in developed countries are the result of a   Fig. 6.27 Phlyctenulosis. (A) Limbal phlycten; (B) corneal  phlycten; (C) healed phlycten   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann 2002 - fig. A; S Tuft - fig. B; J Krachmer ; M Mannis  and E Holland , from Cornea, Mosby 2005 - fig. C)   A short course of topical steroid accelerates healing and is often  given with a topical antibiotic. Recurrent troublesome disease may  require an oral tetracycline, and it is important to treat associated  blepharitis.   Rosacea (acne rosacea) is a common chronic idiopathic dermato¬  sis involving the sun-exposed skin of the face and upper neck.  Ocular complications develop in 6-18% of patients. Facial tel¬  angiectasia, papule and pustule formation, rhinophyma and facial    flushing may occur (Fig. 6.28). In contrast to acne vulgaris, come¬  dones (blackheads or whiteheads) are absent.   The aetiology is probably multifactorial and may involve vascu¬  lar factors, together with an abnormal response to commensal skin  bacteria and Demodex follicular mites. Exacerbation by H. pylori  infection has been suspected.   • Lid signs include margin telangiectasia (Fig. 6.29A) and  posterior blepharitis, often associated with recurrent  meibomian cyst formation.   • Conjunctival hyperaemia, especially bulbar. Rarely,  cicatricial conjunctivitis, conjunctival granulomas and  phlyctenulosis may occur.   Fig. 6.28 Acne rosacea. (A) Nasal and malar telangiectasia;  (B) papulopustular signs; (C) rhinophyma   o Focal or diffuse corneal thinning (Fig. 6.29c), usually  inferiorly, in severe cases.   o Perforation may occur as a result of severe peripheral or  central melting, and may be precipitated by secondary  bacterial infection.   o Topical antibiotics (e.g. fusidic acid, erythromycin,  azithromycin) to the lid margins at bedtime for  4 weeks.   o Steroids are helpful for exacerbations; the lowest potency  preparation compatible with improvement should be  used in order to minimize the promotion of thinning.   o Tetracyclines may work by altering meibomian gland  function to lower free fatty acid production in  conjunction with a reduction in lid flora, and probably  by a direct anti-inflammatory effect. They also have an  anticollagenase action and so may retard thinning. In  relatively low dose but extended duration (e.g.  doxycycline, which has a longer half-life than tetracycline,  100 mg once daily for 4 weeks then 50 mg daily if  required) they may confer an improvement lasting several  months but if necessary can be continued long term;  tetracyclines should not be used in children and pregnant  or breastfeeding women, in whom erythromycin is an  alternative. Efficacy has also been reported with other  antibiotics.   o Retinoids can be helpful, but can worsen some features.  They are absolutely contraindicated in pregnancy.   Peripheral corneal ulceration/thinning, known as ‘peripheral  ulcerative keratitis’ (PUK) when inflammatory, refers to a presen¬  tation characterized by thinning and/or ulceration preferentially  affecting the peripheral rather than central cornea, and spreading  around the margin. It should be noted that any cause of corneal  ulceration can affect the periphery.   • Dellen. Localized corneal disturbance associated with drying  of a focal area, usually associated with an adjacent elevated  lesion (e.g. pinguecula or a large subconjunctival  haemorrhage - Fig. 6.30A) that impairs physiological  lubrication. Generally mild though can occasionally be severe,  including descemetocoele formation/corneal perforation.   • Others. Ocular rosacea, furrow degeneration (mild  peripheral thinning in the elderly, usually benign -  Fig. 6.30B), pellucid marginal degeneration.   Mooren ulcer is a rare autoimmune disease characterized by pro¬  gressive circumferential peripheral stromal ulceration with later    central spread. There are two forms: the first affects mainly older  patients, often in only one eye, and usually responds well to  medical therapy. The second is more aggressive and likely to need  systemic immunosuppression, carries a poorer prognosis, may be  bilateral and associated with severe pain, and tends to occur in  younger patients, including widespread reports in men from the  Indian subcontinent. In at least some (usually milder) cases, there  is a precipitating corneal insult such as surgery or infection. Asso¬  ciated systemic autoimmune disease and corneal infection should  always be ruled out.   • Symptoms. Pain is prominent and may be severe. There is  photophobia and blurred vision.   o Peripheral ulceration involving the superficial one-third  of the stroma (Fig. 6.31A), with variable epithelial loss.  Several distinct foci may be present and subsequently  coalesce.   Fig. 6.30 Non-inflammatory peripheral corneal thinning. (A) Fluorescein-stained dellen secondary to large subconjunctival  haemorrhage following cataract surgery; (B) extensive furrow degeneration    o An undermined and infiltrated leading edge is  characteristic (Fig. 6.31B).   o Limbitis may be present, but not scleritis, which aids in  distinguishing from systemic disease-associated PUK.   o Vascularization involving the bed of the ulcer up to its  leading edge but not beyond,  o The healing stage is characterized by thinning,  vascularization and scarring (Fig. 6.31D).   • Complications include severe astigmatism, perforation  following minor trauma (spontaneous perforation is rare),  secondary bacterial infection, cataract and glaucoma.   • Topical steroids as frequently as hourly are combined with a  low-frequency prophylactic topical antibiotic. If an effective  response is seen, treatment is tapered over several months.   • Topical ciclosporin (up to 2%) may be effective, but can  take weeks to exert a significant effect.   • Adjunctive topical therapy includes artificial tears and  collagenase inhibitors such as acetylcysteine 10-20%.   • Conjunctival resection, which may be combined with  excision of necrotic tissue, is performed if there is no  response to topical steroids. The excised area should extend  4 mm back from the limbus and 2 mm beyond the  circumferential margins. Keratoepithelioplasty (suturing of a  donor corneal lenticule onto the scleral bed) may be  combined to produce a physical barrier against conjunctival  regrowth and further melting. Steroids are continued  postoperatively.   • Systemic immunosuppression may be needed, including  steroids for rapid effect, and should be instituted earlier for  bilateral disease, or if involvement is advanced at first  examination. Biological blockers show some promise.   • Lamellar keratectomy involving dissection of the residual  central island in advanced disease may remove the stimulus  for further inflammation.   • Visual rehabilitation. Keratoplasty (with  immunosuppressive cover) may be considered once  inflammation has settled.   PUK may precede or follow the onset of systemic features. Severe    by evident ocular disease should prompt investigation for a  (potentially life-threatening) systemic collagen vascular disorder.  The mechanism includes immune complex deposition in periph¬  eral cornea, episcleral and conjunctival capillary occlusion with  secondary cytokine release and inflammatory cell recruitment, the  upregulation of collagenases and reduced activity of their inhibi¬  tors. Systemic associations include:   • Rheumatoid arthritis (RA - the most common). PUK is  bilateral in 30% and tends to occur in advanced RA.   • Wegener granulomatosis is the second most common  systemic association of PUK. In contrast to RA ocular  complications are the initial presentation in 50%.   • Other conditions include polyarteritis nodosa, relapsing  polychondritis and systemic lupus erythematosus.   • Crescentic ulceration with an epithelial defect, thinning and  stromal infiltration at the limbus (Fig. 6.32A). Spread is  circumferential and occasionally central; in contrast to  Mooren ulcer, extension into the sclera may occur.   • Limbitis, episcleritis or scleritis are usually present; as with  a Mooren ulcer, there is no separation between the  ulcerative process and the limbus.   thought to be a distinct entity, with a punched-out more  centrally located lesion with little infiltrate in a quiet eye  (Fig. 6.32C). Perforation can occur rapidly, and there is  usually a good response to topical ciclosporin, with bandage  contact lens and tissue glue application if necessary, rather  than systemic treatment.   • Systemic steroids, sometimes via pulsed intravenous  administration, are used to control acute disease, with  immunosuppressive therapy and biological blockers for  longer-term management.   • Topical antibiotics as prophylaxis if an epithelial defect is  present.   • Oral tetracycline (e.g. doxycycline 100 mg once or twice  daily) for its anticollagenase effect.   • Topical steroids may worsen thinning so are generally  avoided; relapsing polychondritis may be an exception.   • Surgical management is generally as for Mooren ulcer,  including conjunctival excision if medical treatment is  ineffective.   Terrien disease is an uncommon idiopathic thinning of the periph¬  eral cornea occurring in young adult to elderly patients. Although   (A) Early peripheral ulcerative keratitis; (B) contact lens  cornea; (C) rheumatoid paracentral ulcerative keratitis with  iris prolapsing through a perforation    usually categorized as a degeneration, some cases are associated  with episodic episcleritis or scleritis. About 75% of affected patients  are male and the condition is usually bilateral but may be  asymmetrical.   • Symptoms. The condition is commonly asymptomatic, but  gradual visual deterioration can occur due to astigmatism. A  few patients experience episodic pain and inflammation.   o Fine yellow-white refractile stromal opacities, frequently  associated with mild superficial vascularization, usually  start superiorly, spread circumferentially and are  separated from the limbus by a clear zone (Fig. 6.33A).  There is no epithelial defect, and on cursory examination  the condition may resemble arcus senilis,  o Slowly progressive circumferential thinning results in a  peripheral gutter, the outer slope of which shelves  gradually, while the central part rises sharply. A band of  lipid is commonly present at the central edge (Fig. 6.33B).  o Perforation is rare but may be spontaneous or follow  blunt trauma.   • Surgery - crescentic or annular excision of the gutter with  lamellar (Fig. 6.33D) or full-thickness transplantation - gives  reasonable results and may arrest progression.   Neurotrophic keratopathy occurs when there is loss of trigeminal  innervation to the cornea resulting in partial or complete anaes¬  thesia. In addition to loss of the protective sensory stimulus,  reduced innervation results in intracellular oedema, exfoliation,  loss of goblet cells and epithelial breakdown with persistent ulcera¬  tion. Causes include trigeminal ganglion surgical ablation for neu¬  ralgia, stroke, tumour, peripheral neuropathy (e.g. diabetes) and  ocular disease such as herpes simplex and herpes zoster keratitis  (when sensation loss may be sectoral).   o Stage 1: interpalpebral epithelial irregularity and staining,  with mild opacification, oedema and tiny focal defects  (Fig. 6.34A).    Fig. 6.33 Terrien marginal degeneration. (A) Early disease; (B) circumferential extension with thinning, vascularization and a  lipid band at the central edge; (C) pseudopterygia; (D) gutter excision with lamellar graft repair    o Stage 2: larger persistent epithelial defect with rolled and  thickened edges (Fig. 6.34B), subsequently assuming a  punched-out configuration with underlying stromal  oedema (Fig. 6.34C).   o Stage 3: stromal melting, often with minimal discomfort,  o Perforation is uncommon but may occur rapidly,  especially with secondary infection (Fig. 6.34D).   • Topical lubricants (non-preserved) for associated dry eye or  corneal exposure. Topical insulin-like growth factor-i,  substance P and neurogenic growth factor have been  evaluated but are not commercially available.   • Anticollagenase agents: topical (e.g. acetylcysteine,  tetracycline ointment) or systemic (e.g. tetracyclines).   o Simple taping of the lids, particularly at night, may  provide modest protection.   o Tarsorrhaphy: temporary or permanent, lateral or central,  according to the underlying pathology and visual  potential.   o Therapeutic silicone contact lenses may be fitted,  provided the eye is carefully monitored for infection.   • Perforation is dealt with as discussed earlier in the chapter.   Exposure keratopathy is the result of incomplete lid closure  (lagophthalmos), with drying of the cornea despite normal tear  production. Lagophthalmos may only be present on blinking or  gentle lid closure, with full forced lid closure. Causes include neu¬  roparalytic, especially facial nerve palsy, reduced muscle tone as   Fig. 6.34 Neurotrophic keratopathy. (A) Early central epithelial changes; (B) persistent epithelial defect with rolled edges;  (C) punched-out epithelial defect with underlying stromal oedema and early melting; (D) secondary infection with marked  thinning    in parkinsonism, mechanical such as lid scarring, eczematous skin  tightening and post-blepharoplasty, and proptosis.   o Mild punctate epithelial changes involving the inferior  third of the cornea, particularly with nocturnal  lagophthalmos.   o Inferior fibrovascular change with Salzmann degeneration  may develop over time.   o Artificial tears (unpreserved) during the day and  ointment at night.   o Taping the lid closed at night may be an alternative to  ointment.   O Permanent central tarsorrhaphy, amniotic membrane  grafting or conjunctival flap when vision is poor.   Fig. 6.35 Exposure keratopathy. (A) Inferior epithelial defect;  (B) stromal melting; (C) secondary bacterial infection   Infectious crystalline keratopathy is a rare indolent infection  usually occurring in a patient on long-term topical steroid therapy  with an associated epithelial defect, most frequently following  penetrating keratoplasty. Streptococcus viridans is most commonly  isolated, although numerous other bacteria and fungi have been  implicated.   Slowly progressive, grey-white, branching stromal opacities are  seen, associated with minimal inflammation and usually intact  overlying epithelium (Fig. 6.36). Culture or biopsy is performed   Fig. 6.36 (A) Infectious crystalline keratitis; (B) crystalline  keratitis in a graft    to determine the organism, and topical antibiotics instilled for  several weeks.   Thygeson superficial punctate keratitis is an uncommon idio¬  pathic, usually bilateral, condition characterized by exacerbations  and remissions. It is commonly of onset in young adulthood but  can affect patients of any age, and may recur over decades.   • Symptoms consist of recurrent attacks of irritation,  photophobia, blurred vision and watering.   o Granular, coarse, slightly elevated greyish epithelial  lesions that stain with fluorescein and mainly involve the  central cornea (Fig. 6.37A).   o A mild subepithelial haze may be present (Fig. 6.37B),  especially if topical antivirals have been used,  o There is little or no conjunctival hyperaemia.   Fig. 6.37 (A) Thygeson superficial punctate keratitis;  (B) associated subepithelial haze   o Lubricants may suffice in mild cases,  o Steroids. A low-potency preparation is used twice daily  initially, with gradual tapering to as little as once-weekly  instillation. Higher intensity treatment may sometimes be  needed initially.   o Ciclosporin 0.05% is generally used if the response to  steroids is inadequate, or as an alternative in longer-term  therapy; some authorities recommend ciclosporin for  initial treatment. Tacrolimus may also be effective,  o Antivirals have not been found to be consistently helpful.   • Contact lenses (extended wear or daily disposable soft) may  be considered if steroids are ineffective or contraindicated,  as an alternative to ciclosporin.   Filamentary keratopathy is a common condition that can cause  considerable discomfort. It is thought that a loose area of epithe¬  lium acts as a focus for deposition of mucus and cellular debris.  The causes are shown in Table 6.6.   • Symptoms consist of discomfort with foreign body  sensation, redness and sometimes photophobia.   o Strands of degenerated epithelial cells and mucus that  move with blinking and are typically attached to the  cornea at one end (Fig. 6.38A).  o Filaments stain well with rose Bengal (Fig. 6.38B) and to  a lesser extent with fluorescein,  o A small epithelial defect may be present at the base of a  filament.   • Topical medication should be changed if a toxic effect is  suspected, and unpreserved preparations used where possible.   Superior limbic keratoconjunctivitis  Bullous keratopathy  Neurotrophic keratopathy  Prolonged or frequent eye closure   Fig. 6.38 Corneal filaments. (A) Comma-shaped lesions  attached to the cornea at one end; (B) stained with rose  Bengal   (Courtesy of S Tuft - fig. A; R Bates - fig. B)   • Hypertonic saline (5% drops four times daily, ointment at  bedtime) may encourage adhesion of loose epithelium.   • Bandage contact lenses may protect the cornea from the  shearing action of the lids.    and their basement membrane. Minor trauma, such as eyelid-  cornea interaction during sleep, can be sufficient to precipitate  detachment. Erosions may be associated with previous trauma or  rarely corneal surgery, and with some corneal dystrophies. Inter¬  vals between episodes can be very variable, even in the same  patient, but may occur in spates over a short period.   • Symptoms. Severe pain, photophobia, redness,  blepharospasm and watering typically waken the patient  during the night or are present on awaking in the morning.  There is usually (but not invariably) a prior history of  corneal abrasion, sometimes years previously, which may  have been minor compared to the recurrent symptoms.   o An epithelial defect (Fig. 6.39A) may not be present by  the time the patient is examined, as healing can often be  very rapid (hours), but the extent of loose epithelium  may be highlighted by areas of pooling of fluorescein and  rapid tear film breakup.   Fig. 6.39 Recurrent corneal erosion syndrome. (A) Epithelial  defect stained with fluorescein; (B) epithelial basement  membrane abnormalities, predominantly non-staining,  signify the region of abnormal healing    o Infiltrate should not be present, though greyish sloughed  and rolled epithelium may sometimes be reminiscent of  this.   o There may be no sign of abnormality once a defect has  healed, but signs of epithelial basement membrane  disturbance, such as microcysts, punctate or linear/  fingerprint opacities are often present (Fig. 6.39B). These  will typically be bilateral in a stromal dystrophy and  unilateral if injury is the cause.   o Antibiotic ointment four times daily and cyclopentolate  1% twice daily.   o Pressure patching should not be used as it may impair  healing and does not improve comfort.   o In severe cases a bandage contact lens alleviates pain but  may not improve healing; antibiotic drops rather than  ointment should be used.   o Debridement of heaped/scrolled areas of epithelium with  a sterile cellulose sponge or cotton-tipped applicator  (cotton bud) may improve comfort and allow healing  from the edges of the defect; irregular underlying  Bowman layer will often be appreciated in the involved  area.   o Topical anaesthetic dramatically relieves pain but should  not be dispensed for patient use.   o Hypertonic sodium chloride 5% drops four times daily  and ointment at bedtime may improve epithelial  adhesion.   o Following resolution, some authorities advise using a  prophylactic topical lubricant such as carbomer gel three  or four times daily for several months.   O Topical lubricant gel or ointment, or hypertonic saline  ointment, instilled at bedtime used long term may be  sufficient.   o Simple debridement of the epithelium in involved areas,  which may be followed by smoothing of Bowman layer  with a diamond burr or excimer laser.   o Anterior stromal puncture for localized areas off the  visual axis; it may not be necessary to remove the  epithelium to facilitate this.   Vitamin A is essential for the maintenance of the body’s epithelial  surfaces, for immune function and for the synthesis of retinal  photoreceptor proteins. Xerophthalmia refers to the spectrum  of ocular disease caused by inadequate vitamin A intake, and is a  late manifestation of severe deficiency. Lack of vitamin A in the    diet may be caused by malnutrition, malabsorption, chronic alco¬  holism or by highly selective dieting. The risk in infants is increased  if their mothers are malnourished and by coexisting diarrhoea or  measles.   A World Health Organization (WHO) grading system is set out  in Table 6.7.   XI = conjunctival xerosis (X1A) with Bitot spots (X1B)  X2 = corneal xerosis   X3 = corneal ulceration, less than one-third (X3A); more  than one-third (X3B)   (Courtesy of N Rogers - fig. A; S Kumar Puri - fig. B)   • Symptoms are night blindness (nyctalopia), discomfort and  loss of vision.   o Xerosis is characterized by dryness of the conjunctiva in  the interpalpebral zone with loss of goblet cells,  squamous metaplasia and keratinization.  o Bitot spots are triangular patches of foamy keratinized  epithelium (Fig. 6.40A) in the interpalpebral zone  thought to be caused by Cory neb acterium xerosis.   o Lustreless appearance due to secondary xerosis,  o Bilateral punctate corneal epithelial erosions in the  interpalpebral zone can progress to epithelial defects but  are reversible with treatment,  o Keratinization.   • Retinopathy, characterized by yellowish peripheral dots,  may occur in advanced cases and is associated with  decreased electroretinogram amplitude.   and should be treated as a medical emergency due to the risk of   • Systemic treatment involves oral (oil-based 200 000 IU) or  intramuscular (aqueous-based 100000 IU) vitamin A for  keratomalacia. Multivitamin supplements and dietary  sources of vitamin A are also administered.   • Local treatment consists of intense lubrication, topical  retinoic acid and management of perforation.   Keratoconus (KC) is a progressive disorder in which central or  paracentral corneal stromal thinning occurs, accompanied by  apical protrusion and irregular astigmatism. Approximately 50%  of normal fellow eyes will progress to KC within 16 years. Both  eyes are affected eventually, at least on topographical imaging, in  almost all cases. It can be graded by the highest axis of corneal  power on keratometry as mild (<48 D), moderate (48-54 D) or  severe (>54 D). Most patients do not have a family history, with  only about 10% of offspring developing KC; autosomal dominant  transmission with incomplete penetrance has been proposed.  Presentation is commonly during the teens or twenties, with fea¬  tures initially in only one eye. Systemic associations include Down,  Ehlers-Danlos and Marfan syndromes and osteogenesis imper¬  fecta; ocular associations include vernal keratoconjunctivitis, blue   • Symptoms. Unilateral impairment of vision due to  progressive myopia and astigmatism; occasionally, initial  presentation is with acute hydrops (see below).   o Retinoscopy shows an irregular ‘scissoring’ reflex,  o Slit lamp biomicroscopy shows very fine, vertical, deep  stromal stress lines (Vogt striae - Fig. 6.41B), which  disappear with pressure on the globe,  o Epithelial iron deposits, best seen with a cobalt blue filter,  may surround the base of the cone (Fleischer ring - Fig.  6.41C).   o Progressive corneal protrusion in a cone configuration  (Fig. 6.41D), with thinning maximal at the apex,  o Bulging of the lower lid in downgaze (Munson sign),  o Acute hydrops is caused by a rupture in the stretched  Descemet membrane that allows a sudden influx of  aqueous into the cornea (Figs 6.42A and B), with  accompanying pain, photophobia and decreased vision.  Although the break usually heals within 6-10 weeks and  the oedema clears, a variable amount of stromal scarring  (Fig. 6.42C) may develop; this sometimes gives improved  vision by flattening the cornea. Acute episodes are  initially treated with cycloplegia, hypertonic (5%) saline  ointment and patching or a soft bandage contact lens.  Accelerated resolution has been reported with  intracameral gas injection in the acute stage.   • Corneal topography (videokeratography) and various novel  corneal profiling techniques are highly sensitive for detection  and essential in monitoring. Characteristically, astigmatism  progresses from a symmetrical bow-tie pattern, through an  asymmetrical appearance to an inferotemporally displaced  steep-sided cone (Fig. 6.43). Sometimes a central (‘nipple’)  cone may develop. Contact lens warpage can sometimes  appear similar to a cone on topography, but is generally  more arcuate-shaped.   • Spectacles or soft contact lenses are generally sufficient in  early cases. If thinning is marked, it may be prudent to  consider wearing safety spectacles over contact lenses.   • Rigid contact lenses, sometimes scleral, are required for  higher degrees of astigmatism to provide a regular refracting  surface.   Fig. 6.41 Keratoconus. (A) ‘Oil droplet’ red reflex; (B) Vogt striae in the deep stroma; (C) Fleischer ring demonstrated by  cobalt blue light as a blue circle; (D) typical cone   (Courtesy of R Fogla - fig. C; C Barry - fig. D)    • Corneal collagen cross-linking (CXL), using riboflavin  drops to photosensitize the eye followed by exposure to  ultraviolet-A light, may stabilize or even reverse ectasia, but  is not without adverse effects. It can be combined with ring  segment insertion. CXL is commonly used only after  progression has been documented.   • Intracorneal ring segment implantation (Fig. 6.44) using  laser or mechanical channel creation is relatively safe, and  typically provides at least a moderate visual improvement,  facilitating contact lens tolerance in advanced cases.   • Keratoplasty, either penetrating or deep anterior lamellar  (DALK), may be necessary in patients with severe disease. A  history of hydrops is a contraindication to DALK due to the  presence of a Descemet membrane discontinuity. Outcomes  may be compromised by residual astigmatism and by  anisometropia, necessitating contact lens correction for  optimal acuity.   Pellucid marginal degeneration is a rare progressive peripheral  corneal thinning disorder, typically involving the inferior cornea  in both eyes. Presentation is usually in adulthood.   o Bilateral, slowly progressive, crescentic 1-2 mm band of  inferior corneal thinning extending from 4 to 8 o’clock,   1 mm from the limbus (Fig. 6.45A).  o The epithelium is intact, and the cornea above the  thinned area is ectatic and flattened,  o In contrast to keratoconus, Fleischer rings and Vogt striae  do not occur and acute hydrops is rare.    KS: 60.68D @110  KF: 52.26D @ 030  KD: 8.42D  Real K/Avg (1.60)    Fig. 6.43 Corneal topography showing  severe keratoconus in the right eye and  an early paracentral cone in the left   Early cases are managed with spectacles and contact lenses. Surgi¬  cal options, none of which is ideal, in patients intolerant to contact  lenses include large eccentric penetrating keratoplasty, thermo¬  cauterization, crescentic lamellar keratoplasty, wedge resection of  diseased tissue, epikeratoplasty and intracorneal ring segment  implantation. Results of collagen cross-linking are encouraging.   Keratoglobus is an extremely rare condition that can be present at  birth when differential diagnosis is from congenital glaucoma and  megalocornea and associations may be present, or acquired, with  onset in adulthood. In contrast to keratoconus, the cornea devel¬  ops globular rather than conical ectasia; corneal thinning is gen¬  eralized (Fig. 6.46). Acute hydrops is rare, but the cornea is more  prone to rupture on relatively mild trauma. Corneal topography  shows generalized steepening. Surgery is difficult and contact lens  wear is often unsatisfactory. Intrastromal ring segments and cross-  linking may have utility. Special care should be taken to protect  the eyes from trauma.    The corneal dystrophies are a group of progressive, usually bilat¬  eral, variable corneal opacifying disorders, many of which are  associated with decreased vision and discomfort. Based on bio-  microscopical and histopathological features they are classified  into epithelial, Bowman layer, stromal, and Descemet membrane  and endothelial. One or more underlying genetic abnormalities  have been identified for most.   Epithelial basement membrane (map-dot-fingerprint) is the most  common corneal dystrophy. Despite this, it is often misdiagnosed,  principally due to its variable appearance.   • Inheritance. The condition is usually sporadic, and these  cases may be degenerations rather than true dystrophies, in  contrast to the rare familial (autosomal dominant - AD)  cases.   Fig. 6.45 (A) Pellucid marginal degeneration; (B) topography  shows severe astigmatism and diffuse steepening of the  inferior cornea   (Courtesy of R Visser - fig. A; R Fogla - fig. B)    • Histology shows thickening of the basement membrane with  deposition of fibrillary protein between the basement  membrane and the Bowman layer. Basal epithelial cell  hemidesmosomes are deficient.   • Onset is in the second decade. About 10% of patients  develop recurrent corneal erosions in the third decade and  the remainder are asymptomatic throughout life. The  occurrence of bilateral recurrent erosions with no history of  trauma suggests basement membrane dystrophy.   • Signs. Lesions are often best visualized by retroillumination  or scleral scatter. Over time pattern and distribution varies;  they may be absent or subtle in a fellow eye. Similar features  can be seen with recurrent erosions from any cause.   o Dot-like and microcystic epithelial lesions (Fig. 6.47A).  o Subepithelial map-like patterns surrounded by a faint  haze (Fig. 6.47B).  o Whorled fingerprint-like lines,  o Bleb-like subepithelial pebbled glass pattern.   • Histology shows irregular thickening of the epithelial  basement membrane and intraepithelial cysts.   • Symptoms. Patients may be asymptomatic, or there may be  recurrent erosions and blurring (usually mild).   o Myriad tiny intraepithelial cysts of uniform size but  variable density are maximal centrally and extend  towards but do not reach the limbus (Fig. 6.47C).   Other epithelial and subepithelial dystrophies are Lisch epithelial  corneal dystrophy (Figs 6.47D and E), subepithelial mucinous  corneal dystrophy and gelatinous drop-like corneal dystrophy  (Fig. 6.47F).   This may be categorized as an anterior variant of granular stromal  dystrophy (GCD type 3 - see below) and is also known as corneal  basement dystrophy type I (CBDi).   • Histology. Replacement of the Bowman layer by connective  tissue bands.   • Symptoms. Severe recurrent corneal erosions in childhood.  Visual impairment may occur.   o Grey-white geographic subepithelial opacities, most  dense centrally (Fig. 6.48), increasing in density with age  to form a reticular pattern. Histopathology, including  electron microscopy, may be required for definitive  distinction from Thiel-Behnke dystrophy in some cases,  o Corneal sensation is reduced.   • Treatment is directed at the recurrent erosions. Excimer  keratectomy achieves satisfactory control in some patients.   Also termed honeycomb-shaped corneal dystrophy and corneal  basement dystrophy type II (CBD2); features are generally less  severe than Reis-Bucklers.   • Signs. Subepithelial opacities are less individually defined  than the granular dystrophy-type lesions (see below) seen in  Reis-Bucklers dystrophy. They develop in a network of tiny  rings or honeycomb-like morphology, predominantly  involving the central cornea (Fig. 6.49).   This is usually regarded as the classic form of lattice dys¬  trophy. Clinical variants (e.g. IIIA - Fig. 6.50) associated with   Fig. 6.47 Corneal epithelial and subepithelial dystrophies. (A) Cogan - dots and microcysts; (B) Cogan - map-like pattern;   (C) Meesmann - myriad intraepithelial cysts; (D) Lisch - grey bands with a whorled configuration; (E) Lisch - retroillumination  shows densely crowded microcysts; (F) gelatinous drop-like dystrophy   (Courtesy of R Fogla - fig. C; W Lisch - figs D and E; D Palay, from J Krachmer ; M Mannis and E Holland, Cornea, Mosby 2005 - fig. F)   • Histology. Amyloid, staining with Congo red (Fig. 6.51A)  and exhibiting green birefringence with a polarizing filter.   • Symptoms. Recurrent erosions occur at the end of the first  decade in the classic form, when typical stromal signs may  not yet be present. Blurring may occur later.   o Retractile anterior stromal dots (Fig. 6.51B), coalescing  into a relatively fine filamentous lattice that spreads  gradually but spares the periphery (Fig. 6.51C).  o A generalized stromal haze (Fig. 6.51D) may progressively  impair vision.   • Treatment by penetrating or deep lamellar keratoplasty is  frequently required. Recurrence is not uncommon.   Also known as LCD2 and Meretoja syndrome, this is a systemic  condition rather than a true corneal dystrophy.   • Ocular symptoms. Ocular irritation and late impairment of  vision; erosions are rare.   • Systemic features. Progressive cranial and peripheral  neuropathy, mask-like facies and autonomic features.  Homozygous disease is rare but severe.   • Histology. Amorphous hyaline deposits staining bright red  with Masson trichrome (Fig. 6.52A).   • Symptoms. Glare and photophobia, with blurring as  progression occurs. Recurrent erosions are uncommon.   resembling sugar granules, breadcrumbs or glass splinters  separated by clear stroma (Fig. 6.52B).  o Gradual increase in number and size of the deposits with  deeper and outward spread, sparing the limbus (Fig.  6.52C).   o Gradual confluence and diffuse haze leads to visual  impairment (Fig. 6.52D).  o Corneal sensation is impaired.   • Treatment by penetrating or deep lamellar keratoplasty is  usually required by the fifth decade. Superficial recurrences  may require repeated excimer laser keratectomy.   Fig. 6.51 Lattice dystrophy type 1. (A) Histology shows amyloid staining with Congo red; (B) glassy dots in the anterior  stroma; (C) fine lattice lines; (D) early central stromal haze   (Courtesy of J Harry - fig. A; C Barry - figs C and D)   Fig. 6.52 Granular dystrophy type 1. (A) Histology shows red-staining material with Masson trichrome; (B) sharply demarcated  crumb-like opacities;   • Symptoms. Recurrent erosions tend to be mild. Visual  impairment is a later feature.   • Signs are usually present by the end of the first decade in  heterozygotes. Fine superficial opacities progress to form  stellate or annular lesions (Fig. 6.53), sometimes associated  with deeper linear opacities.   • Treatment is usually not required. Corneal trauma  accelerates progression; refractive surgery is contraindicated.   • Inheritance. Autosomal recessive (AR); gene CHST 6 ; the  condition is relatively common in Iceland.   • Histology. Aggregations of glycosaminoglycans intra- and  extracellularly; stain with Alcian blue and colloidal iron  (Fig. 6.54A).   • Symptoms. Early (end of first decade) visual deterioration;  recurrent erosions are very common.   o Dense but poorly delineated greyish-white spots centrally  in the anterior stroma and peripherally in the posterior  stroma (Figs 6.54B and C). There is no clear delineation  between opacities, which may be elevated.   O Progression of the lesions occurs in conjunction with  anterior stromal haze, initially involving the central  cornea (Fig. 6.54D).   o There is eventual involvement of full-thickness stroma,  extending to the limbus with no clear zone,  o Thinning is a fairly early feature, with late thickening  from oedema due to endothelial dysfunction,  o Sensation is reduced.   This is a disorder of corneal lipid metabolism, associated in some  patients with systemic dyslipidaemia. The use of crystalline in the  name is no longer recommended as corneal crystals are not a  ubiquitous feature.   Fig. 6.54 Macular dystrophy. (A) Histology shows deposits of abnormal glycosaminoglycans that appear blue with colloidal  iron stain; (B) and (C) poorly delineated deposits increasing in number; (D) increase in size and confluence of lesions, with  stromal haze   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann, 2001 - fig. A; A Ridgway - figs B, C and D)   o Central haze is an early feature (Fig. 6.55A), progressing  to more widespread full-thickness involvement over time  (Fig. 6.55B).   o Prominent corneal arcus is typical, and gradually  progresses centrally leading to diffuse haze.   It is not certain that this entity is a dystrophy; it may be clinically  indistinguishable from the degeneration posterior crocodile  shagreen.   o Cloudy greyish polygonal or rounded posterior stromal  opacities, most prominent centrally (Fig. 6.56).    Fig. 6.55 Schnyder dystrophy. (A) Early lesion; (B) late more  diffuse haze - a prominent arcus is present   (Courtesy of K Nischal - fig. A, W Lisch - fig. B)   Congenital stromal corneal dystrophy, fleck corneal dystrophy,  posterior amorphous corneal dystrophy and pre-Descemet corneal  dystrophy.   This disorder is characterized by bilateral accelerated endothelial  cell loss. It is more common in women and is associated with a  slightly increased prevalence of open-angle glaucoma.   inheritance. Mutation in COL8A2 has been identified in an  early-onset variant.    • Symptoms. Gradually worsening blurring, particularly in the  morning, due to corneal oedema. Onset is usually in middle  age or later.   o Cornea guttata: the presence of irregular warts or  ‘excrescences’ on Descemet membrane secreted by  abnormal endothelial cells (Fig. 6.57A).  o Specular reflection shows tiny dark spots caused by  disruption of the regular endothelial mosaic (Fig. 6.57B);  progression occurs to a ‘beaten metal’ appearance  (Fig. 6.57C).   o Endothelial decompensation gradually leads to central  stromal oedema and blurred vision, worse in the  morning.   o Epithelial oedema develops in more advanced cases, with  the formation of microcysts and bullae (bullous  keratopathy - Fig. 6.57D) accompanied by discomfort;  rupture of bullae is associated with marked acute pain,  thought to be due to the exposure of nerve fibres.  Subepithelial scarring and peripheral vascularization may  be seen in longstanding cases.   o Conservative options include topical sodium chloride 5%  drops or ointment, reduction of intraocular pressure and  use of a hair dryer for corneal dehydration,  o Ruptured bullae can be made more comfortable by the  use of bandage contact lenses, cycloplegia, antibiotic  ointment and lubricants. Anterior stromal puncture may  be helpful.   o Posterior lamellar (e.g. Descemet membrane-stripping  endothelial keratoplasty - DSAEK - or Descemet  membrane endothelial keratoplasty - DMEK) and  penetrating keratoplasty (see Ch. 7) have a high success  rate.   Fig. 6.57 Fuchs endothelial dystrophy. (A) Histology of cornea guttata shows irregular excrescences of Descemet membrane  - PAS stain; (B) cornea guttata seen on specular reflection; (C) ‘beaten-bronze’ endothelium; (D) bullous keratopathy   (Courtesy of J Harry - fig. A; W Lisch - fig. D)    o Options in eyes with poor visual potential include  conjunctival flaps and amniotic membrane  transplantation.   o A promising new treatment, topical Rho-kinase inhibitor  with prior transcorneal endothelial cryotherapy, seems to  stimulate endothelial cell proliferation and improve  function.   significant endothelial cell loss, and protective steps should  be taken. A ‘triple procedure’ (combined cataract surgery,  lens implantation and keratoplasty) may be considered in  eyes with corneal oedema.   There are three forms of posterior polymorphous dystrophy,  PPCD1-3. Associations include iris abnormalities, glaucoma and  Alport syndrome. The pathological basis involves metaplasia of  endothelial cells.   • Inheritance is usually AD; the gene VSXi has been  implicated in PPCDi, PPCD2 is caused by mutations in  COL8A2, and PPCD3 by ZEBi mutations.   Congenital hereditary endothelial dystrophy (CHED) is a rare  dystrophy in which there is focal or diffuse thickening of Descemet  membrane and endothelial degeneration. CHED2 is a more  common, and more severe, form than CHEDi, and is occasionally  associated with deafness (Harboyan syndrome).   • Symptoms. Photophobia and watering are common in  CHEDi, but not in CHED2.   o Corneal clouding and thickening (Fig. 6.59) is neonatal in  CHED2, and develops during the first year or two in  CHEDi.   o Visual impairment is variable and visual acuity may  surpass that expected from the corneal appearance.   Arcus senilis (gerontoxon, arcus lipoides) is the most common  peripheral corneal opacity; it frequently occurs without any pre¬  disposing systemic condition in elderly individuals, but may be  associated with dyslipidaemia in younger patients (arcus juvenilis).   o Stromal lipid deposition, initially in the superior and  inferior perilimbal cornea, progressing circumferentially  to form a band about 1 mm wide (Fig. 6.60A).  o The band is usually wider in the vertical than horizontal  meridian.   o The central border is diffuse and the peripheral edge is  sharp and separated from the limbus by a clear zone that  may undergo mild thinning.   Vogt limbal girdle is an innocuous condition that is present in up  to 60% of individuals over 40 years of age, more commonly in  women. It consists of whitish crescentic limbal bands composed  of chalk-like flecks centred at 9 and/or 3 o’clock, more often  nasally. There may be irregular central extension. Type I may be  a variant of band keratopathy, featuring a ‘Swiss cheese’ hole  pattern and a clear area separating the lesion from the scleral  margin (Fig. 6.60B). Type II is more prevalent, and is distin¬  guished by the absence of holes and typically also of a juxtalimbal  clear zone (Fig. 6.60C); histologically the changes in both are  similar to pinguecula and pterygium.   Fig. 6.58 Posterior polymorphous dystrophy. (A) Vesicles;  (B) confluent vesicles; (C) band-like lesions   (Courtesy of K Nischal - figs A and C; J Krachmer, M Mannis and E Holland,  from Cornea, Mosby 2005 - fig. B)   Cornea farinata is a visually insignificant condition characterized  by bilateral, minute, flour-like deposits in the deep stroma, most  prominent centrally (Fig. 6.60D).   Crocodile shagreen is characterized by asymptomatic, greyish-  white, polygonal stromal opacities separated by relatively clear  spaces (Fig. 6.60E). The opacities most frequently involve the  anterior two-thirds of the stroma (anterior crocodile shagreen),  although on occasion they may be found more posteriorly (pos¬  terior crocodile shagreen). It may be indistinguishable from  Francois central cloudy dystrophy; conventionally the distinction  is on the basis of Francois dystrophy being inherited, but this has  been questioned.   • Primary lipid keratopathy is rare and occurs apparently  spontaneously. It is characterized by white or yellowish,  often with a crystalline element, stromal deposits consisting  of cholesterol, fats and phospholipids and is not associated  with vascularization (Fig. 6.61).   • Secondary lipid keratopathy is much more common and is  associated with previous ocular injury or disease that has  resulted in corneal vascularization. The most common  causes are herpes simplex and herpes zoster keratitis (see  Fig. 6.19A).   • Treatment is primarily aimed at medical control of the  underlying inflammatory disease. Other options include:  o Photocoagulation or needle cautery (suture needle   grasped with cautery forceps) of feeder vessels,  o Penetrating keratoplasty may be required in advanced but  quiescent disease, though vascularization, thinning and  hypoaesthesia may prejudice the outcome.   Band keratopathy consists of the age-related deposition of calcium  salts in the Bowman layer, epithelial basement membrane and  anterior stroma.   o Ocular. Chronic anterior uveitis (particularly in  children), phthisis bulbi, silicone oil in the anterior  chamber, chronic corneal oedema and severe chronic  keratitis.   o Age-related; affects otherwise healthy individuals,  o Metabolic (metastatic calcification). This is rare and  includes increased serum calcium and phosphorus,  hyperuricaemia and chronic renal failure,  o Hereditary causes include familial cases and ichthyosis.   o Peripheral interpalpebral calcification with clear cornea  separating the sharp peripheral margins of the band from  the limbus (Fig. 6.62A).   Fig.6.60 Age-related degenerations. (A) Arcus senilis; (B) Vogt limbal girdle type I; (C) Vogt limbal girdle type II; (D) cornea  farinata; (E) crocodile shagreen    o Gradual central spread to form a band-like chalky plaque  containing transparent small holes (Fig. 6.62B) and  occasionally clefts.   o Advanced lesions may become nodular and elevated with  considerable discomfort due to epithelial breakdown (Fig.  6.62C).   • Treatment is indicated if vision is threatened or if the eye is  uncomfortable. It is important to recognize and treat any  underlying condition.   o Chelation is simple and effective for relatively mild cases  and is performed using a microscope. The corneal  epithelium overlying the opacity and a solid layer of  calcification are first scraped off with forceps and a  scalpel blade (e.g. No. 15). The cornea is then rubbed  with a cotton-tipped applicator dipped in a solution of  ethylenediaminetetraacetic acid (EDTA) i.5-3.o% until all  calcium has been removed; adequate time (15-20  minutes) must be allowed for chelation to occur, and  more than one session may be necessary.  Re-epithelialization can take many days,  o Other modalities: diamond burr, excimer laser  keratectomy and lamellar keratoplasty.   Spheroidal degeneration (Labrador keratopathy, climatic droplet  keratopathy) typically occurs in men whose working lives are  spent outdoors. Ultraviolet exposure is likely to be an aetiological  factor. The condition is relatively innocuous but visual impair¬  ment may rarely occur. A secondary form can follow inflamma¬  tion or injury.   • Histology. Irregular proteinaceous deposits in the anterior  stroma that replace the Bowman layer.   Fig. 6.62 Band keratopathy. (A) Moderate; (B) typical  appearance with small holes; (C) advanced disease with  overlying epithelial breakdown   o Amber-coloured granules in the superficial stroma of the  peripheral interpalpebral cornea,  o Increasing opacification, coalescence and central spread,  o Advanced lesions commonly protrude above the corneal  surface (Fig. 6.63) and the surrounding stroma is often  hazy; the conjunctiva can be involved.   • Treatment. Protection against ultraviolet damage with  sunglasses, and superficial keratectomy or lamellar  keratoplasty in a minority.   Salzmann nodular degeneration consists of nodules of hyaline  tissue, usually located anterior to the Bowman layer. It can occur  in any form of chronic corneal irritation or inflammation such as  trachoma, dry eye, chronic blepharitis and chronic allergic  keratoconjunctivitis.   o Superficial stromal opacities progressing to elevated  whitish or blue-grey nodular lesions that may be round  or elongated (Fig. 6.64).   o The base of a nodule may be associated with pannus and  epithelial iron deposition.   • Treatment consists mainly of lubrication together with  control of the cause. Removal is via manual superficial  keratectomy - the lesions can often be ‘peeled’ away and the  surface flattened with a diamond burr. Adjunctive  mitomycin C applied for 10 seconds with a sponge may  reduce the recurrence rate, though some authorities restrict  its use to reoperations. Excimer laser phototherapeutic  keratectomy or lamellar keratoplasty are occasionally  required.   Advancing wave-like epitheliopathy (AWE) is characterized by an  irregular advancing epithelial plaque encroaching gradually on the  cornea, typically originating at the superior limbus (Fig. 6.65) and  sometimes extending circumferentially from a pterygium. Topical  fluorescein generally demonstrates the lesion well. Irritation and  redness are common; the vision may be affected with central  involvement. Reported risk factors include contact lens wear,  certain contact lens solutions, topical glaucoma medication, prior  ocular surgery and some skin conditions such as rosacea. Treat¬  ment of the cause may be curative, but otherwise is with 1% silver  nitrate solution to the adjacent limbus or cryotherapy (1-2 seconds  twice) to the limbus and abnormal tissue. Distinction from neo¬  plasia may occasionally warrant impression cytology or excision  biopsy.   Fig. 6.64 Salzmann nodular degeneration. (A) Solitary early  elongated lesion; (B) multiple lesions   Cystinosis is a rare AR (gene: CTNS) lysosomal storage disorder  characterized by widespread tissue deposition of cystine crystals,  leading to paediatric renal failure and a range of other severe  systemic problems. Non-nephropathic (ocular), nephropathic  and intermediate forms can occur. Keratopathy may develop in  the first year, with progressive deposition of crystals in the cornea  (Fig. 6.66A) and conjunctiva associated with photophobia, epithe¬  lial erosions and visual impairment. Systemic treatment is with  cysteamine, which can be given in eye drop form to reverse corneal  crystal formation.   The mucopolysaccharidoses (MPS) are a group of lysosomal  storage disorders involving enzyme dysfunction along the path¬  ways for breakdown of glycosaminoglycans, long chain car¬  bohydrates formerly known as mucopolysaccharides. Altered  metabolites accumulate intracellularly in various tissues. Inherit¬  ance is mainly AR. Systemic features vary with the type of MPS,  but can include facial coarseness, skeletal anomalies, heart disease  and learning difficulties. Keratopathy comprises punctate corneal  opacification and diffuse stromal haze (Fig. 6.66B), and occurs in  all MPS except Hunter and Sanfilippo. Other ocular features may  include pigmentary retinopathy and optic atrophy.   Wilson disease (hepatolenticular degeneration) is a rare condition  involving the widespread abnormal deposition of copper in  tissues. It is caused by a deficiency of caeruloplasmin, the major  copper-carrying blood protein. Presentation is with liver disease,  basal ganglia dysfunction or psychiatric disturbances. A Kayser-  Fleischer ring is present in 95% of patients with neurological signs,  and consists of a brownish-yellow zone of fine copper dusting in   Lecithin-cholesterol-acyltransferase (LCAT) deficiency is a disor¬  der of lipoprotein metabolism that has complete (Norum disease,  with systemic manifestations including renal failure) and partial  (fish eye disease, causing only corneal opacification) forms that  are both AR (gene: LCAT). Keratopathy is characterized by  numerous minute greyish dots throughout the stroma, often con¬  centrated in the periphery in an arcus-like configuration (Fig.  6.66D).   Diffuse or focal immunoprotein deposition is a relatively uncom¬  mon manifestation of several systemic diseases, including multiple  myeloma, Waldenstrom macroglobulinaemia, monoclonal gam-  mopathy of unknown cause, some lymphoproliferative disorders  and leukaemia. Corneal involvement may be the earliest manifes¬  tation. Bands of punctate flake-like opacities are seen, mostly at  the level of the posterior stroma (Fig. 6.66E). Treatment is that of  the underlying disease; severe corneal involvement may require  corneal transplantation.   Tyrosinaemia type 2 (oculocutaneous tyrosinaemia, Richner-  Hanhart syndrome) is a very rare AR disease (gene: TAT) in which  an enzyme deficiency leads to elevated plasma tyrosine levels.  Ocular involvement may occasionally be the presenting feature.  Painful palmar and plantar hyperkeratotic lesions and variable  central nervous system involvement are seen. A bilateral pseudo-  dendritic keratitis with crystalline edges often begins in childhood  and causes photophobia, watering and redness.   Fabry disease is an X-linked lysosomal storage disorder caused by  a deficiency of the enzyme alpha-galactosidase A that leads to  abnormal tissue accumulation of a glycolipid. All males with the  gene develop the disease, and some heterozygous females. Sys¬  temic features include periodic burning pain in the extremities  (acroparaesthesia) and GI tract, angiokeratomas (Fig. 6.67A), car¬  diomyopathy and renal disease. Ocular manifestations include  white to golden-brown corneal opacities in a vortex pattern (75%)  that may be the first feature of the disease (Fig. 6.67B), facilitating  early intervention; wedge- or spoke-shaped posterior cataract  (Fabry cataract); conjunctival vascular tortuosity (corkscrew  vessels) and aneurysm formation (Fig. 6.67C); and retinal vascular  tortuosity.   (C) Wilson disease; (D) LCAT (see text) deficiency;  (E) immunoprotein deposits   (Courtesy of L Merin - fig. A; S Chen - fig. C; W Lisch - fig. D)   Fig. 6.67 Fabry disease. (A) Angiokeratomas; (B) vortex  keratopathy; (C) conjunctival vessel tortuosity and  aneurysms   The risks of fitting a contact lens to an already compromised eye  are greater than with lens wear for cosmetic reasons. The benefit-  risk balance should be considered in each case individually, with  education and regular review to ensure early diagnosis and treat¬  ment of complications. The choice of lens type is dictated by the  nature of the ocular pathology.   Optical indications are aimed at improving visual acuity when this  cannot be achieved by spectacles in the following situations:   • Irregular astigmatism associated with keratoconus can be  corrected with rigid contact lenses after spectacles have failed  and before corneal grafting becomes necessary. Patients with  astigmatism following corneal grafting may also benefit.   • Superficial corneal irregularities can be neutralized by rigid  contact lenses, which provide a smoother and optically more  regular surface. Visual acuity can only be substantially  improved if irregularities are not too severe.   • Anisometropia in which binocular vision cannot be  achieved by spectacles due to aniseikonia, such as may occur  following monocular cataract surgery with high refractive  error correction.   • Persistent epithelial defects often heal if the regenerating  corneal epithelium is protected from the constant rubbing of  the lids, allowing the development of hemidesmosomal  attachments to the basement membrane.   • Recurrent corneal erosions associated with basement  membrane dystrophy may require long-term contact lens  wear to reduce the recurrence rate. In post-traumatic cases,  lens wear can usually be discontinued after a few weeks. Lens  wear also improves comfort.   • Bullous keratopathy can be managed with soft bandage  lenses that relieve pain by protecting the exposed corneal  nerve endings from the shearing forces of the lids during  blinking. The lens may also flatten bullae into diffuse fine  epithelial cysts.   • Filamentary keratopathy resistant to topical treatment will  usually achieve some relief from soft contact lens wear.   • Other indications include Thygeson superficial punctate  keratitis and protection of the corneal epithelium from  aberrant lashes in trichiasis; they can also be used as a  temporizing measure in entropion prior to definitive  surgery.   • A descemetocoele can be temporarily capped with a  tight-fitting, large-diameter soft or scleral lens to prevent  perforation and encourage healing.   • Splinting and apposition of the edges of a small corneal  wound can be achieved by means of a contact lens. Slightly  larger perforations may be sealed with glue followed by  insertion of a bandage contact lens to both protect the glue  and prevent irritation of the lids from the glue’s irregular  surface.   • Ptosis props to support the upper lids in patients with  ocular myopathies.   • Maintenance of the fornices to prevent symblepharon  formation in cicatrizing conjunctivitis.   • Drug delivery enhancement by a hydrogel lens imbued with  topical medication is an occasional indication.   • Pathogenesis. Insufficient oxygen transmission through the  lens. A tightly fitting contact lens that does not move with  blinking will impair tear circulation under the lens. This is  exacerbated by lid closure if the lens is worn during sleep.  Hypoxia leads to anaerobic metabolism and lactic acidosis  that inhibits the normal barrier and pump mechanisms of  the cornea.   • Superficial punctate keratitis is the most common  complication. The pattern may give a clue as to the aetiology.  For example, staining at 3 and 9 o’clock is associated with  incomplete blinking and drying in rigid lens wearers.   • The tight lens syndrome is characterized by indentation and  staining of the conjunctival epithelium in a ring around the  cornea.   • Acute hypoxia is characterized by epithelial microcysts (Fig.  6.68A) and necrosis, and endothelial blebs. Very painful  macroerosions may develop several hours after lenses are  removed following a period of overwear.   • Chronic hypoxia may result in vascularization and lipid  deposition (Fig. 6.68B); superficial peripheral  neovascularization of <1.5 mm is common in myopic contact  lens wearers and can be monitored.   O Increasing oxygen permeability by refitting with a thinner  lens, a gas permeable rigid lens or a silicone hydrogel soft  lens.   A hypersensitivity response to bacterial antigen or the chemicals  used in lens care can lead to the development of sterile marginal    corneal infiltrates; the mechanism is thought to be similar to that  of marginal keratitis.   • Signs. Mildly red eye associated with infiltrates, often  marginally located, with no or minimal epithelial defects  (Fig. 6.68C).   • Treatment involves cessation of lens wear until resolution  occurs. Topical antibiotics and steroids may be used in some  cases, but if the diagnosis is uncertain, treatment should be  that of bacterial keratitis.   • Pathogenesis. Acute chemical injury may be caused by  inadvertently placing a contact lens on the eye without first  neutralizing toxic cleaning agents such as hydrogen  peroxide. Chronic toxicity can result from long-term  exposure to disinfecting preservatives such as thiomersal or  benzalkonium chloride.   o Acute pain, redness, and chemosis on lens insertion,  which may take 48 hours to resolve completely.   O Vascularization and scarring of the cornea (Fig. 6.68D)  and limbal conjunctiva in chronic cases.   • Treatment may involve switching to daily disposable lenses  or using a non-preserved disinfectant such as hydrogen  peroxide.   Contact lens wear is the greatest risk factor for the development  of bacterial keratitis; the risk is probably least for rigid contact  lenses. Bacteria in the tear film are normally unable to bind to the  corneal epithelium, but following an abrasion and in association  with hypoxia, they can attach and invade the epithelium. Micro¬  organisms may also be introduced onto the corneal surface by  poor lens hygiene or the use of tap water for rinsing.   The normal neonatal corneal diameter is 10 mm, and the adult  diameter of 12 mm is usually reached by the age of 2 years. Micro-  cornea is a rare autosomal dominant (sometimes sporadic) uni¬  lateral or bilateral condition in which the horizontal corneal  diameter is 10 mm or less over 2 years of age (Fig. 6.69A), or less  than 9 mm in the newborn; there may be hypermetropia and a  shallow anterior chamber but other dimensions are normal.  Ocular associations include glaucoma (angle-closure and open-  angle), congenital cataract, leukoma (Fig. 6.69B), persistent fetal  vasculature, coloboma, optic nerve hypoplasia, aniridia and   Fig. 6.68 Complications of contact lens wear. (A) Epithelial microcysts in acute hypoxia; (B) ghost vessels and lipid  deposition from chronic hypoxia; (C) marginal infiltrates in immune response keratitis; (D) vascularization and scarring in  chronic toxic keratitis   (Courtesy of S Tuft - figs A and B; J Dart - fig. D)   Fig. 6.69 (A) Severe microcornea; (B) microcornea and corneal opacity - leukoma   nanophthalmos. Systemic associations have been reported. Refrac¬  tive error and amblyopia should be managed appropriately.   Microphthalmos (microphthalmia - Fig. 6.70A) is a condition in  which the entire eye is small, with an axial length at least two  standard deviations below the mean for age. Simple or pure  microphthalmos (nanophthalmos - see below) refers to an eye  that is structurally normal apart from a short length, and complex  microphthalmos to eyes with other features of dysgenesis; a colo-  boma (Fig. 6.70B) or orbital cyst (Fig. 6.70C) and a range of other  ocular abnormalities. It may be unilateral or bilateral; when uni¬  lateral, abnormalities may be present in the fellow eye. Vision is  variably affected, in conjunction with severity. It is typically spo¬  radic; mutations in numerous genes have been implicated. Around  50% of cases may be associated with systemic abnormalities,  including of the central nervous system. Potential environmental  causes include fetal alcohol syndrome and intrauterine  infections.   In nanophthalmos (simple microphthalmos) the entire eye is  small but is structurally normal; both eyes are usually affected.  Ocular associations include uveal effusions associated with thick¬  ened sclera, glaucoma (especially angle-closure as the lens is large  relative to the size of the eye), hypermetropia, ametropia, often  bilateral, amblyopia and strabismus. In childhood, management  of refractive error and amblyopia are critical. Cataract surgery  poses particular technical problems; a custom high-power lens  implant may be considered to avoid polypseudophakia with its  attendant risk of precipitating angle-closure.   Anophthalmos (anophthalmia) refers to the complete absence of  any visible globe structure (Fig. 6.71A), though a microphthalmic  remnant or cyst may be present (Fig. 6.71B). It is associated with  other abnormalities such as absence of extraocular muscles, a  short conjunctival sac and microblepharon. Causative factors are  probably broadly similar to those of microphthalmos.   Megalocornea is a rare bilateral non-progressive condition that is  usually X-linked recessive; 90% of affected individuals are male.  The adult horizontal corneal diameter is 13 mm or more, with a  very deep anterior chamber (Fig. 6.72A). There is typically high  myopia and astigmatism but normal corrected visual acuity. Lens  subluxation may occur due to zonular stretching, and pigment  dispersion syndrome (see Ch. 10) is very common (Fig. 6.72B).  Numerous systemic associations have been reported.   Fig. 6.70 (A) Left microphthalmos; (B) left microphthalmos  and bilateral iris colobomas; (C) axial CT shows right  microphthalmos with cyst   Sclerocornea is a very rare, usually bilateral, condition that may  be associated with cornea plana (see below). Sporadic cases are  common, but a milder form can be inherited as AD and a more  severe form as AR. Peripheral corneal opacification, with no  visible border between the sclera and cornea, confers the    appearance of apparently reduced corneal diameter in mild-  moderate disease (Fig. 6.73 A); occasionally the entire cornea is  involved (Fig. 6.73B).   This is an extremely rare bilateral condition in which the cornea  is flatter than normal (Fig. 6.74) - the radius of curvature is larger.  There is a corresponding reduction in refractive power resulting  in high hypermetropia. Two forms are described, cornea plana 1  (CNAi) being milder than cornea plana 2. Associated ocular  abnormalities are common.   Keratectasia is a very rare, usually unilateral, condition thought to  be the result of intrauterine keratitis and perforation. It is charac¬  terized by protuberance between the eyelids of a severely opacified  and sometimes vascularized cornea (Fig. 6.75). It is often associ¬  ated with raised intraocular pressure.   Posterior keratoconus is a sporadic condition in which there is  unilateral non-progressive increase in curvature of the posterior  corneal surface. The anterior surface is normal and visual acuity  relatively unimpaired because of the similar refractive indices of  the cornea and aqueous humour. Generalized (involvement of the  entire posterior corneal surface) and localized (paracentral or  central posterior indentation - Fig. 6.76) types are described.    Deep anterior lamellar  keratoplasty 244  Endothelial keratoplasty 244  Limbal stem cell grafting 245   Corneal transplantation (grafting) refers to the replacement of  diseased host corneal tissue by healthy donor cornea. A corneal  graft (keratoplasty) may be partial-thickness (anterior or posterior  lamellar) or full-thickness (penetrating).   • Optical keratoplasty is performed to improve vision.  Important indications include keratoconus, scarring, corneal  dystrophies (Fig. 7.1A), pseudophakic bullous keratopathy  and corneal degenerations.   • Tectonic grafting may be carried out to restore or preserve  corneal integrity in eyes with severe structural changes such  as thinning with descemetocoele (US spelling -  descemetocele; Fig. 7.1B).   • Therapeutic corneal transplantation facilitates removal of  infected corneal tissue in eyes unresponsive to antimicrobial  therapy (Fig. 7.1C).   • Cosmetic grafting may be performed to improve the  appearance of the eye, but is a rare indication.   Donor tissue should be removed within 12-24 hours of death.  There is an attempt to age-match donors and recipients; corneas  from infants (3 years and under) are used only very occasionally,  even for paediatric transplants, as they are associated with surgical,  refractive and rejection problems. Most corneas are stored in  coordinating c eye banks’ prior to transplantation, where pre¬  release evaluation includes medical history review and donor  blood screening to exclude contraindications, and microscopic  examination of the cornea including endothelial cell count deter¬  mination. Corneas are preserved in hypothermic storage (up to  7-10 days) or organ culture medium (4 weeks) until needed;  culture allows extended testing for infective contamination. Con¬  traindications to ocular tissue donation are set out below, though  there is international variation and the list is not exhaustive:   • Certain systemic infections such as human  immunodeficiency virus (HIV), viral hepatitis, syphilis,  congenital rubella, tuberculosis, septicaemia and active  malaria.   • Prior high-risk behaviour for HIV and hepatitis such as sex  with someone HIV-positive, men who have sex with men,  intravenous drug abuse and prostitution.   • Within the last 12 months: sex with someone who has  engaged in high-risk behaviour, or who lives in parts of  Africa, or who has received blood clotting factor  concentrates; tattooing, acupuncture or ear/body piercing;  imprisonment.   • Infectious and possibly infectious diseases of the central  nervous system, such as Creutzfeldt-Jakob disease, systemic   Fig. 7.1 (A) Optical penetrating keratoplasty for macular  corneal dystrophy; (B) tectonic lamellar patch graft for  descemetocoele; (C) penetrating keratoplasty for  pseudomonas keratitis - a dense cataract and posterior  synechiae are visible    sclerosing panencephalitis, progressive multifocal  leukoencephalopathy, encephalitis, Alzheimer disease and  other dementias, Parkinson disease, multiple sclerosis and  motor neurone disease.   • Ocular disease such as inflammation and disease likely to  compromise graft outcome, some malignant ocular tumours  (e.g. retinoblastoma) and corneal refractive surgery.   The following host factors may adversely affect the prognosis of a   corneal graft and if possible should be optimized prior to surgery.   • Severe stromal vascularization (Fig. 7.2), absence of corneal  sensation, extreme thinning at the proposed host-graft  junction and active corneal inflammation.   • Abnormalities of the eyelids, such as blepharitis, ectropion,  entropion and trichiasis; these should be addressed before  surgery.   • Recurrent or progressive forms of conjunctival inflammation,  such as atopic conjunctivitis and ocular cicatricial pemphigoid.   Fig. 7.3 Excision of host tissue. (A) Partial-thickness  trephination; (B) incision into the anterior chamber;  (C), (D) and (E) completion of excision; (F) injection of  viscoelastic bed    is the appropriate procedure for disease involving all layers of the   • A common graft size is 7.5 mm; smaller grafts may give high  astigmatism, and larger diameters are associated with an  increasing tendency to peripheral anterior synechiae  formation and raised intraocular pressure (IOP).   • The donor button is usually about 0.25 mm larger in  diameter than the host site.   • Preparation of donor cornea should always precede excision  of host tissue (Fig. 7.3), in case a problem with the former  means that the surgery cannot be completed.   • Either mechanically guided manual or automated (including  laser) trephination is commonly used.   • The graft may be secured with either interrupted (see Fig.  7.1C) or continuous (Fig. 7.4) suture techniques, or a  combination of both.   • Topical steroids (e.g. prednisolone acetate 1%,  dexamethasone phosphate 0.1%) are used to decrease the  risk of immunological graft rejection. Initial administration    is typically every 2 hours with gradual tapering depending  on the likelihood of rejection and clinical progress. Long¬  term instillation at low intensity, such as once daily for a  year or more, is usual.   • Other immunosuppressants such as oral azathioprine and  topical and systemic ciclosporin are usually reserved for  high-risk patients.   • Cycloplegia (e.g. homatropine 2% twice daily) is typically  used for 1-2 weeks.   • Oral aciclovir may be used in the context of pre-existing  herpes simplex keratitis to minimize the risk of recurrence.   • Monitoring of IOP. Applanation tonometry is relatively  unreliable so measurement is commonly performed during  the early postoperative period with a non-applanation  method.   • Removal of sutures is performed when the graft-host  junction has healed. This is often after 12-18 months,  although in elderly patients it may take much longer.    Removal of broken or loose individual sutures is performed  as soon as identified, to avoid promoting rejection.   • Early complications include persistent epithelial defects,  loose or protruding sutures (risk of infection - Fig. 7.5A,  marked sterile reaction, papillary hypertrophy), wound leak  (sometimes with flat anterior chamber or iris prolapse),  uveitis, elevation of intraocular pressure, traumatic graft  rupture (Fig. 7.5B), cystoid macular oedema, microbial  keratitis (Fig. 7.5C), endophthalmitis (Fig. 7.5D) and  rejection (see below). A rare complication is a fixed dilated  pupil (Urrets-Zavalia syndrome).   • Late complications include astigmatism, recurrence of  underlying disease, late wound dehiscence, retrocorneal  membrane formation, glaucoma, rejection (see below) and  failure without rejection.   Fig. 7.5 Early postoperative complications. (A) Loose continuous suture with probable infection and rejection; (B) traumatic  graft rupture and extrusion of intraocular lens implant; (C) microbial keratitis; (D) endophthalmitis   (Courtesy of C Barry - fig. A; R Bates - fig. B; S Tuft - fig. D)   Immunological rejection of any layer of the cornea can occur.  Rejection of separate layers (endothelial, stromal and epithelial)  can occur in isolation, but typically a combination is present.  Simple graft failure can occur in the absence of rejection, although  rejection is a common contributory factor.   privileged, with an absence of blood vessels and lymphatics  and the presence of relatively few antigen-presenting cells;  inflammation and neovascularization contribute to loss of  this privilege. Important predisposing factors for rejection  include eccentric or larger grafts (over 8 mm in diameter),  infection (particularly herpetic), glaucoma and previous  keratoplasty. If the host becomes sensitized to  histocompatibility antigens present in the donor cornea,  rejection may result. Human leukocyte antigen (HLA)  matching has a small beneficial effect on graft survival.    • Symptoms. Blurred vision, redness, photophobia and pain  are typical, but many cases are asymptomatic until rejection  is established. The timing of onset is very variable, occurring  from days to years after keratoplasty.   o Ciliary injection associated with anterior uveitis is an  early manifestation (Fig. 7.6A).  o Epithelial rejection may be accompanied by an elevated  line of abnormal epithelium (Fig. 7.6B) in a quiet or  mildly inflamed eye, occurring at an average of 3 months;  increased treatment may not be required,  o Subepithelial rejection is characterized by subepithelial  infiltrates, reminiscent of adenoviral infection (Krachmer  spots - Fig. 7.6C) on the donor cornea, with deeper  oedema and infiltrative opacification,  o Stromal rejection features deeper haze. It can be chronic  or hyperacute, the latter in association with endothelial  rejection.   Fig. 7.6 Allograft rejection. (A) Ciliary injection; (B) elevated epithelial line in epithelial rejection; (C) Krachmer spots;  (D) endothelial rejection with Khodadoust line    o Endothelial rejection is characterized by a linear pattern  of keratic precipitates (Khodadoust line - Fig. 7.6D)  associated with an area of inflammation at the graft  margin.   • Management. Early intensive treatment greatly improves the  likelihood of reversing the rejection. The most aggressive  regimen is generally required for endothelial rejection,  followed in order of severity by stromal, subepithelial and  epithelial. Intraocular pressure monitoring is critical.   o Preservative-free topical steroids hourly for 24 hours are  the mainstay of therapy. The frequency is reduced  gradually over several weeks. Steroid ointment can be  used at bedtime as the regimen is tapered. High-risk  patients can be maintained on the highest tolerated  topical dose (e.g. prednisolone acetate 1% four times  daily) for an extended period.   o Topical cycloplegia (e.g. homatropine 2% or atropine 1%  once or twice daily).   o Topical ciclosporin 0.05% to 2% may be of benefit, but  the onset of action is delayed.   o Systemic steroids. Oral prednisolone 1 mg/kg/day for 1-2  weeks with subsequent tapering; if given within 8 days of  onset intravenous methylprednisolone 500 mg daily for  up to 3 days may be particularly effective, suppressing  rejection and reducing the risk of further episodes,  o Subconjunctival steroid injection (e.g. 0.5 ml of 4 mg/ml  dexamethasone) is sometimes used,  o Other systemic immunosuppressants such as ciclosporin,  tacrolimus or azathioprine.   • Differential diagnosis includes graft failure (no  inflammation), infective keratitis including fungal and  herpetic, uveitis, sterile suture reaction, raised IOP and  epithelial ingrowth.   This involves partial-thickness excision of the corneal epithelium  and stroma so that the endothelium and part of the deep stroma  are left behind as a bed for appropriately partial-thickness donor  cornea. The area grafted depends on the extent of the disease  process to be addressed.   o Opacification of the superficial one-third of the corneal  stroma not caused by potentially recurrent disease.   O Marginal corneal thinning or infiltration as in recurrent  pterygium, Terrien marginal degeneration, and limbal  dermoids or other tumours.   Deep anterior lamellar keratoplasty (DALK) is a technique in  which corneal tissue is removed almost to the level of Descemet  membrane. A theoretical advantage is the decreased risk of rejec¬  tion because the endothelium, a major target for rejection, is not   Fig. 7.7 Deep anterior lamellar keratoplasty for chemical  injury. A superior conjunctival limbal autograft has also  been performed    transplanted. The major technical difficulty lies in judging the  depth of the corneal dissection as close as possible to Descemet  membrane without perforation, and if this is not achieved the  visual outcome may be compromised.   o Disease involving the anterior 95% of corneal thickness  with normal endothelium and the absence of breaks or  scars in Descemet membrane (e.g. keratoconus without a  history of acute hydrops, superficial trauma - Fig. 7.7).  o Chronic inflammatory disease such as atopic   o No risk of endothelial rejection, although epithelial/  subepithelial/stromal rejection may occur,  o Less astigmatism and a structurally stronger globe  compared with penetrating keratoplasty,  o Increased availability of graft material since endothelial  quality is irrelevant.   • Postoperative management is similar to penetrating  keratoplasty except that lower intensity topical steroids are  needed and sutures can usually be removed after 6 months.   Endothelial keratoplasty involves removal only of diseased  endothelium along with Descemet membrane (DM) through a  corneoscleral or corneal incision. Folded donor tissue is intro¬  duced through the same small (2.8-5.o mm) incision. Descemet   and alveolar bone supporting a central optical cylinder, and is  usually covered with a buccal mucous membrane graft. Surgery is  difficult and time-consuming and is performed in two stages, 2-4  months apart.   o Bilateral blindness from severe but inactive anterior  segment disease with no realistic chance of success from  conventional keratoplasty, e.g. Stevens-Johnson  syndrome, ocular cicatricial pemphigoid, chemical burns  and trachoma.   o Visual acuity of counting finger or less in the better eye.  o Intact optic nerve and retinal function, without marked  glaucomatous optic neuropathy,  o High patient motivation.   • Complications include glaucoma (up to 75%),  retroprosthesis membrane formation (Fig. 7.9B), tilting or  extrusion, retinal detachment and endophthalmitis.  Glaucoma management is inevitably extremely challenging.    stripping (automated) endothelial keratoplasty (DSAEK), uses an  automated microkeratome to prepare donor tissue and is cur¬  rently the most commonly performed technique; a small amount  of posterior stromal thickness is transplanted along with DM and  endothelium. Descemet membrane endothelial keratoplasty  (DMEK) is a more recently introduced procedure in which only  the DM and endothelium are transplanted; better visual outcomes  and lower rejection rates seem to be achieved, but intraoperative  complication rates are higher.   • Indications include endothelial disease such as Fuchs  endothelial corneal dystrophy.   O Specialized equipment is required,  o Endothelial rejection can still occur (Fig. 7.8).   Various techniques have been described to attempt to replenish  the limbal stem cell population in patients with severe ocular  surface disease and associated stem cell deficiency. These include  transplantation of a limbal area of limited size from a healthy  fellow eye (see Fig. 7.7), complete limbal transplantation of a  donor annulus and ex vivo expansion by culture of either host or  donor stem cells with subsequent transplantation. A consistently  successful technique has not yet been established, and research is  ongoing.    Keratoprostheses (Fig. 7.9A) are artificial corneal implants used  in patients unsuitable for keratoplasty. The modern osteo-  odontokeratoprosthesis consists of the patient’s own tooth root    Fig. 7.9 (A) Keratoprosthesis; (B) retroprosthesis membrane  formation with associated funnel-shaped retinal  detachment    • Results. Approximately 80% of patients achieve visual acuity  between counting fingers and 6/12, and occasionally even  better. A poor outcome is often associated with pre-existing  optic nerve or retinal dysfunction.   Refractive surgery encompasses a range of procedures aimed at  changing the refraction of the eye by altering the cornea or lens,  the principal refracting components. Myopia, hypermetropia  (hyperopia) and astigmatism can all be addressed, though cor¬  rection of presbyopia is yet to be achieved on a consistently  satisfactory basis.   • Surface ablation procedures (see below) can correct  low-moderate degrees of myopia.   • Laser in situ keratomileusis (LASIK - see below) can  correct moderate to high myopia depending on initial  corneal thickness, but for very high refractive errors one of  the intraocular procedures below is necessary.   • Refractive lenticule extraction (see below) is a newer  technique for the correction of myopia and myopic  astigmatism.   • Clear lens exchange gives very good visual results but carries  a small risk of the complications of cataract surgery (see  Ch. 9), particularly retinal detachment in high myopes.   • Iris clip (‘lobster claw’) implant is attached to the iris (Fig.  7.10A). Complications include subluxation or dislocation  due to dislodgement of one or both attachments (Fig. 7.10B),  an oval pupil, endothelial cell loss, cataract, pupillary-block  glaucoma and retinal detachment.   • Phakic posterior chamber implant (implantable contact  lens, ICL) is inserted behind the iris and in front of the lens  (Fig. 7.10C), and supported in the ciliary sulcus. The lens is  composed of material derived from collagen (Collamer) with  a power of-3 D to -20.50 D. Visual results are usually very  good but complications include uveitis, pupillary block,  endothelial cell loss, cataract formation and retinal  detachment.    Fig. 7.10 Phakic intraocular implants for correction of  myopia. (A) Anterior chamber iris claw implant with anterior  iris attachment at 3 and 9 o’clock; (B) inferior subluxation  with resultant inferior endothelial decompensation -  note also an iridectomy to prevent pupillary block;   (C) emplacement of a posterior chamber phakic implant  between the iris and anterior lens surface   (Courtesy of Y Kerdraon - fig. B; J Krachmer ; M Marinis and E Holland, from  Cornea, Mosby 2005 - fig. C)   • Conductive keratoplasty (CK) involves the application of  radiofrequency energy to the corneal stroma and can correct  low-moderate hypermetropia and hypermetropic  astigmatism. Burns are placed in one or two rings in the  corneal periphery using a probe. The resultant thermally  induced stromal shrinkage is accompanied by an increase in  central corneal curvature. Significant regression may occur  but the procedure can be repeated. CK may also be helpful  for presbyopia (see below). Complications are infrequent.   • Laser thermal keratoplasty with a holmium laser can  correct low hypermetropia. Laser burns are placed in one or  two rings in the corneal mid-periphery (Fig. 7.12). As with   Fig. 7.13 Correction of astigmatism. (A) Arcuate  keratotomies; (B) toric intraocular implant in site -  markings incorporated in the lens (arrows) facilitate correct  orientation    CK, thermally induced stromal shrinkage is accompanied by  increased corneal curvature. Correction decays over time but  treatment can be repeated.   • Other modalities include clear lens extraction and phakic  lens implants as described above for myopia; intraocular  surgical procedures are the only options for high degrees of  refractive error.   • Limbal relaxing incisions/arcuate keratotomy involves  making paired arcuate incisions on opposite sides of the  cornea (Fig. 7.13A) in the axis of the correcting ‘plus’  cylinder (the steep meridian). The resultant flattening of the  steep meridian coupled with a smaller steepening of the flat  meridian at 90° to the incisions reduces astigmatism. The  desired result can be controlled by varying the length and    depth of the incisions and their distance from the optical  centre of the cornea. Arcuate keratotomy may be combined  with compression sutures placed in the perpendicular  meridian, when treating large degrees of astigmatism such as  can occur following penetrating keratoplasty.   • Lens surgery involves using a ‘toric’ intraocular implant  incorporating an astigmatic correction (Fig. 7.13B).  Postoperative rotation of the implant away from the desired  axis occurs in a small minority of cases.   • Lens extraction, either to treat cataract or for purely  refractive purposes. Acronyms used include clear lens  exchange (CLE), refractive lens exchange (RLE) and  presbyopic lens exchange (PreLEx). Much research effort is  being applied to the development of effective  accommodating prosthetic lenses.   o Implantation of a multifocal, bifocal or ‘accommodating’/  pseudoaccommodative intraocular lens implant (IOL)  can optically restore some reading vision; reading glasses  commonly still have to be used for some tasks. Although  many recipients of multifocal IOLs are very happy with  the visual outcome, dissatisfaction occurs in a significant  minority, mainly due to nocturnal glare and reduced  contrast sensitivity. Around 10% of patients receiving  multifocal IOLs subsequently undergo higher-risk IOL  exchange surgery. In some jurisdictions, implantation of  a multifocal IOL is a contraindication to the holding of a  private or commercial pilot’s licence, or to military  service.   o ‘Monovision’ consists of the targeting of IOL-induced  refractive outcomes so that one eye (usually the  dominant) is optimized for clear uncorrected distance  vision and the other for near or intermediate vision, in  order to facilitate both good distance and near vision  when the eyes are used together,  o Some studies show similar levels of functional near vision  using bilateral distance-optimized monofocal IOLs  compared to multifocal IOLs.   • Conductive keratoplasty (see ‘Correction of hypermetropia’  above); there is some evidence that CK can impart a degree  of multifocal functionality to the cornea.   • Laser-induced monovision refers to the use of laser  refractive surgery to optimize one eye for distance and the  fellow for near or intermediate vision (see above under ‘Lens  extraction’).   • Corneal multifocality. Several different approaches are  under development utilizing a laser procedure to alter the  shape of the cornea such that a bifocal or transitional effect  is induced.    • Scleral expansion surgery. Results have been inconsistent  and unpredictable and this technique has not achieved  sustained popularity.   • Intracorneal inlays (Fig. 7.14A-D) commonly provide  substantial benefit in presbyopia, though in the past the  biocompatibility of some materials has been relatively poor,  and complications such as extrusion (Fig. 7.14E) can  mandate explantation.   • Laser modification of the natural lens. Research is ongoing  into the use of a femtosecond laser to modulate crystalline  lens elasticity.   To settle any contact lens-induced corneal distortion prior to  definitive keratometry, soft contact lenses should probably be dis¬  continued for 2 weeks and hard/rigid gas permeable lenses for at  least 3 weeks (some surgeons suggest 1 week for each year of wear  to date).   Laser (or laser-assisted) in situ keratomileusis (LASIK) is a very  common refractive procedure. The excimer laser, which can ablate  tissue to a precise depth with negligible disruption of surrounding  areas, is used to reshape corneal stroma exposed by the creation  of a superficial flap; the flap remains attached by a hinge to facili¬  tate accurate and secure repositioning. Myopia is corrected by  central ablative flattening, and hypermetropia by ablation of the  periphery so that the centre becomes steeper. LASIK can generally  be used to treat higher refractive errors than surface ablation tech¬  niques (see below): hypermetropia up to 4 D, astigmatism up to  5 D and myopia up to 12 D depending on initial corneal thickness.  To decrease the risk of subsequent ectasia, a residual corneal base  at least 250 pm thick must remain after ablation. The amount of  tissue removed, and so the amount of refractive error correctable,  is therefore limited by the original corneal thickness; very high  refractive errors can be addressed only by an intraocular proce¬  dure. In addition to treatment of a wider range of refractive errors,  advantages over surface ablation include greater postoperative  comfort, faster visual rehabilitation, more rapid stabilization of  refraction and milder stromal haze. The major disadvantage is the  potential for serious flap-related complications.   o A suction ring centred on the cornea is applied to the  globe; this raises the intraocular pressure substantially,  o The ring stabilizes the eye and provides the guide track  for a mechanical microkeratome, which is advanced  across the cornea to create a thin flap. The flap can also  be created using a femtosecond (and recently a  picosecond) laser microkeratome.  o The flap is reflected (Fig. 7.15A) and the bed reshaped,  followed by flap repositioning.   • Intraoperative complications include ‘buttonholing’  (penetration) of the flap, flap amputation, incomplete or  irregular flap creation and rarely penetration into the  anterior chamber.   Fig. 7.14 Intracorneal inlays for presbyopia correction. (A) and  (B) Refractive inlay; (C) and (D) small aperture inlay - utilizes  the pinhole effect; (E) partial extruded refractive inlay   O Wrinkling (Fig. 7.15B), distortion or dislocation of the flap,  o Subepithelial haze (Fig. 7.15C) with resultant glare,  especially at night.    o Persistent epithelial defects,  o Epithelial ingrowth under the flap (Fig. 7.15D).  o Diffuse lamellar keratitis (‘sands of the Sahara’ - Fig. 7.15E)  may develop 1-7 days following LASIK. It is characterized  by granular deposits at the flap interface. Treatment is  with intensive topical antibiotic and steroid.   Fig. 7.15 Laser in situ keratomileusis (LASIK). (A) Elevating the flap; (B) wrinkling of the flap; (C) subepithelial haze;  (D) epithelial ingrowth; (E) diffuse lamellar keratitis (‘sands of the Sahara’); (F) bacterial keratitis   (Courtesy of Eye Academy - fig. A; S Tuft - figs B and E; H Nano Jr - fig. C; C Barry - fig. D; R Bates - fig. F)   o Bacterial keratitis (Fig. 7.15F) is rare,  o Corneal ectasia (see Ch. 6). ‘Forme fruste’ (occult/mild)  keratoconus and a low post-ablation corneal thickness are  the major risk factors, and careful pre-procedure  screening should be performed to detect any  predisposition.   Like LASIK, photorefractive keratectomy (PRK) employs excimer  laser ablation to reshape the cornea. PRK is able to correct myopia  up to 6 D (sometimes higher), astigmatism up to around 3 D and  low-moderate hypermetropia. The main disadvantages compared  with LASIK are the somewhat lower degrees of refractive error  correctable, and variably slower epithelial healing with unpredict¬  able postoperative discomfort. However, as a flap is not created  there is a lower risk of serious complications than with LASIK,  including corneal ectasia and late flap dislocation, and it may be  the procedure of choice for patients at higher than average occu¬  pational or leisure-related risk of eye injury. It is also suitable for  patients rendered ineligible for LASIK due to low corneal thick¬  ness; other indications for surface ablation rather than LASIK  include epithelial basement membrane disease, prior corneal  transplantation or radial keratotomy, and large pupil size.   O The corneal epithelium is removed prior to ablation;  methods used may include a sponge, an automated brush  (Amoils epithelial scrubber) and alcohol,  o Ablation of the Bowman layer and anterior stroma (Fig.  7.16) is performed, generally taking 30-60 seconds. In   Fig. 7.16 Corneal ablation during photorefractive keratectomy  (PRK or advanced surface (laser) ablation - ASA/ASLA)    modern systems, sophisticated tracking mechanisms  adjust laser targeting with eye movement, and will pause  the procedure if the eye is significantly decentred.  o The epithelium usually heals within 48-72 hours. A  bandage contact lens is generally used to minimize  discomfort. Subepithelial haze invariably develops within  2 weeks and commonly persists for several weeks to  months. Diminished final visual acuity is rare but there  may be decreased contrast and nocturnal glare.  Intraoperative application of mitomycin C (mitomycin-  LASEK or M-LASEK) may reduce haze.   • Complications include slowly healing epithelial defects,  corneal haze with blurring and haloes, poor night vision and  regression of refractive correction. Uncommon problems  include decentred ablation, scarring, abnormal epithelial  healing, irregular astigmatism, hypoaesthesia, sterile  infiltrates, infection and acute corneal necrosis.   • Variations of PRK. A range of procedural variations with  correspondingly varying terminology have been described.  LASEK (laser epithelial keratomileusis or laser-assisted  subepithelial keratectomy), Epi-LASIK (epipolis or epithelial  LASIK; epipolis is a Greek word meaning superficial),  modified PRK, advanced surface (laser) ablation (ASA or  ASLA) and Trans-PRK (trans-epithelial PRK) are variations  of PRK that utilize a variety of techniques to try to reduce  discomfort and post-laser haze, and to speed visual recovery;  ASA and modified PRK are sometimes used generally to  refer to all surface ablative procedures. In LASEK the  epithelium is detached and peeled back after pre-treatment  with dilute alcohol; laser is then applied and the epithelium  repositioned. Epi-LASIK employs a mechanical device, an  epikeratome, to elevate a hinged sheet of epithelium with an  oscillating blunt plastic blade, and alcohol application is not  usually required. Some recent reports suggest that healing  occurs more rapidly if the epithelium is simply detached  entirely without replacement (flap-off Epi-LASIK). In  Trans-PRK, epithelial ablation is performed with the laser  prior to the refractive ablation, reducing operative time and  possibly conferring other benefits.   Refractive lenticule extraction (ReLEx) is a relatively new tech¬  nique that uses a femtosecond laser to cut a lens-shaped piece of  corneal tissue (a lenticule) within the intact cornea. This is then  removed via either a LASIK-style flap or more recently using  a minimally invasive 4 mm incision (small incision lenticule  extraction - SMILE). Potential advantages include less marked  biomechanical and neurological corneal disturbance than LASIK  and a likely lower risk of infection and other flap complications.  Surface disturbance is minimal in comparison to surface ablation  procedures.   IMMUNE-MEDIATED SCLERITIS 255  Anterior non-necrotizing scleritis 255  Anterior necrotizing scleritis with  inflammation 256    BLUE SCLERA 262  Osteogenesis imperfecta 262  Ehlers-Danlos syndrome type VI 264   Congenital ocular melanocytosis 264  Idiopathic sclerochoroidal  calcification 266  Scleral hyaline plaque and senile  scleromalacia 267    The scleral stroma is composed of collagen bundles of varying size  and shape that are not uniformly orientated as in the cornea, and  so are not transparent. The inner layer of the sclera (lamina fusca)  blends with the uveal tract. Anteriorly the episclera consists of a  connective tissue layer between the superficial scleral stroma and  Tenon capsule. There are three pre-equatorial vascular layers:   • Conjunctival vessels are the most superficial; arteries are  tortuous and veins straight.   • Superficial episcleral plexus vessels are straight with a radial  configuration. In episcleritis, maximal congestion occurs at  this level (Fig. 8.1A). Topical phenylephrine 2.5% will also  constrict the conjunctival and 10% also the superficial  episcleral vessels.   • Deep vascular plexus lies in the superficial part of the sclera  and shows maximal congestion in scleritis (Fig. 8.1B); a  purplish hue, best seen in daylight, is characteristic.    Episcleritis is a common, usually idiopathic and benign, recurrent  and frequently bilateral condition. Females may be affected more  commonly than males, except possibly in children, in whom   Fig. 8.1 (A) Diffuse episcleritis with maximal vascular  congestion in the superficial episcleral plexus; (B) scleritis  with congestion of the deep vascular plexus   (Courtesy of P Watson - fig. A; S Chen - fig. B)    episcleritis is rare; the average patient is middle-aged. It is typically  self-limiting and tends to last from a few days up to 3 weeks, but  rarely longer. Associated disease, either ocular (e.g. dry eye,  rosacea, contact lens wear) or systemic (e.g. collagen vascular dis¬  orders such as rheumatoid arthritis, herpes zoster ophthalmicus,  gout and others) has been identified in up to a third of patients  seen at tertiary centres, with ocular disease the most common.  Infectious causes are very rare but a wide range has been reported.  Investigation of recurrent cases is as for scleritis (see later).   Simple episcleritis accounts for 75% of cases. It has a tendency to  recur (60%), decreasing in frequency with time. Features often  peak within 24 hours, gradually fading over the next few days.   • Symptoms. Redness; discomfort ranges from absent (up to  50%) to moderate and occasionally severe, when scleritis  should be excluded. Grittiness is common, and photophobia  may occur.   • Signs. More than half of cases are simultaneously bilateral,  o Visual acuity is almost always normal.   o Redness may be sectoral (two-thirds - Fig. 8.2A) or  diffuse (Fig. 8.2B). Often it has an interpalpebral  distribution, in a triangular configuration with the base at  the limbus.   o Chemosis, ocular hypertension, anterior uveitis and  keratitis are all rare.   o If mild, no treatment is required; cool compresses or  refrigerated artificial tears may be helpful,  o A weak topical steroid four times daily for 1-2 weeks is  usually sufficient, though occasionally more intensive  instillation is needed initially or a more potent  preparation can be used with rapid tapering. A topical  non-steroidal anti-inflammatory (NSAID) is an  alternative, though may be less effective,  o An oral NSAID is occasionally required (e.g. ibuprofen  200 mg three times daily, or occasionally a more potent  agent such as indometacin). It is very rare for more  aggressive systemic treatment to be required, and this is  typically in patients with a known systemic association.   Nodular episcleritis also tends to affect females but has a less acute  onset and a more prolonged course than the simple variant.   • Symptoms. A red eye is typically first noted on waking. Over  the next 2-3 days the area of redness enlarges and becomes  more uncomfortable.   • Signs. Attacks usually clear without treatment, but tend to  last longer than simple episcleritis.   o A tender red vascular nodule, almost always within the  interpalpebral fissure (Fig. 8.3A). Occasionally more than  one focus is present.   o A slit lamp section shows an underlying flat anterior  scleral surface, indicating the absence of scleritis  (Fig. 8.3B).    o Intraocular pressure (IOP) is very occasionally elevated,  o An anterior chamber reaction may be present, but is  uncommon (io%).   o It is important to exclude other causes of a nodule such  as phlyctenulosis (a phlycten is within rather than  beneath the conjunctiva) or a conjunctival granuloma.   • Treatment is similar to that of simple episcleritis but is  more commonly indicated.    Scleritis is an uncommon condition characterized by oedema and  cellular infiltration of the entire thickness of the sclera. Immune-  mediated (non-infectious) scleritis is the most common type, and  is frequently associated with an underlying systemic inflammatory  condition, of which it may be the first manifestation. Scleritis is  much less common than episcleritis and comprises a spectrum  from trivial and self-limiting disease to a necrotizing process that    can involve adjacent tissues and threaten vision. A classification of  non-infectious scleritis is shown in Table 8.i; recurrences tend to  be of the same type, though io% progress to more aggressive  disease.   Diffuse disease is slightly more common in females and usually  presents in the fifth decade.   • Symptoms. Ocular redness progressing a few days later to  pain that may radiate to the face and temple. The discomfort  typically wakes the patient in the early hours of the morning  and improves later in the day; it responds poorly to  common analgesics.   Fig. 8.3 (A) Nodular episcleritis; (B) slit illumination shows  that the deep beam is not displaced above the scleral  surface   o Vascular congestion and dilatation associated with  oedema. If treatment is started early, which rarely  happens, the disease can be completely inhibited,  o The redness may be generalized (Fig. 8.4A) or localized to  one quadrant. If confined to the area under the upper  eyelid the diagnosis may be missed,  o Secondary features can include chemosis, eyelid swelling,  anterior uveitis and raised IOP.  o As the oedema resolves, the affected area often takes on a  slight grey/blue appearance because of increased scleral  translucency (Fig. 8.4B); this is due to rearrangement of  scleral fibres rather than a decrease in scleral thickness,  o Recurrences at the same location are common unless an  underlying cause is treated.   • Prognosis. The average duration of disease is around 6  years, with the frequency of recurrences decreasing after the  first 18 months. The long-term visual prognosis is very good.   The incidence of nodular and diffuse anterior scleritis is the same   The age of onset is similar to that of diffuse scleritis.   • Symptoms. The insidious onset of pain followed by  increasing redness, tenderness of the globe and the  appearance of a scleral nodule.   o Scleral nodules may be single or multiple and most  frequently develop in the interpalpebral region close to  the limbus (Fig. 8.5 A). They have a deeper blue-red  colour than episcleral nodules and are immobile,  o In contrast to episcleritis, a slit lamp beam shows an  elevated anterior scleral surface (Fig. 8.5B).  o Multiple nodules may expand and coalesce if treatment is  delayed.   O Instillation of 10% phenylephrine drops will constrict the  conjunctival and superficial episcleral vasculature but not  the deep plexus overlying the nodule,  o As the inflammation in the nodule subsides, increased  translucency of the sclera becomes apparent.    o The duration of the disease is similar to diffuse scleritis.  o More than 10% of patients with nodular scleritis develop  necrotizing disease, but if treatment is instituted early  superficial necrosis does not occur and the nodule heals  from the centre leaving a small atrophic scar.   Necrotizing disease is the aggressive form of scleritis. The age at  onset is later than that of non-necrotizing scleritis, averaging 60  years. The condition is bilateral in 60% of patients and unless    Fig. 8.4 (A) Diffuse non-necrotizing anterior scleritis;  (B) scleral translucency following recurrent disease   Fig. 8.5 (A) Nodular non-necrotizing anterior scleritis; (B) slit  illumination shows superficial displacement of the entire  beam   appropriately treated, especially in its early stages, may result in  severe visual morbidity and even loss of the eye.   • Symptoms. Gradual onset of pain that becomes severe and  persistent and radiates to the temple, brow or jaw; it  frequently interferes with sleep and responds poorly to  analgesia.   • Signs vary according to the following three types of  necrotizing disease.   o Vaso-occlusive is commonly associated with rheumatoid  arthritis. Isolated patches of scleral oedema with overlying  non-perfused episclera and conjunctiva are seen (Fig  8 .6 A). The patches coalesce, and if unchecked rapidly  proceed to scleral necrosis (Fig. 8.6B).   O Granulomatous may occur in conjunction with  conditions such as granulomatosis or polyarteritis    nodosa. The disease typically starts with injection  adjacent to the limbus and then extends posteriorly.  Within 24 hours, the sclera, episclera, conjunctiva and  adjacent cornea become irregularly raised and  oedematous (Fig. 8.7).   o Surgically induced scleritis typically starts within 3 weeks  of a procedure, though much longer intervals have been  reported. It may be induced by any type of surgery  including strabismus repair, trabeculectomy (Fig. 8.8) and  scleral buckling, and excision of pterygium with  adjunctive mitomycin C. The necrotizing process starts at  the site of surgery and extends outwards, but tends to  remain localized to one sector.   clinical assessment, and evaluation by a general physician or  rheumatologist should be considered. Specific tests may   Fig. 8.6 Vaso-occlusive necrotizing scleritis with  inflammation. (A) Early stage; (B) moderate disease -  inflammatory signs are commonly more marked than in  these cases   include erythrocyte sedimentation rate (ESR), C-reactive  protein (CRP), full blood count (e.g. anaemia related to  inflammatory connective tissue disease, eosinophilia for  polyarteritis nodosa, atopy or Churg-Strauss syndrome),  rheumatoid factor, antinuclear antibodies (ANA),  antineutrophil cytoplasmic antibodies (ANCA) and  anti-cyclic citrullinated peptide (CCP) antibodies, serum  uric acid, syphilis serology, Lyme serology, hepatitis B  surface antigen (polyarteritis nodosa) and antiphospholipid  antibodies. Investigation for tuberculosis, sarcoidosis or  ankylosing spondylitis maybe appropriate (see Ch. n).   • Radiological imaging. Chest, sinus, joint and other imaging  may be indicated in the investigation of a range of  conditions such as tuberculosis, sarcoidosis, Churg-Strauss  syndrome, Wegener granulomatosis, ankylosing spondylitis  and other conditions.    • Angiography. Fluorescein angiography of the anterior  segment helps to distinguish necrotizing disease by the  presence of non-perfusion, and can be used for monitoring;  occlusion is predominantly venular in inflammatory disease,  and mainly arteriolar in scleromalacia perforans (see below).  Indocyanine green is a more accurate indicator of disease  activity.   • Ultrasonography can help to detect associated posterior  scleritis (see below).   • Biopsy. This may be considered in resistant cases, especially  if infection is suspected.   • Sclerosing keratitis, characterized by chronic thinning and  opacification in which the peripheral cornea adjacent to the  site of scleritis resembles sclera.   • Peripheral ulcerative keratitis is characterized by  progressive melting and ulceration (Fig. 8.9), and may  constitute a severe risk to the integrity of the eye. In  granulomatous scleritis the destruction extends directly from  the sclera into the limbus and cornea; this characteristic  pattern is seen in Wegener granulomatosis, polyarteritis  nodosa and relapsing polychondritis. Peripheral corneal  ulceration can occur at any stage of a necrotizing scleritis  and, in rare cases, precede its onset. (See also Ch. 6.)   • Glaucoma is the most common cause of eventual loss of  vision. The intraocular pressure can be very difficult to  control in the presence of active scleritis.   • Hypotony (rarely phthisis) may be the result of ciliary body  detachment, inflammatory damage or ischaemia.   • Perforation of the sclera as a result of the inflammatory  process alone is extremely rare.   • Scleromalacia perforans (5% of scleritis) is a specific type of  progressive scleral thinning without inflammation that  typically affects elderly women with longstanding  rheumatoid arthritis, but has also been described in  association with other systemic disorders. Despite the  nomenclature, perforation of the globe is extremely rare as  integrity is maintained by a thin layer of fibrous tissue.  Differential diagnosis is from the innocuous scleral hyaline  plaque and senile scleromalacia (see below).   • Symptoms. Mild non-specific irritation; pain is absent and  vision unaffected, and keratoconjunctivitis sicca may be  suspected.   o Necrotic scleral plaques near the limbus without vascular  congestion (Fig. 8.10A).   o Coalescence and enlargement of necrotic areas,  o Slow progression of scleral thinning with exposure of  underlying uvea (Figs 8.10B and C).   • Treatment may be effective in patients with early disease but  by the time of typical presentation, either no treatment is  needed or progression has been marked.   demonstrated, though frequent lubricant instillation,  local (including topical sodium versenate) or systemic  anticollagenase agents, immunosuppressives (including  topical and oral, but not periocular injection of, steroids,  and topical ciclosporin) and biological blockers have  been used.   o Underlying systemic disease should be treated aggressively.  O Protection from trauma is important,  o Surgical repair of scleral perforation (e.g. patch grafting)  is mandatory to prevent phthisis bulbi.   Posterior scleritis is a potentially blinding condition in which diag¬  nosis is commonly delayed, with an adverse prognostic effect. The  inflammatory changes in posterior and anterior scleral disease are  identical and can arise in both segments simultaneously or sepa¬  rately. The age at onset is often less than 40 years; young patients  are usually otherwise healthy but about a third over the age of 55  have associated systemic disease.   • Symptoms. Pain does not correlate well with the severity of  inflammation but tends to be more severe in those with  accompanying orbital myositis; photophobia is not a  dominant feature.   o Choroidal folds (see Ch. 14) are usually confined to the  posterior pole and orientated horizontally (Fig. 8.11A).  o Exudative retinal detachment occurs in around 25%;  yellowish-brown subretinal exudative material can be  mistaken for a choroidal tumour.   (A) Asymptomatic necrotic patch; (B) moderate and  (C) severe thinning and exposure of underlying uvea   (Courtesy of R Bates - fig. A; C Barry - figs B and C)   Fig. 8.11 Signs of posterior scleritis. (A) Choroidal folds;  (B) uveal effusion    o Uveal effusion with choroidal detachment may be present  (Fig. 8.11B).   o Disc oedema with accompanying reduction of vision is  common, and is caused by spread of inflammation into  the orbital tissue and optic nerve; treatment must not be  delayed in these patients as permanent visual loss can  ensue rapidly.   o Myositis is common and gives rise to diplopia, pain on  eye movement, tenderness to touch and redness around a  muscle insertion.   o Proptosis is usually mild and is frequently associated with  ptosis.   o Occasional features include raised IOP, periorbital  oedema and chemosis. Associated anterior scleritis is a  useful diagnostic aid but occurs only in a minority.    • Ultrasonography may show increased scleral thickness,  scleral nodules, separation of Tenon capsule from sclera, disc  oedema, choroidal folds and retinal detachment. Fluid in the  Tenon space may give a characteristic C T’ sign, the stem of  the T being formed by the optic nerve and the cross bar by  the fluid-containing gap (Fig. 8.12).   • Subretinal mass. Alternative lesions include miscellaneous  granulomatous conditions and choroidal neoplasia.   • Choroidal folds, retinal striae and disc oedema may also  occur in orbital tumours, orbital inflammatory disease,  thyroid eye disease, papilloedema and hypotony.   • Exudative retinal detachment. Vogt-Koyanagi-Harada  (VKH) syndrome and central serous retinopathy.   • Orbital cellulitis may cause proptosis and periocular  oedema but is associated with marked pyrexia.   The autoimmune disease rheumatoid arthritis (RA) is the most  common systemic association of scleritis, and is characterized by  a symmetrical deforming inflammatory polyarthropathy, with a  spectrum of possible extra-articular manifestations. Presentation  is commonly in the third decade with joint swelling, usually of the  hands (Fig. 8.13A). It is much more common in females than  males. Rheumatoid factor autoantibodies are present in 80-90%.  All forms of immune-mediated scleritis have been described in  RA, and the clinical course is often more aggressive than when   Fig. 8.12 B-scan ultrasonography in posterior scleritis shows  scleral thickening and fluid in the sub-Tenon space, with  the characteristic T sign’ (see text)   Fig. 8.13 Important systemic associations of scleritis. (A) Severe deformities of the hands in rheumatoid arthritis; (B) CT  showing lung cavitation in Wegener granulomatosis; (C) saddle-shaped nasal deformity in relapsing polychondritis;   (Courtesy of M Zatouroff, from Physical Signs in General Medicine, Mosby 1996 - fig. A; J Nerad , K Carter and M Alford , from ‘Oculoplastic and Reconstructive  Surgery ', in Rapid Diagnosis in Ophthalmology, Mosby 2008 - fig. B; C Pavesio - fig. C)    there is no systemic association. Other ocular manifestations  of RA include keratoconjunctivitis sicca (secondary Sjogren syn¬  drome), ulcerative keratitis and acquired superior oblique tendon  sheath syndrome (very rare).   Wegener granulomatosis (granulomatosis with polyangiitis) is an  idiopathic multisystem granulomatous disorder characterized by  small vessel vasculitis typically affecting primarily the paranasal  sinuses, lower respiratory tract (Fig. 8.13B) and the kidneys. There  is a male predominance. Presentation is in the fifth decade on  average, often with pulmonary symptoms. Antineutrophil cyto¬  plasmic antibodies (cANCA) are found in over 90% of patients  with active disease. Scleritis is often rapidly progressive, necrotiz¬  ing and granulomatous. Other ocular manifestations include  peripheral ulcerative keratitis, occlusive retinal vasculitis, orbital  inflammatory disease, nasolacrimal obstruction, dacryocystitis  and, rarely, tarsal-conjunctival disease.   Relapsing polychondritis is a rare idiopathic condition character¬  ized by small vessel vasculitis involving cartilage resulting in recur¬  rent, often progressive, inflammatory episodes involving multiple  organ systems such as the ears, respiratory system (Fig. 8.13C),  heart and joints. Presentation is frequently in middle age. Scleritis  is often intractable and may be necrotizing or non-necrotizing.  Isolated anterior uveitis may also occur.   Polyarteritis nodosa (PAN) is an idiopathic aneurysmal vasculitis  affecting medium-sized and small arteries, with a wide range of  manifestations across multiple organ systems (Fig. 8.13D). Presen¬  tation is in the third to sixth decades, often with constitutional  symptoms. The male:female ratio is about 3:1. Ocular involve¬  ment may precede the systemic manifestations by several years.  About a third of patients have hepatitis B infection. Scleritis is   • Topical steroids do not affect the natural history of the  scleral inflammation, but may relieve symptoms and oedema  in non-necrotizing disease.   • Systemic NSAIDs should be used alone only in non¬  necrotizing disease; it is often necessary to try a number of  different drugs before finding one that provides adequate  relief of symptoms. A cyclooxygenase (COX)-2 inhibitor  may be optimal for elderly patients or if there is a history of  peptic ulceration, noting concerns regarding cardiovascular  adverse effects for these and some other NSAIDs such as  diclofenac.   • Periocular steroid injections may be used in non-necrotizing  disease but their effects are usually transient; some authorities  view them as contraindicated in necrotizing scleritis.   • Systemic steroids (e.g. prednisolone is 1-1.5 mg/kg/day) are  used when NSAIDs are inappropriate or inadequate  (necrotizing disease). Intravenous methylprednisolone may  be used for emergent cases.   • Immunosuppressives and/or biological blockers should be  considered if control is incomplete with steroids alone, as a  steroid-sparing measure in long-term treatment or for  underlying systemic disease. A wide range of drugs may be  utilized, including cytostatics (e.g. cyclophosphamide,  azathioprine, methotrexate), drugs acting on immunophilins  (e.g. ciclosporin, tacrolimus) and others; in necrotizing  disease, rituximab may be particularly effective.    Infectious scleritis is rare but may present diagnostic difficulty as  the initial clinical features are similar to those of immune-mediated  disease. In some cases infection may follow surgical or accidental  trauma, endophthalmitis, or may occur as an extension of corneal  infection.   • Herpes zoster is the most common infective cause.  Necrotizing scleritis is extremely resistant to treatment and  may result in a thinned or punched-out area (Fig. 8.14A).   • Tuberculous scleritis is rare and difficult to diagnose. The  sclera may be infected by direct spread from a local  conjunctival or choroidal lesion, or more commonly by  haematogenous spread. Involvement may be nodular (Fig.  8.14B) or necrotizing.   • Leprosy. Recurrent necrotizing scleritis can occur, even after  apparent systemic cure. Nodular disease may be seen in  lepromatous leprosy.   • Syphilis. Diffuse anterior scleritis may occur in secondary  syphilis, and occasionally scleral nodules may be a feature of  tertiary syphilis.    • Lyme disease. Scleritis (Fig. 8.14C) is common but typically  occurs long after initial infection.   • Other causes include fungi (Fig. 8.14D), Pseudomonas  aeruginosa and Nocardia.   Once the infective agent has been identified, specific antimicrobial  therapy should be initiated. Topical and systemic steroids may also  be used to reduce the inflammatory reaction. If appropriate, surgi¬  cal debridement can be used to debulk a focus of infection and  facilitates the penetration of antibiotics.   In this autosomal recessive condition a defect in homogentisic acid  oxidase results in the accumulation of homogentisic acid in col¬  lagenous tissues such as cartilage and tendon (ochronosis). Sys¬  temic features include dark urine and arthropathy. Ocular  manifestations include bluish-grey or black generalized pigment¬  ation of the sclera and the tendons of horizontal recti associated  with discrete pigmented globules (Fig. 8.15).   The systemic features of haemochromatosis are caused by increased  iron deposition in various tissues. Features may be more subtle  than the classic triad of a bronze complexion, hepatomegaly and  diabetes. Inheritance is autosomal recessive. Dry eye and rusty-  brown perilimbal conjunctival and scleral discoloration may  develop.    Blue scleral discoloration is caused by thinning or transparency  with resultant visualization of the underlying uvea (Fig. 8.16).  Major associations are discussed below; rare associations include  Marshall-Smith syndrome (accelerated prenatal skeletal matura¬  tion and growth), Russell-Silver syndrome (short stature and  other features) and Hallermann-Streiff-Fran^ois syndrome.   Osteogenesis imperfecta is an inherited disease of connective  tissue, usually caused by defects in the synthesis and structure of  type 1 collagen. There are multiple types, at least two of which have  ocular features.   • Type I is autosomal dominant. Patients suffer few fractures  with little or no deformity, hyper extensible joints, dental  hypoplasia, deafness and easy bruising. Possible ocular  features include blue sclera, megalocornea and corneal arcus.   • Type IIA is either sporadic or inherited in an autosomal  dominant manner. Systemic features include deafness, dental  anomalies, multiple fractures (Fig. 8.17A) and short limbs,  with death in infancy from respiratory infection. Ocular  manifestations include blue sclera and shallow orbits.   Fig. 8.14 Infectious scleritis. (A) Focal necrosis due to herpes zoster; (B) nodular tuberculous disease; (C) nodular scleritis in  Lyme disease; (D) fungal infection   (Courtesy of R Fogla - fig. B, P Watson - fig. C; C Barry - fig. D)   Fig. 8.15 Alkaptonuria - pigmentation (ochronosis) of the  sclera and horizontal rectus tendons   Fig. 8.17 Systemic associations of blue sclera. (A) multiple  fractures in osteogenesis imperfecta type IIA; (B)  cutaneous hyperelasticity and (C) joint hypermobility in  Ehlers-Danlos syndrome type VI   (Courtesy of BJ Zitelli and HW Davis , from Atlas of Pediatric Physical  Diagnosis, Mosby 2002 - fig. A; MA Mir ; from Atlas of Clinical Diagnosis,  Saunders , 2003 - fig. B; JH Krachmer, MJ Mannis and EJ Holland , from  Cornea, Elsevier 2005 - fig. C)   Ehlers-Danlos syndrome VI (ocular sclerotic) is an inherited dis¬  order of collagen formation. Patients have thin and hyperelastic  skin (Fig. 8.17B) that bruises easily and heals slowly; joints are  hypermobile (Fig. 8.17c), which may lead to recurrent dislocation  and falls. Cardiovascular disease can be severe, including a bleed¬  ing diathesis, dissecting aneurysms, spontaneous rupture of large  blood vessels and mitral valve prolapse. There are six major types  but type VI and, rarely, type IV, are associated with ocular features.  As well as blue sclera, these may include scleral fragility (globe  rupture may be caused by mild trauma), epicanthic folds, micro¬  cornea, keratoconus, keratoglobus, ectopia lentis, myopia and  retinal detachment.   Congenital ocular melanocytosis is an uncommon condition char¬  acterized by an increase in number, size and pigmentation of  melanocytes in the sclera and uvea. The periocular skin, orbit,  meninges and soft palate may also be involved.   • Ocular melanocytosis, the least common, involves only the  eye. Multifocal slate-grey pigmentation is seen within the  sclera and episclera (Fig. 8.18A) - the process does not  involve the overlying conjunctival layers, unless there is  incidental conjunctival pigmentation. The overlying  conjunctiva is mobile over the episcleral pigmentation but  the pigmentation itself is intrinsic and cannot be moved  over the globe. The peripheral cornea is occasionally  involved.   • Oculodermal melanocytosis (naevus of Ota) is the most  common type and involves both skin and eye. Naevus of Ota  is bilateral in 5%; it occurs frequently in darker-  complexioned races but is rare in Caucasians. There is deep  bluish hyperpigmentation of the facial skin, most frequently  in the distribution of the first and second trigeminal  divisions (Fig. 8.18B). It may be subtle in pale-skinned  individuals, when it is best detected under good lighting.   O Iris mammillations are uncommon, tiny, regularly spaced  villiform lesions (Fig. 8.19B). They may also be found in   Fig. 8.18 Congenital melanocytosis. (A) Episcleral melanocytosis; (B) cutaneous melanocytosis in naevus of Ota   Fig. 8.19 Ipsilateral associations of naevus of Ota. (A) Iris heterochromia (hyperchromia); (B) iris mammillations; (C) fundus  hyperpigmentation; (D) trabecular hyperpigmentation   (Courtesy of B Gilli - fig. A; L MacKeen - fig. D)   Fig. 8.20 Idiopathic sclerochoroidal calcification. (A) Single  large lesion; (B) early lesions in typical locations  associated with the temporal vascular arcades; (C)  ultrasonogram showing a highly reflective calcific lesion  with orbital shadowing   (Courtesy of A Agarwal, from Gass’ Atlas of Macular Diseases, Elsevier  Saunders 2012 - fig. C)   o Fundus hyperpigmentation (Fig. 8.19C).  o Trabecular hyperpigmentation (Fig. 8.19D); this is  associated with glaucoma in about 10% of cases,  o Uveal melanoma develops in a small minority of patients,  and long-term anterior and posterior segment review is  required.   • Signs. Geographical yellow-white fundus lesions with  ill-defined margins (Fig. 8.20A), often multiple and located  in the superotemporal or inferotemporal mid-periphery  associated with the vascular arcades (Fig. 8.20B).   • Ultrasonography shows highly reflective choroidal plaque-  like lesions with orbital shadowing (Fig. 8.20C).   • Differential diagnosis is mainly from osseous metaplasia  associated with a choroidal haemangioma, and from    choroidal osteoma, which is usually a single - though often  large - lesion that usually (80-90%) involves only one eye.   Scleral hyaline plaques are oval dark-greyish, generally sharply  demarcated, areas located close to the insertion of the horizontal  rectus muscles (Fig. 8.21). Senile scleromalacia refers to a spontane¬  ously occurring irregular, oval or kidney-shaped partial-thickness    scleral defect found at the same location, typically with one or  more scleral hyaline plaques at the opposite location in the same  eye or in the fellow eye; separation of a scleral hyaline plaque to  leave an area of scleromalacia has been described. Both these enti¬  ties typically affect elderly patients, are innocuous, and should not  be confused with scleromalacia perforans (see above), which  occurs in somewhat younger patients, may be located anywhere  in the anterior sclera, is unassociated with hyaline plaques else¬  where and can progress to a full-thickness scleral defect with uveal  exposure.   Age-related cataract 270  Cataract in systemic disease 271  Secondary cataract 273  Traumatic cataract 273    Operative complications 285  Acute postoperative  endophthalmitis 288  Delayed-onset postoperative  endophthalmitis 292  Posterior capsular opacification 293  Anterior capsular fibrosis and  contraction 294  Miscellaneous postoperative  complications 295   Anterior lenticonus 303  Posterior lenticonus 303  Lentiglobus 303  Microspherophakia and  microphakia 303  Coloboma 303   Anterior subcapsular cataract lies directly under the lens capsule  and is associated with fibrous metaplasia of the lens epithelium.  Posterior subcapsular opacity lies just in front of the posterior  capsule and has a granular or plaque-like appearance on oblique  slit lamp biomicroscopy (Fig. 9.1A), but typically appears black  and vacuolated (Fig. 9.1B) on retroillumination; the vacuoles are  swollen migratory lens epithelial cells (bladder or Wedl), similar  to those commonly seen postoperatively in posterior capsular  opacification (see Fig. 9.21A). Due to its location at the nodal point  of the eye, a posterior subcapsular opacity often has a particularly  profound effect on vision. Patients are characteristically troubled  by glare, for instance from the headlights of oncoming cars, and  symptoms are increased by miosis, such as occurs during near  visual activity and in bright sunlight.   Nuclear cataract is an exaggeration of normal ageing change. It is  often associated with myopia due to an increase in the refractive  index of the nucleus, resulting in some elderly patients being able  to read without spectacles again (‘second sight of the aged’); in  contrast, in the healthy ageing eye (and in occasional cases of  cortical and subcapsular cataract) there is mild hypermetropic  shift. Nuclear sclerotic cataract is characterized by a yellowish hue  due to the deposition of urochrome pigment, and is best assessed  with an oblique slit lamp beam (Fig. 9.1C). When advanced, the  nucleus appears brown (Fig. 9.1D) or even black, the latter being  typical of marked post-vitrectomy opacity.   Cortical cataract may involve the anterior, posterior or equatorial  cortex. The opacities start as clefts and vacuoles between lens fibres  due to cortical hydration. Subsequent opacification results in  typical cuneiform (wedge-shaped) or radial spoke-like opacities  (Figs 9.2A and B), often initially in the inferonasal quadrant. As  with posterior subcapsular opacity, glare is a common symptom.   Fig. 9.1 Age-related cataract. (A) Posterior subcapsular; (B) posterior subcapsular on retroillumination, showing Wedl cells;  (C) minimal and (D) moderate nuclear sclerosis    Fig. 9.2 Age-related cataract. (A) Cortical; (B) cortical on  retroillumination; (C) Christmas tree   Christmas tree cataract, which is uncommon, is characterized by  polychromatic needle-like formations in the deep cortex and  nucleus (Fig. 9.2C).   • Immature cataract is one in which the lens is partially  opaque.   • Mature cataract is one in which the lens is completely  opaque (Fig. 9.3A).   • Hypermature cataract has a shrunken and wrinkled  anterior capsule (Fig. 9.3B) due to leakage of water out  of the lens.   • Morgagnian cataract is a hypermature cataract in which  liquefaction of the cortex has allowed the nucleus to sink  inferiorly (Fig. 9.3C).   Hyperglycaemia is reflected in a high level of glucose in the  aqueous humour, which diffuses into the lens. Here glucose is  metabolized into sorbitol, which accumulates within the lens,  resulting in secondary osmotic overhydration. In mild degree, this  may affect the refractive index of the lens with consequent fluctua¬  tion of refraction in line with the plasma glucose level, hypergly¬  caemia resulting in myopia and vice versa. Cortical fluid vacuoles  develop and later evolve into frank opacities. Classic diabetic cata¬  ract, which is actually rare, consists of snowflake cortical opacities  (Fig. 9.4A) occurring in the young diabetic; it may mature within  a few days or resolve spontaneously. Age-related cataract occurs  earlier in diabetes mellitus. Nuclear opacities are common and  tend to progress rapidly.   About 90% of patients with myotonic dystrophy (see Ch. 19)  develop fine iridescent cortical opacities in the third decade, some¬  times resembling Christmas tree cataract; these evolve into visually  disabling wedge-shaped cortical and subcapsular opacities, often  star-like in conformation (Fig. 9.4B) by the fifth decade. Later, the  opacities may become indistinguishable from typical cortical  cataract.   About 10% of patients with severe atopic dermatitis develop cata¬  racts in the second to fourth decades; these are often bilateral and  may mature quickly. Shield-like dense anterior subcapsular plaque  that wrinkles the anterior capsule (Fig. 9.4C) is characteristic.  Posterior subcapsular opacities may also occur.   Neurofibromatosis type 2 (NF2; see Ch. 19) is associated with early  cataract in more than 60% of patients. Opacities are posterior  subcapsular or capsular, cortical or mixed, and tend to develop in  early adulthood.    Fig. 9.3 Cataract maturity. (A) Mature cataract - secondary  divergent squint is present; (B) hypermature cataract with  wrinkling of the anterior capsule; (C) Morgagnian cataract  with liquefaction of the cortex and inferior sinking of the  nucleus   (Courtesy of S Chen - fig. A; C Barry - figs B and C)   Fig. 9.4 Cataract in systemic disease. (A) Diabetic snowflake  cataract; (B) posterior subcapsular cataract spokes  assuming a stellate morphology in myotonic dystrophy;   A secondary (complicated) cataract develops as a result of other  primary ocular disease.   Chronic anterior uveitis is the most common cause of secondary  cataract, the incidence being related to the duration and intensity  of inflammation. Topical and systemic steroids used in treatment  are also causative. The earliest finding is often a polychromatic  lustre at the posterior pole of the lens (Fig. 9.5A). If inflammation  persists, posterior and anterior opacities (Fig. 9.5B) develop. Cata¬  ract appears to progress more rapidly in the presence of posterior  synechiae (Fig. 9.5C).   Acute congestive angle closure may cause small anterior grey-  white subcapsular or capsular opacities, glaukomflecken (Fig.  9.5D), to form within the pupillary area. These represent focal  infarcts of the lens epithelium and are almost pathognomonic of  prior acute angle-closure glaucoma.   High (pathological) myopia can be associated with posterior sub¬  capsular lens opacities and early-onset nuclear sclerosis, which  ironically may increase the myopic refractive error.   Hereditary fundus dystrophies (see Ch. 15) such as retinitis pig¬  mentosa, Leber congenital amaurosis, gyrate atrophy and Stickler  syndrome, may be associated with posterior and, less commonly,  anterior subcapsular lens opacities (Fig. 9.5E). Cataract surgery  may improve visual function even in the presence of severe retinal  changes.   Trauma is the most common cause of unilateral cataract in young  individuals.   • Blunt trauma may cause a characteristic flower-shaped  opacity (Fig. 9.6B).   • Electric shock is a rare cause of cataract, patterns including  diffuse milky-white opacification and multiple snowflake¬  like opacities, sometimes in a stellate subcapsular  distribution (Fig. 9.6C).   • Infrared radiation, if intense as in glassblowers, may rarely  cause true exfoliation of the anterior lens capsule (Fig.   • Ionizing radiation exposure such as for ocular tumour  treatment may cause posterior subcapsular opacities  (Fig. 9.6E); these may not manifest for months or  years.   • Visual improvement is by far the most common indication  for cataract surgery. Operation is indicated when the opacity  develops to a degree sufficient to cause difficulty in  performing essential daily activities. Clear lens exchange  (replacement of the healthy lens with an artificial implant) is  an option for the management of refractive error.   • Medical indications are those in which a cataract is adversely  affecting the health of the eye, for example phacolytic or  phacomorphic glaucoma; clear lens exchange usually  definitively addresses primary angle closure, but less invasive  options are generally preferred (see Ch. 10). Cataract surgery to  improve the clarity of the ocular media may also be required in  the context of monitoring or treatment of fundus pathology.   For elective surgery, a general medical history is taken and any  problems managed accordingly. Table 9.1 sets out suggested  further enquiry and action in relation to a range of systemic dis¬  eases. Routine preoperative general medical examination, blood  tests and electrocardiogram (ECG) are not usually required for  local anaesthesia. If general anaesthesia is planned, assessment is  according to local protocol, e.g. general examination, urea and  electrolytes, random blood glucose, full blood count and ECG; an  anaesthetic opinion may be considered for chronically unwell or  medically complex patients.   • Current medication should be recorded. This will often  guide general medical assessment. Medications relevant to  eye surgery include:   o Systemic alpha-blockers (e.g. tamsulosin) are commonly  associated with intraoperative floppy iris syndrome (IFIS).  o Management of anticoagulant therapy or an antiplatelet  agent should follow local protocol. Most surgeons do not  stop antiplatelet drugs for cataract surgery, though this  may be preferred for larger oculoplastic procedures.  Anticoagulation status, usually expressed as the  international normalized ratio (INR) level, should be  within the therapeutic range appropriate for the  individual indication (e.g. usually higher for heart valve  thrombosis prophylaxis than following deep vein  thrombosis); a common approach is to check the INR  within the 24 hours prior to surgery in stable patients.   o Medication, including sulfonamides and antibiotics  commonly used following cataract surgery,  o Iodine or shellfish - the latter may indicate an iodine  allergy. If allergy to iodine is present an alternative skin   Fig. 9.5 Secondary cataract. (A) Early uveitic posterior subcapsular cataract; (B) uveitic anterior plaque opacities;  (C) extensive posterior synechiae and anterior lens opacity; (D) glaukomflecken; (E) anterior subcapsular cataract  in retinitis pigmentosa    Fig. 9.6 Causes of traumatic cataract. (A) Penetrating trauma; (B) blunt trauma; (C) electric shock and lightning strike;   (Courtesy of S Chen - fig. A; C Barry - fig. B; J Schuman, V Christopoulos, D Dhaliwal, M Kahook and R Noecker, from ‘Lens and Glaucomain Rapid Diagnosis  in Ophthalmology, Mosby 2008 - figs C-E)    Table 9.1 Management of general medical conditions prior to elective surgery   Well-controlled? Will need blood  test (finger-prick may be  sufficient, consider additional  tests if necessary)   Medication and food and drink intake as usual  on the day of surgery for local anaesthesia   If systolic >170 mmHg or  diastolic >100 mmHg may  need physician opinion   Consider contacting physician for optimization;  defer surgery if necessary as risk of  suprachoroidal haemorrhage may be elevated   Defer surgery for 3-6 months from date of Ml.  Contact physician/anaesthetist if concerns  about current cardiovascular status   Bring glyceryl trinitrate (GTN) spray on day of  surgery. If unstable, contact physician or  anaesthetist   If the patient cannot lie flat, may need to discuss  with operating surgeon. Trial of lying flat (at  least half an hour)   Chest function should be optimized as far as  possible prior to surgery   Surgery should be deferred until active infection  has resolved. If healing is not possible (e.g.  chronic leg ulcer) the lesion should be covered  with a sterile dressing during the perioperative  period. A preoperative wound swab for culture,  and prophylactic oral antibiotics may be  considered   Antibiotic prophylaxis only exceptionally required  for ophthalmic surgery, e.g. removal of an  infected eye   Defer surgery for at least 6 months from date of  stroke   Does the patient have any  problems lying flat or with  neck position?   If in doubt about patient’s ability to position  appropriately, may need to discuss with  operating surgeon; intubation for general  anaesthesia may be more difficult in some  patients   If viral hepatitis suspected, note prominently as  special precautions to avoid needlestick injury  may be necessary   If there are any high-risk factors,  has the patient undergone an  HIV test in the past?   For patients of southern Asian  and Afro-Caribbean ethnic  origin, enquire about sickle  status   Is the patient able to maintain  head stability sufficiently to  cooperate with local  anaesthesia and surgery?   If general anaesthesia is planned, an anaesthetic  opinion should be obtained well in advance of  surgery   o Others: latex (latex-free gloves may be necessary), sticking  plaster, local anaesthetics, insect bites (cross-reaction with  hyaluronidase that is often used with local anaesthesia).   • Methicillin-resistant Staphylococcus aureus (MRSA)  carriage. Relevant national and local protocols for the  identification and management of patients at high risk for  MRSA carriage should be followed.   • Transport (to hospital and to the operating theatre within  hospital): special arrangements may be needed for patients  with poor mobility or exceptionally high body mass.   A detailed and pertinent ophthalmic evaluation is required. Fol¬  lowing the taking of a past ophthalmic history, the following   • Visual acuity is usually tested using a Snellen chart, despite  its limitations (see Ch. 14).   • Cover test. A heterotropia may indicate amblyopia, which  carries a guarded visual prognosis, or the possibility of  diplopia if the vision is improved. A squint, usually a  divergence, may develop in an eye with poor vision due to  cataract, and lens surgery alone may straighten the eye.   • Pupillary responses. Because cataract never produces an  afferent pupillary defect, its presence implies substantial  additional pathology.   • Ocular adnexa. Dacryocystitis, blepharitis, chronic  conjunctivitis, lagophthalmos, ectropion, entropion and tear  film abnormalities may predispose to endophthalmitis and  in most cases optimization should be achieved prior to  intraocular surgery.   • Cornea. Eyes with decreased endothelial cell counts (e.g.  substantial cornea guttata) have increased vulnerability to  postoperative decompensation secondary to operative  trauma. Specular microscopy and pachymetry may be  helpful in assessing risk, and precautions should be taken to  protect the endothelium (see below). A prominent arcus  senilis is often associated with a surgical view of decreased  clarity, as are stromal opacities.   • Anterior chamber. A shallow anterior chamber can render  cataract surgery difficult. Recognition of a poorly dilating  pupil allows intensive preoperative mydriatic drops, planned  mechanical dilatation prior to capsulorhexis and/or  intracameral injection of mydriatic. A poor red reflex  compromises the creation of a capsulorhexis, but can be  largely overcome by staining the capsule with trypan blue.   • Lens. Nuclear cataracts tend to be harder and may require  more power for phacoemulsification, while cortical and  subcapsular opacities tend to be softer. Black nuclear  opacities are extremely dense and extracapsular cataract  extraction rather than phacoemulsification may be the  superior option. Pseudoexfoliation indicates a likelihood of    weak zonules (phakodonesis - lens wobble - may be  present), a fragile capsule and poor mydriasis.   • Fundus examination. Pathology such as age-related macular  degeneration may affect the visual outcome.   Ultrasonography may be required, principally to exclude  retinal detachment and staphyloma, in eyes with very dense  opacity that precludes fundus examination.   • Sclera. If a prominent explant/encircling band has been  placed during prior retinal detachment surgery, the eye is  particularly large or the sclera thin (e.g. high myopia),  peri- and retrobulbar local anaesthesia may be avoided and  special care taken with sub-Tenon local anaesthetic  infiltration.   • Current refractive status. It is critical to obtain details of  the patient’s preoperative refractive error in order to guide  intraocular lens (IOL) implant selection. The keratometry  readings (obtained during biometry - see below) should be  noted in relation to the refraction, particularly if it is  planned to address astigmatism by means of targeted wound  placement, a toric IOL or a specific adjunctive procedure. It  is particularly important to obtain a postoperative refractive  result from an eye previously operated upon so that any  ‘refractive surprise’, even if minor, can be taken into account.   It is essential that the patient has arrived at a fully informed deci¬  sion to proceed with cataract surgery. As well as discussing the  benefits, risks should be conveyed at a level appropriate to each  patient’s level of understanding, with an explanation of the more  common and severe potential problems. Points for discussion  with the patient may include:   • Most cataract operations are straightforward, with the  patient achieving good vision.   • Most complications can be dealt with effectively and cause  no long-term difficulties, but some rare problems can be  very serious.   • In about 1 in 1000 cataract operations the eye will be left  with little or no sight; in about 1 in 10 000 the patient will  lose the eye.   • Some complications mean that a second operation will be  necessary.   • Relatively mild and usually easily treatable but common  complications include: periocular ecchymosis, allergy to eye  drops, intraocular pressure (IOP) spike, iridocyclitis,  posterior capsular opacification (currently in decline) and  wound leak.   • Moderate to severe but less common complications:  posterior capsular rupture/vitreous loss (1% or less for  experienced surgeons, higher for trainees dependent on  experience), zonular dehiscence, cystoid macular oedema  (CMO), dropped nucleus (about 0.2%), corneal  decompensation sufficient to need corneal graft, intolerable  refractive outcome (may need contact lens wear, lens  implant exchange or corneal surgery), retinal detachment  (<i%), IOL dislocation, persistent ptosis and diplopia.    • Rare but invariably very serious complications:  endophthalmitis (0.1%) and suprachoroidal haemorrhage  (0.04%).   • The risks of anaesthesia should be conveyed by the person  administering it. Local anaesthesia carries only a low risk of  problems, though some rare complications have the  potential to be very serious including loss of the eye and  even death: allergy to the anaesthetic agent, retrobulbar  haemorrhage (see Ch. 21), perforation of the globe, and  inadvertent infusion of anaesthetic agent into the  cerebrospinal fluid via the optic nerve sheath causing  brainstem anaesthesia.   • There is virtually no risk to the other eye; sympathetic  ophthalmitis is vanishingly rare following modern cataract  surgery.   Biometry facilitates calculation of the lens power likely to result in   • Keratometry involves determination of the curvature of the  anterior corneal surface (steepest and flattest meridians),  expressed in dioptres or in millimetres of radius of  curvature. This is commonly carried out with the  interferometry apparatus used to determine axial length (see  below), but if this is unavailable or unsuitable manual  keratometry (e.g. Javal-Schiotz keratometer) or corneal  topography can be performed.   • Optical coherence biometry (Figs 9.7A and B) is a non-  contact method of axial length measurement that utilizes  two coaxial partially coherent low-energy laser beams to  produce an interference pattern (partial coherence  interferometry). Modern biometry devices also perform  keratometry, anterior chamber depth and corneal white-to-  white measurement, and are able to calculate IOL power  using a range of formulae. Measurements have high  reproducibility and generally require less skill than ultrasonic  biometry (see below).   • A-scan ultrasonography is a generally slightly less accurate  method of determining the axial dimension and can be  acquired either by direct contact (Fig. 9.7C) or more  accurately but with greater technical difficulty by using a  water bath over the eye (immersion ultrasonography). The  sound beam must be aligned with the visual axis for  maximal precision; each reflecting surface is represented by a  spike on an oscilloscope display monitor (Fig. 9.7D).   • IOL power calculation formulae. Numerous formulae have  been developed that utilize keratometry and axial length to  calculate the IOL power required to achieve a given  refractive outcome. Some formulae incorporate additional  parameters such as anterior chamber depth and lens  thickness to try to optimize accuracy. The SRK-T, Haigis,  Hoffer Q and Holladay 1 and 2 are commonly used. Specific  formulae may be superior for very short (possibly the Hoffer    Q) or long eyes, but opinions vary and it is always wise to  plan individually for an unusual eye, consulting the latest  research and recommendations. Short eyes in particular are  prone to unexpected mean spherical and astigmatic errors  following surgery.   • Previous refractive surgery. Any form of corneal refractive  surgery is likely to make a significant difference to the IOL  power required, and standard IOL calculations are  unsuitable. Several different methods have been described to  address this situation. Most involve the calculation of the  post-refractive procedure ‘true’ corneal power using a special  process (refractive history method, contact lens method) and  insertion of this into a standard (e.g. Hoffer Q) or specific  (e.g. Masket) formula, but the Haigis-L regression formula  uses statistical data to facilitate calculation on post-refractive  surgery eyes using only standard inputs. It may prudent to  utilize more than one method of IOL calculation.   • Contact lenses. If the patient wears soft contact lenses, these  should not be worn for up to a week prior to biometry to  allow corneal stabilization; hard/gas permeable lenses may  need to be left out for 3 weeks.   • Personalized A-constant. If a consistent postoperative  refractive deviation is found in most of an individual  surgeon’s cases, it is assumed that some aspects of personal  surgical (or possibly biometric) technique consistently and  similarly influence outcome, and a personalized A-constant  can be programmed into biometry apparatus to take this  into account.   • Emmetropia is typically the desired postoperative refraction,  though usually spectacles will be needed for near vision since  a conventional IOL cannot accommodate. Many surgeons  aim for a small degree of myopia (about -0.25 D) to offset  possible errors in biometry; postoperative hypermetropia,  which necessitates correction for clear vision at all distances,  is typically less well tolerated than myopia.   • Contralateral eye. Postoperative refractive planning must  take account of the contralateral eye. If this has a significant  refractive error but is unlikely to require cataract surgery  within a few years, the postoperative target for the operated  eye might be set for within less than 2.0 D of its fellow, to  avoid problems with binocular fusion. In some cases, such as  when there is an early lens opacity in the fellow eye or when  ametropia is extreme, the patient can be offered lens surgery  to the other eye to facilitate targeting both at emmetropia.   • ‘Monovision’ is a concept in which the (usually) non¬  dominant eye is left with between 1 and 2 dioptres of myopia  to allow reading, whilst emmetropia is targeted in the  dominant eye. This is attractive to some patients, generally  those who have previously been using contact lenses or  spectacles to achieve monovision.   • Multifocal lens options use a variety of optical means to  attempt to achieve satisfactory near, distance and  intermediate vision. Many patients are very satisfied with the   Fig. 9.7 Biometry. (A) Optical coherence biometry; (B) optical biometry monitor display; (C) contact ultrasonic biometry;  (D) ultrasonographic monitor display (A/C, anterior chamber depth; L, lens thickness)    results but a significant minority are unhappy, complaining  of phenomena such as glare. Highly accurate refractive  outcomes, including very limited astigmatism, are necessary  for optimal function and a greater likelihood of tolerance.   • Younger patients. With a conventional monofocal IOL,  patients younger than about 50 need to be aware that they  will experience the sudden loss of active focusing and that it  will often take some time to adjust.   An IOL (Fig. 9.8A) consists of an optic and haptics. The optic is  the central refracting element, and the haptics the arms or loops  that sit in contact with peripheral ocular structures to centralize    the optic. Modern cataract surgery, with preservation of the lens  capsule, affords positioning of the IOL in the ideal location - c in  the bag’ (Fig. 9.8B). Complicated surgery, with rupture of the  posterior capsule, may necessitate alternative positioning in the  posterior chamber with the haptics in the ciliary sulcus (a three-  piece IOL only, not one-piece including those with plate haptics,  as these may not be stable), or in the anterior chamber (AC) with  the haptics supported in the angle - AC positioning requires a  specific lens type. In some circumstances a supplementary IOL  may be placed in the sulcus in addition to an IOL in the capsular  bag, for instance to address a residual refractive error following  primary surgery (secondary pseudopolyphakia), and thin-profile  IOLs are available for this purpose. It is preferable to avoid a sec¬  ondary sulcus IOL (primary pseudopolyphakia) in very short (e.g.  nanophthalmic) eyes due to the risk of angle closure; off-the-shelf  IOLs of power up to 40 D are available, and custom IOLs can be  produced in even higher powers.   Fig. 9.8 Intraocular lens (IOL). (A) One-piece flexible IOL  - note the square-edged optic; (B) IOL in situ in the  capsular bag; (C) implanted toric IOL showing diametrically  opposite sets of three dots marking the lens axis   • Flexible IOLs introduced into the eye via an injector and  subsequently unrolled inside the eye are now in general use.  Injector-based delivery utilizes a very small incision and also  allows avoidance of lens contact with the ocular surface, so  reducing the risk of bacterial contamination; simple folding  of the IOL is an alternative, but requires a larger incision.    Flexible materials available are discussed below; there seems  to be no distinct superiority of one material over another,  o Acrylic IOLs. Hydrophobic (water content <i%) acrylic  materials have a greater refractive index than hydrophilic  lenses and are consequently thinner, though this can  result in dysphotopsia (troublesome glare and  reflections). They have been reported to produce a  greater reaction in uveitic eyes, but outcomes do not  seem to be materially affected. Hydrophilic acrylic  (hydrogel) in theory offers superior biocompatibility, but  the image of hydrogel IOLs has been marred by the  occurrence of severe calcification requiring IOL removal  in some types, and inflammation in others; these  problems have now been resolved by lens manufacturers.  Posterior capsular opacification (PCO) rates may be  higher with hydrogel IOLs than with other materials,  o Silicone IOLs are available in both loop haptic (one- or  three-piece) and plate haptic (one-piece) conformations,  the latter consisting of a roughly rectangular leaf with the  optic sited centrally. Silicone IOLs may exhibit greater  biocompatibility than hydrophobic acrylic IOLs, but may  be prone to significant silicone deposition in silicone  oil-filled eyes. First-generation silicone materials were  associated with a higher rate of PCO than acrylic, but  there is no clear difference in rates with later IOLs.  o Collamer is composed of collagen, a poly-HEMA-based  copolymer and an ultaviolet-absorbing chromophore. It  is marketed principally on the basis of high  biocompatibility and a favourable track record.   • Rigid IOLs are made entirely from polymethylmethacrylate  (PMMA). They cannot be injected or folded so require an  incision larger than the diameter of the optic, typically 5 or   6 mm, for insertion. For economic reasons, they continue to  be widely used in developing countries. PCO rates are higher  with PMMA lenses than silicone and acrylic. Some surgeons  favour heparin-coated IOLs (see below) in uveitic eyes,  particularly in children.   • Sharp/square-edged optics (see Fig. 9.8A) are associated  with a significantly lower rate of PCO compared with  round-edged optics, and the former is now the predominant  design. However, square edges may be associated with a  higher rate of dysphotopsia (see below).   • Blue light filters. Although essentially all IOLs contain  ultraviolet light filters, a number also include filters for blue  wavelengths, in order to reduce the possibility of damage to  the retina by this higher-energy visible light. The blue filters  impart a slight yellow tint to the IOL, though similar only to  that of the physiological young adult lens. Some evidence  suggests slightly poorer visual function in scotopic  conditions of illumination.   • Aspheric optics to counteract corneal spherical aberration  are widely available, and have been shown to improve  contrast, particularly in mesopic conditions. A potential  drawback is that the aspheric element of the manufactured  IOLs is set at a single standardized level (this differs between  manufacturers), but the extent of spherical aberration varies   • Heparin coating reduces the attraction and adhesion of  inflammatory cells, and this may have particular application  in eyes with uveitis. However, there is no clear evidence  about whether heparin surface modification is clinically  beneficial, and indeed about which IOL material is superior  for use in cataract surgery on eyes with uveitis.   • Multifocal IOLs (see also Ch. 7) utilizing refractive or  diffractive mechanisms aim to provide clear vision over a  range of focal distances. So-called accommodative IOLs  attempt to flex and thereby alter focal length but in practice  the amplitude of accommodation is slight.   • Toric IOLs (Fig. 9.8C) have an integral cylindrical refractive  component to compensate for pre-existing corneal  astigmatism. The main potential problem is rotation within  the capsular bag, which occurs in only a small percentage,  and may be corrected by early surgical repositioning.   • Adjustable IOLs allow the alteration of refractive power  following implantation. One version uses low-level  ultraviolet irradiation at the slit lamp about a week after  surgery to induce polymerization of its constituent  molecules in specific patterns with precise spherical and  cylindrical (astigmatism) correction.   The majority of cataract surgery is performed under local anaes¬  thesia (LA), sometimes in conjunction with intravenous or oral  sedation. General anaesthesia is required in some circumstances,  such as children and many young adults, very anxious patients,  some patients with learning difficulties, epilepsy, dementia and  those with a head tremor.   • Sub-Tenon block involves insertion of a blunt-tipped  cannula through an incision in the conjunctiva and Tenon  capsule 5 mm from the limbus inferonasally (Fig. 9.9A), and  passing it around the curve of the globe through the  sub-Tenon space. The anaesthetic is injected beyond the  equator of the globe (Fig. 9.9B). Although anaesthesia is  good and complications minimal, akinesia is variable.  Chemosis and subconjunctival haemorrhage are common  but penetration of the globe is extremely rare.   • Peribulbar block is given through the skin (Figs 9.9C and  D) or conjunctiva with a l-inch (25-mm) needle. It generally  provides effective anaesthesia and akinesia. Penetration of  the globe is a rare but severe complication, and for this  reason peribulbar is avoided, or approached with great  caution, in longer eyes (which also tend to have a larger  equatorial diameter).   • Topical anaesthesia involves drops or gel (proxymetacaine  0.5%, tetracaine 1% drops, lidocaine 2% gel), which can be  augmented with intracameral preservative-free lidocaine  0.2%—1%, often infused during hydrodissection; combined  viscoelastic/lidocaine preparations are also commercially  available. Although analgesia is generally adequate, it tends  to be less effective than peribulbar or sub-Tenon blocks.    Despite the absence of akinesia, most patients can cooperate  adequately. The intraoperative complication rate is probably  higher than with regional blocks, but anaesthesia-related  complications are lower. The possibility of a higher rate of  endophthalmitis compared to other anaesthetic techniques  has been raised, though this may be compensated for by the  use of intracameral antibiotic at the end of surgery.   When posterior chamber IOLs began to be widely used in the  1980s most surgeons adopted extracapsular cataract extraction  (ECCE), abandoning the older intracapsular technique (ICCE). In  ICCE, a cryoprobe is used to remove the lens complete with its  capsule (Fig. 9.10A). In ECCE, after a large anterior capsulotomy  is created, an extensive limbal incision (8-10 mm) is completed  and the lens nucleus is expressed following hydrodissection to free  its cortical attachments (Fig. 9.10B). Cortical matter is then aspi¬  rated, leaving behind a sufficiently intact capsular bag to support  an IOL. Suturing of the incision is required, sometimes inducing  considerable corneal astigmatism. Manual small-incision cataract  surgery (MSICS) is a variant of ECCE used to address the require¬  ment for high-volume surgical throughput of dense cataracts in  less affluent geographical regions; it involves the creation of a  small self-sealing sclerocorneal tunnel (Fig. 9.10C), manual one-  piece expression of the nucleus (Fig. 9.10D), manual aspiration of  the cortex and IOL implantation. Visual rehabilitation is compa¬  rable to phacoemulsification but MSICS is faster and avoids the  need for expensive technology.   • Level of irrigating bottle above the patient’s eye is set to  maintain anterior chamber stability with a reasonable IOP.  Infusion flow is proportional to the height of the bottle.   • Aspiration flow rate (AFR) refers to the volume of fluid  removed from the eye in millilitres per minute. For a higher  AFR the irrigating bottle must be elevated to compensate for  increased fluid loss. High AFR results in attraction of lens  material towards the phaco tip, with faster vacuum build-up  and swifter removal of lens matter but with less effective  power. A high AFR should usually be avoided by trainee  surgeons.   • Vacuum, measured in mmHg, is generated during occlusion  when the pump is attempting to aspirate fluid. Vacuum level  determines how tightly material is held by the phaco tip  when occluded, providing the ability to manipulate lens   Fig. 9.9 Local anaesthesia for cataract surgery. (A) Conjunctival dissection for sub-Tenon anaesthesia; (B) sub-Tenon  infiltration with a blunt cannula; (C) insertion of needle for peribulbar anaesthesia. (D) peribulbar infiltration of anaesthetic  agent    fragments. High vacuum can decrease the total power  required to remove the lens. As with AFR, a lower-vacuum  setting slows down the speed of intraocular events, reduces  the intensity of surge (see below) and makes inadvertent  aspiration of iris or lens capsule less likely.   • Post-occlusion surge. When occlusion of the phaco tip by  lens material is broken, pent-up energy results in a sudden  temporary increase in outflow - ‘surge’. This may result in  complications such as capsular rupture, and as far as  possible is suppressed by modern phaco machines.   The main implication of the type of pump employed by a particu¬  lar phaco machine is the effect on vacuum behaviour.   • Peristaltic (flow) pumps pull fluid and lens material into the  phaco tip by compressing tubing over variable speed rollers.    Vacuum is generated only when occlusion of the tip occurs,  following which the pump slows and stops as a set  maximum is achieved.   • Venturi (vacuum) pumps create a negative pressure in a  vessel by passing compressed gas across its entrance. This  has the practical effect of synchronizing vacuum and AFR so  there is generally no independent means of adjusting AFR.  Depression of the foot pedal increases vacuum towards the  preset maximum independent of occlusion, and tip vacuum  is therefore always available.   The phaco handpiece (Fig. 9.11A) features a tip consisting of a    Fig. 9.10 Manual cataract surgery. (A) Intracapsular extraction; (B) extracapsular extraction; (C) and (D) manual small-incision  cataract surgery   (Courtesy of C Barry - figs A and B; A Hennig - figs C and D)   Fig. 9.11 (A) Phaco handpiece with tip; (B) phaco tip with sleeve    Its emulsifying action is mediated by very high-frequency (ultra¬  sonic) vibration leading to jackhammer, cavitation and other  effects; some machines offer variants such as a torsional phaco  action or water jet-mediated phacoemulsification. Phaco tips of  differing shapes and sizes are available, each having particular  cutting and holding characteristics.   Ophthalmic viscosurgical devices (OVDs or viscoelastics) are  biopolymers playing a critical role in modern cataract surgery.   • Cohesive OVDs are used to create and maintain intraocular  spaces, for example to maintain the anterior chamber during  capsulorhexis and inflation of the capsular bag to facilitate  introduction of an IOL. Higher molecular weight variants  maintain intraocular space more effectively but tend to  promote iris prolapse in shallow anterior chambers and  confer a more sustained postoperative IOP rise.   • Dispersive OVDs are more adherent to surfaces than  cohesive OVDs, and are typically used to protect the  endothelium. They are more difficult to remove from the  eye than cohesive viscoelastics, but tend to cause a less  marked IOP spike. The major practical disadvantage of  dispersive OVDs is their tendency to retain air bubbles and  lens fragments, compromising the surgical view.   • ‘Soft shell’ technique involves the injection prior to the  capsulotomy stage of an outer dispersive layer followed by  an inner cohesive nucleus. Some surgeons use this routinely,  others only for eyes at higher risk of corneal decompensation  (e.g. cornea guttata).   • Pupillary manipulation. In eyes with small pupils a high  molecular weight cohesive viscoelastic (e.g. Healon GV™)  will push the iris away from the lens and help to induce  mydriasis. Adaptive OVDs’ cohesive effect can be used to  dilate a pupil intraoperatively, and their dispersive effect to  maintain the dilatation. OVDs can be used to break  posterior synechiae with minimal trauma.   • Cortical manipulation. OVDs can be useful to dissect cortex  away from the lens capsule to minimize traction on fragile  zonular ligaments.   • Capsulorhexis rescue. If a capsulorhexis shows signs of  running out to the periphery, injecting a cohesive viscoelastic  will flatten the anterior capsule, aiding the exertion of a  centrally directed vector and helping to expand the pupil.   • Capsular rupture. In small posterior capsular tears a  dispersive viscoelastic (an entire vial may be necessary) will  push the vitreous back into the posterior chamber and  maintain plugging of the capsular defect, facilitating  completion of lens removal. Subsequent creation of a  posterior capsulorhexis is possible in some cases.   o Topical anaesthetic is followed by povidone-iodine 5%  (Fig. 9.12A) or chlorhexidine instillation into the    conjunctival sac and cleaning of the eyelids (Fig. 9.12B),  ensuring thorough eyelash application; the antiseptic  should be left to work for a minimum of 3 minutes,  o Careful draping (Fig. 9.12C) is performed, excluding the  lashes and lid margins from the surgical field, and a  speculum is inserted.   Fig. 9.12 Preparation. (A) Povidone-iodine 5% conjunctival  fornix instillation; (B) cleaning the skin with povidone-  iodine; (C) plastic drape and speculum isolating the  operating field from the eyelids   O A side port incision is made around 6o° to the left (in  right-handed surgeons) of the main incision; some  surgeons prefer two side ports approximately 180°  apart.   o Viscoelastic is injected into the anterior chamber,  o Many surgeons locate the main corneal incision (Fig.   9.13A) on the steepest corneal axis, others prefer  consistent siting. Temporal incisions can provide  better access and less induced astigmatism but  may be associated with a slightly higher risk of  endophthalmitis.   • Continuous curvilinear capsulorhexis is performed with a  cystotome, a bent hypodermic needle and/or capsule forceps  (Fig. 9-136).   • Hydrodissection is performed to separate the nucleus and  cortex from the capsule so that the nucleus can be  manipulated. A blunt cannula is inserted just beneath the  edge of the capsulorhexis and fluid injected gently under the  capsule (Fig. 9.13C). A hydrodissection wave should be seen,  provided there is an adequate red reflex.   • ‘Divide and conquer’ is a widely used, safe technique for  removal of the nucleus in which two perpendicular grooves  are created (sculpting), the phaco tip and a second  instrument engaged in opposite walls of the grooves and the  nucleus cracked into quadrants by applying force in opposite  directions (Fig. 9.13D). Each of the quadrants is then  emulsified and aspirated in turn (Fig. 9.13E).   • ‘Phaco chop’ has the advantage of generally greater  speed and a lower total phaco energy requirement, but  commonly takes longer to learn. In horizontal chopping a  blunt-tipped chopper is placed horizontally underneath the  capsule and rotated vertically as the equator is reached.  Vertical chopping is performed with a pointed-tip  chopper that does not need to pass beyond the  capsulorhexis. The nucleus is separated into several pieces  for emulsification.   • Removal of lens cortex. Cortical lens matter segments are  carefully engaged by means of vacuum, peeled away centrally  from the lens capsule and aspirated. Automated coaxial,  bimanual automated (Fig. 9.13F) and manual aspiration (e.g.  Simcoe cannula) methods are available.   • IOL insertion. The capsular bag is filled with cohesive  viscoelastic. A loaded injector cartridge is introduced  through the main section and the IOL slowly injected and  unrolled inside the capsular bag; a toric IOL (see Fig. 9.8C)  should be rotated to the correct alignment. Viscoelastic  may be aspirated prior to or following toric IOL  rotation.   • Completion. Side port incisions and the main wound may  be sealed with corneal stromal saline injection  (hydrosealing). Prophylactic measures at the end of surgery  may include intracameral (anterior chamber) antibiotic  injection, subconjunctival injection of antibiotic and steroid  and/or topical antibiotic.   Femtosecond lasers, used in refractive surgery for several years,  have recently been adopted by many surgeons, replacing several  of the manual steps of phacoemulsification with an automated  process. The corneal incisions, the capsulorhexis and initial frag¬  mentation of the crystalline lens, as well as astigmatism-relieving  incisions (Fig. 9.14), can all be performed with the laser. Potential  advantages include greater precision and integrity of incisions,  reduced phacoemulsification energy, and possibly improved  refractive outcomes due to more precise capsulorhexis placement.  Disadvantages include substantially higher cost, longer total oper¬  ating time and difficulties with technically challenging cases (e.g.  small pupils). There is a substantial learning curve.   Capsular rupture may be accompanied by vitreous loss, posterior  migration of lens material and, rarely, expulsive haemorrhage.  Sequelae to vitreous loss, particularly if inappropriately managed,  include CMO, retinal detachment, endophthalmitis, updrawn  pupil, uveitis, vitreous touch, vitreous wick syndrome, glaucoma  and posterior dislocation of the IOL.   o Sudden deepening or shallowing of the anterior chamber  and momentary pupillary dilatation,  o The nucleus falls away and cannot be approached by the  phaco tip.   o Vitreous aspirated into the phaco tip often manifests with  a marked slowing of aspiration,  o The torn capsule or vitreous gel may be directly visible.   • Management depends on the magnitude of the tear, the size  and type of any residual lens material, and the presence or  absence of vitreous prolapse.   o Dispersive viscoelastic such as Viscoat may be injected  (see above). If a complete or nearly complete nucleus  remains, conversion to extracapsular extraction may be  considered. A vitrector can be employed at this point (see  below) to remove vitreous entangled with nuclear  fragments.   o The incision may be enlarged, if necessary, and a lens  glide (Sheets) may be passed behind lens fragments to  cover the capsular defect (Fig. 9.15), although it is  important to confirm that vitreous has first been  displaced or removed and will not be put under traction,  o Residual nuclear fragments are carefully removed by  phaco using a low bottle height and low AFR, or, if large,  by viscoexpression after extending the main wound,  o Once nuclear remnants have been removed, a common  approach is to re-plug the tear with dispersive OVD,  gently filling the anterior chamber with a cohesive  viscoelastic and using a manual aspiration cannula with  the irrigation off to carefully aspirate residual cortex,  topping up the AC with viscoelastic as necessary.   Fig. 9.13 Phacoemulsification. (A) Corneal incision; (B) capsulorhexis; (C) hydrodissection; (D) cracking of the nucleus;  (E) phacoemulsification and aspiration of nuclear quadrants - ‘divide and conquer’ method; (F) cortical aspiration  using a bimanual automated technique    Fig. 9.14 Femtosecond laser for cataract surgery - graphical  user interface. (A) Capsulotomy completed; (B) nuclear  fragmentation; (C) limbal relaxing incisions for astigmatism   o All vitreous is then removed from the AC and the wound  with a vitrector, including deep to the capsular tear. A  bimanual technique, with separate cutting and infusion  instruments, is viewed as superior by many, as vitreous is  not pushed away from the cutter; the position of the  infusion cannula is kept high and that of the cutter low.  The main practical difficulty is visualization of the  vitreous gel, and this can be enhanced by the instillation  of trypan blue or o.i ml of 40 mg/ml triamcinolone  (shaken well before use). The infusion bottle height  should be sufficient to keep the anterior chamber  maintained without intermittent shallowing.    o A small posterior capsular tear may allow careful  in-the-bag implantation of a posterior chamber (PC)   IOL; it may be possible to convert a small tear into a  posterior capsulorhexis, preventing inadvertent  enlargement of the dehiscence,  o Even a large tear will usually allow ciliary sulcus   placement of a three-piece (but not a one-piece) PC IOL.  The centre of the haptic loops should be placed at 90° to  a peripheral tear. If possible, after placing the IOL in the  sulcus the optic should be captured within an intact  capsulorhexis of slightly smaller diameter by depressing  each side of the optic beneath the capsulorhexis in turn.  With capsulorhexis capture, the originally planned IOL  power, or possibly 0.5 D less, can be used; without  capture, the power is reduced by o.5-1.0 D.  o Acetylcholine solution is used to constrict the pupil  following implantation of a PC IOL or prior to inserting  an AC IOL.   implantation of an AC IOL (Fig. 9.16); a prior iridectomy  is needed to prevent pupillary block. AC IOLs are  associated with a higher risk than PC IOLs of  complications including bullous keratopathy, hyphaema,  iris tuck and pupillary irregularities. An iris-attached  anterior (see Fig. 7.10A) or posterior chamber (see Fig.  9.17D) IOL or a sclerally secured posterior chamber IOL  are alternatives.   o A suture should be used to secure the wound following  capsular rupture, even if this seems adequately self-sealed.   Dislocation of fragments of lens material into the vitreous cavity  (Fig. 9.17A) after zonular dehiscence or posterior capsule rupture  is rare but potentially serious as it may result in glaucoma, chronic   Fig. 9.16 Insertion of an anterior chamber IOL; note that an  iridectomy has been created. (A) Insertion of a lens glide;   (B) OVD (see text) coating the anterior surface of the IOL;   uveitis, retinal detachment or chronic CMO. Initially, any uveitis  or raised IOP must be treated. It may be reasonable to adopt a  conservative approach for small (less than a quadrant) fragments,  but pars plana vitrectomy will virtually always be required for  larger pieces.   Dislocation of an IOL into the vitreous cavity (Fig. 9.17B) is rare;  loss can occur via a posterior capsular dehiscence, or in an eye  with fragile zonular attachments (e.g. pseudoexfoliation) the  entire capsular bag may dislocate (Fig. 9.17C). Complications  include vitreous haemorrhage, retinal detachment, uveitis and  chronic CMO. Treatment involves pars plana vitrectomy with IOL  removal, repositioning or exchange (Fig. 9.17D) depending on the  extent of capsular support.   A suprachoroidal haemorrhage involves a bleed into the supra¬  choroidal space from a ruptured posterior ciliary artery. If suffi¬  ciently severe it may result in extrusion of intraocular contents  (expulsive haemorrhage). It is a dreaded complication, but  extremely rare (0.04%) with phacoemulsification. Contributing  factors include advanced age, glaucoma, increased axial length,  systemic cardiovascular disease, vitreous loss and conversion from  phacoemulsification to ECCE. A high intraoperative index of sus¬  picion is critical, and if there is any suggestion of a suprachoroidal  haemorrhage the operation should be terminated and the incision  sutured immediately.   o Progressive shallowing of the AC, increased IOP and  prolapse of the iris.    o Vitreous extrusion, loss or partial obscuration of the red  reflex and the appearance of a dark mound behind the  pupil.   o In severe cases, posterior segment contents may be  extruded into the AC and through the incision.  Immediate treatment involves filling of the AC with a  cohesive viscoelastic and sutured closure of the incision.  Unless significant glaucomatous damage is present, leaving a  substantial quantity of viscoelastic in the eye has been  advocated, in order to raise the IOP and tamponade the  bleeding vessel; balloon (e.g. Honan) compression to a  pressure of 50 mmHg has also been suggested, perhaps for  up to 30 minutes. It may be helpful to keep the patient in a  sitting rather than lying position. The diagnosis should be  confirmed at the slit lamp as soon as possible. IOP-lowering  medication such as oral acetazolamide is given to address the  pressure spike. Intraoperative posterior sclerotomy is not  recommended. Postoperatively, topical and systemic steroids  should be used aggressively to reduce intraocular  inflammation, with standard postoperative antibiotic  treatment and IOP management as indicated. Non-steroidal  anti-inflammatory drugs (NSAIDs) should be avoided for  analgesia, and any antiplatelet or anticoagulant discontinued  short-term, provided this is safe.   • Subsequent treatment, if spontaneous absorption fails to  occur, consists of drainage of large haemorrhages. This can  be performed 7-14 days later, by which time liquefaction of  blood clot has taken place. The visual prognosis for large  haemorrhages is highly variable; prolonged chorioretinal  apposition (>14 days) has a worse prognosis. Pars plana  vitrectomy may be considered when the retina appears  adherent or detached, though even apposed ‘kissing’  haemorrhages may resolve spontaneously without  apparent retinal problems. If appropriate, completion   of cataract surgery may be considered after a further  1-2 weeks.   The contemporary reported incidence of acute endophthalmitis  following cataract surgery varies substantially between studies, but  is probably at least 0.1%. Acute intraocular infection is invariably  a severe event. Toxins produced by infecting bacteria and the host  inflammatory responses cause rapid and irreversible photorecep¬  tor damage, and ongoing effects can continue long after the ocular  contents have been rendered sterile.   • Risk factors are difficult to establish but may include  operative complications such as posterior capsule rupture,  prolonged procedure time, combined procedure (e.g. with  vitrectomy), clear corneal sutureless incision, temporal  incision, wound leak on the first day, delaying postoperative  topical antibiotics until the day after surgery, topical  anaesthesia, adnexal disease and diabetes.    Fig. 9.17 (A) Large nuclear fragment in the inferior vitreous cavity - a dislocated IOL is also visible; (B) dislocated IOL; (C) IOL  within a dislocated capsular bag in a patient with pseudoexfoliation; (D) ultrasonogram of iris clip (‘lobster claw’) IOL  attached to the posterior iris surface in the eye shown in (C)   (Courtesy of S Milewski - figs A and B; S Chen - figs C and D)    • Pathogens. About 90% of isolates are Gram-positive and 10%  Gram-negative. Staphylococcus epidermidis is the most common,  and with early treatment carries a reasonable prognosis.   • The source of infection usually cannot be identified with  certainty. It is thought that the flora of the eyelids and  conjunctiva are the most frequent source, including  contamination via incisions in the early postoperative stages.  Other potential sources include contaminated solutions and  instruments, environmental air, and the surgeon and other  operating room personnel.   Because of the low rate of endophthalmitis it is very difficult to   • Instillation of 5% povidone-iodine into the conjunctival  fornices and leaving this undisturbed for at least 3 minutes  prior to surgery.    • Scrupulous preparation of the surgical site, with re-draping  if eyelash coverage is inadequate.   • Treatment of pre-existing infections such as blepharitis,  conjunctivitis, chronic dacryocystitis and infection in the  contralateral eye or socket.   O Intracameral cefuroxime (1 mg in 0.1 ml) injected into  the AC at the end of surgery,  o Postoperative subconjunctival injection can achieve  bactericidal levels in the AC for at least 1-2 hours.   O Preoperative topical fluoroquinolone antibiotics are  frequently given in regimens from 1 hour to 3 days  before surgery, but evidence for their efficacy is  lacking.   O Newer-generation quinolones such as moxifloxacin  penetrate the eye effectively to give inhibitory  concentrations, but their routine prophylactic use might  promote the development of resistant organisms.    • Early resuturing of leaking wounds rather than observation  is likely to be prudent.   • Reviewing personal surgical practice to eliminate  potentially risk-prone elements, particularly if a significant  rate of endophthalmitis is encountered.   o Fibrinous exudate and hypopyon (Fig. 9.18A).  o Vitritis with an impaired view of the fundus,  o Severe vitreous inflammation and debris (Fig. 9.18B) with  loss of the red reflex.   (Courtesy of C Barry - fig. A; S Tuft - fig. B)   Fig. 9.19 Retained lens fragment in the anterior chamber  following cataract surgery   If there is any doubt about the diagnosis, treatment should be that  of infectious endophthalmitis, as early recognition leads to a better  outcome.   • Retained lens material in the AC (Fig. 9.19) or vitreous may  precipitate a severe uveitis, corneal oedema and raised IOP.   • Vitreous haemorrhage, especially if blood in the vitreous is  depigmented.   • Postoperative uveitis. A confident diagnosis of infection is  not always straightforward. If signs of inflammation are mild  a trial of topical steroid therapy and early review (6-24  hours) is appropriate. If there is no substantial  improvement, management should be that of  endophthalmitis.   • Toxic reaction to the use of inappropriate or contaminated  irrigating fluid or viscoelastic. An intense fibrinous reaction  with corneal oedema may develop although other signs of  infectious endophthalmitis are absent. Treatment is with  intensive topical steroids and a cycloplegic.   • Complicated or prolonged surgery may result in corneal  oedema and uveitis.   Samples for culture should be obtained from aqueous and vitreous  to confirm the diagnosis; negative culture does not necessarily rule  out infection and treatment should be continued. An operating  theatre with experienced staff is the best setting, but samples can  be taken in a minor procedures room if necessary to avoid delay.   • B-scan ultrasound should be performed prior to vitreous  sampling if there is no clinical view, to exclude retinal  detachment.   o Topical and subconjunctival, sub-Tenon or peribulbar  anaesthesia is administered; the inflamed eye is often  resistant to local anaesthesia and sedation or general  anaesthesia may be necessary.   o The eye is draped as for cataract surgery, with insertion  of a speculum.   • Aqueous sampling - o. 1-0.2 ml of aqueous is aspirated via a  limbal paracentesis using a 25-gauge needle on a tuberculin  syringe; the syringe is capped and labelled.   • Vitreous sampling is more likely to yield a positive culture  than aqueous. A 1 or 2 ml syringe and 23-gauge needle may  be used, or optimally a disposable vitrector. The vitreous  cavity is entered 3.5 mm from the limbus (pseudophakic  eye), measured with a calliper. 0.2-0.4 ml is aspirated from  the mid-vitreous cavity. If using a disposable vitrector, the  tubing is capped and both the vitrector and tubing sent for  analysis.   • Conjunctival swabs may be taken in addition, as significant  culture may be helpful in the absence of a positive result  from intraocular samples.   • Microbiology. Specimens should be sent to the  microbiology laboratory immediately; most laboratories  prefer to receive a sample in the acquiring apparatus and  will divide the specimen for microscopy and culture. PCR  can be helpful in identifying unusual organisms, the cause of  culture-negative disease, and organisms after antibiotic  treatment has been started. However, its high sensitivity  means that contamination can lead to false-positive results.   • Intravitreal antibiotics are the key to management because  levels above the minimum inhibitory concentration of  most pathogens are achieved, and are maintained for days.  They should be administered immediately after culture  specimens have been obtained. Antibiotics commonly used  in combination are ceftazidime, which will kill most  Gram-negative organisms (including Pseudomonas  aeruginosa) and vancomycin to address Gram-positive cocci  (including methicillin-resistant Staphylococcus aureus).   o The concentrations are ceftazidime 2 mg in 0.1 ml and  vancomycin 2 mg in 0.1 ml; amikacin 0.4 mg in 0.1 ml is  an alternative to ceftazidime in patients with a definite  penicillin allergy, but is more toxic to the retina. Table  9.2 provides details of preparation,  o The antibiotics are injected slowly into the mid-vitreous  cavity using a 25 -gauge needle,  o After the first injection has been given, the syringe may  be disconnected but the needle left inside the vitreous  cavity so that the second injection can be given through  the same needle; alternatively a second needle can be  used.   • Subconjunctival antibiotic injections are often given but  are of doubtful additional benefit if intravitreal antibiotics  have been used. Suggested doses are vancomycin 50 mg and  ceftazidime 125 mg (or amikacin 50 mg if penicillin-allergic).   • Topical antibiotics are of limited benefit and are often used  only 4-6 times daily in order to protect the fresh wounds  from contamination. Vancomycin 5% (50 mg/ml) or  ceftazidime 5% (50 mg/ml) applied intensively may   B. Add 10 ml water for injection (WFI) or saline and  dissolve thoroughly (for a 250 mg vial add 5 ml WFI  or saline, for a 1 g vial add 20 ml WFI or saline)   C. Draw up 1 ml of the solution, containing 50 mg of  antibiotic   E. Draw up about 0.2 ml (excess to facilitate priming)  into a 1 ml syringe. When ready to inject, fit the  Rycroft cannula or the needle to be used, and  discard all but 0.1 ml (contains 2 mg of antibiotic)  for injection   As A-E above, again preferably starting with a 500 mg  ampoule    Alternative to ceftazidime; as it carries a higher risk of  retinal infarction, use only if well-defined penicillin or  cephalosporin allergy is present; note the lower  intravitreal dose than ceftazidime and vancomycin   A. Presentation: vial contains 500 mg of amikacin in  2 ml of solution   B. Use a 2.5 ml syringe to draw up 1 ml of amikacin  solution then 1.5 ml of WFI   C. Inject 0.4 ml of the solution, containing 40 mg of  antibiotic, into a 10 ml syringe and dilute to 10 ml  (giving 4 mg per ml)   D. Draw up about 0.2 ml (excess to facilitate priming)  into a 1 ml syringe. When ready to inject, fit the  needle to be used, and discard all but 0.1 ml  (contains 0.4 mg of antibiotic) for injection    penetrate the cornea in therapeutic levels. Third or fourth  generation fluoroquinolones achieve effective levels in the  aqueous and vitreous, even in uninflamed eyes, and may be  considered.   • Oral antibiotics. Fluoroquinolones penetrate the eye well  and moxifloxacin 400 mg daily for 10 days is recommended;  clarithromycin 500 mg twice daily may be helpful for  culture-negative infections. Evidence suggests these may  attack bacterial biofilm.   • Oral steroids. The rationale for the use of steroids is to limit  destructive complications of the inflammatory process.  Prednisolone 1 mg/kg daily may be considered in severe  cases after 12-24 hours provided fungal infection has been  excluded from examination of smears. Contraindications  must be excluded and gastric protection (e.g. lansoprazole  30 mg once daily) prescribed with appropriate monitoring  including baseline blood tests; if necessary, general medical  advice should be requested prior to commencement.    • Periocular steroids. Dexamethasone or triamcinolone  should be considered if systemic therapy is contraindicated.   • Intravitreal steroids may reduce inflammation in the short  term but do not influence the final visual outcome; some  studies even suggest a detrimental effect. Conversely,  improvement in outcome in some bacterial sub-groups has  been reported.   • Pars plana vitrectomy. The Endophthalmitis Vitrectomy  Study (EVS) showed a benefit for immediate pars plana  vitrectomy in eyes with a visual acuity (VA) of perception of  light (not hand movements vision or better) at presentation,  with a 50% reduction in severe visual loss. If vitrectomy is  not immediately available, it is prudent to take samples as  above and give intravitreal antibiotics as a temporizing  measure. The conclusions of the EVS in post-cataract  surgery eyes cannot necessarily be extrapolated to other  forms of endophthalmitis.   • Signs of improvement include contraction of fibrinous  exudate and reduction of AC cellular activity and hypopyon.  In this situation treatment is not modified irrespective of  culture results. Ultrasonography may be useful in vitreous  assessment.   • If the clinical signs are worsening after 48 hours antibiotic  sensitivities should be reviewed and therapy modified  accordingly. Pars plana vitrectomy should be considered if  not previously performed. Intravitreal antibiotics can be  repeated after 2 days; if amikacin has previously been used,  repeated administration should probably be avoided to  reduce the risk of retinal toxicity.   • Outcome is related to the duration of the infection prior to  treatment and the virulence of organisms.   o If VA at presentation is light perception, 30% of eyes  achieve 6/12 following treatment. If VA is better than  light perception, this figure increases to 60%.  o Infection with Bacillus cereus or streptococci often has a  poor visual outcome despite aggressive and appropriate  therapy, with 70% and 55% respectively achieving a final  VA of 6/60 or less. This poor visual outcome may be  related to early retinopathy from exotoxins.   o Persistent vitreous opacification. Aggressive and extended  topical, periocular, and if necessary oral steroid treatment  will often lead to resolution. Vitrectomy can be  considered if unresolving and severe,  o Maculopathy in the form of epiretinal membrane, cystoid  oedema and ischaemia.    should be identified and drained if necessary. Retinal  detachment and anterior vitreous membranes may  require vitrectomy.   o Other problems include chronic uveitis, secondary  glaucoma, retinal detachment and phthisis.   Delayed-onset endophthalmitis following cataract surgery devel¬  ops when an organism of low virulence such as P. acnes , becomes  trapped within the capsular bag (saccular endophthalmitis).  Organisms can become sequestered within macrophages, pro¬  tected from eradication but with continued expression of bacterial  antigen. Onset ranges from 4 weeks to years (mean 9 months)  postoperatively and typically follows uneventful cataract surgery.  It may rarely be precipitated by laser capsulotomy release of the  organism.   • Symptoms. Painless mild progressive visual deterioration is  typical; floaters may be present.   o Low-grade anterior uveitis, sometimes with medium-  large keratic precipitates (Fig. 9.20 A); a degree of vitritis  is common.   o The inflammation initially responds well to topical  steroids, but recurs when treatment is stopped and may  eventually become steroid-resistant.   O An enlarging capsular plaque composed of organisms  sequestrated in residual cortex within the peripheral  capsular bag is common (Fig. 9.20B); gonioscopy under  mydriasis may identify an equatorial plaque.   • Differential diagnosis is principally from other causes of  anterior uveitis, particularly idiopathic, sterile post-surgical  and chronic/recurrent viral infection (see Ch. 11).   • Initial management. Later-generation fluoroquinolones,  such as moxifloxacin, penetrate the eye well, and are  concentrated within macrophages. An empirical 10-14-day  course of moxifloxacin (alternatives include clarithromycin)  may be worthwhile prior to more invasive options.   • Investigation. Sampling of aqueous and vitreous should be  considered if oral antibiotics are ineffective. Anaerobic  culture should be requested if P. acnes infection is suspected,  and isolates may take 10-14 days to grow. The detection rate  can be greatly improved with the use of PCR, which should  also screen for the common causes of viral anterior uveitis.   o Intravitreal antibiotics alone are usually unsuccessful in  resolving the infection.   o Removal of the capsular bag, residual cortex and IOL,  requiring pars plana vitrectomy. Secondary IOL   Intravitreal antibiotics are combined: vancomycin (1-2 mg  in 0.1ml) is the antibiotic of choice and can also be  irrigated into any capsular remnant. P. acnes is also  sensitive to methicillin, cefazolin and clindamycin.   Visually significant posterior lens capsular opacification (PCO),  also known as ‘after cataract’, is the most common late complica¬  tion of uncomplicated cataract surgery, historically occurring  eventually in up to 50% of patients. It is caused by the proliferation  of lens epithelial cells that have remained within the capsular bag  following cataract extraction. The incidence of PCO is reduced  when the capsulorhexis opening is in complete contact with the  anterior surface of the IOL. PMMA (and probably to a lesser  extent hydrogel) IOLs are particularly prone to PCO, but other¬  wise implant design is more important than material; a square   • Symptoms include persistent slowly worsening blurring,  glare and sometimes monocular diplopia.   • VA is variably reduced, though dysfunction may be more  marked on contrast sensitivity testing.   • Signs typically include more than one pattern of opacification,  o Vacuolated (pearl-type) PCO (Fig. 9.21A) consists of   proliferating swollen lens epithelial cells, similar to the  bladder (Wedl) cells seen in posterior subcapsular  cataract (see Fig. 9.1B). They are commonly termed  ‘Elschnig pearls’, particularly when grouped into clusters  at the edge of a capsulotomy (Fig. 9.21B), though strictly  Hirschberg-Elschnig pearls refers to globular or grape¬  like collections of swollen cells seen following traumatic  or surgical anterior capsular rupture,  o Fibrosis-type PCO (Fig. 9.21C) is thought to be due to  fibroblastic metaplasia of epithelial cells, which develop  contractile qualities.   O A Soemmering ring is a whitish annular or doughnut¬  shaped proliferation of residual cells that classically  formed almost in the periphery of the capsular bag  following older methods of cataract surgery, but is  clinically uncommon now. It may form at the edge of a  capsulorhexis or capsulotomy.   capsule, termed a capsulotomy (see Figs 9.21B and D), with the   • Indications. The presence of significant visual symptoms is  the main indication; less commonly, capsulotomy is  performed to improve an inadequate fundus view impairing  assessment and treatment of posterior segment pathology.   • Technique. Safe and successful laser capsulotomy involves  accurate focusing and use of the minimum energy required.  Laser power is initially set at 1 mj/pulse, and may be  increased if necessary. A series of punctures is applied in a  cruciate pattern using single-pulse shots, the first puncture  aimed at the visual axis. The opening should equate  approximately to the size of the physiologically dilated pupil  under scotopic conditions - this averages around 4-5 mm in  the pseudophakic eye. A larger capsulotomy may be  necessary if glare persists, or for retinal examination or  treatment, but the capsulotomy should not extend beyond  the edge of the optic in case vitreous prolapses around its  edge. It may be prudent to adopt a higher threshold for  treatment, and minimizing its extent, in eyes at risk of  retinal detachment (e.g. high myopia), CMO (e.g. history of  uveitis) or lens displacement (e.g. pseudoexfoliation). Some  research suggests that the total energy applied should be less  than 80 mj in order to reduce the risk of a significant IOP  spike or increase in macular thickness.    Fig. 9.21 Posterior capsular opacification. (A) Vacuolated or  pearl-type; (B) Elschnig pearl formation (arrow) following  laser capsulotomy; (C) capsular fibrosis; (D) Soemmering ring  surrounding a slightly contracted capsulotomy; (E) laser  pitting of an IOL    • Complications include pitting of the IOL (Fig. 9.21E) that is  virtually always visually inconsequential, intraocular pressure  elevation (usually mild and transient) and extremely rarely  CMO (less common when capsulotomy is delayed for 6  months or more after cataract surgery), retinal detachment  and IOL subluxation or dislocation.   Since the advent of continuous curvilinear capsulorhexis, contrac¬  tion of the anterior capsular opening (capsulophimosis - Fig. 9.22)  has become a more common complication. It typically progresses    over months, and if severe, YAG laser anterior capsulotomy may  be required. Risk factors include pseudoexfoliation, retinitis pig¬  mentosa and a small capsulorhexis; it may be highest with plate-  haptic silicone IOLs.   Symptomatic CMO (see Ch. 14) is relatively uncommon following  uncomplicated phacoemulsification and in most cases is mild and  transient. It occurs more often after complicated surgery and has  a peak incidence at 6-10 weeks, although the interval to onset may  be much longer.   • Risk factors include epiretinal membrane, a history of CMO  in the other eye, operative complications such as posterior  capsular rupture, particularly with vitreous incarceration  into the incision site (Fig. 9.23A), anterior chamber IOL  (Fig. 9.23B), secondary IOL implantation, prior topical  prostaglandin treatment, diabetes and uveitis.   • Symptoms. Blurring, especially for near tasks, and  sometimes distortion. Subtle CMO may not be readily  visible clinically, but is demonstrated well on OCT.   • Treatment. One or a combination of the following  modalities may be used.   O Anterior vitrectomy or YAG laser vitrotomy to vitreous  incarceration in the anterior segment if present,  o Topical NSAIDs (e.g. ketorolac four times daily,   bromfenac twice daily, nepafenac) may be beneficial even  in long-standing cases; treatment for several months may  be necessary.   (triamcinolone acetate 0.05-0.1 ml of 40 mg/ml) injection,  o Carbonic anhydrase inhibitors given systemically or  topically.   o Pars plana vitrectomy may be useful for CMO refractory  to medical therapy, even in eyes without apparent  vitreous disturbance.   Up to 1 in 10 patients complain of annoying visual phenomena  following uncomplicated cataract surgery with monofocal IOL  implantation; multifocal IOLs have particular issues that are dis¬  cussed separately above. Improvement in and adaptation to the  symptoms typically occurs over several months, and the number   Fig. 9.23 Factors predisposing to cystoid macular oedema.  (A) Vitreous incarceration in the incision; (B) anterior  chamber IOL    of monofocal IOL patients actually requiring further surgery for  the symptoms is very small. Rounded-edged IOLs may be less  prone to negative photopsia, and silicone IOLs may be less liable  in general to dysphotopsia than acrylic. Optic and capsulorhexis  size may also be important.   • Symptoms. A dark shadow in the temporal periphery  (negative dysphotopsia - often the most troublesome),  scintillations, haloes, peripheral or central flaring or flashes  (positive dysphotopsia) and possibly monocular diplopia.   o Encouraging the patient that the symptoms usually  improve over time, both because of anatomical changes  (e.g. capsulorhexis edge thickening) and because the  brain is able to ignore unwanted images; patients may be  able to accelerate this by trying to avoid paying specific  attention to the phenomena.   o Positive nocturnal symptoms can be helped with gentle  pupillary constriction (e.g. brimonidine), but dilatation  may help negative dysphotopsia.  o Successful alleviation of symptoms has been reported  with a variety of techniques, including reverse optic  capture (vaulting the optic forward out of the capsular  bag, leaving the haptics in place), ciliary sulcus IOL  re-implantation, and piggyback IOL implantation in the  sulcus; these can also be considered for second-eye  surgery.   o IOL exchange (round-edged) may be considered,  o Laser capsulotomy is best avoided as it markedly  complicates IOL exchange; in some eyes, YAG laser  removal of a sector of capsulorhexis edge has reduced  symptoms.   Corneal oedema (see Ch. 6) is very common postoperatively but  is usually mild and transient. Eyes with pre-existing corneal  endothelial pathology, particularly low cell counts, are at increased  risk. Causes of more marked oedema include dense nuclei requir¬  ing high phacoemulsification energy, complicated or prolonged  surgery, pseudoexfoliation, intraoperative endothelial trauma and  elevated postoperative IOP. Use of a dispersive viscoelastic, and  possibly a scleral tunnel incision, may help to protect the corneal  endothelium during surgery in higher-risk eyes.   Mild ptosis, probably secondary to a variety of mechanisms, is not  uncommon after cataract surgery, but usually improves; observa¬  tion for at least a year postoperatively is recommended in most  cases.   Although uncommon, malposition (Fig. 9.24) may be associated  with both optical and structural problems. Significant malposition   Fig. 9.24 (A) Decentred optic with one haptic in the angle  and the other in the bag; (B) inferior subluxation of an IOL    may require repositioning or replacement, occasionally with an  iris or sclerally fixated lens.   Rhegmatogenous retinal detachment (RRD) is uncommon. Pre¬  operative risk factors include lattice degeneration and retinal  breaks - both are generally treated prophylactically prior to  cataract surgery (and probably laser capsulotomy) - and high  myopia. The key intraoperative risk is vitreous loss. Pars plana  vitrectomy is usually the surgical modality employed for pseudo-  phakic RRD.   Congenital cataract occurs in about 3 in 10 000 live births. Two-  thirds are bilateral and a cause can be identified in about half of  these. Autosomal dominant (AD) inheritance is the most common  aetiological factor; others include chromosomal abnormalities,  metabolic disorders and intrauterine infections. Isolated inherited  congenital cataracts carry a better visual prognosis than those with  coexisting ocular and systemic abnormality. Unilateral cataracts  are usually sporadic, without a family history or systemic disease,  and affected infants are usually otherwise healthy.   Galactosaemia is an autosomal recessive (AR) condition charac¬  terized by impairment of galactose utilization caused by absence  of the enzyme galactose-i-phosphate uridyl transferase (GPUT).  Unless galactose (milk and milk products) is withheld from the  diet, severe systemic complications culminate in early death. ‘Oil  droplet’ lens opacity (see Fig. 9.25D) develops within the first few  days or weeks of life in a large percentage of patients. Exclusion of  galactose may reverse early lens changes.   Lowe (oculocerebrorenal) syndrome is an X-linked recessive  (gene: OCRLi ) inborn error of amino acid metabolism with neu¬  romuscular, renal and other manifestations. Cataract is universal,  and microphakia may also be present. Congenital glaucoma is  present in about half of patients. Female carriers may have visually  insignificant cortical lens opacities.   Mannosidosis is an AR disorder with deficiency of a-mannosidase.  Infantile and juvenile-adult forms are seen, both of which feature  progressive mental deterioration, musculoskeletal and other  abnormalities. Punctate lens opacities arranged in a spoke-like  pattern in the posterior lens cortex are frequent; corneal clouding  can also occur but is less common.   Congenital rubella results from transplacental transmission of  virus from an infected mother, and may lead to severe fetal mal¬  formations. Pearly nuclear or more diffuse unilateral or bilateral  cataract occurs in around 15%. (See also Ch. 11.)   Ophthalmic features of congenital toxoplasmosis include cataract,  chorioretinitis, microphthalmos and optic atrophy. (See also  Ch. 11.)   Systemic features of congenital cytomegalovirus (CMV) infection  include jaundice, hepatosplenomegaly, microcephaly and intra¬  cranial calcification. Ocular features apart from cataract include  chorioretinitis, microphthalmos, keratitis and optic atrophy.   Systemic features include mental handicap, cortical cerebral  atrophy, cutaneous scarring and limb deformities; death in early  infancy is common. Ocular features may include cataract, micr¬  ophthalmos, chorioretinitis, optic disc hypoplasia and optic atrophy.   Measles, syphilis, herpes simplex and human immunodeficiency  virus (HIV). (See also Ch. 11.)   • Systemic features include learning difficulties, stunted  growth, distinctive facial and peripheral features, thyroid  dysfunction, cardiorespiratory disease and reduced life span.   • Ocular features. Cataract of varied morphology (75%); the  opacities are usually symmetrical and often develop in late  childhood. Other features include iris Brushfield spots (see  Fig. 12.14B) and hypoplasia, chronic blepharitis, myopia,  strabismus and keratoconus.   • Systemic features. Characteristic facial and peripheral  features, deafness, cardiac anomalies, mental handicap and  early death.   • Ocular features apart from cataract include ptosis,  microphthalmos, corneal opacity, uveal and disc coloboma  and vitreoretinal dysplasia.    X-linked condition comprising distinctive dental and facial anom¬  alies together with congenital cataract and microcornea. Female  carriers may show Y suture opacities (see Fig. 9.25F).   opacity is based principally on the appearance of the red reflex and   • A very dense cataract occluding the pupil; the decision to  operate is straightforward.   • A less dense but still visually significant cataract (e.g. central  or posterior opacities over 3 mm in diameter) will permit  visualization of the retinal vasculature with the indirect but  not with the direct ophthalmoscope.   • A visually insignificant opacity will allow clear visualization  of the retinal vasculature with both the indirect and direct  ophthalmoscope.   • Other indicators of severe visual impairment include  absence of central fixation, nystagmus and strabismus.   o Nuclear opacities (Fig. 9.25B) are confined to the  embryonic or fetal nucleus.   o Lamellar opacities affect a particular lamella of the lens  both anteriorly and posteriorly and may be associated  with radial extensions (‘riders’ - Fig. 9.25C). Lamellar  opacities may be autosomal dominant or occur in  isolation as well as in association with metabolic  disorders and intrauterine infections,  o Coronary (supranuclear) cataract lies in the deep cortex,  surrounding the nucleus like a crown. It is usually  sporadic but occasionally hereditary,  o Central ‘oil droplet’ opacities (Fig. 9.25D) are  characteristic of galactosaemia.  o Posterior polar cataract (Fig. 9.25E) may be associated  with posterior lenticonus or fetal vascular remnants  including a Mittendorf dot. This form of opacity is often  closely integrated with the lens capsule and/or a pre¬  existing defect, with a very high risk of dehiscence during  surgery.   o Sutural, in which the opacity follows the anterior or  posterior Y suture (Fig. 9.25F); may be seen in female  Nance-Horan carriers.   o Anterior polar cataract may be flat or project into the  AC. Occasional associations include persistent pupillary  membrane, aniridia, Peters anomaly and anterior  lenticonus.   • Associated ocular pathology may involve the anterior (e.g.  corneal clouding, microphthalmos, glaucoma, persistent fetal  vasculature) or posterior segments (e.g. chorioretinitis, Leber  amaurosis, rubella retinopathy, foveal or optic nerve    hypoplasia). Its presence may give an additional indication  of visual prognosis. The differential diagnosis of leukocoria  may apply (see Ch. 12).   • Assessment of family members for subclinical familial  cataract is prudent.   • Ultrasonography should be performed if the fundus is not  visible, and may reveal a definitive cause such as persistent  fetal vasculature.   • Special tests such as forced-choice preferential looking and  visual evoked potentials may provide useful supporting  information.   Investigation of familial cataract is unnecessary, but otherwise the  following should be considered. Assessment beyond a search for  infection and possibly urinary reducing substance is probably  unnecessary in unilateral cases.   • Screening for intrauterine infections should usually be  performed in all unilateral and bilateral cases.   • Urine. Urinalysis for reducing substance after drinking milk  (galactosaemia) and chromatography for amino acids (Lowe  syndrome).   • Other investigations may include fasting blood glucose,  serum calcium and phosphorus, red blood cell GPUT and  galactokinase levels. Children who have calcium and  phosphorus anomalies severe enough to cause cataract are  likely to be unwell.   • Referral to a paediatrician may be warranted for  dysmorphic features or suspicion of other systemic diseases.  Chromosome analysis may be useful in this context.   The requirement for urgent surgery is balanced by the fact that the  earlier this takes place, particularly before 4 weeks of age, the higher  the chance of glaucoma developing during the juvenile years.   • Bilateral dense cataracts require surgery between 4-10 weeks  of age to prevent the development of stimulus deprivation  amblyopia. If severity is asymmetrical, the eye with the more  dense opacity should be addressed first.   • Bilateral partial cataracts may not require surgery until  later, or indeed at any stage. In cases of doubt it may be  prudent to defer surgery in favour of careful monitoring.   • Unilateral dense cataract merits more urgent surgery; there  is no consensus regarding timing except that 6 weeks is the  latest point at which elective surgery should be performed.  Many authorities would advocate surgery between 4 and 6  weeks, followed by aggressive anti-amblyopia therapy,  despite which results are often disappointing. If the cataract  is detected after 16 weeks of age then the visual prognosis is  particularly poor.   • Partial unilateral cataract can usually be observed or treated  non-surgically with pupillary dilatation and possibly  part-time contralateral occlusion.   • Surgery involves anterior capsulorhexis, aspiration of lens  matter, capsulorhexis of the posterior capsule, limited   Fig. 9.25 Congenital cataracts. (A) Extensive blue dot; (B) nuclear; (C) lamellar with riders; (D) ‘ oil droplet’; (E) posterior polar;  (F) sutural with blue dots   (Courtesy of R Bates - fig. A; C Barry - figs B, C and E; K Nischal - fig. D)    anterior vitrectomy and IOL implantation, if appropriate. It  is important to correct associated refractive errors.   • Posterior capsular opacification is nearly universal if the  posterior capsule is retained, and can have a substantial  amblyogenic effect. Posterior capsulorhexis with vitrectomy  is generally performed during the primary lens extraction.   • Secondary membranes may form across the pupil,  particularly if postoperative uveitis is not treated  aggressively.   • Proliferation of lens epithelium is universal, often forming  a Soemmering ring; it is usually visually inconsequential.   o Secondary open-angle glaucoma may develop in up to  two-thirds of eyes by 10 years after surgery,  o Angle-closure may occur in the immediate postoperative  period secondary to pupillary block, especially in  microphthalmic eyes.   The visual results of cataract surgery in infants are hampered by   • Contact lenses provide a superior optical solution for  unilateral or bilateral aphakia. After the age of about 2 years  compliance may worsen as the child becomes more  independent.   • IOL implantation is increasingly being performed in  younger children and appears to be effective and safe in  selected cases. Hypermetropia (correctable with spectacles) is  initially targeted, and as the child ages decay towards  emmetropia should occur; however, the final refractive  outcome is variable.   Ectopia lentis refers to a hereditary or acquired displacement of  the lens from its normal position. The lens may be completely  dislocated, rendering the eye functionally aphakic (luxated), or  partially displaced, remaining partly within the pupillary area  (subluxated). The early stages of subluxation may manifest with a  tremulous lens (phacodonesis), demonstrated on the slit lamp by  lens wobble on rapid return of the eye to the primary position.    O Inflammation, e.g. chronic cyclitis, syphilis,  o Hypermature cataract,  o Large eye, e.g. high myopia, buphthalmos.  o Anterior uveal tumours.   • Familial ectopia lentis. This is an AD condition  characterized by bilateral symmetrical superotemporal  displacement; it may manifest congenitally or later in life.   • Ectopia lentis et pupillae is a rare congenital bilateral  disorder with AR inheritance characterized by displacement  of the pupil and the lens in opposite directions (Fig. 9.26 A).  The pupils are small and dilate poorly. Microspherophakia  may be present.   o AD inheritance (gene: FBNi) with variable expressivity,  o Musculoskeletal features include a tall, thin stature with  disproportionately long limbs (arm span > height), long  fingers and toes (arachnodactyly), a narrow high-arched  (‘gothic’) palate.   o Kyphoscoliosis, sternal abnormalities, mild joint laxity,  muscular underdevelopment and predisposition to hernias,  o Cardiovascular lesions include dilatation of the aortic  root, mitral valve prolapse and aortic aneurysm  formation.   o Bilateral ectopia lentis (80%); subluxation is most  frequently superotemporal. The zonule is frequently  intact so that accommodation is retained (Fig. 9.26C),  although rarely the lens may dislocate into the AC or  vitreous (Fig. 9.26D).   o Other ocular features: angle anomaly may lead to  glaucoma, and lattice retinal degeneration to retinal  detachment; there may be hypoplasia of the dilator  pupillae, microspherophakia, and strabismus.   • Weill-Marchesani syndrome is a rare systemic connective  tissue disease, conceptually the converse of Marfan  syndrome.   o Inheritance is AR or AD, the latter resulting from  polymorphisms in FBNi , the same gene as Marfan  syndrome.   o Systemic features include short stature, short fingers and  toes (brachydactyly) and learning difficulties,  o Ectopia lentis (50%). Subluxation is in an inferior   direction and occurs in late childhood or early adulthood.  Microspherophakia (Fig. 9.26E) is common, so that  pupillary block with angle closure may ensue.   • Homocystinuria is an AR disorder in which decreased  enzymatic metabolism of the amino acid methionine results  in systemic accumulation of methionine and homocysteine,  o Systemic features include coarse blond hair, blue irides,   malar flush, Marfanoid habitus, neurodevelopmental  delay, marked thrombotic predisposition and early  atherosclerosis.   o Treatment involves oral pyridoxine, folic acid and  vitamin B 12 to reduce plasma homocysteine and  methionine levels.    Fig. 9.26 Ectopia lentis. (A) Ectopia lentis et pupillae; (B) inferior subluxation in aniridia; (C) superotemporal subluxation with  intact zonule in Marfan syndrome; (D) dislocation into the vitreous in Marfan syndrome; (E) dislocation of microspheric lens  into the anterior chamber in Weill-Marchesani syndrome; (F) inferior subluxation with zonular disintegration   (Courtesy of J Schuman, V Christopoulos, D Dhaliwal, M Kahook and R Noecker, from ‘Lens and Glaucomain Rapid Diagnosis in Ophthalmology, Mosby 2008  - figs A and F; U Raina - fig. B; R Curtis - fig. E)   Fig. 9.27 Abnormalities of lens shape. (A) Anterior lenticonus;  (B) posterior lenticonus; (C) microspherophakia;   o Ectopia lentis, typically inferonasal, is almost universal by  the age of 25 years in untreated cases. The zonule, which  normally contains high levels of cysteine (deficient in  homocystinuria), disintegrates (Fig. 9.26F) so that  accommodation is often lost. Pupillary block may occur,  o Other ocular features include iris atrophy, optic atrophy,  cataract, myopia and retinal detachment.   • Other systemic conditions associated with ectopia lentis  include sulfite oxidase deficiency (ectopia lentis is universal),  and occasionally Stickler syndrome (retinal detachment is  the most common ocular manifestation - see Ch. 16),  Ehlers-Danlos syndrome and hyperlysinaemia.   The main complications of ectopia lentis are refractive error  of any type depending on lens position, optical distortion due to  astigmatism and/or lens edge effect, glaucoma (see Ch. 10) and,  rarely, lens-induced uveitis.   • Spectacle correction may correct astigmatism induced by  lens tilt or edge effect in eyes with mild subluxation. Aphakic  correction may also afford good visual results if a significant  portion of the visual axis is aphakic in the undilated state.   • Surgical removal of the lens is indicated for intractable  ametropia, meridional amblyopia, cataract, lens-induced  glaucoma or uveitis, or endothelial touch.   Anterior lenticonus consists of a bilateral axial projection of  the anterior surface of the lens into the anterior chamber (Fig.  9.27A). Almost all patients have Alport syndrome, a hereditary  condition characterized by progressive sensorineural deafness and  renal disease associated with abnormal glomerular basement    membrane; retinal flecks and posterior polymorphous corneal  dystrophy may also occur.   Bulging of the posterior axial lens (Fig. 9.27B) is associated with  local thinning or absence of the capsule in posterior lenticonus.  Most cases are unilateral, sporadic and not associated with sys¬  temic disease. With age, bulging progressively increases and the  lens cortex may opacify. Progression of cataract is variable, but an  acutely opacified lens is sometimes seen in early childhood.   Fentiglobus is a very rare, usually unilateral, generalized hemi¬  spherical deformity of the lens; it may be associated with posterior  polar opacity.   The lens is small and spherical in microspherophakia (Fig. 9.27C),  which maybe seen as an isolated familial (dominant) abnormality,  or in association with a number of systemic conditions including  Marfan and Weill-Marchesani syndromes, hyperlysinaemia and  congenital rubella. Ocular associations include Peters anomaly  and familial ectopia lentis et pupillae. Complications can include  lenticular myopia, subluxation and dislocation. Microphakia (Fig.  9.27D) is the term used for a lens with a smaller than normal  diameter. It may be found in isolation; a systemic association is  Fowe syndrome.   This is characterized by congenital indentation of the lens periph¬  ery (Fig. 9.27E) and occurs as a result of localized zonular defi¬  ciency. It is not a true coloboma, as there is no focal absence of a  tissue layer due to failure of closure of the optic fissure, though  occasionally a lens coloboma is associated with a coloboma of the  iris or fundus.   Introduction 309  Indirect gonioscopy 310  Direct gonioscopy 312  Identification of angle structures 313  Grading of angle width 315  Pathological findings 316   Pachymetry 320  Stereo disc photography 320  Optical coherence tomography 320  Confocal scanning laser  ophthalmoscopy 321  Scanning laser polarimetry 322  Anterior chamber depth  measurement 322   Laser trabeculoplasty 334  Laser iridotomy 335  Diode laser cycloablation 337  Laser iridoplasty 337   Antimetabolites in filtration surgery 339  Shallow anterior chamber 340  Failure of filtration 341  Late bleb leakage 342  Bleb-associated bacterial infection and  endophthalmitis 343   Phacolytic glaucoma 377  Phacomorphic glaucoma 377  Pupillary block from disruption of lens  position 378   Posterior embryotoxon 388  Axenfeld-Rieger syndrome 388  Peters anomaly 390  Aniridia 390   GLAUCOMA IN PHACOMATOSES 394  Sturge-Weber syndrome 394  Neurofibromatosis type 1 394   Aqueous humour is produced from plasma by the ciliary epithe¬  lium of the ciliary body pars plicata, using a combination of active  and passive secretion. A high-protein filtrate passes out of fenes¬  trated capillaries (ultrafiltration) into the stroma of the ciliary  processes, from which active transport of solutes occurs across the  dual-layered ciliary epithelium. The osmotic gradient thereby  established facilitates the passive flow of water into the posterior  chamber. Secretion is subject to the influence of the sympathetic  nervous system, with opposing actions mediated by beta-2 recep¬  tors (increased secretion) and alpha-2 receptors (decreased secre¬  tion). Enzymatic action is also critical - carbonic anhydrase is  among those playing a key role.   • The trabecular meshwork (trabeculum) is a sieve-like  structure (Fig. 10.1) at the angle of the anterior chamber  (AC) through which 90% of aqueous humour leaves the eye.  It has three components (Fig. 10.2).   o The uveal meshwork is the innermost portion, consisting  of cord-like endothelial cell-covered strands arising from  the iris and ciliary body stroma. The intertrabecular  spaces are relatively large and offer little resistance to the  passage of aqueous.   o The corneoscleral meshwork lies external to the uveal  meshwork to form the thickest portion of the  trabeculum. It is composed of layers of connective tissue  strands with overlying endothelial-like cells. The  intertrabecular spaces are smaller than those of the uveal  meshwork, conferring greater resistance to flow.   Fig. 10.2 Anatomy of outflow channels: A, Uveal meshwork;  B, corneoscleral meshwork; C, Schwalbe line; D, Schlemm  canal; E, connector channels; F, longitudinal muscle of the  ciliary body; G, scleral spur    o The juxtacanalicular (cribriform) meshwork is the outer  part of the trabeculum, and links the corneoscleral  meshwork with the endothelium of the inner wall of the  canal of Schlemm. It consists of cells embedded in a  dense extracellular matrix with narrow intercellular  spaces, and offers the major proportion of normal  resistance to aqueous outflow.   • The Schlemm canal is a circumferential channel within the  perilimbal sclera. The inner wall is lined by irregular  spindle-shaped endothelial cells containing infoldings (giant  vacuoles) that are thought to convey aqueous via the  formation of transcellular pores. The outer wall is lined by  smooth flat cells and contains the openings of collector  channels, which leave the canal at oblique angles and  connect directly or indirectly with episcleral veins. Septa  commonly divide the lumen into 2-4 channels.   Aqueous flows from the posterior chamber via the pupil into the   AC, from where it exits the eye via three routes (Fig. 10.3).   • Trabecular outflow (90%): aqueous flows through the  trabeculum into the Schlemm canal and then the episcleral  veins. This is a bulk flow pressure-sensitive route so that  increasing IOP will increase outflow.   • Uveoscleral drainage (10%): aqueous passes across the face  of the ciliary body into the suprachoroidal space, and is  drained by the venous circulation in the ciliary body,  choroid and sclera.    Fig. 10.3 Routes of aqueous outflow: A, trabecular; B,  uveoscleral; C, iris   Intraocular pressure (IOP) is determined by the balance between  the rate of aqueous production and its outflow, the latter in turn  related to factors that include the resistance encountered in the  trabeculum and the level of episcleral venous pressure.   The average IOP in the general population is around 16 mmHg on  applanation tonometry, and a range of about 11-21 mmHg - two  standard deviations either side of the average - has conventionally  been accepted as normal, at least for a Caucasian population.  However, some patients develop glaucomatous damage with IOP  less than 21 mm Hg whilst others remain unscathed with IOP well  above this level. Whilst reduction of IOP is a key modifiable  element in essentially all types of glaucoma, additional incom¬  pletely understood factors are critical in determining whether a  particular individual or eye develops glaucomatous damage. These  include features influencing the IOP reading, such as corneal rigid¬  ity, and probably factors affecting the susceptibility of the optic  nerve to damage, such as the integrity of its blood supply and struc¬  tural vulnerability to mechanical stress at the optic nerve head.   Normal IOP varies with time of day (diurnal variation), heartbeat,  blood pressure and respiration. The diurnal pattern varies, with a  tendency to be higher in the morning and lower in the afternoon  and evening. This is at least partially due to a diurnal pattern in  aqueous production, which is lower at night. Glaucomatous eyes  exhibit greater than normal fluctuation, the extent of which is  directly proportional to the likelihood of progressive visual field  damage, and a single reading may therefore be misleading. It is  good practice always to note the time of day in conjunction with  a recorded IOP.   It is difficult to define glaucoma precisely, partly because the  term encompasses a diverse group of disorders. All forms of the  disease have in common a characteristic potentially progressive  optic neuropathy that is associated with visual field loss as damage  progresses, and in which IOP is a key modifiable factor.   Glaucoma may be congenital (developmental) or acquired.  Open-angle and angle-closure types are distinguished based on  the mechanism by which aqueous outflow is impaired with  respect to the AC angle configuration. Distinction is also made  between primary and secondary glaucoma; in the latter a recog¬  nizable ocular or non-ocular disorder contributes to elevation  of IOP.   Glaucoma affects 2-3% of people over the age of 40 years; 50%  may be undiagnosed. Primary open-angle glaucoma (POAG) is  the most common form in white, Hispanic/Latino and black indi¬  viduals; the prevalence is especially high in the latter. On a world¬  wide basis, primary angle closure (PAC) constitutes up to half of  cases, and has a particularly high prevalence in individuals of  Asian descent, although with improved assessment such as the  routine performance of gonioscopy in a darkened rather than a  bright environment, PAC is known to be more prevalent in Cau¬  casian individuals than previously realized.   Goldmann applanation tonometry (GAT) is based on the  Imbert-Fick principle, which states that for a dry thin-walled  sphere, the pressure (P) inside the sphere equals the force  (P) necessary to flatten its surface divided by the area (A) of  flattening (i.e. P = FI A). Theoretically, average corneal rigidity  (taken as 520 jam for GAT) and the capillary attraction of the  tear meniscus cancel each other out when the flattened area has  the 3.06 mm diameter contact surface of the Goldmann prism,  which is applied to the cornea using the Goldmann tonometer  with a measurable amount of force from which the IOP is  deduced (Fig. 10.4). The tonometer prism should be disinfected  between patients and replaced regularly in accordance with the  manufacturer’s instructions. Disposable tonometer prisms and  caps have been introduced to address concerns of infection from  reusable prisms.   • Topical anaesthetic (commonly proxymetacaine 0.5%) and a  small amount of fluorescein are instilled into the  conjunctival sac.   • The patient is positioned at the slit lamp with his or her  forehead firmly against the headrest and instructed to look  straight ahead (often at the examiner’s opposite ear) and to  breathe normally.   • With the cobalt blue filter in place and illumination of  maximal intensity directed obliquely (approximately 6o°) at  the prism, the prism is centred in front of the apex of the  cornea.   • The prism is advanced until it just touches the apex of the  cornea (Fig. 10.5A).   • Viewing is switched to the ocular of the slit lamp.   • A pattern of two green semicircular mires will be seen, one  above and one below the horizontal midline, which  represent the fluorescein-stained tear film touching the  upper and lower outer halves of the prism. Mire thickness  should be around 10% of the diameter of its total arc (Fig.   10.5B). Care should be taken to horizontally and vertically  centre the mires so that as far as practically possible two  centralized semicircles are observed.   Fig. 10.5 Applanation tonometry. (A) Contact between the  tonometer prism and the cornea; (B) fluorescein-stained  semicircular mires - the diagram at right shows the  correct end-point using mires of appropriate thickness   • The dial on the tonometer is rotated to vary the applied  force; the inner margins of the semicircles align when a  circular area of diameter precisely 3.06 mm is flattened.   • The reading on the dial, multiplied by 10, gives the IOP; a  version is available that shows IOP on a digital display.   • Inappropriate fluorescein pattern. Excessive fluorescein will  result in the mires being too thick, with consequent   over estimation of IOP; insufficient will make the semicircles  too thin, with consequent underestimation (see Fig. 10.5B,  left and centre).   • Pressure on the globe from the examiner’s fingers, eyelid  squeezing or restricted extraocular muscles (e.g. thyroid  myopathy) may give an anomalously high reading.   • Central corneal thickness (CCT). Calculations of IOP by  GAT assume that central corneal thickness is 520 pm, with  minimal normal variation. If the cornea is thinner, an  underestimation of IOP is likely to result, and if thicker, an  over estimation. Corneas tend to be thicker than average in  individuals with ocular hypertension, and thinner in  normal-tension glaucoma (NTG); following refractive  surgery procedures the cornea is both thinner and  structurally altered such that IOP is likely to be  underestimated. Some methods of IOP measurement (e.g.  DCT - see below) may reduce the effect of structural  confounding variables. Other corneal mechanical factors  may also be important but are less well defined.   • Corneal oedema may result in artificial lowering of IOP,  hypothesized to be due to a boggy softening; the associated  increased CCT seems to be more than offset.   • Astigmatism, if significant, may give distorted mires as well  as leading to mechanically induced errors. If over 3 dioptres,  the average reading of two can be taken with the prism  rotated 90° for the second, or optimally the prism is rotated  so that the red line on the tonometer housing is aligned with  the prescription of the minus axis.   • Incorrect calibration of the tonometer can result in a false  reading, and calibration should optimally be checked before  each clinical session using the manufacturer’s calibration  arm.   • Wide pulse pressure. It is normal for there to be a small  oscillation of IOP in concert with the rhythm of ocular  perfusion. If this ‘pulse pressure’ is substantial, either the  midpoint or the highest level observed may be taken.   • Repeated readings over a short period will often be  associated with a slight fall in IOP due to a massaging effect  on the eye.   • Other factors include a tight collar and breath-holding, both  of which obstruct venous return and can raise IOP.   • Pneumotonometry (Fig. 10.6 A) is based on the principle of  applanation, but the central part of the cornea is flattened by  a jet of air rather than a prism. The time required to    sufficiently flatten the cornea relates directly to the level of  IOP. Contact is not made with the eye and topical  anaesthesia is not required, so it is particularly useful for  screening in the community. The sudden jet of air can startle  the patient. Accuracy is improved if an average of at least  three readings is taken.   • Portable applanation tonometry (Perkins) uses a Goldmann  prism in conjunction with a portable light source (Fig.   10.6B). It is hand-held, and can therefore be used in  bed-bound or anaesthetized patients.   • Dynamic contour tonometry (DCT) (e.g. PASCAF®) uses a  solid state sensor and a corneal contour-matching surface,  with the aim of measuring IOP relatively independently of  corneal mechanical factors such as rigidity. It is mounted on  a slit lamp in similar fashion to the Goldmann tonometer,  and IOP is shown on a digital display. Studies comparing  DCT and GAT IOP readings with manometric intracameral  IOP seem to confirm DCT as providing a more physiological  measurement.   • Ocular response analyser (e.g. Reichert®) is a form of  pneumotonometer that measures IOP whilst attempting to  compensate for corneal biomechanical properties by using  two sequential measurements to assess corneal hysteresis, a  function of viscous damping.   • Electronic indentation/applanation tonometry (e.g.  Tono-Pen® - Fig. 10.6C) is a hand-held electronic contact  tonometer (a modified version of the older Mackay-Marg  tonometer). The probe tip contains a transducer that  measures applied force. Besides portability, its main  advantage is the facility to measure IOP reasonably  accurately in eyes with distorted or oedematous corneas, and  through a soft contact lens.   • Rebound tonometry (e.g. iCare® - Fig. 10.6D) involves a  1.8 mm plastic ball attached to a wire; deceleration of the  probe upon contact with the cornea is proportional to IOP.  Anaesthesia is not required. The instrument can be used for  self-monitoring - a tailored personal version is available   • Indentation (impression) tonometry (e.g. Schiotz) is a  portable device that measures the extent of corneal  indentation by a plunger of known weight; it is now seldom  used.   • Implantable tonometers are under development and if a  clinically workable device is realized should facilitate  accurate lifelong 24-hour IOP measurement.   • Gonioscopy is a method of evaluating the AC angle, and can  be used therapeutically for procedures such as laser  trabeculoplasty and goniotomy.    • Other means of angle assessment such as anterior segment  optical coherence tomography (OCT) and high-frequency  ultrasound biomicroscopy (UBM) offer advantages in some  aspects of angle analysis, but current clinical opinion  suggests they should supplement rather than replace visual  gonioscopic analysis.   The angle of the AC cannot be visualized directly through the  intact cornea because light from angle structures undergoes ‘total  internal reflection’ at the anterior surface of the precorneal tear  film (Fig. 10.7, top). When light travels from a medium of higher  to one of lower refractive index (such as cornea to air) it will be  reflected at the interface between the two unless the angle of inci¬  dence is less than a certain ‘critical angle’ dependent on their  refractive index difference (46° for the tear film-air interface). The  phenomenon is utilized in optical fibre signal transmission, where    it ensures that light is retained within the core of a cable. Because  the refractive index of a goniolens is similar to that of the cornea,  it eliminates total internal reflection by replacing the tear film-air  interface with a tear film-goniolens interface (Fig. 10.7, bottom).  Light rays can then be viewed as they exit the contact lens, directly  or indirectly (see below).   Lenses must be cleaned between patients to remove any particulate  matter and then sterilized; a suggested regimen is soaking in 2%  hypochlorite solution (this has activity against transmissible  spongiform encephalopathies) for at least 5 minutes followed by  thorough rinsing in sterile saline, then air-drying.   Indirect goniolenses use a mirror to reflect rays from the angle  such that they exit the goniolens at much less than the critical   Fig. 10.7 Optical principles of gonioscopy; n = refractive  index; / = angle of incidence    angle. They provide a mirror image of the opposite angle and can  be used only in conjunction with a slit lamp.   o The classic Goldmann lens consists of three mirrors (Fig.  10.8 A), one of which is specifically for gonioscopy; some  goniolenses have one (Fig. 10.8B), two or four mirrors.   o Lenses of similar basic structure but with modifications  include the Magna View, Ritch trabeculoplasty and the  Khaw direct view.   o Because the curvature of the contact surface of the lens is  steeper than that of the cornea, a viscous coupling  substance of refractive index similar to the cornea is  required to bridge the gap between cornea and lens.   o It is essential that the examination takes place in a room  in which the ambient illumination is very low -  completely dark if possible.    o The size and intensity of the slit beam should be reduced  to the absolute minimum compatible with an adequate  view, in particular avoiding any of the beam being  directed through the pupil.   o The patient is seated at the slit lamp and advised that the  lens will touch the eye but will not usually cause  discomfort; the forehead must be kept against the  headband and both eyes should remain open,  o A drop of local anaesthetic is instilled,  o A drop or two of coupling fluid (e.g. hypromellose 0.3%)  is placed on the contact surface of the lens.    o The patient is asked to look upwards and the lens is  inserted rapidly so as to avoid loss of the coupling fluid.  The patient then looks straight ahead,  o Indirect gonioscopy gives an inverted view of the portion  of the angle opposite the mirror,  o Once the initial examination has been performed and the  findings noted, increasing the level of illumination may  help in defining the angle structures,  o When the view of the angle is obscured by a convex iris,  it is possible to see ‘over the hilT by asking the patient to  look in the direction of the mirror. Only slight movement  is permissible, otherwise the structures will be distorted  and a closed angle may appear open,  o Excessive pressure with a non-indentation lens narrows  the angle appearance (in contrast to the effect of pressure  during indentation gonioscopy - see below). Excessive  pressure also causes folds in the cornea that compromise  the clarity of the view.   o In some eyes, suction on the cornea from the lens may  artificially open the angle; awareness of the need to avoid  retrograde, as well as anterograde, pressure on the lens  will tend to prevent inadvertent distortion.   • Goniolenses include the Zeiss (Fig. 10.9), Posner and  Sussman (no handle), all of which are four-mirror  gonioprisms.   o The contact surface of the lenses has a curvature flatter  than that of the cornea, negating the need for a coupling  substance.   o The lenses do not stabilize the globe and are relatively  unsuitable for laser trabeculoplasty,  o A common criticism is that it is easy to inadvertently  open the angle, giving a misleadingly reassuring  impression, especially if inexperienced.   o The first stages are as set out above for non-indentation  gonioscopy.   o Indentation is performed by gently pressing the lens  posteriorly against the cornea; this forces aqueous into  the angle, pushing the peripheral iris posteriorly,  o If the angle is closed only by apposition between the iris  and cornea it will be forced open, allowing visualization  of the angle recess (Fig. 10.10).  o If the angle is closed by adhesions between the peripheral  iris and cornea - peripheral anterior synechiae (PAS) - it  will remain closed.   o Dynamic gonioscopy can be invaluable in helping to  define the structures in angles that are difficult to assess,  such as in distinguishing an extensive or double highly  pigmented Schwalbe line from the pigmented meshwork.   lens in a domed or slanted configuration such that exiting light   Fig. 10.9 (A) Zeiss goniolens; (B) slit lamp view with lens in  place on the cornea    rays strike the contact lens/air interface at a steeper than critical  angle so that they will pass through to the observer. This approach  is called ‘direct’ because light rays from the angle are viewed  directly, without reflection inside the lens. They do not require a  slit lamp and are used with the patient in the supine position,  typically under general anaesthesia in the evaluation and surgical  treatment of infantile glaucoma.   • Direct goniolenses include the Koeppe (Fig. 10.11A), Medical  Workshop, Barkan and Swan-Jacob (Fig. 10.11B).   o Gonioscopy is performed with the patient in the supine  position (note that this may deepen the angle) in  conjunction with an operating or hand-held microscope  or magnifying loupes.    Fig. 10.10 Indentation gonioscopy in appositional angle  closure. (A) Total angle closure prior to indentation;   (B) during indentation the entire angle becomes visible  (arrow) - the corneal folds seen are typical   o The technique cannot be used with a desktop slit lamp so  clarity, illumination and variable magnification are not  comparable with indirect lenses.   Accurate identification of angle structures (Fig. 10.12) is not always  straightforward, even for highly experienced gonioscopists.   appearing whitish to variably pigmented. Anatomically it  demarcates the peripheral termination of Descemet  membrane and the anterior limit of the trabeculum. It may  be barely discernible in younger patients. In contrast, there  may be pigment deposits on or anterior to the Schwalbe    line - a Sampaolesi line - especially in heavily pigmented  angles (e.g. pseudoexfoliation syndrome). It may have a  double-line configuration, when the posterior component  may be mistaken for the pigmented meshwork.   • The corneal wedge is useful in locating an inconspicuous  Schwalbe line. Using a narrow slit beam, two distinct linear  corneal reflections can be identified, one on the inner and  one on the outer corneal surface; the outer reflection will arc  round across the corneoscleral interface - due to the sclera  being opaque - to meet the inner reflection at the apex of  the corneal wedge that coincides with the Schwalbe line.   • The trabeculum extends from the Schwalbe line to the  scleral spur, with an average width of 600 pm. In younger  people it has a ground-glass translucent appearance. The  anterior non-functional part lies adjacent to the Schwalbe  line and has a whitish colour. The posterior, pigmented  functional part lies adjacent to the scleral spur and has a  greyish-blue translucent appearance in the young.   Trabecular pigmentation is rare prior to puberty, but in  older eyes involves the posterior trabeculum to a variable  extent, most marked inferiorly. Patchy trabecular  pigmentation in a suspiciously narrow angle raises the  possibility of intermittent iris contact.    Fig. 10.12 Normal angle structures. (A) Schematic  representation - inset painting demonstrates corneal  wedge; (B) goniophotograph - a broad Schwalbe line is  indicated by the white arrow, below which are the non-  pigmented meshwork, the pigmented meshwork, the scleral  spur and the ciliary body (black arrow) - the ciliary body is  relatively lightly pigmented   (Courtesy of W Alward, from Color Atlas of Gonioscopy, Wolfe 1994 - fig. A)    The Schlemm canal may be identified in the angle, especially  if non-pigmented, as a slightly darker line deep to the  posterior trabeculum. Blood can sometimes be seen in the  canal (Fig. 10.13), either physiologically (sometimes due to  excessive pressure on the episcleral veins with a goniolens),  or in the presence of low intraocular or raised episcleral  venous pressure.   The scleral spur is the most anterior projection of the sclera  and the site of attachment of the longitudinal muscle of the  ciliary body. Gonioscopically it is situated immediately  posterior to the trabeculum and appears as a narrow whitish  band that yellows with age.   The ciliary body stands out just behind the scleral spur as a  pink, dull brown or slate grey band. Its width depends on  the position of iris insertion and it tends to be narrower in  hypermetropic eyes and wider in myopic eyes. The angle  recess represents the posterior dipping of the iris as it inserts  into the ciliary body. It may not be visible in some eyes due    to a physiological anterior iris insertion, though fixed  pathological angle narrowing due to peripheral anterior  synechiae (PAS) - adhesions between the iris and angle  structures - should be excluded.   • Iris processes are small, usually tenuous extensions of the  anterior surface of the iris that insert at the level of the  scleral spur and cover the ciliary body to a varying extent  (see Fig. 10.13). They are present in about one-third of  normal eyes and are most prominent during childhood and  in brown eyes. The processes should not be confused with  PAS, which typically extend more anteriorly and are more  substantial.   • Blood vessels. Radial vessels at the base of the angle recess  are often seen in normal eyes. Pathological blood vessels  run randomly in various directions. As a general principle,  any blood vessel that crosses the scleral spur onto the  trabecular meshwork is abnormal. Larger circumferential  vessels may also be seen.    Fig. 10.13 Blood in the Schlemm canal (arrow), and iris  processes   (Courtesy of J Schuman, V Christopoulos, D Dhaliwal, M Kahook and R  Noecker, from 1 Lens and Glaucomain Rapid Diagnosis in Ophthalmology,  Mosby 2008)   In practice, the angle is graded by many practitioners simply  according to the number of structures visible (Fig. 10.14), together  with qualifying comments relating to the width of the iris approach;  many angles are narrowest superiorly, though this difference may  be reduced by decreasing the ambient illumination.   The Shaffer system records the angle in degrees between two imag¬  inary lines tangential to the inner surface of the trabeculum and  the anterior surface of the iris about one-third of the distance from  its periphery. The system assigns a numerical grade to each quad¬  rant of the angle.   • Grade 4 (35-45 0 ) is the widest angle, characteristic of myopia  and pseudophakia; the ciliary body can be visualized without  tilting the lens.   • Grade 3 (25-35 0 ) is an open angle in which the scleral spur is  visible.    • Grade 2 (20°) is an angle in which the trabeculum but not  the scleral spur can be seen.   • Grade 1 (io°) is a very narrow angle in which only the  Schwalbe line and perhaps the top of the trabeculum can be  identified.   • Slit angle is one in which there is no obvious iridocorneal  contact but no angle structures can be identified.   • The Spaeth system is detailed but underused. It allows  formal description of the position of iris insertion, the  angular approach and peripheral iris curvature.   • The Scheie classification refers to the angle structures visible  and allocates a Roman numeral accordingly. In contrast to  common clinical use, in the original system a higher  numeral (e.g. IV) actually signifies a narrower angle.   • The van Herick method (Table 10.1) uses the slit lamp alone  to estimate the AC angle width:   perpendicularly to the corneal surface (offset from the  optics by about 6o°) to the patient’s temporal side for  each eye.   o The beam is used to estimate the ratio of the corneal  thickness to the most peripheral part of the AC.    o It is useful as a screening tool, but overestimates angle  width in a proportion of patients, particularly those with  a plateau iris conformation.   O Pigment dispersion syndrome,  o Pseudophakic pigment dispersion,  o Pseudoexfoliation syndrome,  o Blunt ocular trauma,  o Anterior uveitis.   o Following acute angle-closure glaucoma,  o Following YAG laser iridotomy.  o Iris or angle melanoma or naevus.  o Iris pigment epithelial cysts,  o Naevus of Ota.   o Angle recession,  o Trabecular dialysis,  o Cyclodialysis,  o Foreign bodies.   o Carotid-cavernous fistula and dural shunt,  o Sturge-Weber syndrome,  o Obstruction of the superior vena cava.   The neuroretinal rim (NRR) is the orange-pink tissue between the  outer edge of the cup and the optic disc margin. The inferior rim  is the broadest followed by the superior, nasal and temporal (the  TSNT’ rule - Fig. 10.15); this has high sensitivity for glaucoma but  is not very specific, i.e. eyes without glaucoma often do not respect  the rule.   The C/D ratio indicates the diameter of the cup expressed as a  fraction of the diameter of the disc; the vertical rather than the    horizontal ratio is generally taken. Small diameter optic discs have  small cups (Fig. 10.16A) and vice versa (Fig. 10.16B); only 2% of  the population have a C/D ratio greater than 0.7. In any individual,  asymmetry of 0.2 or more between the eyes should also be regarded  with suspicion, though it is critical to exclude a corresponding  difference in overall disc diameter (see next).   Optic disc size is important in deciding if a cup/disc (C/D) ratio  is normal (see above), and is also a prognostic indicator. Farge  discs are believed to be more likely to sustain damage, particularly  in NTG. This may be the result of the larger diameter conferring  relative mechanical weakness and hence greater vulnerability to  IOP-induced displacement of the lamina cribrosa; the lamina cri-  brosa has been found to be thinner in eyes with NTG. Disc size  varies on average between racial groups, and is largest in black  individuals. Imaging can objectively measure disc area, but vertical  diameter is the parameter most frequently used clinically; normal  median vertical diameter (for non-glaucomatous discs) is  1.5-1.7 mm in a white population.   o A narrow slit beam is focused on the disc using a fundus  lens.   o The height of the beam is adjusted until it matches the  distance between the superior and inferior limits of the  NRR (not the scleral rim surrounding the neural tissue),  and the diameter in millimetres is read from the slit lamp  graticule.   o A correction factor may be necessary, depending on the  lens used (Table 10.2). Refractive error affects  measurement only minimally, although myopia above -8  dioptres may distort the result.   In many cases it is not possible to be certain whether an individual  optic disc is glaucomatous. The clinical findings and results of    Fig. 10.16 Normal discs. (A) Small disc with a low cup/disc  ratio; (B) larger disc with a proportionally larger cup   investigation should be considered together to guide management.  Glaucomatous damage results in characteristic signs involving (a)  the optic nerve head, (b) the peripapillary area and (c) the retinal  nerve fibre layer.   Pathological cupping is caused by an irreversible decrease in the  number of nerve fibres, glial cells and blood vessels. A documented    increase in cup size is always significant. If an eye with a small optic  disc and correspondingly small cup develops glaucoma, the cup  will increase in size, but even in the presence of substantial damage  may still be smaller than that of a large physiological cup.   Four ‘pure’ glaucomatous disc appearances have been described,  and although the majority of discs are unclassifiable the descrip¬  tions encompass a useful overview of patterns of glaucomatous  damage, and may provide clues to underlying pathological  processes.   • Focal ischaemic discs (Fig. 10.17A) are characterized by  localized superior and/or inferior notching and may be  associated with localized field defects with early threat to  fixation.   • Myopic disc with glaucoma (Fig. 10.17B) refers to a tilted  (obliquely inserted), shallow disc with a temporal crescent of  parapapillary atrophy, together with features of  glaucomatous damage. Dense superior or inferior scotomas  threatening fixation are common. This morphology is most  common in younger male patients.   • Sclerotic discs (Fig. 10.17C) are characterized by a shallow,  saucerized cup and a gently sloping NRR, variable  peripapillary atrophy and peripheral visual field loss. The  peripapillary choroid is thinner than in other disc types.  Patients are older, of either gender, and there is an  association with systemic vascular disease.   • Concentrically enlarging discs (verified by serial  monitoring) are characterized by fairly uniform NRR  thinning (Fig. 10.17D) and are frequently associated with  diffuse visual field loss. IOP is often significantly elevated at  presentation.   • Disc haemorrhages (Figs 10.18A and B, and see Fig. 10.17A)  often extend from the NRR onto the retina, most commonly  inferotemporally. Their presence is a risk factor for the  development and progression of glaucoma. They are more  common in NTG, but can also occur in healthy individuals  as well as patients with systemic vascular disease.   • Baring of circumlinear blood vessels is a sign of early  thinning of the NRR. It is characterized by a space between  the neuroretinal rim and a superficial blood vessel (Fig. 10.18C).   • Bayoneting is characterized by double angulation of a blood  vessel. With NRR loss, a vessel entering the disk from the  retina may angle sharply backwards into the disk and then  turn towards its original direction to run across the lamina  cribrosa (Fig. 10.18D).   • Collaterals between two veins at the disc (Fig. 10.18E),  similar to those following central retinal vein occlusion  (CRVO), are relatively uncommon. They are probably  caused by chronic low-grade circulatory obstruction. Retinal  vascular tortuosity may also occur.   Fig. 10.17 Classic subtypes of glaucomatous damage. (A) Focal ischaemic - inferior notch and disc haemorrhage; (B) myopic;  (C) sclerotic; (D) concentrically enlarging    • Loss of nasal NRR (Fig. 10.18F) is a sign of moderately  advanced damage; a space may develop between the NRR  and the central retinal vasculature.   • The laminar dot sign occurs in advancing glaucoma. Grey  dot-like fenestrations in the lamina cribrosa (see Fig. 10.18F)  become exposed as the NRR recedes. The fenestrations  sometimes appear linear, and this itself may be a sign of  advanced damage, indicating distortion of the lamina. The  dots may be seen in normal eyes.   • ‘Sharpened edge’ or ‘sharpened rim’ is a sign of advancing  damage. As NRR is lost adjacent to the edge of the disc, the  disc margin contour assumes a sharper angle backwards.  Bayoneting of vessels is often seen at a sharpened edge. This  should not be confused with a ‘sharpened nasal polar edge’,  which refers to the sharp angulation of the NRR at the nasal  margin of a focal vertical polar notch.   Peripapillary atrophy (PPA) surrounding the optic nerve head  may be of significance in glaucoma (Fig. 10.19), and may be a sign  of early damage in patients with ocular hypertension.    • Alpha (outer) zone is characterized by superficial retinal  pigment epithelial changes. It tends to be larger and possibly  more common in glaucomatous eyes.   • Beta (inner) zone is characterized by chorioretinal atrophy;  it is distinct from the scleral rim, the white band of exposed  sclera central to the beta zone. The beta zone is larger and  more common in glaucoma, and is a risk factor for  progression; the location of beta-zone PPA seems to indicate  the orientation of likely visual field loss.   In glaucoma subtle retinal nerve fibre layer (RNFL) defects precede  the development of detectable optic disc and visual field changes;  their onset often follows disc haemorrhages. Two patterns occur:  (a) localized wedge-shaped defects and (b) diffuse defects that are  larger and have indistinct borders. Defects are sometimes evident  following disc haemorrhages (Fig. 10.20A). Red-free (green) light  increases the contrast between normal retina and defects on slit  lamp biomicroscopy or fundus photography (Fig. 10.20B) and  typically makes identification easier. OCT and scanning laser  polarimetry are highly effective means of quantifying the RNFL.   Fig. 10.18 Non-specific signs of glaucomatous damage. (A) and (B) Disc haemorrhages; (C) baring of inferior circumlinear  blood vessel; (D) bayoneting of blood vessels; (E) collateral vessels; (F) loss of nasal neuroretinal rim and laminar dot sign    Fig. 10.19 Parapapillary changes. Alpha zone (white arrow)  and beta zone (black arrow)    It should be noted that RNFL defects are not specific to glaucoma,  and can be seen in a range of neurological disease, as well as appar¬  ently normal individuals.   Pachymetry, the measurement of corneal thickness, in recent years  has become an essential part of the assessment of glaucoma  patients. Ultrasonic (e.g. Pachmate) and optical methods are  available.   Stereo photography has historically been regarded as the reference  standard in optic disc imaging, and remains a valuable option. The  images are taken by repositioning slightly between shots, either  manually or using a stereo separator built into the camera.   OCT has become a routine part of the management of macular  and other retinal disease; the same machine can be used for the  assessment of glaucoma (Fig. 10.21) and has been widely adopted  for this purpose. Sensitivity and specificity utilizing comparison  with a normative database are as high as 90%.The principles are  discussed in detail in Chapter 14.   • Peripapillary retinal nerve fibre layer (RNFL). This involves  the acquisition of a circular scan of the retina around the  optic nerve head. Retinal thickness is compared with  normals.    • Optic nerve head. Radial cross-sectional scans permit an  objective and repeatable assessment of disc morphology,  with reasonable discriminatory value. This function has  tended to be less commonly used than RNFL analysis in  practice.   • Ganglion cell complex (GCC) analysis involves  measurement of retinal thickness at the macula in an  attempt to detect early stage glaucomatous damage. Using  older time domain OCT, it was found to be regarded as  inferior to assessment of other parameters such as  peripapillary RNFL assessment; with newer OCT technology  interest in GCC analysis has been renewed and it is regarded  as comparable and supplementary.   • Progression analysis software has been introduced on  several machines, providing a computed assessment of the  extent of damage over time presented in graphical form.   Fig. 10.20 Retinal nerve fibre layer defects. (A)  Superotemporal wedge-shaped defect associated with a  disc margin haemorrhage; (B) red-free photograph of the  same eye    Fig. 10.21 Glaucoma-protocol OCT showing optic nerve head, peripapillary retinal nerve fibre layer and ganglion cell complex  analysis   This employs a scanning laser ophthalmoscope (SLO) to build a  three-dimensional image of the optic nerve head and retina.   • The Heidelberg Retinal Tomograph (HRT) is in widespread  clinical practice As with the OCT, it is used to distinguish  normal from glaucomatous eyes by comparison against a  normative database (Moorfields regression analysis), and to  monitor disease progression.    • Keratometry values must be entered and significant (>i.o  dioptre) astigmatism corrected by means of a cylindrical  lens. High-quality images can usually be acquired without  pupillary dilatation and through mild-moderate lens  opacity. After image capture, for greatest accuracy the  operator must manually mark the contour line defining the  edge of the neuroretinal rim.   • Images, data and analysis can be examined on a computer  screen or printed (Fig. 10.22).   0 0 0.4 0.0 1.2 1.5 2.0 2,4 2,0 3,2 3.6 4.0 4.4 -0,4 0,0 0.4 0.0 1.2 1.6 0 0 0.4 O.fi 12 t.fl 2.0 2.4 2.B 3.2 3.6 4,0 4.4   The GDx (Glaucoma Diagnosis) RNFL analyser assesses the nerve  fibre layer thickness by using its ‘birefringent’ (resolving or split¬  ting a light wave into two unequally reflected or transmitted  waves) nature to change the polarization of incident polarized  diode laser light; the amount of alteration is directly related to the  thickness of the layer.   • A display provides colour images of the optic nerve head,  together with RNFL maps in four quadrants; deviation maps  show the location and magnitude of RNFL defects as tiny  colour-coded squares, and parameters for each eye are  displayed in a table (Fig. 10.23).    • A global value based on the entire thickness map is the  optimal parameter for discriminating normal from  glaucoma.   Objective measurement of the depth of the AC is often clinically  useful in glaucoma management. Indications include assessment  of PAC risk, and monitoring of progression in conditions where  the AC is shallowed, such as post-trabeculectomy hypotony and  cilio-lenticular block. Older methods used a slit lamp with or  without a special attachment, but an accurate and repeatable  measurement can be obtained using ultrasonographic or optical  interferometric methods (e.g. Zeiss IOLMaster).   Fig. 10.23 GDx VCC (variable corneal compensation) shows reduction in retinal nerve fibre density in the right eye and  abnormal parameters   • The visual field can be represented as a three-dimensional  structure akin to a hill of increasing sensitivity (Fig. 10.24A).  The outer aspect extends approximately 50° superiorly, 6o°  nasally, 70° interiorly and 90° temporally. Visual acuity is  sharpest at the very top of the hill (i.e. the fovea) and then  declines progressively towards the periphery, the nasal slope  being steeper than the temporal. The ‘bottomless pit’ of the  blind spot is located temporally between io° and 20°, slightly  below the horizontal.    An isopter is a line connecting points of the same sensitivity,  and on a two-dimensional isopter plot encloses an area  within which a stimulus of a given strength is visible. When  the field is represented as a hill, isopters resemble the  contour lines on a map (Fig. 10.24B).   A scotoma is an area of reduced (‘relative’) or total  (‘absolute’) loss of vision surrounded by a seeing area.  Luminance is the intensity or ‘brightness’ of a light stimulus,  measured in apostilbs (asb). A higher intensity stimulus has  a higher asb value; this is related inversely to sensitivity.   A logarithmic rather than a linear scale is used for stimulus  intensity and sensitivity, so that for each log unit intensity  changes by a factor of 10. With a log scale, greater   significance is given to the lower end of the intensity range.  The normal eye has a very large sensitivity range, and  assessment of the lower end of the scale is of critical  significance so that early damage can be detected. With a  linear scale, the lower end would be reduced to a very small  portion of a graphical chart axis. The visual system itself  operates on close to a logarithmic scale, so using this  method more closely matches the physiological situation.   • Decibels. Simple log units are not used in clinical perimetry,  but rather ‘decibels’ (dB), where 10 dB = 1 log unit. Decibels  are not true units of luminance but a representation, and  vary between visual field machines. Perimetry usually  concentrates on the eye’s sensitivity rather than the stimulus  intensity. Therefore, the decibel reading goes up as retinal    sensitivity increases, which obviously corresponds to  reducing intensity of the perceived stimulus. This makes the  assessment of visual fields more intuitive, as a higher  number corresponds with higher retinal sensitivity. If the  sensitivity of a test location is 20 dB (= 2 log units), a point  with a sensitivity of 30 dB would be the more sensitive. The  blind spot has a sensitivity of 0 dB. If, on a given machine,  seeing a stimulus of 1000 asb gives a value of 10 dB, a  stimulus of 100 asb will give 20 dB.   • Differential light sensitivity represents the degree by which  the luminance of a target must exceed background  luminance in order to be perceived. The visual field is  therefore a three-dimensional representation of differential  light sensitivity at different points.   • Threshold at a given location in the visual field is the  brightness of a stimulus at which it can be detected by the  subject. It is defined as ‘the luminance of a given fixed-  location stimulus at which it is seen on 50% of the occasions  it is presented’. In practice we usually talk about an eye’s  sensitivity at a given point in the field rather than the  stimulus intensity. The threshold sensitivity is highest at the  fovea and decreases progressively towards the periphery.  After the age of 20 years the sensitivity decreases by about   • Background luminance. The retinal sensitivity at any  location varies depending on background luminance. Rod  photoreceptors are more sensitive in dim light than cones,  and so owing to their preponderance in the peripheral  retina, at lower (scotopic) light levels the peripheral retina  becomes more sensitive in proportion to the central retina;  the hill of vision flattens, with a central crater rather than a  peak at the fovea due to the high concentration of cones,  which have low sensitivity in scotopic conditions. Some  diseases give markedly different field results at different  background luminance levels e.g. in retinitis pigmentosa the  field is usually much worse with low background luminance.  It should be noted that it takes about 5 minutes to adapt  from darkness to bright sunlight and 20-30 minutes from  bright sunlight to darkness. The HFA (see below) uses a  photopic (preferentially cone) level of background  luminance at 31.5 asb.   • Static perimetry. A method of assessing fields, usually  automated, in which the location of a stimulus remains  fixed, with intensity increased until it is seen by the subject  (threshold is reached - Fig. 10.25A) or decreased until it is  no longer detected.   • Kinetic (dynamic) perimetry is now much less commonly  performed than static perimetry. A stimulus of constant  intensity is moved from a non-seeing area to a seeing area  (Fig. 10.25B) at a standardized speed until it is perceived, and  the point of perception is recorded on a chart; points from  different meridia are joined to plot an isopter for that  stimulus intensity. Stimuli of different intensities are used to  produce a contour map of the visual field. Kinetic perimetry  can be performed by means of a manual (Goldmann) or an  automated perimeter if the latter is equipped with an  appropriate software program.   • Manual perimetry involves presentation of a stimulus by the  perimetrist, with manual recording of the response. It was  formerly the standard method of field testing but has now  largely been superseded by automated methods. It is still  used occasionally, particularly in cognitively limited patients  unable to interact adequately with an automated system, and  for dynamic testing of peripheral fields.   • Standard automated perimetry (SAP) is the method used  routinely in most clinical situations. Automated perimeters  in common use include the Humphrey Field Analyser  (HFA), the Octopus, Medmont, Henson and Dicon. These  predominantly utilize static testing, though software is  available on some machines to perform dynamic assessment.    Fig. 10.25 Principles of perimetry. (A) Static - stimulus  intensity (red arrow) at a single location is increased until  perceived - areas of lower sensitivity perceive only stimuli  of greater intensity (longer red arrows); (B) kinetic -  stimulus of constant intensity is moved from a non-seeing  area until perceived   Threshold perimetry is used for detailed assessment of the hill of  vision by plotting the threshold luminance value at various loca¬  tions in the visual field and comparing the results with age-  matched ‘normal’ values. A typical automated strategy is to present  a stimulus of higher than expected intensity; if seen, the intensity  is decreased in steps (e.g. 4 dB) until it is no longer seen (‘staircas¬  ing’). The stimulus is then increased again (e.g. 2 dB steps) until  seen once more (Fig. 10.26). If the stimulus is not seen initially, its  intensity is increased in steps until seen. Essentially, the threshold  is crossed in one direction with large increments, then crossed  again to ‘fine-tune’ the result with smaller increments. Threshold  testing is commonly used for monitoring glaucoma.   Suprathreshold perimetry involves testing with stimuli of lumi¬  nance above the expected normal threshold levels for an age-  matched population to assess whether these are detected; in other  words, testing to check that a subject can see stimuli that would  be seen by a normal person of the same age. It enables testing to  be carried out rapidly to indicate whether function is grossly  normal or not and is usually reserved for screening.   In recent years strategies have been introduced with shorter testing  times, providing efficiency benefits with little or no detriment to  testing accuracy. The HFA offers the SITA (Swedish Interactive  Thresholding Algorithm), which uses a database of normal and  glaucomatous fields to estimate threshold values, and takes  responses during the test into account to arrive at adjusted esti¬  mates throughout the test. Full threshold values are obtained at  the start of the test for four points. SITA-Standard and SITA-Fast  (Fig. 10.27) versions are available; their relative superiority is  subject to debate. The Octopus Perimeter uses G-TOP (Glaucoma  Tendency Oriented Perimetry), which again estimates thresholds  based on information gathered from more detailed assessment of  adjacent points. TOP presents each stimulus once at each location,  instead of 4-6 times per location with a standard technique.   o Importance of central area. Most important defects in  glaucoma occur centrally - within a 30° radius from  the fixation point - so this is the area most commonly  tested.   o 24-2 is a glaucoma-orientated pattern used routinely. ‘24’  denotes the extent in degrees to which the field is tested  on the temporal side (to 30° on the nasal side). The  number after the hyphen (2) describes the pattern of the  points tested. 30-2 is an alternative,  o 10-2 is used to assess a central area of radius io°.   Glaucomatous defects here may threaten central vision;  the 10-2 pattern facilitates more detailed monitoring of  the extent of damage, especially in advanced glaucoma.   • Peripheral field. Patterns that include central and peripheral  points (e.g. FF-120) are typically limited to the assessment of  neurological defects.   • Binocular field testing (e.g. Esterman strategy) is used to  assess statutory driving entitlement in many jurisdictions.   SAP provides the clinician with an array of clinically relevant  information via monitor display or printout. The patient’s name  and age are confirmed and a check made that any appropriate  refractive error compensation was used. General information  should be reviewed, such as the type of algorithm performed, the  time taken for the test and the order in which the eyes were tested;    in some cases these must be interpreted to discern likely learning  or fatigue-induced effects.   Reliability indices (see Fig. 10.27, top left corner) reflect the extent  to which the patient’s results are reliable, but it is important to  note that there is relatively little research-based evidence in this  area, with limited absolutes in branding a field as clearly reliable  or unreliable. With SITA strategies, false negatives or false posi¬  tives over about 15% should probably be regarded as highly sig¬  nificant, and with full-threshold strategies, fixation losses over  20% and false positives or negatives over 33%. In patients who  consistently fail to achieve good reliability it may be useful to  switch to a suprathreshold strategy or kinetic perimetry.   • Fixation losses indicate steadiness of gaze during the test.  Methods of assessment include presentation of stimuli to the  blind spot to ensure no response is recorded, and the use of  a ‘gaze monitor’.   • False positives are usually assessed by decoupling a stimulus  from its accompanying sound. If the sound alone is  presented and the patient still responds, a false positive is  recorded. With a high false-positive score the grey scale  printout appears abnormally pale (Fig. 10.28). In SITA  testing, false positives are estimated based on the response  time.   • False negatives are registered by presenting a stimulus much  brighter than threshold at a location where the threshold has  already been determined. If the patient fails to respond, a  false negative is recorded. A high false-negative score  indicates inattention, tiredness or malingering, but is  occasionally an indication of disease severity rather than  unreliability. The grey scale printout in individuals with high  false-negative responses tends to have a clover leaf shape  (Fig. 10.29).   • A numerical display (see Fig. 10.27, upper left display) gives  the measured or estimated (depending on strategy)  threshold in dB at each point. In a full-threshold strategy,  where the threshold is rechecked either as routine or because  of an unexpected (>5 dB) result, the second result is shown  in brackets next to the first.   • A grey scale represents the numerical display in graphical  form (see Fig. 10.27, upper right display) and is the simplest  display modality to interpret: decreasing sensitivity is  represented by darker tones - the physiological blind spot is  a darker area in the temporal field typically just below the  horizontal axis. Each change in grey scale tone is equivalent  to a 5 dB change in sensitivity at that location.   • Total deviation (see Fig. 10.27, middle left display) shows  the difference between a test-derived threshold at a given  point and the normal sensitivity at that point for the general  population, correcting for age. Negative values indicate  lower than normal sensitivity, positive values higher than  normal.   Fixation Monitor: Gaze/Blind Spot  Fixation Target: Central  Fixation Losses: 0/10  False POS Errors; 0%    • Pattern deviation (see Fig. 10.27, middle right display) is  derived from total deviation values adjusted for any  generalized decrease in sensitivity in the overall field (e.g.  lens opacity), and demonstrates localized defects.   • Probability value plots of the total and pattern deviation  (see Fig. 10.27, left and right lower displays) are a  representation of the percentage (<5% to <0.5%) of the    normal population in whom the measured defect at each  point would be expected. Darker symbols represent a greater  likelihood that a defect is significant.    FIXATION nCNlTOR: GWE/8LIWSWT  FIXATION TARGET: CEMRRL  FIXATION LOSSES: 9/14  FALSE POS ERRORS: 66  FALSE NEC ERRORS: 33 1    FIXATION MONITOR*. GAZE/BlIK05FCT  FIXATION TARGET: CENTRAL  FIXATION LOSSES: 0/17  FALSE POS ERRORS: 3 X  FALSE NEC ERRORS: 53 X  TEST DURATION: 99:52   Fig. 10.29 High false-negative score (arrow) with a clover leaf-shaped grey scale display    taking into account age-matched normal data, and are principally  used to monitor progression of glaucomatous damage rather than  for initial diagnosis.   • Visual field index (VFI) in the HFA is a measure of the  patient’s overall visual field function expressed as a  percentage, the normal age-adjusted value being ioo%.   • Mean deviation (MD) on the HFA (mean defect on the  Octopus) gives an indication of the overall sensitivity of  the field. It is derived from averaging the total deviation  values.    • Pattern standard deviation (PSD) is a measure of focal loss  or variability within the field taking into account any  generalized depression in the hill of vision. An increased  PSD is therefore a more specific indicator of glaucomatous  damage than MD.   • Loss variance (LV) is a summary measure on the Octopus  perimeter similar to PSD.   • Probability values. Abnormal summary values are followed  by a probability value, representing the percentage likelihood  that an abnormal value of this level will occur in a normal   subject; the lower the P value, the more likely the result is  abnormal.   • The glaucoma hemifield test (GHT) used with some HFA  testing patterns assesses the visual field for damage  conforming to a pattern commonly seen in glaucoma.   Computed analysis of serial visual fields for progression is now  becoming more widespread. A disadvantage is the requirement for  several reliable fields to be carried out before analysis is effective.  The quality of available software has been improving steadily, with  integrated programs such as GPA (Guided Progression Analysis)  on the HFA and several trend analysis options on the Octopus.   SAP tends to detect field damage only after substantial ganglion  cell loss is established. Attempts at detecting change at an earlier  stage include the adoption of stimuli intended to target specific  ganglion cell types.   • Short-wave automated perimetry (SWAP) uses a blue  stimulus on a yellow background. Sensitivity to blue light  (mediated by blue cone photoreceptors) is adversely affected  relatively early in glaucoma. SWAP is more sensitive to early  glaucomatous defects but has not been widely adopted  because cataract decreases sensitivity to blue light (the  brunescing lens acts as a yellow filter) and patients  frequently dislike the lengthy test. It is available on newer  HFA models.   • Frequency-doubling test (FDT). Large diameter axon  (magnocellular) ganglion cells appear to be preferentially  lost in early glaucoma. The frequency-doubling illusion is  produced when a low spatial frequency sinusoidal grating  undergoes high temporal frequency counter phase flicker  (>15 Hz). The rapid alternation in which the light bars  become dark and vice versa produces the illusion of the  grating having doubled its frequency; magnocellular  ganglion cells are believed to mediate the pathways used.  Screening (Fig. 10.30) and extended testing (Humphrey  Matrix) perimeter versions are available, the latter being  suitable for detailed assessment and monitoring of  glaucoma.   • Inexperienced or unskilled perimetrist. Though less  important with SAP than manual perimetry, correctly setting  up the test, explaining the procedure to and reassuring the  patient, and monitoring performance are fundamental to  obtaining an accurate field.   • Incorrect patient details. The patient’s date of birth must be  entered correctly to facilitate appropriate normative database  matching.   • Uncorrected refractive error can cause a significant decrease  in central sensitivity. If a hypermetropic patient who usually    wears contact lenses is tested wearing spectacles, this will  have the effect of magnifying and enlarging any scotomas as  compared with contact lenses. Most perimetry is performed  with a stimulus at approximately reading distance, so a near  correction should be used for presbyopic patients.   • Spectacle rim artefact. Spectacles can cause rim scotomas if  small aperture lenses are used or if incorrectly dispensed  (Fig. 10.31). Narrow-aperture trial frame lenses are  unsuitable for perimetry.   • Miosis decreases sensitivity in the peripheral field and  increases variability in the central field in both normal and  glaucomatous eyes. Pupils less than 3 mm in diameter  should therefore be dilated prior to perimetry; a consistent  mydriatic should be used for serial tests.   • Media opacities (usually cataract) can have a profound  effect, exaggerated by miosis.   • Ptosis, even if mild, can suppress the superior visual field.  Similar effects result from dermatochalasis, prominent  eyelashes and deeply set eyes.   • Inadequate retinal adaptation may lead to error if  perimetry is performed soon after ophthalmoscopy.   It is important to attempt to maximize compliance by providing  an explanation of the disease and the rationale for treatment. A    discussion of the medication being prescribed including technique  and timing of administration, and its potential adverse effects, is  also essential. The provision of written information may be  helpful. Most glaucoma medications are administered topically,  but significant systemic absorption can still occur, with resultant  systemic adverse effects. Systemic absorption may be minimized  by lacrimal occlusion following instillation: simply closing the eyes  for 3 minutes will reduce systemic absorption by about 50%, and  this can be enhanced by applying digital pressure over the lacrimal  sac - these measures also prolong eye-drug contact. Effects on the  periocular skin may be reduced by blotting overflow from the  eyelids with a clean dry tissue immediately after instillation. Glau¬  coma medications should be avoided in pregnancy if possible,  with systemic carbonic anhydrase inhibitors perhaps carrying the  greatest risk due to teratogenicity concerns. A promising new  route of administration is subconjunctival injection of a liposomal  depot preparation of medication that would conventionally be  administered topically, which may exert a useful IOP-lowering  effect over several months.   The major mode of prostaglandin (PG) action is the enhancement  of uveoscleral aqueous outflow, although increased trabecular  outflow facility and other mechanisms have been identified. Their  IOP-lowering effect is typically greater than alternatives, though  beta-blockers (see below) are sometimes equivalent. A prostaglan¬  din derivative is now typically preferred to a beta-blocker as first-  line treatment for glaucoma due to the latter’s potential for  systemic side effects. Duration of action may extend for several  days, though administration once every day (at bedtime) is gener¬  ally recommended. Systemic side effects are few; the most com¬  monly troublesome ocular side effect is conjunctival hyperaemia.  Periorbital fat loss is common, especially with bimatoprost, mani¬  festations including deepening of the upper lid sulcus. If one pros¬  taglandin fails to show adequate efficacy, inter-individual receptor  variation means that an alternative preparation may be superior  in a given patient. Although some research has suggested that  using more than one PG at a time may have an additive effect,  consensus currently is that PG overdosing - twice a day or more  - raises the IOP in many patients.   • Latanoprost may cause fewer ocular adverse events than  other PG agents and so is often used first line, although as a  proportion of patients show no response many practitioners  prefer initial use of an alternative.   • Travoprost is similar to latanoprost, though it may lower  IOP to a slightly greater extent, particularly in black patients.  Polyquad® is a novel proprietary preservative introduced by  a major pharmaceutical manufacturer in its travoprost  formulation that may reduce ocular surface-related adverse  effects.   • Bimatoprost has been shown to have a greater IOP-lowering  effect than the other PG agents in several studies, but may  cause more conjunctival hyperaemia but fewer headaches  and perhaps also less iris hyperpigmentation. A newer 0.01%  (versus the older 0.03%) preparation may have a comparable  IOP-lowering effect but with less hyperaemia. Preservative-  free bimatoprost is now available.   • Tafluprost is a newer prostaglandin derivative, and was the  first available in preservative-free form. Its IOP-lowering  efficacy may be slightly less than that of other PG agents, but  it is well tolerated and seems to cause less disruption of the  ocular surface.   O Eyelash lengthening, thickening, hyperpigmentation  (Fig. 10.32A) and occasionally increase in number.   O Irreversible iris hyperpigmentation (Fig. 10.32B) occurs in  up to a quarter of patients after 6 months. The highest  incidence is in green-brown irides, less in yellow-brown  irides and least in blue-grey/brown irides. It is caused by  an increase in the number of pigmented granules within  the superficial stroma rather than an increase in the  number of melanocytes. Iris naevi and freckles are not  affected.   o Hyperpigmentation of periocular skin (see Fig. 10.32B) is  common but reversible.   o Preoperative use of PG agents may increase the likelihood  of cystoid macular oedema following cataract surgery.    o Anterior uveitis is rare, but prostaglandins should be used  with caution in inflamed eyes,  o Promotion of herpetic keratitis can occur, so   prostaglandins should be used with caution in patients  with a history of the condition.   precipitation of migraine in susceptible individuals, malaise,  myalgia, skin rash and mild upper respiratory tract  symptoms.   Beta-blockers reduce IOP by decreasing aqueous production,  mediated by an effect on the ciliary epithelium. In approximately  10% of cases the response decreases with time (tachyphylaxis),  sometimes within only a few days. There may be limited supple¬  mentary effect if a topical beta-blocker is added when a patient  already takes a systemic beta-blocker; the combination may also  involve a relatively high risk of systemic side effects. Beta-blockers  should not be instilled at bedtime as they may cause a profound  drop in blood pressure while the individual is asleep, thus reduc¬  ing optic disc perfusion and potentially causing visual field dete¬  rioration; the IOP-lowering effect is also believed to be less marked  during sleep, as nocturnal aqueous production is normally less  than half the daytime rate. However, a beta-blocker may be pre¬  ferred under some circumstances such as monocular treatment to  avoid the cosmetic disadvantage of the asymmetrical periocular   Fig. 10.32 Side effects of topical medication. (A) Lengthening and hyperpigmentation of lashes with prostaglandin analogue  treatment; (B) monocular prostaglandin analogue treatment - darkening of left iris and eyelid skin; (C) allergic conjunctivitis  due to brimonidine; (D) blepharoconjunctivitis due to topical carbonic anhydrase inhibitors   (Courtesy of S Chen - figs A and B; J Salmon - fig. C)   • Ocular. Ocular side effects are few but include allergy and  punctate keratitis. Granulomatous uveitis has been reported  with metipranolol.   • Systemic. Though severe problems are extremely rare,  numerous deaths have been associated with topical beta-  blocker use.   o Bronchospasm. This may be fatal in asthma or other  reversible airways disease, and it is critical to exclude a  history of asthma before prescribing a beta-blocker.   About 1 in 50 patients without asthma will develop  reversible airways disease requiring treatment within 12  months of commencing a topical beta-blocker,  o Cardiovascular. There is a strong suggestion that  cardiovascular mortality is higher in patients taking a  topical beta-blocker. Effects include heart block,  bradycardia, worsening of heart failure and hypotension,  induction of the latter by topical beta-blocker having  been reported as a common cause of falls in elderly  patients. The pulse should be assessed before  prescription. A peripheral vasoconstrictive effect means  that they should be avoided or used with caution in  patients with peripheral vascular disease, including  Raynaud phenomenon.   o Unpleasant but less severe side effects include sleep  disorders, reduced exercise tolerance, hallucinations,  confusion, depression, fatigue, headache, nausea,  dizziness, decreased libido and dyslipidaemia.   • Timolol is available in various forms, including 0.25% and  0.5% solutions used twice daily; there is no evidence of a  clinically significant difference in efficacy between the two  solution concentrations. Gel-forming preparations of 0.1%,  0.25% and 0.5% are used once daily.   • Betaxolol twice daily has a lower hypotensive effect than  timolol. However, optic nerve blood flow may be increased  due to a calcium-channel blocking effect, so that visual field  preservation may be superior. Betaxolol is relatively  cardioselective (beta-i receptors), so causes less  bronchoconstriction.   • Levobunolol once or twice daily has a broadly similar profile  to timolol.   • Carteolol twice daily is similar to timolol and also exhibits  intrinsic sympathomimetic activity. It has a more selective  action on the eye than on the cardiopulmonary system and  so may have a lower systemic side effect incidence.   • Metipranolol twice daily is similar to timolol but has been  linked with granulomatous anterior uveitis.   Ocular alpha-2 receptor stimulation decreases aqueous synthesis  via an effect on the ciliary epithelium, and increases uveoscleral  outflow. There is probably a neuroprotective effect. They cross the  blood-brain barrier and should be used with great caution in  young children, in whom severe central nervous system (CNS)  depression and hypotension been reported, and are contraindi¬  cated under the age of 2 years. They may potentiate vascular insuf¬  ficiency. They should not be given with oral monoamine oxidase  inhibitor antidepressants due to the risk of hypertensive crisis.   • Brimonidine 0.2% twice daily in isolation generally has a  slightly less marked IOP-lowering effect than timolol.   Allergic conjunctivitis (Fig. 10.32C) is relatively common;  its onset may be delayed for up to 18 months after  commencement of therapy. Granulomatous anterior  uveitis can occur, but is rare. Systemic side effects include  xerostomia and fatigue, the latter sometimes being severe.   A brimonidine preparation, Alphagan-P®, containing a  proprietary preservative, Purite®, has been introduced   as an alternative to the more common benzalkonium-  containing forms and may have greater ocular surface  tolerability.   • Apraclonidine 1% (or 0.5%) is used principally to prevent  or treat an acute rise in I OP following laser surgery on the  anterior segment. The 0.5% concentration is typically used  as a temporizing measure over the course of several weeks,  such as whilst a patient is awaiting glaucoma surgery. It is  generally not suitable for long-term use because of a loss of  therapeutic effect over weeks to months and a high  incidence of local side effects.   The carbonic anhydrase inhibitors (CAI) are chemically related to  sulfonamide antibiotics. They lower IOP by inhibiting aqueous  secretion, and via the topical route are used three times daily as  monotherapy or twice daily as adjunctive treatment. In general,  they are slightly less effective than beta-blockers but are hypoth¬  esized to have a supplementary neuroprotective effect. They may  precipitate corneal decompensation in patients with corneal  endothelial dysfunction, but some benefit has been reported in the  treatment of cystoid macular oedema. Idiosyncratic bone marrow  suppression can occur. Though cross-reaction is uncommon,  topical (and systemic) CAI are relatively contraindicated in  patients allergic to sulfonamide antibiotics. Research suggests that  concomitant treatment with a topical and systemic CAI does not  usually give an additive effect.   • Dorzolamide. The main adverse effects are stinging and a  transient bitter taste following administration; allergic  blepharoconjunctivitis (Fig. 10.32D) is not uncommon.   • Brinzolamide is similar to dorzolamide, but with a lower  incidence of stinging and local allergy. It is a suspension, and  a white residue may be left on the eyelids after instillation if  excess is not wiped away.   Miotics are cholinergic agonists that are now predominantly used  in the treatment of angle closure, though were formerly a mainstay  of the treatment of open-angle glaucoma. In angle-closure glau¬  coma, miotic-induced contraction of the sphincter pupillae pulls  the peripheral iris away from the trabeculum, opening the angle.  Miotics also reduce IOP by contraction of the ciliary muscle,  which increases the facility of aqueous outflow through the trabec¬  ular meshwork. Local side effects include miosis, brow ache,  myopic shift and exacerbation of the symptoms of cataract. Visual  field defects appear denser and larger. Systemic side effects are rare  but include confusion, bradycardia, bronchospasm, gastrointesti¬  nal symptoms and urinary frequency.   • Pilocarpine 0.5%, 1%, 2%, or 4% solution as four times  daily monotherapy is equal in efficacy to beta-blockers.  Pilocarpine gel (Pilogel®) 4% is instilled once daily at  bedtime so that induced myopia and miosis are  predominantly confined to sleep. Gel, or drops twice daily,  may be used to prevent angle closure following laser  iridotomy in the presence of a substantial non-pupillary  block element.   Combined preparations with similar ocular hypotensive effects to  the sum of the individual components improve convenience and  patient compliance. They are also more cost effective. Proprietary  examples include:   • Simbrinza®: brimonidine and brinzolamide; a new  combination - the only one that does not contain the  beta-blocker timolol; administered twice daily.   Systemically administered CAI are generally used for short-term  treatment, particularly in patients with acute glaucoma. Because  of their systemic side effects, long-term use is reserved for patients  at high risk of visual loss. Sulfonamide (‘sulfa’) allergy is a relative  contraindication.   • Acetazolamide is available as 250 mg tablets (250-1000 mg  daily in divided doses), sustained-release 250 mg capsules  (250-500 mg daily) and 500 mg powder vials for injection  (single dose, typically used in acute angle-closure  glaucoma).   • Dichlorphenamide 50 mg tablets (50-100 mg two or three  times daily).   • Methazolamide 50 mg tablets (50-100 mg two or three times  daily); this has a longer duration of action than  acetazolamide but is less widely available.   • Ocular. Choroidal effusion, particularly after cataract  surgery. Angle closure may result.   • Systemic. Paraesthesia (‘pins and needles’ sensation in the  extremities), hypokalaemia (reduced blood potassium level -  common), malaise and lowered mood, gastrointestinal  symptoms, renal stones, Stevens-Johnson syndrome   (very rare), dose-related bone marrow suppression,  idiosyncratic aplastic anaemia (exceptionally rare but with  50% mortality).   Osmotic agents lower IOP by creating an osmotic gradient so that  water is ‘drawn out’ from the vitreous into the blood. They are  employed when a short-term reduction in IOP is required that  cannot be achieved by other means, such as in resistant acute  angle-closure glaucoma or when the IOP is very high prior to  intraocular surgery. They are of limited value in inflammatory  glaucoma, in which the integrity of the blood-aqueous barrier is  compromised. Side effects include cardiovascular overload as a  result of increased extracellular volume (caution in patients with  cardiac or renal disease), urinary retention (especially elderly  men), headache, backache, nausea and confusion.   • Mannitol is given intravenously (1 g/kg body weight or 5 ml/  kg body weight of a 20% solution in water) over 30-60  minutes; peak action occurs within 30 minutes.    • Glycerol is an oral agent (1 g/kg body weight or 2 ml/kg  body weight of a 50% solution) with a sweet and sickly taste,  and can be given with lemon (not orange) juice to avoid  nausea. Peak action occurs within 1 hour. Glycerol is  metabolized to glucose, and careful monitoring with insulin  cover may be required if administered to a (well-controlled  only) diabetic patient.   • Isosorbide is a metabolically inert oral agent with a minty  taste; the dose is the same as for glycerol. It may be safer for  diabetic patients.   Laser trabeculoplasty (LTP) involves the delivery of laser to the  trabecular meshwork with the aim of enhancing aqueous outflow  and thereby lowering IOP.   popularity over recent years and is now widely performed. A  532 nm frequency-doubled, Q-switched Nd:YAG laser is  used to selectively target melanin pigment in trabecular  meshwork (TM) cells, leaving non-pigmented structures  unscathed. It is probably similar in efficacy to medical  monotherapy and argon laser trabeculoplasty (see below).  The mechanism is incompletely understood, but potentially  includes stimulation of TM cell division, macrophage  recruitment and extracellular matrix recruitment. Laser  application is made easier by a broad targeted and treated  area (Fig. 10.33, left), which may lead to more consistent  results. Reported protocols (e.g. 180° or 360° TM treatment)  and results vary markedly, but IOP reductions of 10-40%  can be expected after 6 months in responsive patients, with   Fig. 10.33 Targeted area in selective (left) and conventional  argon (right) and micropulse laser trabeculoplasty    25% being common. Probably around two-thirds of patients  will achieve a reasonable IOP fall within 6 months of 18o°  TM treatment. The contralateral untreated eye also tends to  sustain a small IOP fall. The effects generally wane over  time, but as there is no thermal tissue damage, treatment  can be repeated with a successful outcome, even if initial  treatment has been unsuccessful. The prior use of topical  glaucoma medication does not seem to affect results. Energy  delivered to the TM is much lower than with argon laser,  and complications are relatively mild but include transient  mild inflammation with mild discomfort, PAS formation  and IOP elevation; the latter is usually mild but substantial  rises have been reported, especially in heavily pigmented  angles, for which overtreatment should be avoided. The  concern has been raised that the extensive treated area  causes damage to corneal endothelial cells, with rare reports  of endothelial decompensation. Herpes simplex keratitis  reactivation has been reported, as has macular oedema.   • Argon laser trabeculoplasty (ALT) is a long-established  procedure that uses laser burns to achieve IOP reduction  comparable to SLT; there is an extensive body of published  research reporting good outcomes. Mechanisms are likely to  overlap with those of SLT, and there may also be a  mechanical opening of the trabecular spaces. As the TM  sustains thermal damage, repeat treatment is of limited  benefit and is infrequently performed. Complications  include peripheral anterior synechiae, acute elevation of IOP  (should be monitored carefully over subsequent weeks in  patients with severe glaucomatous damage), cystoid macular  oedema and anterior uveitis (usually mild); there is concern  that there may be an adverse effect on the outcome of  subsequent filtration surgery.   • Micropulse laser trabeculoplasty (MLT) is a relatively new  modality that uses extremely short duration pulses of laser  to deliver thermal energy to the TM to stimulate cells  without damage. Unlike SLT and ALT, there is no visible  tissue reaction. A smaller area is targeted than in SLT (Fig.  10.33, right), limiting potential collateral effects on adjacent  tissue. Initial results suggest a benign safety profile with  results comparable to other LTP forms.   • Type of glaucoma. LTP can be used in a range of open-  angle glaucomas including primary, pseudoexfoliative and  pigmentary, and can also be used in ocular hypertension.  Success has been reported in less common circumstances,  e.g. steroid-induced glaucoma has been treated with SLT.   • Primary therapy. As SLT has increasingly demonstrated a  favourable safety profile, its use as a primary alternative to  topical medication has increasingly been considered.   • Failure of medical therapy, as a less aggressive treatment  measure than surgery.   • A drop of apraclonidine or brimonidine is instilled 30-60  minutes pre-procedure with the aim of preventing or  minimizing an early post-laser IOP rise. A similar drop is  instilled post-procedure.   • Some practitioners instil a drop of pilocarpine prior to the  procedure, particularly if the angle is not wide. There is  likely to be greater potential for PAS formation in narrower  angles, particularly with ALT, and this should be borne in  mind when considering a particular patient’s suitability for  LTP.   • A goniolens is inserted; with the mirror at the 12 o’clock  position, the inferior angle is visualized.   • ALT: initial settings are commonly 50 pan spot size, 0.1 s  duration, and 700 mW power (range of 400-1200 mW,  largely dependent on angle pigmentation). The aiming beam  is focused at the junction of the pigmented and non-  pigmented TM ensuring that the spot is round and has a  clear edge. The optimal reaction is a very light blanching or  the appearance of a minute gas bubble. If the reaction is  inadequate, the power is increased by 50-200 mW. Fifty  burns are applied at regularly spaced intervals over 18o° of  the angle. Many practitioners apply initial treatment of 180°  of the angle, treating the other 180° if the initial response is  unsatisfactory; primary treatment of the entire circumference  is associated with a higher risk of IOP spikes. Topical  fluorometholone or prednisolone 0.5% four times daily for  one week is prescribed post-laser.   • SLT: a common initial power setting is 0.8 mj; as with ALT,  this should be varied depending on angle pigmentation  (range 0.3-1.o mj); the spot size and duration are fixed at  400 pm and 0.3 ns respectively. The TM is brought into  focus rather than the aiming beam; the beam is centred on  the pigmented TM and then fired, an optimal reaction  consisting of a few tiny (‘champagne’) bubbles with  adjustment of the power higher or lower as required to  achieve this. The number of burns applied is as for ALT. The  total energy used for SLT is considerably less than for ALT,  and it is common not to prescribe any post-laser anti¬  inflammatory drops, though non-steroidal or weak steroid  drops can be used if significant inflammation occurs.   • With practice it is possible to perform LTP by continually  rotating the goniolens and applying each burn through the  centre of the mirror; using this technique, treatment of the  entire inferior half of the angle is accomplished by first  rotating the lens to one side (e.g. anticlockwise) by 90°  whilst applying 25 shots, then returning to the 12 o’clock  position before applying an additional 25 shots whilst  rotating the lens to the opposite side (clockwise in this  example).   • An IOP check should be performed 30-60 minutes after the  laser to exclude a substantial early spike, with further IOP  measurement, treatment and review as appropriate if this  occurs, depending on each patient’s risk profile.   • Follow-up is dependent on the perceived level of risk; 1-2  weeks is typical in the absence of pertinent considerations.   Laser iridotomy is used principally in the treatment of primary  angle closure, but may also be indicated in secondary angle closure  with pupillary block. It is also sometimes performed in pigment  dispersion syndrome, though its effectiveness in this scenario  remains under investigation.   • The pupil is miosed with topical pilocarpine (e.g. one drop  of 2%).   • A special iridotomy contact lens (e.g. Abraham - Fig. 10.34A,  Volk MagPlus) is inserted.   • Many practitioners target a site under the upper eyelid  between 11 and 1 o’clock, though some prefer 3 or 9 o’clock.  The highest risk of monocular diplopia or glare (see below)  occurs when an iridotomy is half-covered by the lid margin.  Radially, the iridotomy should be located within the outer  third in order to reduce the risk of damage to the crystalline  lens (see Fig. 10.34D). Targeting an iris crypt, if present, is  usually associated with much easier achievement of an  adequate opening.   • It is critical to note that effective power settings vary  somewhat between machines. The spot size and duration are  fixed. Most iridotomies are made with power settings of  4-5 mj; the risk of crystalline lens damage may be higher at   5 mj or above. For a thin blue iris the typical required  energy level is 2-4 mj. Some practitioners prefer single pulse  shots, others shots of up to three pulses.   • Pre-treatment with thermal (argon or diode) laser is often  required in thick dark irides. Suitable parameters include  power of 600-900 mW using a small spot size of 50 pm and  relatively short duration of 0.03-0.05 s, though larger, lower  power, longer duration settings can be equally effective.   • The beam is focused precisely and the laser fired. Successful  penetration is characterized by a gush of pigment debris.   The number of shots required to produce an adequate  iridotomy is very variable. The optimal size is uncertain,  recommendations ranging from 150 to 500 pm   • Over-treatment should be avoided due to the risk of  substantial postoperative inflammation and pressure spikes;  further treatment can be applied after a few days; in urgent  circumstances re-treating the same site after allowing a few  minutes for pigment and debris to clear, or moving to a  different site, may be adequate.    Fig. 10.34 Nd:YAG iridotomy. (A) Abraham lens; (B) approximately appropriate iridotomy size; (C) probably too small;  (D) probably too large - may also be insufficiently peripheral    A second drop of apraclonidine is instilled following the  procedure; oral acetazolamide may also be given in patients  at high risk such as those with advanced glaucomatous  damage or high IOP pre-treatment.   A potent topical steroid (e.g. dexamethasone 0.1%) is  prescribed post-procedure. Varying regimens have been  described, with a limited evidence base for the optimal  approach; four times daily for 1 week is typical, though  instillation every hour for several hours immediately  post-laser is common.   The IOP should be checked 1-2 hours after the procedure to  exclude an early spike. Routine review is usually at 1 or 2  weeks, with subsequent monitoring according to individual  circumstances. Patients with marked glaucomatous damage  may require extended ocular hypotensive cover and earlier  review.   • Bleeding occurs in around 50% but is usually mild and  stops after only a few seconds; persistent bleeding can be  terminated by increasing contact lens pressure.   • Iritis. Especially if excessive laser is applied or post-laser  steroid therapy is inadequate, or in darker irides (including  those due to prostaglandin derivative treatment).   • Corneal burns may occur if a contact lens is not used or if  the AC is shallow; these usually heal very rapidly without  sequelae.   • Cataract. Localized lens opacities occasionally develop at the  treatment site; age-related cataract formation may be  accelerated by iridotomy.   Diode laser ablation (cyclodiode) lowers IOP by destroying part  of the secretory ciliary epithelium, thereby reducing aqueous  secretion. In the past it was used mainly in uncontrolled end-stage  secondary glaucoma with minimal visual potential, mainly to  control pain. However, its use in eyes with good vision, especially  those with a poor prognosis for penetrating drainage surgery, has  been well described over recent years. More than one treatment  session is commonly required for adequate pressure control. Mod¬  erate post-procedure pain and anterior segment inflammation are  common. A temporary IOP rise is not uncommon during the first  few weeks. Serious complications are rare but include chronic  hypotony, phthisis bulbi, suprachoroidal haemorrhage, corneal  decompensation and retinal detachment.   • Laser settings are 1.5-2 s and 1500-2000 mW; the spot size is  fixed.   • Approximately 12-24 burns are placed posteriorly to the  limbus over 360°, avoiding the neurovascular bundles at 3  and 9 o’clock (Fig. 10.35). Fewer shots (e.g. treatment of only  one or two quadrants) can be used for eyes with good  vision, in order to reduce the risk of complications; more  treatment sessions are likely to be required using this  approach.   • A strong topical steroid is prescribed hourly on the day of  treatment and then 2-hourly for 2 days and four times daily  for at least 2 weeks. A topical antibiotic and a cycloplegic  (e.g. cyclopentolate 1% twice daily) are used for 3 days.   • Oral non-steroidal anti-inflammatory agents may be  prescribed for 2 days.   • Review is generally after 1-4 days, depending on risk, to  exclude significant reactive inflammation and/or an IOP  spike.   Laser iridoplasty is performed to widen the anterior chamber angle  by contraction of the peripheral iris away from the angle recess  (Fig. 10.36). It can be used to attempt to break an episode of acute  angle closure, but is more commonly applied on an elective basis,  for example in plateau iris syndrome. Complications tend to be  mild, but heavy treatment can be associated with a substantial and  persistent IOP spike that may be potentiated by heavy iris pigmen¬  tation. Altered accommodation is fairly common but almost  always transient.   Fig. 10.35 (A) Diode laser cycloablation; (B) cyclodiode probe  during laser application; (C) early postoperative appearance  in a patient with prior penetrating keratoplasty   (Courtesy of J Salmon - fig. A; Krachmer, Mannis and Holland, from Cornea,  Mosby 2005 - fig. B)   Fig. 10.36 Gonioscopic appearance following treatment of  part of the angle circumference with laser iridoplasty - the  white arrow indicates a laser burn. The narrower region on  the left has not yet been treated   • One drop each of 1% pilocarpine and 1% apraclonidine is  instilled.   • Via an iridotomy lens, 1-2 burns per clock hour are applied  to the periphery, 500 pm size, 100-400 mW, 0.2-0.5 s  duration, aiming for slight visible iris contraction.   • Post-procedure 1% apraclonidine is given (oral prophylaxis  - e.g. acetazolamide - may be given if significant  glaucomatous optic neuropathy is present).   • Topical ketorolac, prednisolone 1% or dexamethasone 0.1%  four times daily for a week is a common regimen.   • Review is typically 1-2 hours post-laser, then after 1 week  and subsequently depending on progress and glaucomatous  damage - patients with significant glaucomatous neuropathy  may need frequent review for the first few weeks to exclude  an IOP spike.    Trabeculectomy is glaucoma filtration surgery that lowers IOP by  creating a fistula, protected by a superficial scleral flap, to allow  aqueous outflow from the anterior chamber to the sub-Tenon  space (Fig. 10.37). Indications include:   • Progressive deterioration despite seemingly adequate IOP  control (including poor compliance with medical treatment).   • Primary therapy. Advanced disease requiring a very low  target pressure may achieve a superior long-term outcome  from early surgery, particularly in younger patients.   • Patient preference. Occasionally patients express a strong  desire to be free of the commitment to chronic medical  treatment.   • A bridle suture is inserted (commonly superior cornea or  superior rectus muscle).   • A limbal or fornix-based flap of conjunctiva and Tenon  capsule is fashioned superiorly.   • Incisions are made through about 50% of scleral thickness,  to create a ‘trapdoor’ lamellar scleral flap (Fig. 10.38A). This  flap may be rectangular (3 x 3-4 mm), trapezoidal or  triangular, according to preference.   • The superficial flap is dissected forwards until clear cornea is  reached (Fig. 10.38B).    Fig. 10.37 Trabeculectomy principles. (A) Pathway of aqueous  egress following trabeculectomy; (B) schematic  representation of appearance from inside the eye following  completion    Fig. 10.38 Trabeculectomy technique. (A) Outline of superficial scleral flap; (B) dissection of superficial scleral flap;  (C) excision of deep scleral tissue with a punch; (D) peripheral iridectomy    • The AC is entered along most of the width of the trapdoor  base.   • A block of deep sclera is excised, usually a punch (e.g. Kelly  - Fig. 10.38C).   • A peripheral iridectomy is created in order to prevent  blockage of the internal opening (Fig. 10.38D); some  surgeons omit this step in pseudophakic eyes or those with a  deep anterior chamber.   • The superficial scleral flap is sutured at its posterior corners,  either so that it is lightly apposed to the underlying bed or  tightly with releasable or lysable sutures to reduce the risk of  postoperative leakage Some surgeons insert a suture into  each of the radial edges to reduce the risk of a substantial  lateral leak.   • Balanced salt solution is injected through the paracentesis to  deepen the anterior chamber and test the patency of the  fistula.    • Conjunctiva/Tenon capsule flap is sutured. Irrigation  through the paracentesis is repeated to produce a bleb,  which is checked for leakage.   • A drop of atropine 1% is instilled; when no iridectomy has  been performed, pilocarpine 2% may be used instead.   • Steroid and antibiotic drops are used four times daily for 2  weeks and then changed to steroid alone for a further 8-12  weeks.    used with caution because of potential complications, and are  usually considered in the presence of risk factors for surgical  failure. In uncomplicated glaucoma the use of low-dose antime¬  tabolites may improve long-term control of IOP.   • High-risk factors include neovascular glaucoma, previous  failed trabeculectomy or filtering device, and certain  secondary glaucomas (e.g. inflammatory, post-traumatic  angle recession and iridocorneal endothelial syndrome). A  glaucoma drainage device would be advocated by many  authorities in some or all of these circumstances; a  mitomycin C-enhanced trabeculectomy with the Ex-Press™  mini-shunt is an alternative.   • Intermediate- and lower-risk factors include patients on  topical medication (particularly sympathomimetics) for over  3 years, previous conjunctival or cataract surgery, black  ethnicity, and age under 40.   5-fluorouracil (5-FU) inhibits fibroblast proliferation by retarding  DNA synthesis. It is a less aggressive antimetabolite than mitomy¬  cin C (see below), but substantial complications can still occur,  notably persistent corneal epithelial defects and bleb leakage.   • Intraoperative use involves the application of one or more  small cellulose sponges soaked in a 50 mg/ml solution,  placed under the dissected flap of Tenon’s capsule at the site  of filtration for 5 minutes prior to creation of the scleral  trapdoor.   • Post-operative subconjunctival injection of 0.1 ml of 25 mg/  ml or 50 mg/ml solution can be used; placement may be  away from the fistula, even at the opposite limbus. Various  regimens are described, including daily injections for several  postoperative days, and ad hoc use if a drainage bleb appears  to be unduly vascularized or fibrotic; it is also often used as  an adjunct to a limited ‘needling’ revision of a  trabeculectomy (see below).   Mitomycin C (MMC) is an alkylating agent that inhibits prolifera¬  tion of fibroblasts and suppresses vascular ingrowth; it is much  more potent than 5-FU. It is generally used intraoperatively in the  manner described above for 5-FU, a typical exposure protocol  being 0.2 mg/ml for 2 minutes, though a higher concentration  (e.g. 0.4 mg/ml) may be used for particularly high-risk patients;  higher concentrations and extended exposure times are associated  with an increased risk of complications; a cystic thin-walled bleb  is common following the use of mitomycin C and may predispose  to chronic hypotony, late-onset bleb leak and endophthalmitis.   A shallow anterior chamber (Figs 10.39A and B) following trab¬  eculectomy may be due to pupillary block, overfiltration or malig¬  nant glaucoma. Severe and sustained shallowing is uncommon,  the chamber re-forming spontaneously in most cases. However,  those that do not may develop severe complications such as    peripheral anterior synechiae, corneal endothelial damage (Fig.  10.39C) and cataract (Fig. 10.39D).   • Treatment involves YAG laser to the pigment epithelium at  the iridectomy site if the anterior iris stroma appears to have  been largely removed (common), or the creation of a new  laser iridotomy.   Overfiltration may be caused by insufficient resistance to outflow  at the lamellar scleral flap, but bleb leakage through an inadvertent  buttonhole or due to inadequate closure of the conjunctiva and  Tenon capsule is more common.   o Fow IOP with a well-formed bleb in a scleral flap leak  and flat in a bleb leak.   o The Seidel test is negative in a scleral flap leak but  positive (Fig. 10.40A) in a bleb leak,  o The cornea may show signs of hypotony such as folds in  Descemet membrane.   as may be caused by a very small bleb leak, may consist  simply of observation, with atropine to prevent PAS  formation and reduce the risk of malignant glaucoma,  o Subsequent treatment if the above measures are ineffective  involves temporary tamponade of the conjunctiva to  enhance spontaneous healing by simple pressure patching,  a large diameter soft bandage contact lens, a collagen shield  or a Simmons shell designed for the purpose,  o Definitive treatment often consists of the insertion of  additional conjunctival sutures, and if necessary  placement of a transconjunctival scleral flap suture. If  potentially serious shallowing is present, the anterior  chamber can be reformed with a viscoelastic. Choroidal  detachments rarely require drainage.   Malignant glaucoma is rare but serious. It is caused by anterior  rotation of the ciliary processes and iris root, commonly with  aqueous misdirection (ciliolenticular block) in which blockage of  aqueous flow occurs in the vicinity of the pars plicata of the ciliary  body, so that aqueous is forced backwards into the vitreous.    Fig. 10.39 Shallow anterior chamber. (A) Peripheral iris-corneal apposition; (B) pupillary border-corneal apposition;   (C) lenticulo-corneal apposition with associated corneal oedema; (D) cataract following shallow anterior chamber   (Courtesy of J Schuman, V Christopoulos, D Dhaliwal, M Kahook and R Noecker, from ‘Lens and Glaucomain Rapid Diagnosis in Ophthalmology, Mosby 2008  - fig■ A)   O Initial treatment is with mydriatics (atropine 1% and  phenylephrine 10%) to dilate the ciliary ring and increase  the distance between the ciliary processes and the equator  of the lens, thereby tightening the zonule and pulling the  lens posteriorly into its normal position. Intravenous  mannitol may be used if mydriatics are ineffective, in  order to shrink the vitreous gel and allow the lens to  move posteriorly.   o Subsequent treatment if medical therapy fails is with  Nd:YAG laser fired through the iridectomy in order to  disrupt the anterior hyaloid face, reduce the vitreous  volume and break any ciliary block. In pseudophakic    eyes, laser posterior capsulotomy and disruption of the  anterior hyaloid face should be performed. Cyclodiode  may be effective. Pars plana vitrectomy is performed if  laser therapy fails: sufficient vitreous gel is excised to  allow free flow of aqueous to the anterior chamber.   A normally functioning bleb should be slightly elevated, relatively  avascular (Fig. 10.41A) and show superficial microcysts - tiny   Fig. 10.40 (A) Positive Seidel test - a wave of egressing fluid  is delineated by a fluorescein band; (B) wide-field image of  choroidal detachments    spherical clear intraepithelial formations thought to indicate the  current passage of aqueous across the conjunctival barrier. Poor  filtration is indicated by increasing IOP and a bleb with one of the  following appearances:   • Encapsulated bleb (Tenon cyst - Fig. 10.41D), characterized  by a localized, highly elevated, dome-shaped, fluid-filled  cavity of hypertrophied Tenon capsule, often with engorged  surface blood vessels.   Causes of failure can be classified according to the site of  obstruction:   • Extrascleral causes include subconjunctival and episcleral  fibrosis, sometimes with bleb encapsulation.    • Scleral causes include over-tight suturing of the scleral flap  and gradual scarring in the scleral bed.   • Intraocular causes are uncommon and include blockage of  the sclerostomy by vitreous, blood or uveal tissue or by a  variety of thin membranes derived from surrounding cornea  or sclera.   Management of filtration failure depends on the cause and may  involve one or more of the following:   • Ocular ‘digital massage’ in an effort to force outflow  through the surgical fistula may be performed by digital  compression through the upper lid whilst looking  downwards; this can be carried out by the patient 4-8 times  a day for up to several weeks until the bleb is deemed stable.   • Suture manipulation may be considered 7-14 days  postoperatively if the eye has high IOP, a flat bleb and a  deep anterior chamber. Releasable sutures can be cut or  released according to the technique of initial placement.  Argon or diode laser suture lysis is useful if releasable  sutures have not been used. It may be performed through a  suture lysis lens or a Zeiss four-mirror goniolens.   • Needling of an encysted bleb may be performed at the slit  lamp or using an operating microscope under topical  anaesthesia. It can be augmented with 5-fluorouracil to  enhance the success rate.   • Subconjunctival injection of 5-fluorouracil may be used in  the first 7-14 days to suppress episcleral fibrosis; 2.5-5 m g  (0.1 ml of 25-50 mg/ml solution) is injected (see above)  using a 30-gauge needle directed away from the fistula, and  can be repeated as necessary.   This occurs due to disintegration of conjunctiva overlying a scle¬  rostomy, typically following peroperative application of antime¬  tabolites, particularly mitomycin C. Necrosis of the surface  epithelium results in transconjunctival drainage of aqueous. Com¬  plications of untreated leaks include infection and hypotony mac-  ulopathy (see Ch. 14).   o Low IOP and an avascular cystic bleb (Fig. 10.42).  o Seidel testing may initially be negative with only multiple  punctate staining areas (‘sweating’), though this alone  may well be sufficient to cause hypotony. The formation  of a hole may result in gross leakage with a positive test,  and a very low IOP.   o A shallow anterior chamber and choroidal detachments  may be present in severe cases.   • Treatment can be difficult. The following are options:  o Initial treatment is as for early postoperative    blebs may be treated by injection of autologous blood  into the bleb, ‘compression’ sutures or a transconjunctival  scleral flap suture, or sometimes surgery,  o Full-thickness holes usually require surgical revision, such  as conjunctival advancement to hood the existing bleb, a  free conjunctival patch autograft or amniotic membrane  graft removal of the existing bleb, or a scleral graft to  limit flow through the sclerostomy.   Glaucoma filtration-associated infection is classified as limited to  the bleb (blebitis) or endophthalmitis, although there is some  overlap. The incidence of blebitis following trabeculectomy with  mitomycin has been estimated to be up to 5% per year, though    many studies show a far lower rate. Patients who have undergone  trabeculectomy should be warned of the possibility of late infec¬  tion and strongly advised to report immediately should they  develop a red and sticky eye, or blurred vision.   • Risk factors include blepharitis, antimetabolite use,  long-term topical antibiotics, an inferior or nasally placed  bleb, and bleb leak. Late bleb leaks should be treated  aggressively to reduce the risk of infection.   • Pathogens. The most frequent are Haemophilus influenzae ,  Streptococcus spp., and Staphylococcus spp. The often poor  visual prognosis is related to the virulence of these  organisms.   • Symptoms consist of a sore, red, photophobic and typically  sticky eye.   o A white bleb that appears to contain inflammatory  material (Fig. 10.43A).   o Anterior uveitis may be absent or mild, but may be  moderate and a hypopyon may be present,  o The red reflex is normal.   o A conjunctival swab should be taken; a sample should  not be aspirated from within the bleb,  o Broad-spectrum topical antibiotics instilled every hour,  e.g. ofloxacin and a cephalosporin; the latter may be  prepared from an intravenous ampoule,  o Oral co-amoxiclav 500/125 mg three times daily, and  ciprofloxacin 750 mg twice daily for at least 5 days;  azithromycin 500 mg daily is an alternative,  o The role of topical steroids is undefined; their   Fistula-related endophthalmitis, even with early treatment, can be  associated with a very poor outcome, including blindness or even  loss of the eye (Fig. 10.43B).   • Symptoms are generally much more severe than those of  blebitis.   o Severe anterior uveitis; a substantial hypopyon is typical  (Fig. 10.43C).   immediately on presentation, though antibiotic treatment  should not be delayed if samples cannot be taken straight  away.   (A) Blebitis; (B) phthisis following bleb-related  endophthalmitis; (C) endophthalmitis showing marked  anterior chamber involvement including a large hypopyon   endophthalmitis following cataract extraction (see Ch. 9).  o Topical and systemic therapy as for blebitis.   In non-penetrating filtration surgery the anterior chamber is not  entered and the internal trabecular meshwork is preserved, thus  reducing the incidence of postoperative overfiltration with hypo-  tony and its potential sequelae. Two concentric lamellar scleral  flaps are fashioned and the deep flap excised leaving behind a thin  membrane consisting of trabeculum/Descemet membrane  through which aqueous diffuses from the AC to the subconjunc¬  tival space. The surgery is technically challenging and requires  meticulous dissection of a deep scleral flap to avoid entering the  anterior chamber through the delicate Descemet membrane.   The main indication for non-penetrating surgery is POAG,  although other open-angle glaucomas may also be amenable. In  general the IOP reduction is less than that achieved by    trabeculectomy, so that topical medication often needs to be  recommenced. Conventional filtration is therefore still the proce¬  dure of choice when the target IOP is in the low teens though  non-penetrating surgery is probably associated with a lower risk  of ‘snuffing out’ central vision when advanced damage is present.   • Deep sclerectomy (Fig. 10.44). A Descemet window is  created to allow aqueous migration from the AC.   Subsequent egress is subconjunctival, resulting in a shallow  filtration bleb, as well as along deeper suprachoroidal routes.  The long-term results can be enhanced by using a collagen  implant at the time of surgery and postoperative application  of Nd:YAG laser to the meshwork at the surgical site using a  gonioscopy lens (goniopuncture).   • Viscocanalostomy involves the creation of a filtering  window, with identification and dilatation of the Schlemm  canal with high density viscoelastic. The superficial scleral  flap is sutured tightly so that subconjunctival fluid outflow  and bleb formation are minimized. The procedure probably  causes inadvertent microscopic ruptures in the  juxtacanalicular tissue and meshwork.   • Canaloplasty is a variant of viscocanalostomy involving  cannulation of the entire circumference of the Schlemm  canal with a microcatheter.   Fig. 10.44 Non-penetrating filtration surgery: deep sclerectomy. (A) Dissection of deep scleral flap; (B) dissection into clear  cornea exposing the Schlemm canal; (C) collagen implant; (D) shallow diffuse avascular bleb    • Trabectome. The Trabectome is a novel microelectrosurgical  device that approaches the angle ab interno under direct  vision using a gonioscopy lens, to remove a strip of  trabecular meshwork and inner wall of the Schlemm canal  (‘trabeculotomy’). Whilst it does not seem to lower the IOP  as effectively as trabeculectomy, the safety profile is better.   Glaucoma drainage devices (GDD) create a communication  between the anterior chamber and the sub-Tenon space via a tube  attached to a posteriorly explanted episcleral reservoir. Some  contain pressure-sensitive valves for the regulation of aqueous  flow. Reduction of IOP is due to passive, pressure-dependent flow  of aqueous, limited by the wall of a tissue capsule that forms  around the explant over the course of several weeks postopera-  tively. Over recent years the use of GDD has increased, with a large  trial, the Tube Versus Trabeculectomy Study, providing good-  quality evidence of their safety and comparability to mitomycin  C-enhanced trabeculectomy. In practice the threshold for GDD  implantation has been lowered, though the number of trabeculec¬  tomies being performed remains significantly higher than the rate  of GDD implantation. Examples of GDD implants include:   • Molteno. This consists of a silicone tube connected to one  or two polypropylene plates 13 mm in diameter (Fig. 10.45).   • Baerveldt. This implant consists of a silicone tube connected  to a silicone plate of large area; silicone may elicit little tissue  reaction in comparison with polypropylene.   • Ahmed. This is a valved implant consisting of a silicone tube  connected to a silicone sheet valve held in a polypropylene  body. The valve mechanism consists of two thin silicone  elastomer membranes, with the aim of reducing early  postoperative hypotony and its complications.   The circumstances under which GDD may be superior to trab¬  eculectomy are incompletely defined, and many factors must be  taken into account, including an individual surgeon’s experience  and expertise. The introduction of the Ex-Press™ mini-shunt  implant modification may have extended the repertoire of trab¬  eculectomy to include some of the previously clearly defined indi¬  cations for GDD implantation such as ICE syndrome. GDD may  be considered in the following cases, though the list is not  exhaustive:   • Eyes with severe conjunctival scarring precluding accurate  dissection of the conjunctiva.   • Secondary glaucoma where routine trabeculectomy, with or  without adjunctive antimetabolites, is less likely to be    successful. Examples include neovascular glaucoma and  glaucoma following traumatic anterior segment disruption.   The rate of serious complications is similar to that of mitomycin   • Excessive drainage, resulting in hypotony and a shallow  anterior chamber.   • Malposition (Fig. 10.46A) may result in endothelial or  lenticular touch with corneal decompensation and cataract  respectively. Ciliary sulcus or pars plana tube placement can  be used in some eyes to negate the possibility of corneal  touch.   • Double vision due to extraocular muscle interference; this  may be a higher risk with some implants than others.   • Early drainage failure may occur as a result of blockage of  the end of the tube by vitreous, blood or iris (Fig. 10.46C).   • Late drainage failure occurs in about 10% of cases per year  and is comparable to, or perhaps slightly better than, that  following trabeculectomy.   (Courtesy of J Salmon - fig. B; R Bates - fig. C)   The results depend on the type of glaucoma. In general, an IOP  in the mid-teens is achieved, though as with trabeculectomy  topical medication is frequently required in the medium and  longer term. The success rate in some conditions such as neovas-  cular glaucoma is often disappointing. Adjunctive mitomycin C  may enhance the success rate of drainage shunt surgery but is  associated with a higher complication rate.   This is a valveless titanium MRI-compatible stent inserted under  a scleral flap during a modified trabeculectomy, with a principal  aim of increased standardization of drainage (Fig. 10.47). Follow¬  ing creation of the scleral flap as for a standard trabeculectomy, a  needle is used to enter the anterior chamber instead of creating a  punch sclerostomy. A peripheral iridectomy is not performed. The  rate of complications such as hypotony appears to be lower than  with standard trabeculectomy, with fewer postoperative interven¬  tions, but IOP control is equivalent. It is not generally viewed as  suitable in angle-closure glaucoma without prior or contempora¬  neous cataract surgery.   This consists of a tiny hooked titanium tube inserted ab inferno  into the Schlemm canal via the trabecular meshwork (Fig. 10.48),  and shows promise for adequate IOP reduction in mild-to-  moderate glaucoma. Implantation is considerably more straight¬  forward than conventional glaucoma surgery, and can be  performed during phacoemulsification. More than one iStent can  be implanted to give more profound IOP reduction.    Table 10.3 Risk of developing glaucoma according to IOP (intraocular pressure) and CCT (central corneal thickness)   In the general population the mean IOP is 16 mmHg; two standard  deviations either side of this gives a ‘normal’ IOP range of  ii-2i mmHg. The distribution is Gaussian with the curve skewed  to the right (Fig. 10.49). It is estimated that 4-10% of the popula¬  tion over the age of 40 years have IOP >21 mmHg without detect¬  able glaucomatous damage: ‘ocular hypertension’ (OHT). An  absence of angle closure is implicit, and there should be no detect¬  able cause of secondary glaucoma, though sometimes the term  OHT is used to describe raised IOP in these contexts.   The Ocular Hypertension Treatment Study (OHTS) was a multi¬  centre longitudinal trial. In addition to looking at the effect of  treatment in ocular hypertensives (IOP <32 mmHg), invaluable  information was gained about the effect of a range of putative  risks for conversion from OHT to glaucoma; the percentage of  OHT patients likely to develop glaucoma taking key factors into  account is set out in Tables 10.3 and 10.4; median follow-up  was 72 months. Additional considerations are discussed below.  Limitations included the possibility that early glaucomatous  damage was already present in some of the patients classified as  having OHT.    Table 10.4 Risk of developing glaucoma according to  vertical C/D ratio and CCT   • Intraocular pressure. The risk of developing glaucoma  increases with increasing IOP.   • Central corneal thickness (CCT). The risk is greater in eyes  with low CCT and lower in eyes with higher CCT. This is  probably due to resultant under- and over-estimation of IOP  although it has been proposed that associated structural  factors, perhaps at the lamina cribrosa, might also be  important.   • Cup/disc (C/D) ratio. The greater the C/D ratio the higher  the risk. This may be because an optic nerve head with a  large cup is structurally more vulnerable, or it may be that  early damage is already present.   (Courtesy of Glaukos Corporation) Fig. 10.49 Distribution of IOP the general population   • Pattern standard deviation (PSD). A greater PSD result  represented a significant risk. It is possible that this signified  early glaucomatous field change.   The following factors were significant on univariate analysis only;  they were not significant in isolation but were over-ridden when  the factors considered above were taken into account.   Factors examined in the OHTS but not found to be significant are  listed below.   • Myopia, although it is suspected that myopic discs are more  susceptible to glaucomatous damage at a lower IOP than  emmetropic discs.   • Diabetes. An apparent protective effect of diabetes was  initially found, but later analysis with refreshed data did not  confirm this.   • Family history of glaucoma was not found to be a risk  factor for conversion.   Other factors that were not examined in the OHTS but may be  important include retinal nerve fibre defects (though the presence  of these may be taken to indicate pre-perimetric glaucoma - see  below) and specific peripapillary atrophic changes.   History and examination should be carried out as for glaucoma  (see below). Of particular note, consideration should be given to  whether any systemic medication is being taken that might be  influencing IOP, either upwards (e.g. steroids) or downwards (e.g.  beta-blockers).   This concept refers to glaucomatous damage, usually manifested  by a suspicious optic disc and/or the presence of retinal nerve fibre  layer defects, in which no visual field abnormality has developed.  The field testing modality for this purpose is usually taken as  standard achromatic automated perimetry.   In the OHTS, untreated patients with ocular hypertension had a  9.5% cumulative risk of developing POAG after 5 years; treatment  (which aimed to reduce IOP by 20% or more and to reach  24 mmHg or less) reduced this to 4.4%. Hence, when deciding on  whether to start treatment it is important to take into account that  it will be necessary to treat a large number of patients in order to  prevent the development of glaucoma in a single individual.  Various guidelines exist, but there is a high level of disagreement  even between glaucoma specialists.   • In general, only those at higher risk should be treated,  although patient preference may be a decisive factor.   • Age, and so life expectancy, is a key point to consider.    • Most practitioners would treat every patient with an IOP of  30 mmHg or more (>40% 5-year risk of glaucoma). The  decision to treat in patients with varying risk profiles is  commonly less than straightforward, and has to be made on  an individual basis.   • OHT almost certainly increases the risk of retinal venous  occlusion, an additional point to take into account when  considering whether to start treatment.   • Treatment options are the same as for POAG, although a  less aggressive pressure-lowering approach is frequently  taken, e.g. alternate day prostaglandin dosing and low-  intensity selective laser trabeculoplasty have been proposed;  filtration surgery is only occasionally indicated. Cataract  surgery commonly results in a significant IOP reduction.   • Careful monitoring is a reasonable alternative in many  circumstances: baseline visual fields and RNFL/disc imaging  should be performed.   Primary open-angle glaucoma (POAG) is a commonly bilateral  disease of adult onset. It is characterized by:   • Absence of signs of secondary glaucoma or a non-  glaucomatous cause for the optic neuropathy.   POAG is the most prevalent type of glaucoma in individuals of  European and African ethnic origin, in a meta-analysis of those  older than 70 years of age having a prevalence of 6% in white  populations, 16% in black populations and around 3% in Asian  populations. It affects both genders equally.   • IOP. The higher the IOP, the greater the likelihood of  glaucoma. Asymmetry of IOP of 4 mmHg or more is also  significant.   • Race. It is significantly (perhaps four times) more common,  develops at an earlier age and may be more difficult to  control in black individuals than in whites.   • Family history of POAG. First-degree relatives of patients  with POAG are at increased risk. An approximate risk to  siblings is four times and to offspring twice the normal  population risk, though surveyed figures vary.   • Diabetes mellitus. Many studies suggest a correlation  between diabetes and POAG.   • Myopia is associated with an increased incidence of POAG  and myopic eyes may be more susceptible to glaucomatous    damage. It is speculated that this may be due to mechanical  factors, particularly the region of the optic disc.   • Contraceptive pill. Recent research suggests that long-term  use of the oral contraceptive pill may substantially increase  the risk of glaucoma, perhaps by blocking a protective  oestrogen effect.   • Vascular disease. A range of systemic conditions linked to  vascular compromise may be associated, though clear-cut  relationships have proved difficult to demonstrate  consistently. Systemic hypertension, cardiovascular disease,  diabetes and vasospastic conditions such as migraine have all  been implicated. Poor ocular perfusion may be a risk factor  for glaucoma progression.   • Translaminar pressure gradient. Studies suggest that a  difference in the levels of IOP and orbital CSF pressure may  increase the likelihood of the development and progression  of glaucomatous damage, perhaps due to associated  deformation of the lamina cribrosa.   • Optic disc area. Large discs may be more vulnerable to  damage, again with some commentators speculating that  causation may be linked to mechanical factors associated  with laminar deformation.   • Ocular perfusion pressure is the difference between the  arterial BP and the intraocular pressure (IOP), and has been  shown in population studies to be linked to increased risk  for the development and progression of glaucoma.   POAG has been associated with at least 20 loci in the human  genome, but mutations in only the MYOC gene, coding for the  protein myocilin that is found in the trabecular meshwork, and  the OPTN gene, which codes for optineurin, are broadly accepted  as causing glaucoma. A number of different mutations have been  described in the MYOC gene, though the normal function of myo¬  cilin and its role in glaucoma is as yet undetermined. If a single  family member develops glaucoma prior to age 35 years, the  chances of a mutation in the myocilin gene may be as high as 33%.  Genetic investigation of a patient and family may be considered if  three or more first-degree relatives from two generations are  affected, or for research purposes.   Around one in three individuals develop some degree of elevation  of IOP in response to a course of potent topical steroid, dividing  the population into steroid ‘responders’ and ‘non-responders’.  Responders are more likely than non-responders to develop  POAG, and a majority of patients with POAG are responders.  Close relatives of patients with POAG are also more likely to  exhibit a steroid response. Steroids of greater potency have a  greater propensity to elevate IOP, as does higher frequency of  instillation, and this tendency is more marked in patients with  POAG and their close relatives. Intra- and periocular steroid  administration, including periocular application of steroid skin  cream and nasal administration, are also prone to elevate IOP.    Systemic steroids are much less prone to cause elevation of IOP,  but substantial, probably dose-dependent, rises can occur and  some authorities have advocated screening for all patients taking  systemic steroids, perhaps dexamethasone in particular. The  precise mechanism of the ‘steroid response’ is uncertain, but it is  thought to be mediated by an alteration in the composition and  function of the trabeculum, including altered expression of myo¬  cilin production.   Retinal ganglion cell death in glaucoma occurs predominantly  through apoptosis (programmed cell death) rather than necrosis.  The preterminal event is calcium ion influx into the cell body and  an increase in intracellular nitric oxide; glutamine metabolism is  intrinsically involved. After initial injury, a cascade of events  results in astrocyte and glial cell proliferation, and alterations in  the extracellular matrix of the lamina cribrosa, with subsequent  optic nerve head remodelling. Multiple factors are likely to be  involved, but the mechanisms remain relatively speculative: the  process of glaucomatous damage and the relationship with IOP  and other potential influences is still poorly understood. One or  both of the following mechanisms may be involved:   • Direct mechanical damage to retinal nerve fibres at the  optic nerve head, perhaps as they pass through the lamina  cribrosa; accumulating evidence of the influence of  mechanical deformability in the region of the lamina  cribrosa supports this.   • Ischaemic damage, possibly due to compression of blood  vessels supplying the optic nerve head; this may relate to  ocular perfusion pressure as a possible risk factor for  glaucoma.   • Common pathways of damage. Both mechanisms might  lead to a reduction in axoplasmic flow, interference with the  delivery of nutrients or removal of metabolic products,  deprivation of neuronal growth factors, oxidative injury and  the initiation of immune-mediated damage.   Universal population screening for glaucoma has not been dem¬  onstrated to be cost-effective, and current practice restricts screen¬  ing to high-risk groups, such as older individuals, those over the  age of 40 with a history of POAG in a close family member, and  people of black ethnicity. In these groups, screening tends to be  performed sporadically via routes such as commercial optometric  eye examinations, which may lead to the relative exclusion of  underprivileged economic groups. Population screening with  tonometry alone is unsatisfactory, since it will label as normal a  significant number of cases with other features of POAG such as  cupping and visual field loss, and routine screening eye examina¬  tions should include visual field assessment as well as tonometry  and ophthalmoscopy.   • Visual symptoms will usually be absent, unless damage is  advanced. Sometimes symptomatic central field defects may  occur at an early stage, in the presence of a relatively normal  peripheral field.   o Refractive status as myopia carries an increased risk of  POAG, and hypermetropia of primary angle-closure  glaucoma (PACG).   o Causes of secondary glaucoma such as ocular trauma or  inflammation; previous eye surgery, including refractive  surgery, may affect IOP readings.   o POAG or related conditions such as OHT.  o Other ocular disease in family members.   • Past medical history. Asking specifically about the following  may be indicated.   o Asthma, heart failure or block, peripheral vascular  disease: contraindications to the use of beta-blockers,  o Head injury, intracranial pathology including stroke: may  cause optic atrophy or visual field defects,  o Vasospasm: migraine and Raynaud phenomenon,  o Diabetes, systemic hypertension and cardiovascular  disease may increase the risk of POAG.  o Oral contraceptive pill for several years may be associated  with an increased risk of glaucoma.   o Steroids including skin cream and inhalants,  o Oral beta-blockers may lower IOP.   • Social history including smoking and alcohol intake,  especially if toxic/nutritional optic neuropathy is suspected.   • Allergies, particularly to any drugs likely to be used in  glaucoma treatment, e.g. sulfonamides.   • Visual acuity is likely to be normal except in advanced  glaucoma.   • Pupils. Exclude a relative afferent pupillary defect (RAPD);  if initially absent but develops later, this constitutes an  indicator of substantial progression.   • Colour vision assessment such as Ishihara chart testing if  there is any suggestion of an optic neuropathy other than  glaucoma.   • Slit lamp examination. Exclude features of secondary  glaucomas such as pigmentary and pseudoexfoliative.   • Optic disc examination for glaucomatous changes (see earlier  in chapter) should always be performed with the pupils  dilated, provided gonioscopy does not show critically narrow  angles. Red-free light can be used to detect RNFL defects.   • Imaging of the optic disc, peripapillary RNFL and/or  ganglion cell complex, e.g. red-free photography, stereo disc  photography, OCT, confocal scanning laser ophthalmoscopy  and/or scanning laser polarimetry.   Nerve damage in glaucoma is believed to be inflicted at the optic  nerve head, and the resultant visual field defect corresponds to the  pattern of fibres in the retinal area served.   • Early changes include increased variability of responses in  areas that subsequently develop defects, and slight  asymmetry between the two eyes. Special modalities such as  FDT and SWAP may demonstrate defects at an earlier stage.   • Small paracentral depressions (Fig. 10.50) can form at a  relatively early stage, often superonasally; they are probably  more common in NTG.   • Nasal step represents a difference in sensitivity above and  below the horizontal midline in the nasal field; the defect is  bounded by the horizontal midline, corresponding to the  retinal nerve fibre layer horizontal raphe. Inferior optic disc  and OCT changes with a corresponding superior nasal step  are shown in Fig. 10.51.   • Temporal wedge is less common than a nasal step but has  similar implications.   • Arcuate defects (see Fig. 10.51C) develop as a result of  coalescence of paracentral scotomas. They typically develop  between io° and 20° of fixation as downward or upward  extensions from the blind spot (‘baring of the blind spot’   - Fig. 10.52) around fixation. With time, they tend to  elongate circumferentially along the distribution of arcuate  nerve fibres.   • A ring scotoma develops when superior and inferior arcuate  defects become continuous, usually in advanced glaucoma  (Fig. 10.53).   • End-stage changes are characterized by a small island of  central vision, typically accompanied by a temporal island.  The 10-2 perimetry pattern facilitates monitoring of the  residual central field.   • Summary measures should always be taken into account; on  average an annual deterioration in mean total deviation of  just over 1.0 dB can be expected in treated patients (Fig.  10.54).   The primary aim of treatment is to prevent functional impairment  of vision within the patient’s lifetime by slowing the rate of gan¬  glion cell loss closer to that of the normal population. Currently  the only proven method of achieving this is the lowering of IOP.  Both higher mean IOP and substantial variation in IOP are   Fig. 10.51 Moderate to marked glaucoma. (A) and (B) Stereo disc photographs showing inferior neuroretinal rim shelving;   MD -11.85 dB P <0.5%  PSO 10 02 dB P < 0.5%    Fig. 10.51, Continued (C) visual field from the same eye showing superior arcuate scotoma and nasal step (but note  suboptimal reliability); Continued    Fig. 10.51, Continued (D) OCT from the same patient - note inferior abnormality on ganglion cell complex analysis of the left  eye corresponding to the superior nasal step    Fig. 10.53 Severe glaucomatous damage. (A) and (B) Stereo  disc photographs showing marked cupping; (C) grey scale  display of dense superior and inferior arcuate scotomata  merging into superior nasal step   Fig. 10.54 Progression of visual field defect and deterioration of global indices over a period of 30 months    predictive of progressive visual field loss in patients with glau¬  coma, whether newly diagnosed or advanced, and aggressive treat¬  ment should be considered in these circumstances.   An explanation should be offered concerning the nature of the  disease, and relevant literature provided. The timing of medica¬  tion use should be specified, and the patient educated in the    technique of eye drop instillation. At follow-up visits the patient’s  proficiency at instilling drops should be checked. In order to maxi¬  mize drug contact time with the anterior segment and to minimize  systemic absorption the patient should be instructed either to  perform lacrimal sac occlusion by applying fingertip pressure at  the medial canthus or to close the eyes for about 3 minutes after  instillation. Common or severe potential adverse effects should be  explained at the commencement of treatment and their occur¬  rence enquired about at review visits.   • Target pressure. It is assumed that the pre-treatment level  of IOP has damaged the optic nerve and will continue to do  so. An IOP level is identified below which further damage is  considered unlikely: the target pressure. This is identified  taking into account the severity of existing damage  (particularly a greater vertical C/D ratio and a greater mean  deviation on visual fields), the level of IOP, CCT, the  rapidity with which damage occurred if known, and the age  and general health of the patient; greater age is associated  with a higher likelihood of rapid progression, but a shorter  life expectancy may also be taken into account. Therapy  should maintain the IOP at or below the target level. If not  achievable by more conservative measures, a decision is  made regarding whether to proceed with surgery or to  continue monitoring with an above-target IOP.   • Proportional reduction. An alternative strategy is to aim for  a reduction in IOP by a certain percentage - often 30%   - and then monitor, aiming for a further reduction if  progression occurs. There may be a smaller margin for error  with this approach if advanced damage is present, and it  may not be as well supported by research-based evidence.   • Response to progression. As damage progresses the loss of  each remaining ganglion cell has a greater proportional  impact on visual function, and there is less reserve capacity.  If damage progresses despite a target pressure having been  reached consistently, the target IOP is set to a lower level;  there is evidence that each 1 mmHg reduction in IOP leads  to a 10% reduction in the rate of nerve fibre loss. If further  damage is sustained despite apparently good IOP control,  surgery may be appropriate.   o Any drug chosen should be prescribed in the lowest  concentration consistent with the desired therapeutic  effect, and administered as infrequently as possible,  o Ideally the drug with the fewest potential side effects  should be used.   o Initial treatment is usually with one type of medication,  typically a prostaglandin analogue or beta-blocker.   o The interval to review after starting medication is set  according to the individual patient, but is usually 4-8  weeks.   o Response to the drug is assessed against the target IOP.  o If the response is satisfactory, subsequent assessment is  generally set for a further 3-6 months,  o If there has been little or no response the initial drug is  withdrawn and another substituted,  o If there has been an apparently incomplete response  another drug may be added or a fixed combination  substituted.    o When two separate drugs are used the patient should be  instructed to wait 5 minutes before instilling the second  drug to prevent washout of the first,  o Sometimes it may be worthwhile to allow a further  month or two of treatment before altering a regimen, as  response may improve over time.   O Inadequate drop instillation technique should be  considered as a cause of unsatisfactory IOP response,  o Poor compliance should always be borne in mind, e.g. if  progression occurs despite excellent IOP readings at  review assessments.   O When drops are administered in the morning, it is good  practice always to enquire about whether that day’s dose  has been used prior to attendance.   • Perimetry. If IOP control is good and glaucomatous damage  mild or moderate with no substantial threat to central  vision, perimetry every 6-12 months is generally sufficient.   • Gonioscopy should be performed annually in most patients  because the anterior chamber angle tends to narrow with  age.   • Optic disc examination should be performed at each visit,  as a disc haemorrhage may indicate ongoing damage; a new  haemorrhage should be recorded pictorially, optimally by  photography.   o Inappropriate target pressure. If the IOP is maintained in  the upper part of the statistically normal range,  progressive field loss is relatively common,  o Poor compliance with therapy occurs in at least 25% of  patients.   O Wide fluctuations in IOP are not uncommon in patients  treated medically, and are associated with a tendency to  progression.   o Patients may deteriorate despite apparently good IOP  control. Causes include occult compliance failure,  undetected diurnal variation, and possibly other  mechanisms not readily detectable clinically such as  impaired optic nerve perfusion. The possibility of an  alternative pathology, particularly a compressive lesion,  should always be considered in these circumstances.   SLT is often as effective as medical monotherapy, and has been  gaining in popularity as a first-line treatment.   Trabeculectomy is the surgical procedure most commonly per¬  formed for POAG. Over recent years, the threshold for glaucoma  drainage device implantation has been lowered by many surgeons,  the procedure having previously been performed only in a small  minority of complex cases at very high risk of failure. Non¬  penetrating surgery (e.g. deep sclerectomy, viscocanalostomy) is    utilized extensively in POAG by some authorities. Phacoemulsifi¬  cation alone is frequently associated with a significant fall in IOP,  but is generally only offered to patients in whom significant lens  opacity is present; it can be combined with a filtration procedure  (phacotrabeculectomy). Progressive damage is thought to be less  likely after surgery than with medical therapy, probably because  the resultant IOP is often significantly lower and less likely to  fluctuate, and because compliance is no longer a factor.   The great majority of patients with POAG will not become blind  in their lifetime, but the incidence of blindness varies considerably  depending on multiple factors such as the presence of advanced  damage at diagnosis, non-compliance with treatment and ethnic  origin (e.g. the prognosis is better for white than black patients).  Data are incomplete, but in a white population with POAG the  lifetime chance of blindness in both eyes has historically been  5-10%; given the long-term nature of progression in glaucoma,  the prognosis may have been significantly improved with newer  treatment strategies. The average period from diagnosis to death  has been estimated at around 15 years.   Normal-tension glaucoma (NTG), also referred to as low-tension  or normal-pressure glaucoma, is usually regarded as a variant of  POAG. It is characterized by:   • Signs of optic nerve damage in a characteristic glaucomatous  pattern.   • Visual field loss as damage progresses, consistent in pattern  with the nerve appearance.   • No features of secondary glaucoma or a non-glaucomatous  cause for the neuropathy.   The distinction between NTG and POAG is based on an epide-  miologically derived range of normal IOP. It is essentially an arbi¬  trary division that may not have significant clinical value, though  it is possible that a spectrum exists in which, towards the NTG  end, IOP-independent factors are of increasing relative impor¬  tance. Up to two-thirds of Japanese patients and 30% of Cauca¬  sians with OAG may have normal IOP at initial assessments.   Any aetiological factors distinct from those in POAG have not  been conclusively determined, although various mechanisms have  been postulated including anomalies of local and systemic vascular  function, structural optic nerve anomalies and autoimmune  disease. With the introduction of widespread central corneal  thickness (CCT) assessment, NTG in some patients has been  explained by very low CCT, and overall CCT in patients with NTG  is lower than in POAG. A small proportion of NTG patients have   • Age. Patients tend to be older than those with POAG,  though this may be due to delayed diagnosis.   • Gender. Some studies have found a higher prevalence in  females.   • Race. NTG occurs more frequently in people of Japanese  origin than in European or North American Caucasians.   • Family history. The prevalence of POAG is greater in  families of patients with NTG than in the normal  population. Mutations in the OPTN gene coding for  optineurin have been identified in some patients with NTG,  though also in patients with POAG.   • Abnormal vasoregulation, particularly migraine and  Raynaud phenomenon, has been found more commonly in  NTG than POAG by some investigators; others have found  abnormalities just as commonly in POAG. Other systemic  diseases associated with vascular risk, such as diabetes,  carotid insufficiency, hypertension and hypercoagulability,  may also be important.   • Systemic hypotension including nocturnal blood pressure  dips of >20%, particularly in those on oral hypotensive  medication.   • Obstructive sleep apnoea syndrome may be associated,  perhaps via an effect on ocular perfusion.   • Autoantibody levels have been found to be higher in some  groups of NTG patients by some investigators.   • Translaminar pressure gradient. This may on average be  larger than in POAG.   • Ocular perfusion pressure may be relatively lower than in  POAG.   • Myopia is associated with a greater likelihood of glaucoma  and of its progression.   • Angle closure should always be ruled out by meticulous  dark-room gonioscopy.   • Low CCT leading to underestimation of IOP; suspicion has  also been raised that a thin posterior ocular wall may  increase mechanical stress in the region of the lamina  cribrosa. Prior refractive surgery and corneal ectasia also  lead to falsely low IOP readings, sometimes dramatically so.   • POAG presenting with apparently normal IOP because of  wide diurnal fluctuation. Plotting a diurnal IOP curve over  an 8-hour period (phasing) during office hours may detect  daytime elevation, but detection of nocturnal IOP spikes  requires substantial resource commitment.   • Previous episodes of raised IOP may have occurred as a  result of ocular trauma, uveitis or local or systemic steroid  therapy.   • Masking by systemic treatment such as an oral beta-  blocker, commenced after glaucomatous damage has already  been sustained.   • Spontaneously resolved pigmentary glaucoma. The typical  examination features of pigmentary glaucoma tend to  become less evident with increasing age. The IOP in some  cases of POAG may also spontaneously normalize over time.   • Progressive retinal nerve fibre defects not due to glaucoma  such as may occur in myopic degeneration and optic disc  drusen.   • Congenital disc anomalies simulating glaucomatous  cupping, such as disc pits and colobomas.   • Neurological lesions causing optic nerve or chiasmal  compression can produce visual field defects that may be  misinterpreted as glaucomatous, and neuroimaging should  be performed if there is any suspicion; some practitioners  routinely perform a cranial MRI in all cases of NTG.   • Previous anterior ischaemic optic neuropathy (AION) may  give rise to a disc appearance and visual field defect consistent  with glaucoma. Non-arteritic AION often occurs in a ‘crowded’  disc, and the fellow eye should be examined for this; prior  retinal vascular occlusion should also be considered.   • Previous acute optic nerve insult such as hypovolaemic or  septicaemic shock, or head injury.   • Miscellaneous optic neuropathies including inflammatory,  infiltrative and drug-induced pathology will often be  clinically obvious, but can occasionally masquerade as NTG.   History and examination are essentially the same as for POAG but   o Migraine and Raynaud phenomenon,  o Episodes of shock,  o Head or eye injury.   • IOP is usually in the high teens, but may rarely be in the low  teens. In asymmetrical disease the more damaged disc  typically corresponds to the eye with the higher IOP.   o The optic nerve head may be larger on average in NTG  than in POAG.   O The pattern of cupping is similar, but acquired optic disc pits  and focal nerve fibre layer defects may be more common,  o Peripapillary atrophic changes may be more prevalent,  o Disc (splinter, Drance - see Figs 10.18A and B)   haemorrhages may be more frequent than in POAG, and  are associated with a greater likelihood of progression,  o Pallor disproportionate to cupping should prompt a  suspicion of an alternative diagnosis.   • Visual field defects are essentially the same as in POAG  although there is some evidence that they tend to be closer  to fixation, deeper, steeper and more localized. In probably    more than half of patients, field changes are non-progressive  over a period of 5 years or more without treatment.   However, perhaps because of delayed diagnosis, patients  tend to present with more advanced damage than in POAG.  A high level of suspicion for a deficit pattern suggesting a  lesion posterior to the optic nerve is important.   • Other investigations are as for POAG although in selected  patients the following can be considered.   o Assessment of systemic vascular risk factors,  o Blood pressure measurement can be used to calculate  ocular perfusion pressure; 24-hour ambulatory  monitoring will exclude nocturnal systemic hypotension  in selected patients.   o Blood tests for other causes of non-glaucomatous optic  neuropathy such as vitamin B 12 , red cell folate, full blood  count, erythrocyte sedimentation rate/C-reactive protein,  treponemal serology including Lyme disease, serum  angiotensin-converting enzyme level, plasma protein  electrophoresis and autoantibody screen,  o Cranial MRI.  o Carotid Duplex imaging.   o Ocular blood flow assessment (e.g. laser flowmetry) may  have useful clinical potential.   Further lowering of IOP is effective in reducing progression in  many or most patients. However, as a large proportion of untreated  patients will not deteriorate (approximately 50% at 5 years), in  many cases progression should be demonstrated before com¬  mencing treatment. Exceptions include advanced glaucomatous  damage, particularly if threatening central vision, and young age.  Regular assessment including perimetry should be performed at  4-6 monthly intervals initially.   • Medical treatment. The alpha-2 agonist brimonidine may  have a neuroprotective effect on the retina and optic nerve  in addition to its IOP-lowering effect and may be superior to  beta-blockers. Carbonic anhydrase inhibitors, particularly  dorzolamide, may improve ocular perfusion. Prostaglandin  derivatives tend to have a greater ocular hypotensive effect,  which may be an over-riding consideration. Topical  beta-blockers can have a dramatic effect on BP in a  minority, and may contribute to nocturnal dips, though  selective blockade (e.g. betaxolol) may actually have a  beneficial effect on optic nerve perfusion.   • Laser trabeculoplasty, particularly SLT, is a reasonable  option to achieve IOP targets.   • Surgery may be considered if progression occurs despite  IOP in the low teens; antimetabolite enhancement of  trabeculectomy is likely to be indicated in order to achieve a  satisfactorily low pressure.   • Control of systemic vascular disease such as diabetes,  hypertension and hyperlipidaemia may be important, in  order theoretically to optimize optic nerve perfusion.   • Systemic calcium-channel blockers to address vasospasm  have been advocated by some authorities.    • Antihypotensive measures. If significant nocturnal dips in  BP are detected, it may be necessary to reduce  antihypertensive medication, especially if taken at bedtime.  Non-selective topical beta-blockers in particular may cause a  profound drop in systemic blood pressure in some  individuals. Selected patients might be encouraged to  increase their salted food intake, in consultation with the  patient’s cardiovascular physician.   • Neuroprotective agents of proven benefit are not yet  available; memantine is used to retard neuronal death in  some CNS disorders, and its use has been adopted in  glaucoma by some practitioners. Ginkgo biloba (40 mg three  times daily) or an antiplatelet agent may confer some benefit  in selected cases.   The term ‘angle closure’ refers to occlusion of the trabecular mesh-  work by the peripheral iris (iridotrabecular contact - ITC),  obstructing aqueous outflow. Angle closure can be primary, when  it occurs in an anatomically predisposed eye, or secondary to  another ocular or systemic factor. PACG may be responsible for  up to half of all cases of glaucoma globally, with a particularly high  prevalence in individuals of Far Eastern descent. It is typically  associated with greater rapidity of progression and visual morbid¬  ity than POAG.   As knowledge about the epidemiology and mechanisms of angle  closure has increased, classification has moved away from a  symptom-based approach (acute, subacute and chronic) to reflect  the stages in the natural history of the disease. This takes into  account the fact that the majority of patients are asymptomatic,  and can be linked to prognosis and management. The scheme  below has been suggested by a consensus group of the Association  of International Glaucoma Societies.   o Gonioscopy shows posterior meshwork ITC (Fig. 10.55A)  in three or more quadrants but no PAS.  o Many patients with less ITC have evidence of intermittent  angle closure, and a lower threshold for diagnosis such as  two quadrants of ITC, pigment smudging (Figs 10.55B  and C) or even a very narrow angle approach (perhaps  20 0 or less - Fig. 10.55D) may be justified,  o Normal IOP, optic disc and visual field,  o No peripheral anterior synechiae (PAS),  o The risk of PACG at 5 years may be around 30%.   o Gonioscopy shows three or more quadrants of ITC (Fig.  10.56A) with raised IOP and/or PAS (Fig. 10.56B), or  excessive pigment smudging on the TM.   o Some authorities further classify PAC into non-ischaemic  and ischaemic, the latter showing anterior segment  evidence of prior substantial IOP elevation such as iris  changes or glaukomflecken (see Fig. 10.61).   O ITC in three or more quadrants, with glaucomatous optic  neuropathy.   o Optic nerve damage from an episode of severe IOP  elevation, such as acute angle closure, may not appear as  typical glaucomatous cupping.   The mechanisms involved in angle closure can be categorized  according to the anatomical level (anterior to posterior) at which  causative forces act. In many patients more than one level is  contributory.   o Failure of physiological aqueous flow through the pupil  leads to a pressure differential between the anterior and  posterior chambers, with resultant anterior bowing of the  iris (Fig. 10.57).   o Usually anatomically relieved by iridotomy, which  equalizes anterior and posterior chamber pressure.  Control of IOP if elevated will be achieved provided the  angle has opened adequately; this may not occur if there  are substantial PAS or an additional mechanism of angle  closure is in effect. TM damage can prevent  normalization of IOP even with an anatomically open  angle.   o The lens vault quantifies the portion of the lens located  anterior to the anterior chamber angle; a common  definition is the distance between the anterior pole of the  lens and a horizontal line joining the scleral spur at  diametrically opposite locations. A large lens vault is  independently associated with angle closure, though it is  not clear whether this is entirely via a pupillary block or  non-pupillary block (see next) mechanism, or both.   o Associated with a deeper anterior chamber (AC) than  pure pupillary block.   o Patients with non-pupillary block, particularly those with  plateau iris, tend to be younger than those with pure  pupillary block.   o An element of pupillary block is invariably present, but  angle closure is not fully relieved by iridotomy. The term  ‘mixed mechanism’ has been suggested to describe  glaucoma in which both significant pupillary block and  non-pupillary block iris-induced mechanisms coexist.   10.58), and a thicker or more anteriorly positioned iris; a  ‘thick peripheral iris roll’ concept has been introduced by  some authorities. A thicker peripheral iris may be relatively  important in patients of Far Eastern ethnic origin.   Fig. 10.55 Primary angle closure suspect. (A) On gonioscopy only a double Schwalbe line and part of the non-pigmented  trabecular meshwork are visible - the iris is apposed to the pigmented meshwork; (B) pigment smudging of the non-  pigmented meshwork seen on indentation gonioscopy; (C) moderately but not critically narrow angle for comparison  - sparsely pigmented Schwalbe line, non-pigmented and pigmented meshwork; (D) very narrow angle on dark-room anterior  segment OCT   Fig. 10.56 Primary angle closure. (A) Closed inferior angle on gonioscopy; (B) PAS on indentation gonioscopy - superior angle   Fig. 10.57 Angle closure due to pupillary block, with anterior  iris bowing and iridocorneal contact   o Plateau iris configuration is characterized by a flat or only  slightly convex central iris plane, often in association with  normal or only slightly shallow central anterior chamber  depth. The angle recess is typically very narrow, with a  sharp backward iris angulation over anteriorly positioned  and/or orientated ciliary processes. A characteristic  ‘double hump’ sign is seen on indentation gonioscopy,  the central hump being due to the underlying central lens  supporting the iris and the peripheral hump resulting  from the underlying ciliary processes,  o Plateau iris syndrome describes the persistence of   gonioscopic angle closure despite a patent iridotomy in a  patient with morphological plateau iris; factors such as a  dark environment or pharmacological pupillary dilatation  may be necessary to demonstrate the angle closure. It is  divided into a complete form in which occlusion of the  functional TM is present and the IOP is elevated, and an  incomplete form with occlusion to a lesser extent and  normal IOP.   Fig. 10.58 Ultrasound biomicroscopy in plateau iris  configuration shows loss of the ciliary sulcus due to  anteriorly located ciliary processes   (Courtesy of J Schuman, V Christopoulos, D Dhaliwal, M Kahook and R  Noecker, from ‘Lens and Glaucomain Rapid Diagnosis in Ophthalmology,  Mosby 2008)    Lens-induced angle-closure. Angle closure that is  predominantly lens-induced or due to a retrolenticular cause  is often categorized as secondary (see below),  o Includes only those cases in which a sudden change in  lens volume and/or position leads to an acute or subacute  IOP rise.   (phacomorphic glaucoma) or anterior lens subluxation,  o Virtually all pupillary block can be said to have a   • Reduced aqueous outflow in angle closure has been postulated  to be caused by the following mechanisms in varying degree:   intermittent contact with the iris or damage sustained  due to elevated IOP.   o Permanent occlusion of the TM by PAS; the prognosis  for IOP control correlates well with the extent of PAS.   • Age. The average age of relative pupillary block is about 6o  years at presentation. Non-pupillary block forms of primary  angle closure tend to occur at a younger age.   • Race. Particularly prevalent in Far Eastern and Indian  Asians; in the former non-pupillary block is relatively more  significant.   • Family history. Genetic factors are important but poorly  defined, with an increased prevalence of angle closure in  family members.   • Refraction. Eyes with ‘pure’ pupillary block are typically  hypermetropic, although this is not as clear-cut with  non-pupillary block, which can occur in myopic eyes. Up to  one in six patients with hypermetropia of one dioptre or  more are primary angle closure suspects, so routine  gonioscopy should be considered in all hypermetropes.   • Axial length. Short eyes tend to have a shallow AC (Fig.  10.59); eyes with nanophthalmos have a very short eye with a  proportionally large lens and are at particular risk.   • Most patients with angle closure are asymptomatic,  including a majority of those with intermittently or  chronically elevated IOP.    • Presentation can be with intermittent mild symptoms of  blurring (‘smoke-filled room’) and haloes (‘rainbow around  lights’) due to corneal epithelial oedema, or acutely with  markedly decreased vision, redness and ocular/periocular  pain and headache; abdominal pain and other  gastrointestinal symptoms may occur.   • Precipitating factors include watching television in a  darkened room, pharmacological mydriasis or rarely miosis,  adoption of a semiprone position (e.g. reading), acute  emotional stress and occasionally systemic medication:  parasympathetic antagonists or sympathetic agonists  including inhalers, motion sickness patches and cold/flu  remedies (mydriatic effect), topiramate and other sulfa  derivatives (ciliary body effusion).   o VA is normal unless damage is advanced,  o The AC is usually shallower in relative pupillary block  than non-pupillary block,  o IOP elevation may be only intermittent,  o ‘Creeping’ angle closure is characterized by a gradual  band-like anterior advance of the apparent insertion of  the iris. It starts in the deepest part of the angle and  spreads circumferentially.    • The AC is shallow, and aqueous flare is usually present.   • The fellow eye typically shows an occludable angle; if not  present, secondary causes should be considered.   o Early: low IOP (ciliary body shutdown and effect of  intensive treatment), folds in Descemet membrane if IOP  has reduced rapidly (Fig. 10.61A), optic nerve head  congestion, choroidal folds,  o Late: iris atrophy with a spiral-like configuration,   glaukomflecken (white foci of necrosis in the superficial  lens) and other forms of cataract, and irregular pupil due  to iris sphincter/dilator damage and posterior synechiae  (Fig. 10.61B); the optic nerve may be normal or exhibit  varying signs of damage, including pallor and/or cupping  (Fig. 10.61C).   (A) Corneal epithelial oedema, with very numerous tiny  epithelial cysts; (B) mid-dilated vertically oval pupil   Fig. 10.61 Resolved acute primary angle closure. (A) Stromal  corneal oedema and folds in Descemet membrane;   (B) glaukomflecken, spiral-shaped atrophic iris, dilated  pupil and posterior synechiae; (C) optic atrophy - combined  pallor and cupping    o The greater (i) the duration of an attack of APAC and (ii)  the extent of post-APAC PAS, the lower the likelihood of  IOP control with medical treatment alone.   • Subacute angle closure is sometimes used to describe the  clinical scenario of intermittent episodes of spontaneously  resolving mild/moderate APAC, usually in patients with  predominant pupillary block. The clinical course may be  chronic, or may culminate in a more severe/unresolving  episode of APAC.   • Anterior segment OCT (AS-OCT - see Fig. 10.55D),  ultrasound biomicroscopy or Scheimpflug photography may  be useful to supplement gonioscopic findings and for patient  education.   • Posterior segment ultrasonography in atypical cases to  exclude causes of secondary angle closure.   • Provocative testing. This may aid decision-making in some  circumstances, such as to assess the propensity to develop a  steep increase in IOP with only partially opened angles  post-iridotomy, and hence determine whether further  intervention (e.g. iridoplasty) might be appropriate.   o Pharmacological mydriasis probably discriminates poorly.  It carries a small risk of precipitating APAC in susceptible  patients without a patent iridotomy.  o Dark room/prone provocative test (DRPPT): the patient  sits in a dark room, face down for one hour without  sleeping (sleep induces miosis). The IOP is checked  (immediately after the test, as IOP can normalize very  rapidly), and an IOP rise of 8 mmHg or more is  frequently taken as being of significance; a positive result  is not uncommon in normal eyes, so AS-OCT or  gonioscopy without indentation should be used to  confirm a compatible angle appearance. A positive  response is virtually always abolished following lens  extraction.   • Lens-induced angle closure due to a swollen or subluxated  lens.   • Other causes of secondary angle closure, with or without  pupillary block; see below.   • Neovascular glaucoma may occasionally cause the sudden  onset of pain and congestion.   • Hypertensive uveitis, e.g. iridocyclitis with trabeculitis  (particularly herpetic including cytomegalovirus),  glaucomatocyclitic crisis (Posner-Schlossman syndrome).   • Orbital/retro-orbital lesions including orbital  inflammation, retrobulbar haemorrhage and carotid-  cavernous fistula.   • If significant ITC persists after iridotomy, options include  observation (most), laser iridoplasty, and long-term  pilocarpine prophylaxis, e.g. 1% twice daily; provocative  testing may be helpful in some patients. If symptomatic  cataract is present, lens extraction usually definitively opens  the angle. If IOP is elevated, then by definition PAC is present.   • Management is as for PACS, but with a lower threshold for  further intervention if angle widening is inadequate after  iridotomy, particularly if IOP remains elevated.   • Urgency and intensity of treatment, and frequency of  review is tailored to the individual patient, taking into   Fig. 10.62 Effect of peripheral iridotomy. (A) Very narrow  angle before treatment; (B) substantially wider angle  following laser - pigment smudging is present    account IOP, extent of angle closure and glaucomatous  damage, if present.   • Medical treatment as for POAG may be required for eyes  with substantial synechial closure or with persistently  elevated IOP despite an opened angle.   encourage the lens to shift posteriorly under the influence  of gravity.   o Acetazolamide 500 mg is given intravenously if IOP  >50 mmHg, and orally (not slow-release) if IOP is  <50 mmHg.   o If treatment is intravenous an additional oral dose of  acetazolamide 500 mg may be given provided the patient  is not of low body weight. Contraindications include  sulfonamide allergy and angle closure secondary to  topiramate/other sulfa derivatives),  o A single dose of each of apraclonidine 0.5% or 1%,  timolol 0.5%, and prednisolone 1% or dexamethasone  0.1% to the affected eye, leaving 5 minutes between each,  o Pilocarpine 2-4% one drop to the affected eye, repeated  after half an hour; one drop of 1% into the fellow eye.  Some practitioners omit pilocarpine until a significant  IOP fall, as when IOP is high ischaemia may compromise  its action, and excessive dosing carries a toxicity risk and  may exert a forward vector,  o Analgesia and an antiemetic may be required.   O Central corneal indentation with a squint hook or  indentation goniolens to force aqueous into the angle;  epithelial oedema can be cleared first with topical  50% glycerol to improve visualization and avoid  abrasion.   O Further pilocarpine 2-4%, timolol 0.5%, apraclonidine  1% and topical steroid.   o Mannitol 20% 1-2 g/kg intravenously over 1 hour, oral  glycerol 50% 1 g/kg, or oral isosorbide 1-1.5 g/kg, having  checked for contraindications,  o Early laser iridotomy or iridoplasty after clearing corneal  oedema with glycerol.   o Surgical options: peripheral iridectomy, lens extraction,  goniosynechialysis, trabeculectomy and cyclodiode.   o Pilocarpine 2% four times daily to the affected eye and  1% four times daily to the fellow eye.  o Topical steroid (prednisolone 1% or dexamethasone  0.1%) four times daily if the eye is acutely inflamed,  o Any or all of the following should be continued as  necessary according to response: timolol 0.5% twice  daily, apraclonidine 1% three times daily and oral  acetazolamide 250 mg four times daily.    • Bilateral laser iridotomy is performed once an attack has  been broken, signified by a clear cornea and preferably  normalized IOP. Topical steroids and any necessary  hypotensives are continued for at least a week.   • Subsequent management is as for post-iridotomy chronic  PAC/PACG. A low threshold may be adopted for cataract  surgery, particularly if a significant phacomorphic element is  suspected. Trabeculectomy is occasionally necessary for  persistent IOP elevation despite a successfully opened angle.   Secondary open-angle glaucoma can be subdivided on the basis of  the site of aqueous outflow obstruction.   • Pre-trabecular, in which aqueous outflow is obstructed by a  membrane covering the trabeculum (Fig. 10.63 A), which  may consist of:   o Fibrovascular tissue (neovascular glaucoma),  o Endothelial cellular membranous proliferation  (iridocorneal endothelial syndrome),  o Epithelial cellular membranous proliferation (epithelial  ingrowth).   • Trabecular, in which the obstruction occurs as a result of  ‘clogging up’ of the meshwork (Fig. 10.63B) and secondary  degenerative changes.   o Pigment particles (pigmentary glaucoma),  o Red blood cells (red cell glaucoma),  o Degenerate red cells (ghost cell glaucoma),  o Macrophages and lens proteins (phacolytic glaucoma),  o Proteins (probably an element in hypertensive uveitis),  o Pseudoexfoliative material (pseudoexfoliation glaucoma),  o Trabecular glaucomas may also be caused by alteration of  the trabecular fibres themselves by oedema (e.g. trabeculitis  in hypertensive uveitis) or scarring (e.g. post-traumatic  angle recession).   • Post-trabecular in which the trabeculum itself is normal but  aqueous outflow is impaired as a result of elevated episcleral  venous pressure.   o Carotid-cavernous fistula,  o Sturge-Weber syndrome,  o Obstruction of the superior vena cava.   o Seclusio pupillae (360° posterior synechiae), usually  secondary to recurrent iridocyclitis,  o Subluxated lens,  o Phacomorphic glaucoma.   o Capsular block syndrome with 360° iris-capsule  adhesion in a pseudophakic eye.  o Aphakic pupillary block.   o Secondary causes of PAS such as advanced neovascular  glaucoma and chronic anterior uveitis,  o Cilio-choroidal effusion.   o Capsular block syndrome without iris-capsule adhesion,  o Ciliary body/iris cyst or other ciliary body or posterior  segment tumour.   o Contraction of retrolenticular fibrovascular tissue such as  in proliferative vitreoretinopathy and retinopathy of  prematurity.   Pseudoexfoliative material (PXF), the presence of which in the eye  is termed pseudoexfoliation syndrome (PXS), is a common cause  of secondary open-angle glaucoma, but is easily overlooked if signs  are mild. It is rare before the age of 50, though after this age its  prevalence increases rapidly. It is more common in women than  men. The prevalence is up to 5% in many older populations but  is particularly common in Scandinavia and several other areas,  including parts of Africa; rates of 25% or more have been reported  in members of some ethnic groups with symptomatic cataract.  The incidence of glaucoma (PXG) at diagnosis of PXS is 15-30%,  and the cumulative risk of eyes with PXS requiring glaucoma treat¬  ment may be as high as 60% at 5 years. It should be distinguished  from true capsular exfoliation, which occurs due to chronic infra¬  red exposure (‘glassblower’s cataract’ - see Fig. 9.6D).   PXF is a grey-white fibrillary amyloid-like material; it may derive  from abnormal extracellular matrix metabolism in ocular and  other tissues. The material is deposited on various ocular struc¬  tures including the lens capsule (Fig. 10.64), zonular fibres, iris,  trabeculum and conjunctiva. PXF has been found in skin and  visceral organs, leading to the concept of PXS as the ocular mani¬  festation of a systemic disorder; PXS is associated with an increased  prevalence of vascular disorders, hearing loss and Alzheimer  disease. Plasma homocysteine tends to be higher than controls,  and inadequate dietary folate intake (folate reduces homocysteine)  may be a risk factor. The aetiopathogenesis is multifactorial, but  in at least some populations almost all patients with PXS have  certain single nucleotide polymorphisms (SNPs) in the LOXLi  gene, which is involved in elastin fibre production. However, the  SNPs are very common in the general population and most indi¬  viduals with them do not develop PXS. Open-angle glaucoma  associated with PXF (sometimes termed capsular glaucoma) is  conventionally due to elevated IOP, likely mechanisms including  trabecular obstruction by PXF and liberated iris pigment, with  secondary degenerative outflow dysfunction. However, a high  prevalence of glaucomatous optic neuropathy has been reported    Fig. 10.63 Pathogenesis of secondary glaucoma. (A) Pre-trabecular obstruction; (B) trabecular obstruction; (C) angle closure  with pupillary block; (D) angle closure without pupillary block    in eyes with visible PXF but normal IOP, and in fellow eyes of PXS  with no visible PXF and apparently normal IOP. Aggressive inves¬  tigation such as conjunctival biopsy will usually reveal subclinical  PXF in fellow eyes.   • Diagnosis is usually incidental, though follows vision loss  from advanced glaucoma more commonly than POAG.   • Cornea. PXF may be deposited on the endothelium, and  scattered pigment deposits are common; a vertical  (Krukenberg) spindle may rarely form, similar to that seen  in pigment dispersion syndrome. Endothelial cell  abnormalities such as low density are more common than  average.   • Anterior chamber. PXF particles are sometimes seen; mild  aqueous flare from an impaired blood-aqueous barrier is    • Iris. Granular PXF deposits (Fig. 10.65A), pupillary ruff loss  and patchy transillumination defects (Figs 10.65B and C) at  the pupillary margin.   • Lens. The anterior lens capsule typically shows a central disc  and a radially indented peripheral layer of PXF material,  separated by a clear zone maintained by pupillary abrasion  (Fig. 10.65D). Peripheral capsular deposition is often visible  only with pupillary dilatation (Fig. 10.65E). Deposits may be  flaky, with scrolled edges. Cataract is more common than  average. Phacodonesis (lens instability) due to zonular  weakness may be present, but spontaneous subluxation is  rare.   • Anterior chamber angle. Regular gonioscopy - at least  annually in most cases - is important.   o Patchy trabecular and Schwalbe line hyperpigmentation  is common, especially inferiorly.  o A Sampaolesi line is seen in PXF and other causes  of a heavily pigmented angle: an irregular band of   Fig. 10.64 Christmas-tree like deposits of pseudoexfoliative  material on the lens capsule   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann 2001)    pigment running on or anterior to the Schwalbe line  (Fig. 10.65F).   o Dandruff-like PXF angle deposits may be seen,  o There is an increased risk of angle closure and of   • IOP. In most eyes the presence of glaucomatous damage is  associated with elevated IOP. The majority of patients have a  chronic open-angle glaucoma that is usually unilateral at  first. Occasionally the IOP may rise acutely despite a wide  angle, mimicking acute angle closure.   • Prognosis. This is worse than POAG; the IOP is often  higher and may exhibit marked fluctuation. Severe damage  may be present at diagnosis, or can develop rapidly. It is  therefore important to monitor patients closely, and it may  be prudent for review in patients with PXS to take place at  intervals of no more than 6 months.   • Medical treatment is similar to that of POAG, but failure is  more common.   • Laser trabeculoplasty is probably more effective than in  POAG, with mean IOP reduction around 30% following  SLT. Care should be taken not to apply excessive energy, as  trabecular pigmentation may confer higher absorption;  transient IOP spikes are not uncommon.   • Phacoemulsification alone may significantly lower IOP,  though it may give better control combined with  trabeculectomy. There is a higher risk of complications, due  to poor mydriasis, increased fragility of the zonule and lens    capsule, and endothelial deficiency; there is also an increased  risk of a postoperative IOP spike, postoperative corneal  oedema, capsular opacification, capsulorhexis contraction  (capsular phimosis) and late IOL decentration or  dislocation.   • Filtration surgery in PXG has a similar success rate to  POAG.   • Trabecular aspiration alone seems to confer at least a  short-term benefit, and can be performed at the same time  as other intraocular procedures.   Pigment dispersion syndrome (PDS) is characterized by the libera¬  tion of pigment granules from iris pigment epithelium (IPE), and  their deposition throughout the anterior segment. Secondary pig¬  mentary glaucoma (PG) is common. PDS and PG are more  common in males, particularly young myopic white men; there is  also a cluster of disease in older hypermetropic black women.  About a third of patients with PDS will have developed elevated  IOP or glaucoma after 15 years. Although PDS is rare in black  individuals, PG tends to be more severe than in whites. AD inher¬  itance with incomplete penetrance seems to be present in at least  some families; a range of genetic loci have been linked, with any  genetic basis likely to be multifactorial. Myopia is a risk factor for  clinical manifestation, higher degrees of myopia being associated  with earlier and more severe glaucoma. Secondary pigment dis¬  persion can occur, causes including trauma, intraocular tumour  and rubbing of a malpositioned IOL on the IPE.   In primary PDS/PG, pigment shedding is precipitated by rubbing  of the posterior pigment layer of the iris against the zonule as a  result of excessive posterior bowing of the mid-peripheral portion  of the iris (Fig. 10.66A). It is believed that an increase in anterior  chamber pressure relative to the posterior chamber occurs due to  reverse pupillary block, supported by the observation that periph¬  eral iridotomy flattens the iris and decreases iridozonular contact  (Fig. 10.66B). The pigment epithelium itself may be abnormally  susceptible to shedding in affected individuals. Pigment shedding  decreases from middle age onwards due to physiological changes  resulting in decreased iridozonular contact. Acute IOP elevation  can occur due to direct trabecular obstruction by shed melanin  granules; chronic elevation appears to be caused by pigmentary  obstruction of the intertrabecular spaces and damage to the  trabeculum secondary to denudation, collapse and sclerosis.  Patients with pigmentary glaucoma have an increased incidence  of steroid responsiveness.   • Presentation. PDS and PG are typically detected at a routine  eye examination; the myopic patients who tend to develop  the conditions are likely to be under regular optometric    Fig. 10.65 Anterior segment signs in pseudoexfoliation syndrome. (A) PXF on the pupillary margin; (B) and (C) loss of the  pupillary ruff and marginal transillumination defects corresponding to iris sphincter atrophy; (D) and (E) PXF on the lens;  (F) gonioscopy shows patchy trabecular hyperpigmentation and a markedly irregular Sampaolesi line   Fig. 10.66 Ultrasound biomicroscopy in pigment dispersion  syndrome. (A) Very deep anterior chamber and posterior  bowing of the peripheral iris; (B) flattening of the peripheral  iris following laser iridotomy    review. Occasionally symptoms from glaucomatous visual  loss lead to attendance, or from corneal oedema due to an  acute IOP rise following the release of pigment granules  (particularly after physical exercise). Signs of PDS are usually  bilateral; they may be subtle and go undetected.   • Cornea. Pigment is deposited on the endothelium in a  vertical spindle shape (Krukenberg spindle - Fig. 10.67A) in  many patients, and its presence may mean that progression  to PG is more likely. The spindle tends to shrink in  long-standing cases.   • Anterior chamber (AC). The AC is typically deep. Melanin  granules may be seen in the aqueous.   • Iris. Characteristic radial spoke-like transillumination  defects (Fig. 10.67B) are seen in lighter, but often not in  dark, irides. To best demonstrate these, the room should be  minimally illuminated and a short, narrow but intense slit  beam directed through the pupil; visualization may be aided  by asking the patient to look up. Melanin granules may be  present on the surface of the iris, usually interiorly (Fig.  10.67C), but in extreme cases conferring a general increase in  pigmentation. There may be partial loss of the pupillary ruff.  The iris (and other) signs tend to lessen with age.    • Gonioscopy. The angle is wide in the myopic patients who  constitute the majority, and there is often a characteristic  mid-peripheral iris concavity where the iris bows backwards.  The trabecular meshwork is heavily pigmented, with a dense  homogeneous circumferential posterior meshwork band  (Fig. 10.67D). Pigment may also be seen on or anterior to  the Schwalbe line, forming a Sampaolesi line (see Fig.   • Lens. Pigment granules may be deposited on the anterior  surface. There may be a line (Scheie stripe) or a (Zentmayer)  ring of pigment on the peripheral/equatorial surface around  the zonular insertions.   • IOP. This may be volatile, some patients exhibiting higher  levels and wider fluctuations of IOP than in POAG. Over  time the control of IOP may become easier as pigment  liberation decreases and occasionally the IOP may revert  to normal. NTG can be erroneously diagnosed if the IOP  has normalized spontaneously and the PDS signs  resolved.   • Posterior segment. Peripheral retinal pigmentation may be  seen, and lattice degeneration may be more common than in  myopic patients without PDS or PG; the incidence of retinal  detachment may also be higher. Glaucomatous optic  neuropathy is dependent on disease stage and extent and  may be markedly asymmetrical; it is common to find  advanced disease in one eye and relatively mild damage in  the other.   It is important to review patients with PDS regularly - at least   annually in low-risk cases - to exclude the development of raised   • Lifestyle measures. Forms of exercise involving jolting have  been associated with acute iris pigment liberation, and it  may be better to avoid activities such as jogging and running  up and down stairs. Pilocarpine may have a prophylactic  effect in exercise.   • Medical treatment is similar to that of POAG. Miotics are  theoretically of particular benefit because they decrease  iridozonular contact in addition to facilitating aqueous  outflow. However, they have the disadvantage of  exacerbating myopia, and also carry a risk of precipitating  retinal detachment in short-sighted eyes. They are often not  tolerated well by younger patients. Topical thymoxamine, a  selective alpha-adrenergic antagonist, induces miosis without  causing spasm of accommodation, but is also poorly  tolerated as it causes irritation.   • Laser trabeculoplasty is often effective. It is important not  to over-treat eyes with heavily pigmented angles.   • Laser iridotomy has been proposed to retard pigment  liberation by reversing iris concavity and eliminating  iridozonular contact. It may have utility especially in  patients under the age of 40 years but benefit has not been  conclusively demonstrated.    Fig. 10.67 Pigment dispersion syndrome. (A) Krukenberg spindle; (B) radial spoke-like iris transillumination defects;  (C) pigment granules on the inferior iris surface; (D) homogeneous band of trabecular hyperpigmentation    • Filtration surgery is indicated more commonly than in  POAG. The use of adjunctive antimetabolites may improve  surgical outcome, particularly in younger patients in whom  the risk of failure is higher. Post-surgical hypotony may be  more common in young myopic eyes.   Bilateral acute depigmentation of the iris (BADI) and bilateral  acute iris transillumination (BAIT) have recently been proposed  as distinct idiopathic clinical syndromes involving pigment disper¬  sal from the iris into the anterior chamber. They are said to be  more common in young to middle-aged women, occurring spon¬  taneously or following a flu-like illness and possibly after oral  antibiotic treatment, especially moxifloxacin. It is possible that the  primary process is uveitic, but there is evidence that the mecha¬  nism is phototoxicity following sensitization in predisposed indi¬  viduals. Presentation is usually with acute bilateral ocular redness  and photophobia. Both may be associated with an IOP rise, but    this has been reported to be more severe and resistant in BAIT.  Findings described in the two differ in that pigment is lost from  the iris stroma in BADI and the iris pigment epithelium in BAIT,  with marked iris transillumination defects and irregular mydriasis  in the latter. It is possible that BADI and BAIT represent different  points on a common disease spectrum. Differential diagnosis is  principally from viral anterior uveitis and pigment dispersion  syndrome.   Neovascular glaucoma (NVG) occurs as a result of aggressive iris  neovascularization (rubeosis iridis). The common aetiological  factor is severe, diffuse and chronic retinal ischaemia. It is postu¬  lated that hypoxic retinal tissue produces angiogenic factors in an  attempt to revascularize hypoxic areas; the most important of  these is probably vascular endothelial growth factor (VEGF). The    mediators induce both retinal and anterior segment neovasculari¬  zation, the latter initially impairing aqueous outflow in the pres¬  ence of an open angle, with subsequent progression to typically  severe and relentless secondary synechial angle-closure glaucoma  (Fig. 10.68A).   • Ischaemic central retinal vein occlusion accounts for over a  third of cases. Up to 50% of eyes develop NVG following  ischaemic CRVO. Extensive peripheral retinal capillary  non-perfusion on fluorescein angiography is a useful  predictor of the risk of subsequent NVG. Glaucoma typically  occurs 3 months after the occlusive event ( c ioo-day  glaucoma’) but intervals from 4 weeks to 2 years have been  documented.   • Diabetes mellitus accounts for a slightly smaller proportion.  The risk of glaucoma is decreased by appropriate panretinal  photocoagulation, but may be increased by cataract  extraction. Pars plana vitrectomy in diabetics may  precipitate NVG (7% overall in a large study), especially if  angle neovascularization is present preoperatively.   • Arterial retinal vascular disease such as central retinal  artery occlusion and ocular ischaemic syndrome are less  common causes.   • Miscellaneous causes include intraocular tumours, long¬  standing retinal detachment (RD) and chronic intraocular  inflammation.   • Symptoms vary from none to severe pain, decreased vision,  redness and photophobia.   • Cornea. Elevated IOP, particularly when substantial and  acute, leads to corneal oedema.   • IOP may be normal early in the disease process, but is  frequently extremely high later on. The anterior segment will  often be congested once progression to elevated IOP has  occurred. In advanced disease hypotony may supervene.   • Anterior chamber. Flare, cells and posterior synechiae may  be present, depending on severity and stage. Presentation is  sometimes with anterior chamber haemorrhage (Fig.   • Pupillary margin. Subtle vessels at the pupillary margin are  often an early sign (Fig. 10.68C), but may be missed unless  the iris is examined carefully under high magnification.  Diagnosis at this stage is likely to substantially improve the  prognosis.   • Iris surface. New vessels grow radially over the surface of  the iris towards the angle (Fig. 10.68D), sometimes joining  dilated blood vessels at the collarette. At this stage the IOP  may still be normal, but elevation can occur fairly acutely.   • Gonioscopy. Angle neovascularization may commonly occur  without other signs, particularly after CRVO, and it is  important to perform careful non-mydriatic gonioscopy in  eyes at risk; early signs may be very subtle, even in the  presence of moderate IOP elevation. Neovascular tissue    proliferates across the face of the angle, forming an  obstructing fibrovascular membrane that subsequently  contracts to close the angle. The angle closes  circumferentially (Fig. 10.68E) leading to very high IOP,  severe visual impairment, congestion of the globe and pain;  the visual prognosis is generally poor by this stage, but  aggressive management can achieve comfort and retain  useful sight in some cases.   • Posterior segment. Signs correspond to aetiology.  Glaucomatous optic neuropathy may be present.   • Investigations. FA may be helpful in confirming aetiology  and delineating ischaemia. B-scan ultrasonography will help  to exclude potential causes such as RD when the posterior  segment view is impaired. Anterior segment OCT has been  proposed as a useful tool for angle assessment.   It is critical to address the cause of the neovascularization as well   • Review. Frequent review during high-risk periods is critical:  the first few months following an ischaemic CRVO, and the  first few weeks following diabetic vitrectomy.   • Medical treatment of elevated IOP is as for POAG but  miotics should be avoided, and prostaglandin derivatives  used with relative caution due to their inflammation-  promoting potential. Topical atropine 1% once or twice  daily will resist posterior synechiae and PAS formation, and  topical steroids should be given if significant inflammation is  present, watching for secondary raised IOP. Steroids and  atropine alone may be adequate if there is no visual  potential. Topical apraclonidine and oral acetazolamide may  be useful temporizing measures; acetazolamide can be  associated with renal dysfunction in diabetes, especially type  1, and should be used with caution in these patients.   • Panretinal photocoagulation (PRP) is usually effective in  inducing regression of neovascularization and, if performed  early, preventing progression to glaucoma. It will not reverse  an established fibrovascular membrane. The timing of PRP  in CRVO is discussed in Chapter 13. If the retinal view is  poor, indirect ophthalmoscopic application may provide  better access, if necessary performed in the operating room  with iris hooks to open a small pupil caused by posterior  synechiae. Trans-scleral cryotherapy may be used in eyes  with opaque media or as an adjunct for increasing peripheral  retinal coverage.   • Goniophotocoagulation. Laser application directly to angle  new vessels has been described, but has largely been  supplanted by intravitreal anti-VEGF injection (see below).  Photodynamic therapy to the iris and angle has also been  described.   • Intraocular VEGF inhibitors, e.g. bevacizumab (Avastin®)  at a dose of 1.25 mg in 0.05 ml, can be an effective adjunctive   Fig. 10.68 Neovascular glaucoma. (A) Rubeosis iridis and angle closure by PAS; (B) anterior chamber haemorrhage from iris  new vessels; (C) early pupillary margin neovascularization; (D) extension of new vessels across the iris surface;   (E) progressive synechial angle closure; (F) cataract associated with established rubeosis iridis   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 - fig. A; C Barry - figs B and F; S Chen - figs C and D)    measure whilst waiting for PRP to take effect, particularly if  fibrovascular angle closure has not yet supervened.  Intracameral (AC) injection is an alternative to the  intravitreal route. The duration of control from a single  injection is limited. There may be a substantial risk of CRAO  in ocular ischaemic syndrome.   • Retinal detachment repair should be performed where this  is a factor, including reattachment of a diabetic tractional  detachment.   • Ciliary body ablative procedures. Cyclodiode or - now  rarely - cyclocryotherapy should be considered if medical  IOP control is not possible. These have conventionally been  used only in eyes with poor visual potential, but can be  employed if there is reasonable vision in order to prevent  severe glaucomatous damage occurring whilst  neovascularization is brought under control. Lowering a  substantially raised IOP generally improves comfort, and  clearing corneal oedema may facilitate an adequate retinal  view for PRP. Care should be taken not to use excessive  treatment, which can lead to hypotony. Endoscopic  cyclophotocoagulation is an alternative to trans-scleral  treatment.   • Filtration surgery may be considered if VA is HM or better.  Options include an artificial filtering shunt (glaucoma  drainage device) and trabeculectomy with mini-shunt  implantation, adjunctive mitomycin C and postoperative  subconjunctival 5-fluorouracil. Active neovascularization  and inflammation should be controlled preoperatively  (perhaps including preoperative anti-VEGF treatment) to  improve the chances of surgical success; there is a relatively  high risk of hypotony. Postoperative anti-inflammatory  treatment should be aggressive and may include systemic  steroids.   • Pars plana vitrectomy with peroperative endolaser at an  early stage may improve the prognosis in eyes with vitreous  haemorrhage, especially in CRVO. Preoperative intravitreal  anti-VEGF may be of benefit.   • Retrobulbar alcohol injection is useful in relieving pain but  may cause permanent ptosis and does not relieve congestion.   Elevation of IOP secondary to intraocular inflammation fre¬  quently presents a diagnostic and therapeutic challenge. The eleva¬  tion of IOP may be transient and innocuous, or persistent and  severely damaging. The prevalence of secondary glaucoma  increases with chronicity and severity of disease. Secondary glau¬  coma is particularly common in Fuchs uveitis syndrome and  chronic anterior uveitis associated with juvenile idiopathic    arthritis. Posterior uveitis is less likely to affect the aqueous outflow   • IOP fluctuation may be dramatic in uveitic glaucoma and  phasing may be helpful in patients with borderline IOP.   • Ciliary body shutdown caused by acute exacerbation of  chronic anterior uveitis is frequently associated with  lowering of IOP that may mask the underlying tendency to  glaucoma. Even eyes with considerably elevated IOP  (30-35 mmHg) may become hypotonous during acute  exacerbations of uveitis. Return of ciliary body function with  subsidence of uveitis may be associated with a rise in IOP in  the presence of permanently compromised outflow facility.   • Pathogenesis of elevation of IOP may be uncertain; multiple  mechanisms may be involved. Steroid-responders often  represent a therapeutic challenge.   • Assessment of glaucomatous damage may be hampered by  a small pupil or opacities in the media. Poor visual acuity  may also compromise accurate perimetry.   • Iris vessels may give rise to diagnostic confusion with  neovascular glaucoma.   Secondary angle closure is caused by posterior synechiae extend¬  ing for 360° (seclusio pupillae), which obstruct aqueous flow  from the posterior to the anterior chamber (Fig. 10.69A). The  resultant increased pressure in the posterior chamber produces  anterior bowing of the peripheral iris (iris bombe - Fig. 10.69B)  resulting in shallowing of the anterior chamber and apposition of  the iris to the trabeculum and peripheral cornea (Fig. 10.69C).  Such an inflamed iris easily sticks to the trabeculum and the iri¬  docorneal contact may become permanent, with the development  of peripheral anterior synechiae (PAS).   • Slit lamp biomicroscopy shows seclusio pupillae, iris bombe  and a shallow anterior chamber.   • Gonioscopy shows angle closure from iridotrabecular  contact. Indentation may be used to assess the extent of  appositional as opposed to synechial angle closure.   • Pathogenesis. Chronic anterior uveitis causes the deposition  of inflammatory cells and debris in the angle (Figs 10.70A  and B). Subsequent organization and contraction pulls the  peripheral iris over the trabeculum, causing gradual and  progressive synechial angle closure (Fig. 10.70C) and   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann 2001 - fig. A)    eventual elevation of IOP. The eye with a pre-existing  narrow angle may be at higher risk.   • Diagnosis. The anterior chamber is deep but gonioscopy  shows extensive angle closure by PAS.   In acute anterior uveitis the IOP is usually normal or subnormal  due to concomitant ciliary shutdown. Occasionally, however, sec¬  ondary open-angle glaucoma develops due to obstruction of  aqueous outflow, most commonly as acute inflammation is sub¬  siding and ciliary body function returning. This effect, which is  often transient and innocuous, may be steroid-induced or caused  by a combination of the following mechanisms:   • Trabecular obstruction by inflammatory cells and debris,  which may be associated with increased aqueous viscosity  due to leakage of protein from inflamed iris blood vessels.   • Acute trabeculitis involving inflammation and oedema of  the trabecular meshwork with secondary diminution of  intertrabecular porosity may result in a reduction in outflow  facility. It is thought that this is especially relevant in  anterior uveitis associated with herpes zoster, herpes  simplex, other viral anterior uveitides and toxoplasma  retinitis.   In chronic anterior uveitis the main mechanism for reduced  outflow facility is thought to be trabecular scarring and/or sclero¬  sis secondary to chronic trabeculitis. The importance of this mech¬  anism is, however, difficult to determine as most eyes also have  some degree of synechial angle closure. Because of the variable  appearance of the angle on gonioscopy, definitive diagnosis of  trabecular damage is difficult. In some eyes, a gelatinous exudate  is seen on the trabeculum.   • Medical control of IOP is more likely to be achieved if the  angle is completely open.   • The target IOP is lower in eyes with advanced glaucomatous  optic neuropathy.   • Long-acting depot steroid preparations should be used with  caution, and minimized in known or suspected  steroid-responders.   • The effect of ocular hypotensive drugs is less predictable in  uveitis, e.g. some cases may be unexpectedly sensitive to  topical carbonic anhydrase inhibitors (CAI).   • Prostaglandin derivatives should be avoided if possible as  they may promote inflammation and macular oedema.    • The choice of additional agents often depends on the IOP  level. If this is very high, oral acetazolamide may be  required. For moderate elevation (e.g. less than 35 mmHg on  a beta-blocker) in the absence of significant glaucomatous  damage, an alpha-adrenergic agonist or topical CAI might  be adequate.   • Miotics are contraindicated as they increase vascular  permeability, and as miosis promotes the formation of  posterior synechiae.   • Laser iridotomy is performed to re-establish communication  between the posterior and anterior chambers in eyes with  pupillary-block angle-closure glaucoma.   • An iridotomy is likely to become occluded in the presence of  active uveitis, and intensive topical steroid should be used  following the laser.   • Correction of pupillary block alone may not control the IOP  if there is insufficient exposed functional angle, though a  patent iridotomy may retard progressive PAS formation.   • Surgical iridectomy is the definitive method of preventing  further pupil block, and may be required if laser fails to  maintain a viable iridotomy.   O Control of chronic uveitis for a minimum of 3 months  before surgery is ideal but often impractical,  o Preoperative topical steroids should be used, not only  as prophylaxis against recurrent inflammation but  also to reduce the conjunctival inflammatory cell  population.   o In patients with particularly labile inflammatory disease  oral prednisolone should be considered (0.5 mg/kg/day).   • Trabeculectomy with mitomycin C enhancement or  glaucoma drainage device implantation are the major  options; modification of the former with an Ex-Press™  mini-shunt may improve outcomes.   o Combined cataract and glaucoma surgery is relatively  contraindicated, but may sometimes be performed in  conjunction with goniosynechialysis; occasionally cataract  surgery alone can be appropriate. In most cases cataract  surgery should be deferred for at least 6 months after  trabeculectomy.   o Postoperative hypotony is a particular risk as a delicate  balance may exist between reduced aqueous production  and restricted outflow.   o Following surgery, steroids are tapered more slowly than  in non-inflammatory glaucomas.   • Cyclodestructive procedures should be used with caution as  they may exacerbate inflammation. Possible underlying  ciliary body insufficiency also carries the risk of profound  hypotony that may progress to phthisis bulbi.   PSS (glaucomatocyclitic crisis) is a rare condition characterized by  recurrent attacks of unilateral acute raised IOP associated with  mild anterior uveitis. The mechanism is speculated to be acute  trabeculitis, and there is evidence that infection, possibly cytome¬  galovirus (CMV) or H. pylori , may play a role; anterior chamber  sampling for viral PCR is sometimes employed. PSS typically  affects young to middle-aged adults. Males are affected more fre¬  quently than females. Episodes are unilateral, although 50% of  patients have involvement of the other eye at different times. The  intervals between attacks vary, but usually become longer with  time. Patients should be followed even after the attacks have com¬  pletely subsided, because a significant proportion will develop  chronic IOP elevation, with the fellow eye also at risk.   An acute IOP rise in PDS and demonstrable CMV or other viral  anterior uveitis can present in an almost identical manner; the  signs of the former may be atypical in older patients and those  with dark irides. Simple IOP volatility in POAG, especially the  juvenile variant, must also be distinguished.   • Presentation is with mild discomfort, haloes around lights  and slight blurring of vision in one eye, and sometimes  redness.   • Slit lamp biomicroscopy typically shows a few anterior  chamber cells and one to several fine white central keratic  precipitates. Injection is likely to be absent or minimal. Mild  corneal epithelial oedema is frequent.   • IOP is typically raised to over 40 mmHg, out of proportion  to iritis severity, and untreated persists for hours to weeks;  elevation precedes the inflammatory signs.   • Glaucomatous optic neuropathy is relatively uncommon in  most cases. Reversible cupping has been described.   Topical steroids are used to control inflammation, with aqueous  suppressants to lower the IOP. Topical or oral non-steroidal anti¬  inflammatory agents may also be beneficial. The benefit of anti¬  viral treatment is unclear.   Phacolytic glaucoma is a secondary open-angle glaucoma occur¬  ring in association with a hypermature cataract. Trabecular  obstruction is caused by high molecular-weight lens proteins that    leak through the intact capsule into the aqueous humour leading  to trabecular obstruction; macrophages containing lens proteins  may also contribute (Fig. 10.71A). Phacolytic glaucoma should not  be confused with phacogenic (previously phacoanaphylactic)  uveitis, an autoimmune granulomatous reaction to exposed lens  proteins occurring with a compromised lens capsule (see Ch. 11).   • Presentation is with pain; vision is poor due to cataract.   • Slit lamp biomicroscopy shows corneal oedema, a  hypermature cataract and a deep anterior chamber. There  may be large floating white particles in the AC, consisting of  lens protein and protein-containing macrophages (Fig.  10.71B), which may impart a milky appearance to the  aqueous if very dense (Fig. 10.71C), and can form a  pseudohypopyon (Figs 10.71B-D).   • Gonioscopy, if a reasonable view can be obtained, shows an  open angle with lens-derived material and inflammatory  cells that are most substantial inferiorly.   After IOP is controlled medically, proteinaceous material is  washed out from the anterior chamber and the cataract is removed.  Care should be taken not to rupture the zonule, which is likely to  be more fragile than usual.   Phacomorphic glaucoma is an acute secondary angle-closure glau¬  coma precipitated by an intumescent cataractous lens. Equatorial  age-related growth of the lens slackens the suspensory ligament  and allows the lens to move anteriorly. Associated anteroposterior  growth leads to increased iridolenticular contact and potentiates  pupillary block and iris bombe.   • Presentation is similar to acute PACG with a shallow  anterior chamber (AC) and mid-dilated pupil; cataract is  evident (Fig. 10.72).   • The fellow eye. Phacomorphic glaucoma is more likely in  eyes with a shorter axial length and shallower AC, but the  fellow eye may demonstrate a deep AC and an open angle.   • Medical treatment is initially similar to that of acute PACG.   • Miotics are omitted as they tend to increase iris-lens  apposition and shift the lens anteriorly; dilatation is  sometimes helpful but should be implemented with caution.   • Systemic hyperosmotic agents may be required more  commonly than in PACG.   Fig. 10.71 Phacolytic glaucoma. (A) Lens protein-containing macrophages in the angle; (B) hypermature cataract, lens  protein-containing macrophages floating in the aqueous, and a pseudohypopyon; (C) dense milky aqueous with  pseudohypopyon; (D) mature pseudohypopyon   Fig. 10.72 Intumescent cataract, shallow anterior chamber,  dilated pupil and corneal oedema in phacomorphic  glaucoma    • Laser iridotomy may be worthwhile but is often not possible  (due to corneal oedema or lens-cornea proximity) or  ineffective. A similar procedure should be considered for the  fellow eye.   • Cataract extraction constitutes the definitive treatment,  ideally once the IOP has been normalized and the eye is  quiet; the surgery can be difficult and carries a higher risk of  complications.   • Blunt ocular trauma, even if relatively trivial, may result in  lens dislocation in eyes with a weak zonule as in  pseudoexfoliation and homocystinuria.    Fig. 10.73 Lens-induced pupillary block glaucoma -  dislocated lens incarcerated in the pupil   Dislocation may be into the AC, the zonules may be stretched or  only part of the attachments may be disrupted so that the intact  part acts as a hinge, and the lens may remain fully or partially in  the posterior chamber. Vitreous herniation may be contributory.   A lens fully or partially dislocated into the anterior chamber  will usually be evident (Fig. 10.73). Acute pupillary block will  cause a sudden severe elevation of IOP with associated visual  impairment. Imaging such as ultrasound biomicroscopy may be  diagnostic.   The IOP is initially reduced with osmotic agents, which reduce  vitreous volume. Treatment should be urgent; prolonged lenticu-  locorneal contact, particularly in the presence of high IOP, may  cause permanent endothelial damage.   • Initial treatment. The patient should adopt a supine posture  with the pupil dilated, to attempt to reposition the lens in  the posterior chamber, following which a miotic can be used  with caution. Bilateral laser iridotomy may provide extended  control in some cases, but lens extraction may be necessary.   • Definitive treatment consists of surgical lens extraction; the  approach will be dictated by the clinical situation. An  anterior chamber-, iris- or sclerally fixated IOL will be  necessary.   Although most traumatic hyphaemas (see Ch. 21) are relatively  small (Fig. 10.74), innocuous and transient, IOP elevation may  result from trabecular obstruction by red blood cells or occasion¬  ally from angle closure due to pupillary occlusion by a blood clot.  Severe and prolonged elevation of IOP may cause corneal blood  staining and damage the optic nerve. The size of a hyphaema is a  useful indicator of visual prognosis and risk of complications: if  the entire anterior chamber is occupied by blood, eventual good  vision is achieved in only about one in three eyes, though impair¬  ment is commonly due to injury sustained during the initial insult.  Secondary haemorrhage, often more severe than the primary  bleed, may develop within 3-5 days of the initial injury and is  associated with a poorer visual outcome. Patients with sickle-cell  haemoglobinopathy are at increased risk of complications, espe¬  cially IOP elevation due to trabecular meshwork obstruction by  deformed red cells, and vascular occlusion due to elevated IOP.   o A coagulation abnormality, particularly a  haemoglobinopathy, should be excluded,  o Any current anticoagulant medication should be   discontinued after liaison with a general physician to assess  the risk; NSAIDs should not be used for analgesia. Likewise,  specialist advice should be sought regarding the management  of a patient with a haemoglobinopathy, particularly before  administering high-risk medication (see below).   o Strict bed rest is probably unnecessary, but substantially  limiting activity is prudent, and the patient should  remain in a sitting or semi-upright posture, including  during sleep.   administered, depending on the IOP; CAI are avoided in  sickle haemoglobinopathies if possible. Miotics should  also be avoided as they may increase pupillary block and  disrupt the blood-aqueous barrier, and prostaglandins as  they may promote inflammation. Alpha-agonists can be  useful, but are avoided in small children and sickling  disorders.   o Occasionally a hyperosmotic agent is needed, though as  with CAI and alpha-agonists a high threshold is adopted  in sickle patients.   o Topical steroids should be used since they reduce  inflammation and possibly the risk of secondary  haemorrhage.   o Atropine is recommended by some authorities to achieve  constant mydriasis and reduce the chance of secondary  haemorrhage, but clear evidence is lacking,  o Antifibrinolysis with systemic aminocaproic acid (ACA)  or tranexamic acid or with topical ACA may be  considered under higher-risk circumstances such as  recurrent bleeding.   • Laser photocoagulation of angle bleeding points via a  gonioprism has been described, though gonioscopy should  probably be deferred for 5-6 days post-injury.   • Surgical evacuation of blood is required in around 5%. If a  total hyphaema or persistently intolerable IOP lasts for more  than 5 days surgery should be considered to reduce the risk  of permanent corneal staining (rare) and optic atrophy, and  to prevent the occult development of peripheral anterior  synechiae and chronic secondary glaucoma; a lower  threshold is required in haemoglobinopathy patients (even  moderate pressure elevation can lead to optic atrophy),  patients with prior glaucomatous optic neuropathy and in  young children with a risk of amblyopia. A glaucoma  filtration procedure may be necessary in some cases. A  bleeding point should be cauterized if possible.   • On discharge the patient should be advised to avoid any  activity with a risk of even minor eye trauma for several  weeks; symptoms of a rebleed should prompt immediate  review.   Angle recession involves rupture of the face of the ciliary body, the   portion between the iris root and the scleral spur, due to blunt    trauma. Although a large percentage of eyes with traumatic  hyphaema exhibit some degree of angle recession, glaucoma only  develops in fewer than 10% after 10 years. The rise in IOP is sec¬  ondary to associated trabecular damage rather than from angle  recession itself; but the risk of glaucoma is directly related to the  extent of angle recession.   • Slit lamp examination may show signs of previous blunt  trauma; these may be mild, such as a small sphincter  rupture.   • Gonioscopy may initially reveal irregular widening of the  ciliary body face (Fig. 10.75A). In long-standing cases, the   Fig. 10.75 (A) Angle recession; (B) old angle recession with  hyperpigmentation    cleft may become obscured by fibrosis and the angle may  show hyperpigmentation (Fig. 10.75B).   • Medical treatment is as for other types of secondary  open-angle glaucoma but is frequently unsatisfactory; laser  trabeculoplasty is likely to be of little benefit.   • An artificial filtering shunt or cyclodiode should be  considered if trabeculectomy fails.   Iridocorneal endothelial (ICE) syndrome typically affects one eye  of a middle-aged woman. It consists of the following three clinical  presentations: Chandler syndrome, progressive (also termed  essential) iris atrophy and iris naevus (Cogan-Reese) syndrome.  The pathological basis in all three is an abnormal corneal endothe¬  lial cell layer with a predilection for proliferation and migration  across the anterior chamber angle and onto the surface of the iris,  with subsequent progression to glaucoma (50%) and corneal  decompensation in a substantial proportion of involved eyes.  Glaucoma is due to trabecular obstruction by proliferating tissue  followed by angle closure secondary to contraction. PCR shows  the presence of herpes simplex virus DNA in a substantial percent¬  age of ICE syndrome corneal specimens, suggesting a possible viral  aetiology.   Clear differentiation between the three presentations may be dif¬  ficult; apparent transition from one to another has been reported.  Differentiation depends primarily on iris appearance, but there is  often substantial overlap. Gonioscopically visible changes in some  patients may be subtle despite elevated IOP, particularly in early  disease. The specular microscopic appearance is characteristic.   • Chandler syndrome is the most common clinical  presentation and is characterized by an abnormal corneal  endothelial appearance said to resemble hammered silver  (Fig. 10.76A). It frequently presents with blurred vision and  haloes due to corneal oedema (Fig. 10.76B). Iris atrophy is  absent in about 60% and in the remainder is variable in  severity; corectopia is mild to moderate when present. When  glaucoma occurs it is usually less severe than in the other  two presentations.   • Progressive (essential) iris atrophy is characterized by  severe iris changes including corectopia (pupil malposition -  Fig. 10.77A), pseudopolycoria (supernumerary false pupil -  Fig. 10.77B), ectropion uveae, iris atrophy of varying severity    (Figs 10.77C-E) and broad-based PAS that often extend  anterior to the Schwalbe line (Fig. 10.77F).   • Iris naevus (Cogan-Reese) syndrome is characterized by  either a diffuse naevus that covers the anterior iris, or by iris  nodules (Fig. 10.78). Iris atrophy is absent in 50% of cases  and in the remainder it is usually mild to moderate,  although corectopia may be severe. The appearance may be  mimicked by a diffuse iris melanoma.   • Medical treatment of glaucoma is often ineffective in the  longer term.   Fig. 10.77 Iridocorneal endothelial syndrome. (A) Corectopia; (B) pseudopolycoria; (C) relatively early iris atrophy;  (D) transillumination of the eye in (C); (E) marked iris atrophy; (F) broad peripheral anterior synechiae   (Courtesy of C Barry - figs A, C and D; L MacKeen - fig. F)    • Trabeculectomy with mitomycin C is frequently  unsuccessful; the Ex-Press™ mini-shunt may afford a better  prognosis.   • Glaucoma drainage device or cyclodiode is eventually  required in many cases.   • Corneal treatment. Oedema can be treated with topical  hypertonic saline in early disease and transplantation  later on.    Approximately 5% of eyes with intraocular tumours develop a  secondary elevation of IOP. Potential mechanisms are set out  below:   o Trabecular infiltration by neoplastic cells originating  from an iris melanoma (Fig. 10.79B). Rarely, tumour  seeding from a retinoblastoma may also invade the  trabeculum.   o Melanomalytic glaucoma may occur in some eyes with  iris melanoma; it is due to trabecular blockage by  macrophages that have ingested pigment and tumour  cells, similar to phacolytic glaucoma (Fig. 10.79C).   o Neovascular glaucoma is the most common  mechanism in eyes with choroidal melanoma or  retinoblastoma.   o Anterior displacement of iris-lens diaphragm may occur  in an eye with a ciliary body melanoma or a large tumour  of the posterior segment.   (A) Angle invasion by a solid iris melanoma; (B) melanoma  cells infiltrating the trabeculum; (C) melanomalytic  glaucoma   (Courtesy of J Harry - fig. B; R Curtis - fig. C)   Epithelial ingrowth (downgrowth) is a rare but potentially blind¬  ing complication of anterior segment surgery or trauma, occurring  when conjunctival or corneal epithelial cells migrate through a  wound and proliferate in the anterior segment (Fig. 10.80A). Ele¬  vation of IOP is due to trabecular obstruction by one or more of  an epithelial membrane, secondary synechial angle closure, and  desquamated epithelial and inflammatory cells. The associated  glaucoma can be particularly intractable and the prognosis poor.   • Diffuse epithelialization characterized by a greyish  translucent membrane with a scalloped border that involves  the posterior corneal surface in the area of a surgical or  traumatic wound (Fig. 10.80B).   • Cystic and fibrous proliferative patterns sometimes occur,  and tend to have a better prognosis.   The aim of treatment is the eradication of all invading epithelium  to avoid recurrence.   • Block excision involves the simultaneous excision of  adjacent iris and pars plicata of the ciliary body, together  with all layers of the sclera and cornea in contact with the  lesion. The resultant defect is covered with a tectonic  corneoscleral graft. The area of iris involvement may be  delineated by applying argon laser burns, which will cause  whitening of the affected area.   • Cryotherapy may be applied trans-sclerally to devitalize the  epithelium remaining on the posterior surface of the cornea,  in the angle and on the ciliary body. Intraocular air is used  to insulate other tissues from the effects of the cryotherapy.   • 5-fluorouracil. Favourable results have been reported with a  novel technique using intracameral 5-fluorouracil.   • Glaucoma drainage devices are of value for medically  uncontrolled glaucoma associated with extensive epithelial  ingrowth unsuitable for surgical excision. Antimetabolite-  enhanced trabeculectomy with mini-shunt implantation is  an alternative.    Iridoschisis is a rare condition typically affecting both eyes of an  older patient; glaucoma, particularly angle-closure, is associated  in up to 90%. The mechanism is incompletely understood, but it  has been proposed that in many cases intermittent substantial  elevation of IOP results in iris atrophy, with severity ranging from  stromal atrophy to fibrillar disintegration of the anterior layer;  changes are more marked inferiorly (Fig. 10.81). The anterior   Fig. 10.80 Diffuse epithelial ingrowth. (A) Stratified squamous  epithelium lining the anterior iris surface and filtration  angle; (B) translucent membrane with a scalloped border  involving the posterior corneal surface   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann 2001 - fig. A)   chamber is typically shallow. Gonioscopy commonly shows an  occludable angle, often with PAS. Angle closure is treated if  present, with a laser iridotomy initially.   Primary congenital glaucoma (PCG) is rare, with an incidence of  1:10 000 in many populations; boys are more commonly affected   (Courtesy of R Bates - fig. A; S Chen - fig. B)   in most surveys. Involvement is more often bilateral, but fre¬  quently asymmetrical. It can be classified as follows:   • True congenital glaucoma (40%) in which IOP is elevated  during intrauterine life.   • Juvenile glaucoma, the least common, in which IOP rises  between 3 and 16 years of age.   PCG, by definition unassociated with other major ocular abnor¬  malities, is thought to be caused by impaired aqueous outflow due  to maldevelopment of the anterior chamber angle (trabeculodys-  genesis). It is usually sporadic, but approximately 10% are AR with  variable penetrance. Several genes have been implicated, promi¬  nently CYP1B1. The prognosis is dependent on severity and age at  onset/diagnosis; in true congenital glaucoma, legal blindness is the  outcome in at least 50% of eyes. Secondary infantile glaucoma can  be caused by a range of conditions including tumours such as  retinoblastoma, persistent fetal vasculature (persistent hyperplas¬  tic primary vitreous) and uveitis.   • Presentation usually occurs when an abnormality such as  corneal haze, large (buphthalmos - see below) or  asymmetrical eyes (Fig. 10.82), watering, photophobia or  blepharospasm (Fig. 10.83) is noticed by parents or a health  professional.    • Corneal haze (Fig. 10.84A) is due to diffuse oedema  secondary to raised IOP, or localized oedema due to breaks  in Descemet membrane.   • Buphthalmos (Fig. 10.84B) is a large eye as a result of  stretching due to elevated IOP prior to the age of 3 years.  The thinned sclera often appears blue due to increased  visualization of the underlying uvea. Complications include  myopia and lens subluxation.   • Haab striae (Fig. 10.84C) are curvilinear healed breaks in  Descemet membrane.   • Optic disc cupping in infants may regress once IOP is  normalized. Most normal infants exhibit no apparent cup.   • Evaluation under general anaesthesia is generally required;  intravenous ketamine lowers IOP less than other agents.   o IOP measurement should be performed first, optimally  with more than one method (e.g. Perkins, Tono-Pen,    iCare). It is preferable where possible for this to be  measured in a conscious or sedated child; 10-12 mmHg is  normal.   O Anterior chamber examination with an operating  microscope and/or portable slit lamp.   O Optic disc examination; asymmetry or a cup/disc ratio of  >0.3 is suspicious.   o Corneal diameter measurement; >12 mm prior to the age  of one year is highly suspicious.   o Gonioscopy using a direct goniolens may be normal or  reveal trabeculodysgenesis, vaguely characterized by an  anteriorly located iris insertion and a hypoplastic¬  appearing peripheral iris (Fig. 10.85). An older concept of  a discrete (Barkan) membrane has not been definitively  confirmed.   Fig. 10.84 Congenital glaucoma. (A) Corneal haze; (B) severe buphthalmos, worse in the right eye, which exhibits marked  diffuse corneal oedema; (C) Haab striae; (D) corneal scarring and vascularization   (Courtesy of M Parulekar - fig. A; U Raima - fig. D)    Fig. 10.85 (A) Normal infant angle shows the iris root,  prominent ciliary body band but no discernible scleral spur  and trabeculum; (B) one angle variant in congenital  glaucoma shows the iris root but not the ciliary body band  due to translucent amorphous tissue that obscures the  trabeculum   Management is essentially surgical; angle surgery alone is success¬  ful in 80-90%. Medication may be used as temporary or supple¬  mentary therapy; caution is required with selection of medication  in young children, as most are relatively contraindicated.   incision is made at the midpoint of the trabecular meshwork  (Fig. 10.86).    • Trabeculotomy may be necessary if corneal clouding  prevents an adequate view of the angle, and is also an option  when repeated goniotomy has failed. A partial-thickness  scleral flap is created (Fig. 10.87A), and a trabeculotome (Fig.  10.87B) inserted into the Schlemm canal and rotated into the  anterior chamber.   • Other procedures when angle surgery fails include  trabeculectomy, tube shunt implantation and ciliary body  ablative procedures.   • Monitoring of IOP, corneal diameter and other parameters  is required long term.   o Rubella keratitis; congenital rubella is also associated with  congenital glaucoma.   o Delayed/failed canalization of the nasolacrimal duct,  o Lacrimation secondary to ocular irritation, e.g.  conjunctivitis, aberrant eyelashes, entropion.   Posterior embryotoxon refers to a prominent and anteriorly  displaced Schwalbe line, seen as a thin grey-white arcuate ridge  adjacent to the limbus on the inner surface of the cornea (Fig.  10.88 A). It is an innocuous isolated finding in up to 15% of  the general population, but is one of the features of Axenfeld-  Rieger anomaly; it is seen as well in the multisystem genetic dis¬  order Alagille syndrome, in which optic disc drusen are also  common.   Axenfeld-Rieger syndrome is the umbrella term for a spectrum of  disorders featuring bilateral developmental ocular anomalies:  Axenfeld anomaly, Rieger anomaly and Rieger syndrome. It is  caused by defective neural crest cell-related processes during fetal  development; an abnormal endothelial cell membrane has been  identified on anterior segment structures in some patients. The  key implication of the syndrome is a 50% risk of glaucoma.  Associated variants in several different genes have been found,  including PITX2, PAX 6 , FOXCi and RIEG2 ; that is, different  genetic abnormalities can give a similar clinical picture. Cases may  be sporadic, but a family history is common, when inheritance is  autosomal dominant with variable expressivity but very high pen¬  etrance. There is no gender predilection.   • Axenfeld anomaly is characterized by posterior  embryotoxon (see Fig. 10.88 A) with attached strands of  peripheral iris, the latter best viewed with gonioscopy (Figs  10.88B and C).   • Rieger anomaly often manifests with an anterior segment  appearance similar to that of iridocorneal endothelial (ICE)  syndrome.   o Posterior embryotoxon,  o Iris stromal hypoplasia (Figs 10.89A and B).  o Ectropion uveae (Fig. 10.89C).   (B) and (C) gonioscopy showing strands of peripheral iris  tissue extending to the cornea    Fig. 10.89 Rieger anomaly and syndrome. (A) Mild iris stromal hypoplasia; (B) severe iris stromal hypoplasia; (C) ectropion  uveae; (D) corectopia and full-thickness iris defects - pseudopolycoria; (E) peripheral anterior synechiae; (F) iris adhesion to  anterior cornea   • Gonioscopy in mild cases shows the Axenfeld anomaly. In  severe cases, broad leaves of iris adhere to the cornea  anterior to the Schwalbe line (Figs 10.89E and F).   • Glaucoma develops in about 50%, usually during childhood  or early adulthood. Surgical management is often necessary.   • Rieger syndrome is characterized by the Rieger anomaly  together with extraocular malformations that, as with the  ocular features, are caused by defective neural crest cell-  related tissue development (Fig. 10.90):   o Facial anomalies: maxillary hypoplasia, broad nasal  bridge, telecanthus and hypertelorism,  o Other anomalies include redundant paraumbilical skin  and hypospadias. Hearing loss, hydrocephalus, cardiac  and renal anomalies and congenital hip dislocation are  rare.   Peters anomaly is a rare but often severe condition that is bilateral  in more than half of cases. It is the result of defective neural crest  cell migration during fetal development. Manifestations range  from mild to severe. Most cases are sporadic, although autosomal  recessive inheritance has been described.   Peters type I affects the cornea alone, type II shows both corneal  and lens abnormalities.    • Posterior corneal defect involving the posterior stroma,  Descemet membrane and endothelium with or without  iridocorneal (Fig. 10.91B) or lenticulocorneal (Fig. 10.91C)  adhesions.   • Glaucoma occurs in about 50% due to associated angle  anomaly. Onset is usually in infancy but occasionally in  childhood or later. The prognosis tends to be worse than in  primary congenital glaucoma.   • Systemic associations including craniofacial and central  nervous system anomalies have been reported. ‘Peters plus’  syndrome includes a particular constellation of systemic  abnormalities.   Aniridia (AN) is a rare bilateral condition that may have life-  threatening associations. It occurs as a result of abnormal neuro¬  ectodermal development secondary to a mutation in the PAX 6  gene. PAX 6 is adjacent to gene WTi , mutation of which predis¬  poses to Wilms tumour.   • Autosomal dominant aniridia accounts for about two-thirds  of cases and has no systemic implications. Penetrance is  complete (all patients with the genotype will have the  phenotype) but expressivity (severity) is variable.   • Sporadic, including WARG, previously known as Miller,  syndrome (Wilms tumour, Aniridia, mental Retardation,  Genitourinary abnormalities), includes about a third of  patients. Children with sporadic aniridia have about a 30%  chance of developing Wilms tumour.   • Gillespie syndrome accounts for only about 1% of  cases. Inheritance is AR but is not caused by PAX 6  mutations. Cerebellar ataxia and mental handicap are  features.   All patients with sporadic aniridia should have abdominal ultra¬  sonography every 3 months until 5 years of age, every 6 months  until 10 years of age and annually until 16 years of age to detect  the development of Wilms tumour or until molecular genetic  analysis confirms the absence of a WTi mutation.   • Presentation is typically at birth with nystagmus and  photophobia. The parents may have noticed the absence of  irides or apparently large pupils.   • Aniridia is variable in severity, ranging from minimal,  detectable only by retroillumination, to total absence (Figs  10.92A and B).   o Tear film instability, dry eye and epithelial defects are  common.   o Limbal stem cell deficiency may result in  ‘conjunctivalization’ of the peripheral cornea.    o Total corneal central stromal scarring and vascularization  may occur in end-stage disease.   • Lens changes can include cataract (Fig. 10.92C) and  subluxation (usually superiorly - Fig. 10.92D).   • Gonioscopy even in eyes with apparently total aniridia  usually shows a hypoplastic or rudimentary frill of iris tissue  (Fig. 10.93A).   • Glaucoma (75%) usually presents in late childhood or  adolescence. It is caused by synechial angle closure  secondary to the contraction of rudimentary iris tissue  (Fig. 10.93B). Treatment is difficult and the prognosis  guarded.   o Goniotomy may be helpful if performed before the  development of irreversible angle closure,  o Trabeculectomy or combined trabeculectomy-   trabeculotomy may be successful; an antimetabolite and a  mini-shunt may be utilized,  o Glaucoma drainage devices may be effective,  o Diode laser cycloablation may be necessary if other  modalities fail.   • Painted contact lenses may be used to create an artificial  pupil and improve both vision and cosmesis; simple  tinted lenses are an alternative; both may improve  nystagmus.   • Cataract surgery is often required; a tinted artificial lens  implant may be used to try to improve photophobia.   Trauma to the corneal limbus should be minimized in order  to preserve stem cell function.   • Prosthetic iris implantation has been described in  pseudophakic aniridic eyes, but may be complicated by, or  worsen, glaucoma.   • Limbal stem cell transplantation with or without  keratoplasty may be required.   Fig. 10.92 Aniridia. (A) Partial; (B) total; (C) transillumination of pseudophakic eye showing silhouetted ciliary processes;  (D) superior subluxation of cataractous lens; (E) foveal hypoplasia    Fig. 10.93 Gonioscopy in aniridia. (A) Open angle showing remnants of the iris root; (B) angle closed synechially by iris  rudiments   Fig. 10.94 Glaucoma in Sturge-Weber syndrome. (A) Bilateral  naevus flammeus and buphthalmos; (B) episcleral  haemangioma   Sturge-Weber syndrome (encephalotrigeminal angiomatosis) is a  congenital, sporadic phacomatosis (see Ch. 1). Glaucoma ipsilat-  eral to the facial haemangioma develops in about 30%, and in 60%  of these IOP elevation occurs before the age of 2 years and may  result in buphthalmos (Fig. 10.94A). In the remainder, glaucoma  may develop at any time from infancy to adulthood. The patho¬  genesis is uncertain; putative mechanisms include trabeculodys-  genesis in infants and raised episcleral venous pressure associated  with arteriovenous communication in an episcleral haemangioma  (Fig. 10.94B) in older patients.    • Combined trabeculotomy-trabeculectomy gives good  results in early-onset cases, but carries a relatively high risk  of choroidal effusion and suprachoroidal haemorrhage;  other surgical options may be utilized.   Neurofibromatosis is a disorder that primarily affects cell growth  of neural tissues. Inheritance is AD with irregular penetrance and  variable expressivity (see Ch. 19). Glaucoma is relatively rare and,  when present, usually unilateral and congenital. About 50% of  patients with glaucoma have an ipsilateral plexiform neurofi¬  broma of the upper eyelid, or facial hemiatrophy (Fig. 10.95).  Various mechanisms have been identified, including congenital  angle anomaly.   SYMPATHETIC OPHTHALMITIS 416  LENS-INDUCED UVEITIS 419  SARCOIDOSIS 420  BEHQET DISEASE 424   Cytomegalovirus retinitis 439  Progressive retinal necrosis 439  Acute retinal necrosis 440  Herpes simplex anterior uveitis 442  Varicella zoster virus (VZV) anterior  uveitis 443   Presumed ocular histoplasmosis  syndrome (POHS) 444  Pneumocystis choroiditis 444  Cryptococcal choroiditis 444  Endogenous Candida  endophthalmitis 445  Aspergillus endophthalmitis 447  Coccidioidomycosis 447   Acute idiopathic blind spot enlargement  syndrome (AIBSE) 456  Acute posterior multifocal placoid  pigment epitheliopathy (APMPPE) 456  Serpiginous choroidopathy 457  Relentless placoid chorioretinitis  (RPC) 458   Punctate inner choroidopathy (PIC) 459  Multifocal choroiditis and panuveitis  (MFC, MCP) 459   Progressive subretinal fibrosis and uveitis  syndrome (SFU) 460  Birdshot retinochoroidopathy 461  Acute retinal pigment epitheliitis  (ARPE) 463   (Unilateral) acute idiopathic  maculopathy (AIM) 463  Acute multifocal retinitis 463  Solitary idiopathic choroiditis (SIC) 463  Frosted branch angiitis (FBA) 465  Idiopathic retinal vasculitis, aneurysms  and neuroretinitis syndrome  (IRVAN) 465    The Standardization of Uveitis Nomenclature (SUN) Working  Group guidance on uveitis terminology, endorsed by the Interna¬  tional Uveitis Study Group (IUSG), categorizes uveitis anatomi¬  cally (Fig. 11.1):   • Anterior: the anterior chamber is the primary site of  inflammation.   An IUSG clinical classification based on aetiology is also in use:   The SUN Working Group guidance includes the following  descriptions relating to the timing of inflammatory activity:   • Clinical course: acute (of sudden onset and limited  duration), recurrent (repeated episodes separated by  untreated inactive periods), or chronic (persistent duration,  with relapse less than 3 months after discontinuation of  treatment). Remission is defined as inactivity (no visible  cells) for 3 months or longer.   HLA-B27 positivity - around 20%  of AAU - with or without  manifestations of HLA-B27-  related systemic disease  (see text)   Juvenile idiopathic arthritis  Sarcoidosis  Behget disease  Tubulointerstitial nephritis and  uveitis syndrome  Systemic lupus erythematosus  Multiple sclerosis   Anterior uveitis is inflammation involving the anterior uveal  tract - the iris and the anterior part (pars plicata) of the ciliary    body - and is the most common form of uveitis. Iritis refers  to inflammation primarily involving the iris, and iridocyclitis  to involvement of both the iris and anterior ciliary body; in prac¬  tice these are interchangeable as they cannot be distinguished  clinically.   Acute anterior uveitis (AAU) is the most common presentation,  of which HLA-B27-related and idiopathic forms make up the  largest proportion. Aetiology in these cases is uncertain, but may  involve cross-reactivity with particular microbial antigens in  genetically predisposed individuals. AAU can be a feature of a wide  variety of ocular conditions such as trauma (including surgery),  lens-related inflammation and herpes simplex infection, or can be  secondary to inflammation elsewhere in the eye, such as bacterial  keratitis and scleritis. AAU can also be the presenting clinical  scenario, without accompanying intermediate or posterior uveitis,  in a range of systemic conditions including chronic inflammatory  disorders such as sarcoidosis.   Chronic anterior uveitis (CAU) is less common than AAU. It is  more commonly bilateral, and associated systemic disease is more  likely. Granulomatous inflammatory signs (see below) are often  present.   Surveys of systemic associations of anterior uveitis vary in their  findings; Table 11.1 lists important possibilities, but is not  exhaustive.   The prognosis is usually good in most idiopathic and HLA-B27-  related AAU provided management is adequate. Outcomes are  more variable in CAU and in cases where there is an underlying  ocular or systemic disorder.   • Symptoms in AAU consist of the rapid onset of unilateral  pain, photophobia, redness and watery discharge, sometimes  preceded by mild ocular discomfort for a few days. Blurring  of vision is related to severity. As recurrent disease is very  common, especially with the idiopathic and HLA-B27-  related types, there will often be a history of previous similar  episodes. CAU may be of insidious or acute onset, and can  be asymptomatic until the development of complications  such as cataract.   • Visual acuity is variably impaired depending on the severity  of inflammation and the presence of complications. It is  frequently only mildly reduced in AAU.   • ‘Ciliary injection’ (perilimbal injection, ciliary flush or just  ‘injection’) is circumcorneal conjunctival hyperaemia with a  violaceous (purplish) hue due to involvement of deeper  blood vessels (Fig. 11.2A), and is typically seen in anterior  uveitis of acute onset. Ciliary injection is characteristically  absent in some forms of CAU, and occasionally AAU.   • Miosis due to pupillary sphincter spasm (Fig. 11.2B)  predisposes to the formation of posterior synechiae (see  below).   Table 11.2 Standardization of Uveitis Nomenclature  (SUN) Working Group grading of anterior chamber cells  (1 mm by 1 mm slit beam)    • Anterior chamber cells (Fig. 11.2C) are a dependable  indicator of inflammatory activity. Grading (SUN Working  Group) is performed by estimating the number of cells in a  1 mm by 1 mm slit beam field, employing adequate light  intensity and magnification (Table 11.2). This must be  performed before pupillary dilatation, which can lead to  shedding of pigment cells into the aqueous. Inflammatory  cells are commonly also seen in the anterior vitreous.   • Hypopyon (Fig. 11.2D) refers to a whitish purulent exudate  composed of myriad inflammatory cells in the inferior part    Fig. 11.2 Signs of acute anterior uveitis. (A) Ciliary injection; (B) miosis; (C) anterior chamber cells in mild anterior uveitis;  (D) hypopyon    of the anterior chamber (AC), forming a horizontal level  under the influence of gravity. Hypopyon is common in  HLA-B27-associated AAU (see below), when a high fibrin  content makes it immobile and slow to absorb. In patients  with Behcet disease the hypopyon contains minimal fibrin  and so characteristically shifts according to the patient’s  head position.    • Keratic precipitates (KP) are deposits on the corneal  endothelium (Fig. 11.3A) composed of inflammatory cells  such as lymphocytes, plasma cells and macrophages (Fig.  11.3B). They are usually concentrated inferiorly, often in a  triangular pattern with the apex pointing up (Arlt triangle)  under the influence of gravity and aqueous convection  currents; a notable exception is Fuchs uveitis syndrome   Fig. 11.3 Keratic precipitates (KP). (A) Highly magnified view of fresh KP in early anterior uveitis; (B) histology showing typical  aggregate of inflammatory cells on the corneal endothelium; (C) large ‘mutton fat’ keratic precipitates; (D) stellate KPs in  Fuchs uveitis syndrome; (E) old pigmented granulomatous KP; (F) endothelial cellular ‘dusting’ and early KP formation   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 - fig. B)    (FUS), in which they are diffusely distributed. Their  characteristics indicate the probable type of uveitis: typically  smaller in the non-granulomatous inflammation typical of  AAU, and medium to large in (classically chronic)  granulomatous inflammation in which cell types may  include epithelioid and multinucleated cells. Large greasy-  appearing granulomatous KP are said to have a ‘mutton fat’  appearance (Fig. 11.3C). KP are small to medium and  adopt a star-shaped (‘stellate’ - Fig. 11.3D) or filamentous  morphology in FUS. KP usually resolve as acute  inflammation subsides: long-standing non-granulomatous  KP may become pigmented; granulomatous KP may become  pigmented (Fig. 11.3E) and/or assume a ‘ground glass’  appearance. Endothelial dusting by numerous individual  cells precedes the formation of true KP aggregates  (Fig. 11.3F).   • Aqueous flare is haziness of the normally clear fluid in the  anterior chamber, reflecting the presence of protein due to  breakdown of the blood-aqueous barrier. Based on work in  children with juvenile idiopathic arthritis-associated CAU, it  is now thought that in most or all patients the presence of  flare indicates active inflammation with a resultant higher  risk of complications over the longer term. Flare may be  graded clinically using a slit lamp to assess the degree of  interference with visualization of iris and lens (Table 11.3).  When available, laser flare photometry gives greater  objectivity.   • Fibrinous exudate in the anterior chamber (Fig. 11.4) is  common in severe AAU, and as with hypopyon is often seen  with HLA-B27-related inflammation.   • Iris nodules: Koeppe nodules are located on the pupillary  margin (Fig. 11.5A), and may be the site of posterior  synechiae formation (see below). They can occur in both  granulomatous and non-granulomatous anterior uveitis.  Busacca nodules involve the iris stroma (Figs 11.5B and C)  and are a feature of granulomatous uveitis. Yellowish  nodules can develop from dilated iris vessels (roseolae) in  syphilitic uveitis. Iris ‘pearls’ may be seen in lepromatous  chronic anterior uveitis. Iris crystals (Russell bodies),  thought to consist of immunoglobulin deposits, are a rare  finding in some cases of chronic uveitis (Fig. 11.5D),  including FUS.   • Posterior synechiae (PS) are inflammatory adhesions  between the pupil margin and the anterior lens capsule (Figs  11.6A and B), and may be particularly likely to form at the    location of a Koeppe nodule. They can develop rapidly, and  to prevent their formation initial prophylaxis with a  mydriatic agent is routine in all but very mild AAU. Once  established, every attempt must be made to break PS (Fig.   • Iris atrophy may offer useful diagnostic clues. Diffuse  stromal atrophy is seen in FUS, and patchy or sectoral  atrophy can occur in herpetic uveitis (Fig. 11.7); both  patterns may be seen in both simplex and zoster-related  inflammation, though the latter is said to more commonly  give a sectoral pattern.   • Heterochromia iridis refers to a difference in colour  between the iris of the two eyes, best seen in daylight. In the  context of uveitis, heterochromia characteristically occurs in  FUS; see also Table 11.6.   • Iris neovascularization (rubeosis iridis) can occur,  particularly in chronic inflammation. The process tends to  be less acute than with a primary vascular cause such as  central retinal vein occlusion. Abnormal iris vessels are very  common in FUS, but do not cause synechial angle closure.  Iris neovascularization may also occur in posterior uveitis,  particularly when retinal perfusion is compromised. New iris  vessels may be difficult to differentiate from dilated normal  vessels (sometimes called ‘pseudorubeosis’); normal vessels  course radially in contrast to the irregular distribution of  neovascularization. Fluorescein angiography may show  leakage from new vessels, though this can also be seen with  dilated normal vessels, particularly in the presence of active  inflammation.   • Intraocular pressure (IOP) may be reduced as the result of  impairment of aqueous secretion by the ciliary epithelium,  or elevated due to a variety of mechanisms (see  ‘Inflammatory glaucoma’ in Chapter 10), including  therapeutic steroids.   • Posterior segment examination should always be performed  to detect a masquerading cause of anterior uveitis (e.g.    Fig. 11.5 Iris nodules in anterior uveitis. (A) Koeppe nodules in Fuchs uveitis syndrome; (B) Busacca and Koeppe nodules;  (C) very large nodule in sarcoid uveitis; (D) iris crystals (Russell bodies) in chronic syphilitic uveitis   (Courtesy of C Barry - fig. A; C. Pavesio - figs B and C; S Chen - fig. D)    retinal detachment, tumour), primary intermediate or  posterior segment inflammation, and complications of  anterior uveitis such as cystoid macular oedema.   Investigations are often negative, with no clear underlying cause  determined in many patients. Rather than performing a battery of  screening tests, investigation is tailored to each patient, directed  by clinical features. Sometimes a likely cause may be obvious,  such as severe anterior uveitis following intraocular surgery  when endophthalmitis will lead the differential diagnosis list. In  most cases, a careful review for systemic symptoms is essential  to detect any clues to underlying disease, with referral to a special¬  ist physician for further assessment where appropriate. Many  associations of uveitis can present with a wide range of systemic  features.   • A single episode of unilateral mild/moderate (no hypopyon)  non-granulomatous AAU with no ocular or systemic  suggestion of underlying disease.    • Typical clinical features of a specific entity for which  investigation is not usually indicated (e.g. FUS).   • A systemic diagnosis compatible with the clinical features  (e.g. sarcoidosis) has already been confirmed.   • Anterior uveitis that is persistent, chronic or resistant to  treatment.   • Granulomatous inflammatory signs (note that  granulomatous conditions may give non-granulomatous  AAU).   • Some authorities advocate routine syphilis serology for all  uveitis patients at first presentation; a history of high-risk  sexual behaviour in particular must prompt this.   • Repeating targeted previously negative investigations several  years later is sometimes fruitful.    Fig. 11.6 Posterior synechiae. (A) Adhesions in active acute  anterior uveitis; (B) extensive synechiae and pigment on  the lens following severe acute anterior uveitis; (C) recently  broken synechiae in a patient with HLA-B27-associated  acute anterior uveitis   • HLA tissue typing (HLA-B27). The major histocompatibility  complex (MHC) is a group of genes involved in white  cell-antigen interaction and other immune functions,  including the encoding of cell surface glycoproteins. In  humans the MHC, found on chromosome 6, is called the   Fig. 11.7 Extensive iris atrophy following herpes zoster  ophthalmicus - predominantly sectoral pattern   human leukocyte antigen (HLA) system. HLA typing is used  to determine organ transplantation compatibility and can  also indicate predisposition to particular diseases. It has  conventionally been performed by serological antigen  identification, but increasingly involves analysis of DNA.  HLA-B27 is a common (e.g. 6-8% of Caucasians in the USA,  0.5% of patients of Japanese ethnic origin) cell surface  protein that presents peptides to T cells. The phenotype has  a very strong association with acute anterior uveitis,  ankylosing spondylitis and some other inflammatory  conditions such as reactive arthritis (Reiter syndrome),  psoriatic arthritis and arthritis in inflammatory bowel  disease. It is present in 50% of patients with AAU who are  otherwise fit and well, and 90% of patients with AAU who  have an associated spondyloarthropathy, notably ankylosing  spondylitis. Many HLA-B27 subtypes have been identified  and their significance is subject to ongoing investigation.  HLA types associated with ocular inflammatory disease are  listed in Table 11.4. HLA-B27 testing should be performed in  any adult or child with recurrent or chronic non¬  granulomatous anterior uveitis.   o Treponemal antibody tests such as the ELISA (enzyme-  linked immunosorbent assay) are highly sensitive and  specific, but take around 3 months to become positive.    o Non-specific titratable cardiolipin antibody tests such as  the rapid plasma reagin (RPR) or venereal disease  research laboratory (VDRL) are more commonly positive  in early infection, and are used to help monitor disease  activity; they become negative over time, typically in  treated disease. False-positive results can occur,  o Both categories of test should be performed when  screening for ocular syphilis.   o Clinical features suggesting a diagnosis of syphilis should  prompt urgent referral to a physician specializing in  infectious or sexually transmitted diseases.   • Serum angiotensin-converting enzyme (ACE): a non¬  specific test that indicates the presence of a granulomatous  disease such as sarcoidosis, tuberculosis and leprosy.  Elevation occurs in up to 80% of patients with acute  sarcoidosis but may be normal during remissions. In  children serum ACE levels tend to be higher and  diagnostically less useful. Vigorous exercise can elevate ACE.   • Lysozyme is a group of enzymes found in polymorphonuclear  neutrophils and numerous secretions including tears. It has a  strong antibacterial action, mediating breakdown of the  bacterial cell wall. Serum lysozyme assay is generally slightly  less sensitive and specific than serum ACE in the diagnosis of  sarcoidosis, but performing both tests may increase sensitivity  and specificity.   • Erythrocyte sedimentation rate (ESR) and C-reactive  protein (CRP): acute-phase reactants that are probably of  limited value, but may be elevated in a range of systemic  inflammatory disorders.   • Complete blood count: leukocytosis may raise suspicion of  infection and, exceptionally, haematological malignancy.  Eosinophilia may occur in parasitic infection.   • Lyme disease: serology may be considered, particularly in  endemic areas. Serology for other infectious diseases such as  brucellosis and leptospirosis can be requested if relevant  risk factors are present (e.g. endemic region).   • Antinuclear antibody (ANA): limited use, except in  children. In those with juvenile idiopathic arthritis (JIA) its  presence is associated with a higher risk of CAU; cases of  possible subclinical JIA have been reported in ANA-positive  children with CAU.   • Antineutrophil cytoplasmic antibody (ANCA): limited use  in anterior uveitis unless associated with scleritis and/or  peripheral ulcerative keratitis, when cytoplasmic ANCA  (c-ANCA) testing should be considered as evidence of  Wegener granulomatosis.   • Interferon-gamma release assay (e.g. QuantiFERON-TB  Gold™) blood test for tuberculosis.   • HIV serology: indicated for selected patients, usually those  in whom an opportunistic infection has been diagnosed or is  suspected.   • Sacroiliac joint X-ray may show evidence of sacroiliitis in  ankylosing spondylitis and other seronegative  spondyloarthropathies.   • Chest X-ray may show evidence of sarcoidosis or  tuberculosis; a high level of suspicion for both of these    treatable conditions (as well as syphilis) should always be  adopted, particularly if inflammation is granulomatous.   o B-scan ultrasonography, if the posterior segment view is  compromised by very small pupils or opaque media,  o Optical coherence tomography (OCT) may reveal   posterior segment complications such as cystoid macular  oedema and epiretinal membrane,  o Fundus autofluorescence (FAF) may demonstrate  suspected posterior segment pathology as the lesions of  several inflammatory conditions, such as multiple  evanescent white dot syndrome (MEWDS), which may  give mild anterior chamber inflammation, are often  shown more effectively than on clinical examination,  o Fluorescein angiography (FA) is useful in some cases of  anterior uveitis such as the confirmation or exclusion of  suspected posterior segment pathology, e.g. vasculitis,  white dot syndromes, or identifying macular ischaemia as  the cause of reduced vision if no macular abnormality is  visible on OCT.   indicated in anterior uveitis, but might be used to look  for subtle associated choroidal pathology,  o Ultrasound biomicroscopy (UBM) is particularly  indicated in cases of hypotony, and may demonstrate  pathology such as subtle choroidal effusion, cyclodialysis  cleft and cyclitic membrane.   • Aqueous tap: historically rarely performed in anterior  uveitis, but viral causes are now recognized as being more  frequent than previously realized. Herpesviruses (including  cytomegalovirus) and rubella in particular should be  considered in clinically suspicious cases, especially  unexplained hypertensive uveitis and cases relatively  unresponsive to topical steroids. An aqueous humour  sample may be sent for polymerase chain reaction (PCR)  analysis for evidence of viral genetic material, and for  microscopy, culture and antibody assay; PCR may also help  to exclude propionibacter infection in chronically inflamed  pseudophakic eyes.   • Vitreous biopsy tends to be confined to the investigation of  obscure posterior segment inflammation and suspected  infectious endophthalmitis.   • Conjunctival biopsy: sampling of tissue such as a suspected  granuloma or infiltrative lesion is occasionally indicated.   • Referral to a specialist physician with resultant further  investigation. This is vital when systemic disease is  suspected. For instance, if respiratory symptoms are present,  a chest physician may arrange additional testing such as a  high resolution computed tomography (CT) chest scan, a  whole-body gallium scan (sarcoidosis), a purified protein  derivative skin test for tuberculosis (negative test is a  diagnostic indicator in sarcoidosis), and bronchoscopy with  lavage/biopsy. Similarly neurological referral may lead to a  cranial magnetic resonance imaging (MRI) and lumbar  puncture, and gastroenterological referral to endoscopy.   For patients with a treatable cause of inflammation such as an  infection, specific treatment (see individual topics) is given either  instead of or in addition to the general anti-inflammatory meas¬  ures discussed below. Review frequency is set according to the  severity and chronicity of inflammation; patients with severe  inflammation may need to be seen within a day or two of initiating  treatment. Those with mild recurrent idiopathic AAU may not  need to be seen for several weeks after treatment is commenced.  • Topical steroids   o Prednisolone 1% or dexamethasone 0.1% is commonly  utilized as a first choice. Other preparations, of varying  availability geographically, include difluprednate 0.05%  (may be administered at a lower frequency), loteprednol  etabonate 0.2% and 0.5% (moderate to marked potency  but a lower tendency to elevate IOP), betamethasone,  prednisolone 0.5%, fluorometholone and rimexolone; the  latter three are of moderate to lower potency. The  selection of topical steroid preparation can be modified  according to severity and other factors such as a known  tendency to IOP elevation. Steroid ointment (e.g.  betamethasone) may be instilled at bedtime to  supplement the drops. Additional anti-inflammatory  treatment (see below) is necessary in some cases.   o Treatment of AAU initially involves instillation at a  frequency appropriate to the severity of inflammation,  typically starting with one drop hourly in moderate to  severe cases. Once the inflammation is controlled the  instillation frequency should be carefully tapered; a  commonly adopted regimen might consist of:   • once a day for 1 week and stop; treatment is often  discontinued by 5-6 weeks.   Periodic review is undertaken as appropriate during  the treatment course, with further assessment a week or  two after cessation, following which the patient can be  discharged but cautioned to re-attend urgently should  symptoms recur.   o Treatment of CAU is generally targeted at complete  suppression of inflammation, with no anterior chamber  cellular activity or flare - the latter is now thought to be  an indicator of active inflammation in most or all cases.  Even low-grade ongoing activity is associated with a  greater incidence of complications that outweighs the risk  of complications from treatment. Exacerbations are  initially treated in the same way as AAU, though with  more gradual tapering and typically a maintenance  regimen; Fuchs uveitis syndrome is an exception to this  approach.   o Common complications of topical steroids include  transient elevation of IOP in susceptible individuals    (‘steroid responders’); long-term treatment may lead to  permanent IOP elevation with glaucomatous damage.  Cataract can be induced, but is less common than with  systemic steroid administration; the risk increases with  dose and duration of therapy. Corneal complications are  uncommon; they include secondary infection with  bacteria and fungi, recrudescence of herpes simplex  keratitis, and corneal melting. Systemic side effects are  rare with topical steroids, but may occur following  prolonged administration, particularly in children, in  whom measures to reduce systemic absorption such as  medial canthal pressure and blotting away of overspill  from the eyelids following instillation should be  discussed.   • Cycloplegic agents. These are used in AAU and in  exacerbations of CAU to prevent the formation of posterior  synechiae (PS), to break down recently formed synechiae  and to promote comfort by relieving spasm of the pupillary  and ciliary muscle. Commonly used anticholinergic agents in  order of increasing potency and duration of action include  cyclopentolate (duration 12-24 hours), homatropine and  atropine (10-14 days). In the acute stage, phenylephrine 2.5%  or 10% may be used to supplement anticholinergics and  break PS. In mild or chronic anterior uveitis, a cycloplegic  can be instilled at bedtime to prevent difficulties with  accommodation during the day. In children, care should be  taken to avoid systemic toxicity; a range of systemic adverse  effects have occurred including seizures. Prolonged  uniocular cycloplegia may induce amblyopia in the  susceptible age group.   • Mydricaine® No. 2. This is a preparation containing  adrenaline and atropine that is used to try to break fresh PS  when drops are ineffective; it also contains local anaesthetic  to improve comfort. Constituent quantities vary according  to manufacturer but 0.3 ml containing 0.12 mg adrenaline,   1 mg atropine and 6 mg procaine is typical. It is usually  administered by subconjunctival injection; division between  the four conjunctival quadrants may enhance the effect. An  alternative to injection is insertion of a cotton pledget  soaked in Mydricaine into the superior and inferior fornices  for 5 minutes. Serious cardiovascular events have been  reported following injection (a transient sinus tachycardia is  common), and the patient should be monitored after  injection. Mydricaine No. 1 is a paediatric version that may  also be effective in adults.   • Tissue plasminogen activator (TPA). In severe fibrinous  anterior uveitis 12.5-25 pg of TPA in 0.1 ml injected into the  anterior chamber (intracamerally) with a 30-gauge needle  under topical anaesthesia will dissolve dense fibrinous  exudate and may break down recently formed PS. Antiseptic  precautions similar to those for intravitreal injection should  be taken.   • Subconjunctival steroid can be administered in severe cases  or to patients in whom poor compliance is likely. For  example, betamethasone sodium phosphate solution (4 mg  in 1 ml) can be given alone or in a combined preparation    with betamethasone acetate suspension for a sustained effect  (e.g. Celestone, 6 mg in 1 ml).   • Regional steroid injection. The use of an inferior approach  (‘orbital floor’) or posterior sub-Tenon (Fig. 11.8) injection  of depot steroid preparations (e.g. triamcinolone acetonide,  methylprednisolone acetate) is common in the treatment of  posterior segment inflammation, but is generally reserved in  anterior uveitis patients for the treatment of cases  complicated by cystoid macular oedema (CMO), and for  patients noncompliant with topical administration.  Periocular injections may also be administered at the time of  surgery, and may rarely be used to supplement systemic  therapy or when systemic steroids are contraindicated. The  peak action is at about four weeks, with a maximum  duration of action of around 3 months. Complications  include subconjunctival haemorrhage, globe penetration,  refractory elevation of IOP (up to 25%), cataract, ptosis,  eyelid haemorrhage, eyelid ischaemic necrosis, retrobulbar  haemorrhage, subdermal fat atrophy, extraocular muscle  paresis, optic nerve injury, retinal and choroidal vascular  occlusion and cutaneous hypopigmentation; systemic  adverse effects are rare but can occur. Table 11.5 gives  injection procedures; there is no clear evidence of the  superiority of one route over the other, but advocates  suggest there may be a lower risk of ocular perforation, of  raised IOP and of ptosis with the orbital floor approach.  Utilizing a plastic intravenous cannula via a superior  sub-Tenon route has been described and is thought to offer   • Intraocular steroids. Intravitreal triamcinolone acetonide  (4 mg in 0.1 ml, i.e. one-tenth of the orbital dose) is  occasionally used in anterior uveitis for CMO unresponsive  to other forms of therapy (see Fig. 13.34E), and rarely may be  considered at the time of intraocular surgery in high risk  anterior uveitis patients. Complications include elevation of  IOP, cataract, endophthalmitis (sterile or infectious),   Fig. 11.9 Pseudohypopyon formed by crystalline steroid  following intravitreal triamcinolone injection    haemorrhage, retinal detachment and pseudohypopyon  (Fig. 11.9). Slow-release intravitreal implants may  occasionally be indicated.   • Systemic steroids are very rarely required for anterior  uveitis but may be needed where the response to less  aggressive treatment is inadequate. They are sometimes  given as a short course prior to intraocular surgery as  prophylaxis against worsening inflammation, having the  advantage of rapid cessation of effect in comparison with  depot peri- or intraocular steroid injection, but have major  potential adverse effects.   • Non-steroidal anti-inflammatory drugs (NSAIDs) such as  naproxen and tolmetin may be effective in CAU and can be  used long-term under appropriate specialist physician  supervision.   • Antimetabolites such as methotrexate are generally not  required in the treatment of anterior uveitis, though may be  necessary in exceptional patients such as juvenile idiopathic  arthritis-associated CAU when other measures fail to control  inflammation, or as a steroid-sparing measure.    The spondyloarthropathies are a group of disorders featuring  HLA-B27 positivity and enthesitis as common factors. There is  often a family history of one or more of the group, which com¬  prises ankylosing spondylitis, undifferentiated spondyloarthro¬  pathy, psoriatic arthritis, reactive arthritis (Reiter syndrome) and  spondyloarthropathy with inflammatory bowel disease (ulcerative  colitis and Crohn disease). They are often referred to as seronega¬  tive spondyloarthropathies, in that rheumatoid factor is not  present and the pathophysiological basis differs. The American  Uveitis Society has recently endorsed the use of biological blockers  such as infliximab for second-line systemic immunosuppression  in vision-threatening chronic uveitis.    Table 11.5 Procedure for inferior transseptal and posterior sub-Tenon regional steroid injection   A topical anaesthetic such as tetracaine (amethocaine) is instilled to prevent stinging by  the antiseptic agents   The skin of the lower eyelid and maxillary area is cleaned with an antiseptic agent such  as an alcohol swab or povidone-iodine 5%   1 ml steroid (triamcinolone acetonide or methylprednisolone acetate 40 mg/ml) is drawn  up into a 2 ml syringe and the drawing-up needle replaced with a 25-gauge 5/8 inch  (16 mm) needle   The needle is inserted through the skin (some practitioners inject via the conjunctiva), at  approximately the junction of the outer third and inner two-thirds of the lower orbital  rim, entering close to the bony margin whilst clearing the margin itself   The needle is slowly advanced tangentially to (or, anatomy permitting, away from) the  globe in similar fashion to a peribulbar local anaesthetic block up to the needle hub   The skin may be indented to ensure the needle tip is sufficiently posterior to deposit the  steroid away from the anterior subconjunctival area   The tip may be felt to engage the bony orbital floor, and/or to pierce the orbital septum;  as with the superior injection technique, the needle can be moved from side to side to  ensure the sclera has not been engaged   The plunger is slightly withdrawn and, if no blood enters the syringe, the full 1 ml is  slowly injected and the needle carefully withdrawn   Special care is required in a patient with a large eye (e.g. myopia) to avoid penetration of  the globe   A small cotton pledget impregnated with tetracaine, lidocaine (lignocaine) 2% gel or an  alternative is placed into the superior fornix at the site of injection for 2 minutes   1 ml steroid (triamcinolone acetonide methylprednisolone acetate or 40 mg/ml) is drawn  up into a 2 ml syringe and the drawing-up needle replaced with a 25-gauge 5/8 inch  (16 mm) needle   The patient is asked to look in the direction opposite to the superotemporal injection site  The bulbar conjunctiva is penetrated with the tip of the needle, bevel towards the globe,  slightly on the bulbar side of the fornix   The needle is slowly inserted posteriorly, following the contour of the globe, keeping it as  close to the globe as possible. In order not to penetrate the globe accidentally, wide  side-to-side motions are made as the needle is being inserted and the limbus  watched; movement of the limbus means that the sclera has been engaged   When the needle has been advanced to the hub the plunger is slightly withdrawn and, if  no blood enters the syringe, the full 1 ml is slowly injected   A method utilizing a plastic intravenous cannula introduced via the same route following  conjunctival incision and limited blunt dissection has been described   Ankylosing spondylitis (AS) is characterized by inflammation, cal¬  cification and finally ossification of ligaments and capsules of  joints with resultant bony ankylosis of the axial skeleton. It more  commonly affects males, of whom 90% are HLA-B27-positive.   • Presentation is commonly in the third to fourth decades  with the insidious onset of pain and stiffness in the lower  back or buttocks.   • Spondyloarthritis causes progressive limitation of spinal  movements; eventually the spine may become fixed in  flexion (Fig. 11.10A). Spinal stenosis and fractures may occur.    • Enthesitis is characterized clinically by inflammation and  pain at ligamentous attachments to bone.   • Radiology of the sacroiliac joints shows juxta-articular  osteoporosis in the early stages, followed by sclerosis and  bony obliteration of the joint (Fig. 11.10B). Calcification of  spinal ligaments gives rise to a ‘bamboo spine’. Radiological  changes often predate clinical symptoms.   • AAU is by far the most common ocular association, and  occurs in about 25% of patients with AS; 25% of males with  AAU will have AS. Either eye is frequently affected at  different times but bilateral simultaneous involvement is  rare. There is often no correlation between the severity and  activity of eye and joint involvement. Chronicity occurs in a   Fig. 11.10 Ankylosing spondylitis. (A) Fixed flexion deformity  of the spine; (B) sclerosis and bony obliteration of the  sacroiliac joints   (Courtesy of MA Mir ; from Atlas of Clinical Diagnosis, Saunders 2003 - fig. A)    few patients. HLA-B27-positive ankylosing spondylitis  patients tend to have worse disease across a range of  parameters, including earlier onset and greater intensity of  inflammation with an increased frequency of complications.   • Other ocular features include scleritis, episcleritis, keratitis  and mechanical ptosis.   Reactive arthritis (ReA, also known as Reiter syndrome) is char¬  acterized by a triad of non-specific urethritis, conjunctivitis and    arthritis. Around 75% of patients are positive for HLA-B27. A  range of infective agents can trigger the syndrome, which develops  in 1-3% of men after non-specific urethritis, and around 4% of  individuals after enteric infections caused by a range of organisms  including Shigella , Salmonella and Campylobacter. Chlamydia  pneumoniae respiratory infection and others may also precede  ReA.   • Presentation is with the acute onset of malaise, with fever  and dysuria 1-4 weeks after a linked infection in a patient  aged between 20 and 40, with arthritis that may be preceded  by conjunctivitis. A variety of other features may be present,  though not always the defining triad.   • Peripheral oligoarthritis is acute, asymmetrical and  migratory; 2-4 joints tend to be involved, most commonly  the knees, ankles and toes.   • Spondyloarthritis affects about 50% of patients, manifesting  with low back pain. This sometimes becomes chronic.   • Enthesitis manifests with plantar fasciitis, Achilles  tenosynovitis, bursitis and calcaneal periostitis; reactive bone  formation in the latter may result in a calcaneal spur.   • Mucocutaneous lesions include painless mouth ulceration,  circinate balanitis and keratoderma blennorrhagica - skin  lesions resembling psoriasis - involving the palms and soles  (Fig. 11.11).   The eye is involved in 50% of cases with a urogenital inciting  infection and 75% of enteric ReA syndrome.   • Conjunctivitis is very common; it classically follows  urethritis but precedes arthritis. The inflammation is usually    mild, bilateral and mucopurulent with a papillary and/or  follicular reaction. Spontaneous resolution occurs within  7-10 days and treatment is not required. Some patients  develop peripheral corneal infiltrates.   Up to 40% of patients with psoriasis develop arthritis. The arthritis  is more common in whites than other racial groups and affects  both sexes equally. There is a first-degree family history in 40% or  more, and many genetic markers have been identified.   • Presentation of psoriatic arthritis is usually in middle age  - later than skin features.   • Skin. There are multiple types of psoriasis. Plaque-type, the  most common form, is characterized by well-demarcated  raised silvery inflamed plaques (Fig. 11.12A) on the scalp,  trunk, arms and legs. Psoriatic erythroderma features  widespread exfoliative skin changes with associated  inflammation, and pustular psoriasis inflamed but non-  infectious pustules limited or generalized in distribution.   • Nail changes (dystrophy) include pitting, transverse  depression and onycholysis (Fig. 11.12B).   • Arthritis is typically asymmetrical and involves the distal  interphalangeal joints (sausage digits). Some patients  develop enthesitis.   AAU occurs in approximately 7%; conjunctivitis, marginal corneal  infiltrates and secondary Sjogren syndrome may occur but are  uncommon.   Fuchs uveitis syndrome (FUS), also known as Fuchs heterochro-  mic iridocyclitis or cyclitis (FHC), is a chronic non-granulomatous  condition diagnosed at an average of 40 years old. There is no  gender or racial predilection. The cause is uncertain, but there is  evidence that implicates the rubella virus. Signs in toxoplasmosis  can be similar, and T. gondii has also been suspected as a cause. It  is possible that most of the anterior chamber activity is due to  blood-aqueous barrier breakdown rather than inflammation.   Fig. 11.12 Psoriasis. (A) Skin plaques; (B) arthritis and severe  nail dystrophy    • Symptoms. Gradual blurring due to cataract is a common  presentation, as are persistent floaters; heterochromia (see  next) may be noted.   • Heterochromia iridis (Table 11.6) is demonstrated most  effectively in daylight; most commonly the affected eye is  hypochromic (Fig. 11.13A). Its quality is determined by the  relative degrees of atrophy of the stroma and posterior  pigment epithelium. It may be absent or subtle, particularly  in brown eyes. In blue eyes, stromal atrophy allows the  posterior pigmented layer to show through and become the  dominant pigmentation, so that the eye sometimes becomes  hyperchromic.   • Anterior chamber shows faint flare and usually only mild  cellular activity, though exacerbations can sometimes be  marked. The eye is virtually always white, even during  exacerbations.   Diffuse iris naevus or melanoma  Sturge-Weber syndrome  Hypo- or hyperchromic  Fuchs uveitis syndrome  Other chronic anterior uveitides    • Keratic precipitates are characteristically stellate and  grey-white in colour; they are located diffusely over the  entire corneal endothelium (Fig. 11.13B and see Fig. 11.3D).   • Iris nodules (30%) on the pupillary border (Koeppe - Fig.  11.13C and see Fig. 11.5A) or occasionally in the stroma  (Busacca). Tiny crystals (Russell bodies) may be present on  the iris surface (see Fig. 11.5D).   • Iris atrophy is diffuse with loss of crypts; the iris appears  smooth, with a prominent sphincter pupillae and sometimes  blood vessels (see Fig. 11.13C); pigment epithelial atrophy can  be demonstrated by retroillumination (Fig. 11.13D).   • Cataract is extremely common; a posterior subcapsular  morphology is seen initially.   • Glaucoma is typically a later manifestation but is  occasionally advanced at diagnosis. It develops in up to 60%  of involved eyes. Several mechanisms are suspected.   • Gonioscopy may show fine radial angle vessels or small  irregular peripheral anterior synechiae (Fig. 11.13E); the  vessels are typically the source of the haemorrhage  sometimes seen on incision into the anterior chamber  (Amsler sign).   • Fundus: peripheral choroiditis foci/scarring have been  reported. There may be an increased incidence of retinal  dialysis. Macular oedema essentially does not occur, except  following surgery.   • Long-term monitoring is indicated to detect glaucoma and  other complications.   • Topical steroids may be used short-term for moderate/  severe exacerbations, but are generally not thought to be  helpful in the management of chronic low-grade  inflammation.    • Cataract surgery carries a higher risk of complications. Poor  mydriasis and the possibility of postoperative hyphaema,  increased inflammation, worsening of glaucoma control and  zonular dehiscence should be taken into account.  Preoperative topical or systemic steroids are used by some  practitioners.   • Glaucoma can be difficult to control medically. The place of  laser trabeculoplasty is undefined, but is probably ineffective  if PAS are present. Options include a glaucoma drainage  device or trabeculectomy with mitomycin-C enhancement.   • Pars plana vitrectomy may be considered for visually  problematic vitreous opacification.   Juvenile idiopathic arthritis (JIA) is by far the most common sys¬  temic disease associated with childhood anterior uveitis; the prev¬  alence is about 1:1000. It is defined as arthritis of unknown  aetiology that begins before the age of 16 years and persists for at  least 6 weeks; up to 50% of children affected have persistently  active disease after 10 years. It may result from exposure to one or  more unknown antigens in genetically predisposed individuals.   • Arthritis. JIA is classified by the International League of  Associations for Rheumatology (ILAR, 2004 revision),  according to the extent of joint involvement during the first  6 months:   o Oligoarticular is the most common form. Four or fewer  joints are involved, the knees most commonly, followed  by the ankles and wrists. Girls are affected five times as  often as boys, with a peak age of onset around 2 years.  Some patients subsequently develop polyarthritis. About  75% of children are antinuclear antibody (ANA) positive,  a strong risk factor for uveitis, which is common,  affecting about 20% of children in this group,  o Polyarticular (rheumatoid factor negative) affects five or  more joints, typically both small and large joints  symmetrically. The female: male ratio is about 3:1; the  disease may commence at any age throughout childhood.  Systemic features such as fever and rash may occur but  are milder than in the systemic onset form (see below).  About 40% of children are ANA-positive. Uveitis occurs  in 5-10% of cases.   o Polyarticular (rheumatoid factor positive) again affects  five or more joints, and may resemble adult rheumatoid  arthritis; there is a very low risk of uveitis,  o Systemic, also known as Still (Still’s) disease. Systemic  features such as fever, episodic erythematous  maculopapular rash, lymphadenopathy and  hepatosplenomegaly may precede arthritis. The disease    Fig. 11.13 Fuchs uveitis syndrome. (A) Left hypochromic  heterochromia and cataract; (B) diffuse stellate keratic  precipitates; (C) Koeppe nodules, stromal atrophy and  prominent blood vessels including neovascularization; (D)  band-like posterior pigment layer atrophy seen on  retroillumination; (E) angle vessels and small peripheral  anterior synechiae   (Courtesy of C Pavesio - fig. B; C Barry - fig. C)    occurs with equal frequency in boys and girls and may  occur at any age throughout childhood. The majority are  negative for ANA, and uveitis is rare,  o Enthesitis-related, psoriatic and undifferentiated are three  other forms under the ILAR classification; the first two  have a relatively high risk of uveitis, risk in the latter is  variable but often low.    • Anterior uveitis is a key cause of morbidity in JIA. It is  particularly common in oligoarticular JIA, and relatively  frequent in several other types. Progression to blindness has  been high in historical data but shows a declining trend in  recent years associated with improved screening and  management. Arthritis usually antedates the diagnosis of  uveitis.    o Presentation. The uveitis of JIA is particularly dangerous  because it is invariably asymptomatic and must generally  be detected by screening with slit lamp examination.  Even during acute exacerbations with +4 aqueous cells, it  is rare for patients to complain, although a few report an  increase in vitreous floaters. Often uveitis may not be  suspected until the parents recognize complications such  as strabismus, or an abnormal appearance of the eyeball  due to band keratopathy or cataract.   o Injection is usually absent even in the presence of severe  uveitis.   O Inflammation is chronic and non-granulomatous. Both  eyes are affected in 70%; when bilateral, the severity of  inflammation is usually symmetrical. During acute  exacerbations, the entire endothelium shows ‘dusting’ by  many hundreds of cells, but hypopyon is absent.   o Band keratopathy and cataract (Fig. 11.14) are extremely  common in severe cases.   (common), amblyopia, maculopathy (cystoid macular  oedema, epiretinal membrane), cyclitic membrane and  phthisis.   o Prognosis. In about 10% the uveitis is mild, with never  more than +1 aqueous cells, and persists for less than  12 months. About 15% of patients have one attack  lasting less than 4 months, the severity of inflammation  varying from +2 to +4 aqueous cells. In 50% of cases,  the uveitis is moderate to severe and persists for more  than 4 months, and in 25%, the uveitis is very severe,  lasts for several years and responds poorly to treatment.  The presence of complications at initial examination  appears to be an important risk factor for the  development of subsequent complications, regardless  of therapy.   Fig. 11.14 Band keratopathy, posterior synechiae and mature  cataract in chronic anterior uveitis associated with juvenile  idiopathic arthritis   • Systemic diagnosis and management should be performed  by a physician familiar with the management of JIA,  typically a paediatric rheumatologist.   • Antinuclear antibody (ANA). Positivity denotes an  increased risk of uveitis.   • HLA-B27 testing is useful in differential diagnosis (see  above) and if present may indicate an increased risk of  uveitis.   • Screening. There has been a shift in recommendation  towards long-term 3-4 monthly review intervals in all  higher-risk categories. Review should continue in most cases  until the age of 12 years.   o Initial examination within 6 weeks of first diagnosis of  JIA. Delayed early examination is an important cause of  morbidity.   (synechiae, cataract, band keratopathy) should lead to  urgent ophthalmological referral and slit lamp  examination within a week.   O Initial 2-monthly examinations for 6 months may be  considered for all newly diagnosed oligoarticular,  psoriatic, polyarticular and enthesitis-related patients,  regardless of ANA status, followed by 3-4 monthly  intervals.   o Polyarticular: every 3-4 months; some guidelines reduce  the interval to 6-monthly after a number of years.  Higher-risk factors that might be taken into account in  deciding whether to alter the interval include the  presence of ANA, onset before 7 years of age and female  gender.   o Systemic onset and polyarticular RF-positive patients:  most authorities recommend at least an initial screening  examination, with some guidelines suggesting annual  review.   o Information for parents should include an emphasis on  the importance of compliance with screening, as well as  the need to seek urgent advice should there be any cause  for concern such as visual symptoms, ocular redness or  clouding, or abnormal pupils,  o Self-monitoring. At eventual discharge from screening,  patients should be warned to self-monitor by checking  the monocular vision at least once a week; the risk of  uveitis has not entirely disappeared by this age. They  should also attend an optometrist annually for an eye  examination. Selected patients such as those with learning  difficulties may require ongoing ophthalmological  screening.   • Differential diagnosis: investigations as appropriate.  Particular considerations in children include:   o Idiopathic juvenile chronic iridocyclitis: otherwise healthy  patients with juvenile CAU; also generally asymptomatic  until complications occur.    o Other types of juvenile arthritis and uveitis including  juvenile reactive arthritis, juvenile inflammatory bowel  disease-associated arthritis.   o Juvenile sarcoidosis: rare; pulmonary involvement is less  common than in adults; may be granulomatous and  involve the posterior segment.   o Lyme disease usually presents with intermediate uveitis in  conjunction with significant anterior uveitis,  o Intermediate uveitis: 20% of all cases of paediatric uveitis,  o Neonatal-onset multisystem inflammatory disease is a  rare, idiopathic, chronic relapsing disease that  predominantly involves the skin, joints and the central  nervous system. About 50% of children develop recurrent  anterior uveitis. The absence of posterior synechiae and  no tendency to glaucoma and cataract formation are  characteristic.   o Masquerade syndromes such as anterior segment  involvement by retinoblastoma,  o Familial juvenile systemic granulomatosis (Blau  syndrome), is a rare autosomal dominant disorder  characterized by childhood onset of granulomatous  disease of skin (panuveitis and multifocal choroiditis),  eyes and joints.   The aim of treatment should be the suppression of all active   • Topical steroids are effective in most cases (80%); acute  exacerbations require very frequent instillation.   • Mydriatic agents may be required for exacerbations to  prevent synechiae formation. A relatively short-acting  preparation such as cyclopentolate should be used and  discontinued as early as possible, particularly in monocular  treatment of younger children susceptible to the  development of amblyopia.   • Systemic immunosuppressive agents will be required in  resistant cases (e.g. methotrexate, infliximab, adalimumab,  ciclosporin) and should be managed by a specialist  ophthalmologist, typically in collaboration with a paediatric  rheumatologist. Doses required are often low.   Ulcerative colitis (UC) is an idiopathic chronic relapsing inflam¬  matory disease, involving the rectum and extending proximally to  involve part or all of the large intestine. The disease is character¬  ized by contiguous surface ulceration of the bowel mucosa with  the development of crypt abscesses and pseudopolyps (Fig. 11.15A).    Fig. 11.15 Ulcerative colitis. (A) Barium enema shows  pseudopolyposis, lack of haustral markings and  straightening of the ascending colon; (B) pyoderma  gangrenosum   Long-standing disease carries an increased risk of carcinoma of  the colon. A genetic predisposition is thought to be important;  inflammatory bowel disease is more common in patients with  other autoimmune diseases such as ankylosing spondylitis, psoria¬  sis and multiple sclerosis.   • Presentation is in the second to third decades with bloody  diarrhoea, lower abdominal cramps, urgency and tenesmus.  Constitutional symptoms include tiredness, weight loss,  malaise and fever.   • Cutaneous lesions include oral aphthous ulceration,  erythema nodosum and pyoderma gangrenosum (Fig. 11.15B).    • Arthritis is typically asymmetrical and involves large joints  of the legs; sacroiliitis and ankylosing spondylitis (AS) may  develop in HLA-E>27-positive patients.   • Hepatic disease may be in the form of autoimmune  hepatitis, sclerosing cholangitis and cholangiocarcinoma.   • AAU occurs in about 5% and may coincide with  exacerbations of colitis. As expected, uveitis is more  common in patients with associated arthritis, AS and  HLA-B27 positivity.   • Other ocular features: conjunctivitis, episcleritis and scleritis  may all be more common than in the general population.   Crohn disease (CD) is an idiopathic chronic relapsing disease  characterized by multifocal full-thickness granulomatous inflam¬  mation of the intestinal wall. It most frequently involves the ter¬  minal ileum and colon but in contrast to UC any area of the  gastrointestinal tract, including the mouth, may be affected. There  is strong evidence for a genetic aetiological component such as  mutations in the CARD15 (previously NOD2) gene. Infective  agents almost certainly play a role.   • Presentation is typically in the second-third decades with  abdominal pain and diarrhoea. Weight loss, fever, vomiting,  oral aphthous ulceration and perirectal lesions such as  abscesses and fistulae may occur.   • Cutaneous lesions include erythema nodosum and  pyoderma gangrenosum (see Fig. 11.15B).   • Skeletal features include finger clubbing, acute peripheral  arthritis, sacroiliitis and ankylosing spondylitis (especially if  HLA-B27-positive).   AAU occurs in about 3%; dry eye, conjunctivitis and scleritis may  be more common than in the general population.   Whipple disease (intestinal lipodystrophy) is a rare chronic gastro¬  intestinal inflammatory condition caused by infection with the  bacterium Tropheryma whipplei. It occurs mainly in white middle-  aged men and when diagnosed (duodenal biopsy; DNA detection  in blood, ocular and other fluids) can be cured with antibiotics.   • Uveitis. Keratitis, anterior uveitis, vitritis, retinitis with  retinal haemorrhages, cotton-wool spots and potentially  vascular occlusion, and multifocal choroiditis.   • Neuro-ophthalmic manifestations can be varied, e.g. gaze  palsy, nystagmus, ophthalmoplegia, papilloedema and optic  atrophy. Oculomasticatory myorhythmia is characteristic.   Tubulointerstitial nephritis and uveitis (TINU) is an uncommon  disorder of immune origin characterized by a combination of  acute tubulointerstitial nephritis and uveitis. It typically occurs in  adolescent girls; renal disease usually precedes uveitis.   Presentation is with constitutional symptoms, proteinuria,  anaemia, hypertension and renal failure. The response to systemic  steroid therapy is good and renal function usually returns to  normal within a few months without complication.   • Bilateral non-granulomatous (occasionally granulomatous)  anterior uveitis that usually responds well to topical  steroids. Disc and macular oedema may occur. Many cases  are relapsing and some require systemic steroids or  immunosuppressive therapy.   IgA nephropathy (Berger disease) is a relatively common kidney  disease in which immunoglobulin A is deposited in the glomerular  mesangium. Presentation is usually at age 16-35 with recurrent  haematuria, often associated with an upper respiratory tract infec¬  tion, but may be asymptomatic. AAU and other ocular inflamma¬  tory phenomena may occur but are uncommon.   Intermediate uveitis (IU) is a chronic, relapsing disease of insidi¬  ous onset in which, according to the SUN Working Group, the  vitreous is the primary site of inflammation as determined clinically.    It incorporates pars planitis, posterior cyclitis and hyalitis. The  diagnosis is essentially clinical; IU maybe idiopathic (at least half)  or associated with a systemic disease, and systemic investigations  are routinely performed, especially in the presence of suggestive  findings and/or in older individuals. Pars planitis (PP) is the term  used for a subset of IU in which there is snowbanking and/or  snowball formation (see below), but only if the inflammation is  idiopathic - that is, with no identifiable underlying infection or  systemic disease - otherwise the term intermediate uveitis is  reverted to. IU accounts for up to 15% of all uveitis cases and about  20% of paediatric uveitis. A minority of patients have a benign  course, with spontaneous resolution within several years. In other  patients the disease is more severe and prolonged with episodic  exacerbations. IU associated with systemic disease has a variable  course.   • Symptoms. Presentation is with the insidious onset of  blurred vision, often accompanied by vitreous floaters; there  is usually no pain or redness. Though initial symptoms are  often unilateral, objective findings are typically present  asymmetrically in both eyes.   • Visual acuity is variably affected depending on  inflammatory activity and complications, particularly CMO.  The disease may last as long as 15 years and preservation of  vision will depend largely on control of macular disease. In  follow-up of up to 4 years, 75% of patients maintain a visual  acuity of 6/12 or better.   • Anterior uveitis. In PP there may be a few cells and small  scattered KP which occasionally have an inferior linear  distribution. In other forms of IU, anterior uveitis and its  associated findings such as PS can be more prominent,  especially in children, and in sarcoidosis and Lyme disease.   • Vitreous. Vitreous cells with anterior predominance (Fig.  11.16A) are universal, with vitreous condensation and haze  (Table 11.7) in more severe cases (Fig. 11.16B). Snowballs are  whitish focal collections of inflammatory cells and exudate,  usually most numerous in the inferior vitreous (Fig. 11.17A).   • Peripheral periphlebitis (Fig. 11.17B) is common,  particularly in MS. Careful examination of a normal fellow  eye in apparently unilateral disease may reveal mild vascular  sheathing.   • Snowbanking (Figs 11.17C) is characterized by a grey-white  fibrovascular and/or exudative plaque that may occur in any  or all quadrants, but is most frequently found inferiorly.    • Neovascularization may occur, particularly in the retinal  periphery (often associated with snowbanks) and on the  optic nerve head; the latter usually resolves when activity is  controlled. This can sometimes lead to vitreous  haemorrhage, retinal detachment and cyclitic membrane  formation. Focal peripheral retinal vasoproliferative tumours  (see Ch. 12) are uncommon. Vitreous haemorrhage is more  common in children.   • CMO occurs in up to half of patients and is the major cause  of impaired visual acuity.   • Cataract can be caused by steroid treatment or by the  inflammation itself; both are probably contributory in the  majority of patients.   • Glaucoma may occur in eyes with prolonged inflammation,  particularly if receiving long-term steroid therapy.   • Retinal detachment is generally uncommon, but as it can  progress to hypotony and phthisis in advanced cases,    Fig. 11.17 Intermediate uveitis. (A) Snowballs; (B) peripheral  periphlebitis and snowballs; (C) inferior snowbanking and  snowballs   (Courtesy of CL Schepens, ME Hartnett and T Hirose, from Schepens’ Retinal  Detachment and Allied Diseases, Butterworth-Heinemann, 2000 - fig. B)    prevention should be a major goal of management. The  aetiology may be tractional, rhegmatogenous and  occasionally exudative. Retinoschisis has also been described.   Inflammatory markers such as ESR and/or CRP should be  checked, together with a complete blood count, as they may raise  suspicion of a systemic inflammatory process. OCT is key to  excluding subtle CMO, and FA will help in assessing severity.  Other investigations are targeted at the exclusion of an underlying  cause as below.   • Multiple sclerosis. Enquiry should be made in all patients  about neurological symptoms, noting that IU may precede  other symptoms of demyelination. MS should be suspected  in patients aged 20-50; it is twice as common in women.  Granulomatous AAU may occur. Cranial MRI imaging  should be performed if any suspicion is raised.   • Sarcoidosis. A review of systems should include respiratory  function. Sarcoid-associated IU is relatively uncommon and  as with MS may antedate the onset of systemic disease. The  presence of associated granulomatous anterior uveitis should  arouse suspicion. A serum ACE level and chest X-ray should  be performed in all adult patients.   • Lyme disease-associated IU is often associated with severe  anterior uveitis. Serology should be performed if residence  in or a visit to an endemic area is elicited.   • Syphilis serology - treponemal and cardiolipin antibody  tests - should be performed.   • Tuberculosis is an uncommon association that may give  respiratory symptoms and be demonstrated on chest X-ray.  Tuberculin skin and/or blood (e.g. QuantiFERON™) testing  should be performed prior to steroid treatment in the  presence of any suspicion.   • Other conditions that may give vitritis mimicking IU  include Fuchs uveitis syndrome, intraocular lymphoma  (older patients), Toxocara granuloma, Whipple disease,  endogenous Candida endophthalmitis (risk factors such as  IV drug use) and toxoplasmosis. These will commonly be  suspected on the basis of the history and specific clinical  findings.   An identified infection or other underlying disease should be  treated specifically, supplemented by anti-inflammatory measures  below as appropriate. Many authorities aim to abolish all active  inflammation regardless of whether vision has been affected;   • Topical steroids do not reach the posterior segment in high  concentrations so have only a limited role, and are used  principally to treat any anterior uveitic component. It has  been proposed that in mild intermediate uveitis a course of  frequent topical steroid of a few weeks’ duration may exert  some benefit and identify individuals at high risk of IOP  elevation without committing to the extended action of  depot injection.   • Regional steroid injection. Orbital floor or posterior  sub-Tenon injection as described for anterior uveitis.  Depending on severity, injection is performed 4-6 times at  intervals of 2-4 weeks, accompanied by careful IOP  monitoring.   • NSAID. If inflammation persists after regional injection, an  agent such as naproxen 500 mg twice daily can be  commenced.   • Cryotherapy (double freeze-thaw) to the pars plana and  retinal periphery under peribulbar anaesthesia can be highly  effective if inflammation is steroid-resistant, and may be  appropriate prior to systemic steroids. It can be associated  with transiently increased vitritis and other complications  including retinal detachment, cataract, vitreous and anterior  chamber haemorrhage, epiretinal membrane formation and  hypotony. A repeat application may be needed after several  months. Some authorities reserve cryotherapy for peripheral  neovascularization with haemorrhage.   • Peripheral retinal laser adjacent to snowbanking and/or to  ischaemic areas on FA is an alternative to cryotherapy, and  may be as effective with a lower rate of complications.   • Intraocular steroid. Intravitreal triamcinolone has shown  benefit, but the effect is of relatively short duration.  Slow-release implants have demonstrated promising results.   • Systemic steroids. This modality is preferred over regional  steroid by some practitioners if symptomatic inflammation  is bilateral, though others prefer to avoid systemic steroids  in most cases, proceeding directly to immunosuppressive  chemotherapeutic agents. A large dose of 1-2 mg/kg/day is  commenced, tapered slowly over months according to  response. Familiarity with precautions to be taken,  contraindications to and potential adverse effects of steroids  is essential before prescribing; optimally steroids should be  prescribed in conjunction with a specialist physician, such as  a rheumatologist.   • Immunosuppressive agents. Mycophenolate, methotrexate,  tacrolimus, ciclosporin and others are alternatives in  steroid-resistant inflammation or as steroid-sparing agents.  One or more of these may be available as local sustained-  release preparations in the near future.   • Other agents demonstrating efficacy in refractory and other  patients include interferon-beta (in MS-related IU), the  anti-tumour necrosis factor infliximab, intravitreal  bevacizumab and others.   • Pars plana vitrectomy typically substantially reduces  inflammatory intensity and recurrence, though the    mechanism is imperfectly understood. It may be particularly  indicated in patients with tractional retinal detachment,  epiretinal membrane, refractory CMO, dense vitreous  opacity, vitreous haemorrhage or substantial peripheral  neovascularization.   • Cataract and glaucoma are managed medically and  surgically as indicated.   VKH is an idiopathic multisystem autoimmune disease featuring  inflammation of melanocyte-containing tissues such as the uvea,  ear and meninges. VKH predominantly affects Hispanic, Japanese  and pigmented individuals; it is associated with HLA-DRi and  HLA-DR4 across different racial groups. VKH is sometimes sub¬  divided into Vogt-Koyanagi disease, characterized mainly by skin  changes and anterior uveitis, and Harada disease, in which neuro¬  logical features and exudative retinal detachments predominate.   • Prodromal phase lasting a few days: neurological  (meningitis and rarely encephalopathy with cranial nerve  paresis and other focal lesions) and auditory manifestations  (tinnitus, vertigo and deafness). Cranial nerve palsies and  optic neuritis may occur.   • Acute uveitic phase. Bilateral granulomatous anterior and  multifocal posterior uveitis with diffuse choroidal  infiltration, Dalen-Fuchs nodules (see also sympathetic  ophthalmitis below), vitritis, papillitis and exudative retinal  detachments (Fig. 11.18 and see Fig. 11.21). Ciliary effusion  with iris-lens diaphragm rotation can occur.   Fig. 11.18 Multifocal exudative retinal detachments in the  acute uveitic phase of Vogt-Koyanagi-Harada syndrome    • Convalescent phase follows several weeks later: localized  alopecia, poliosis and vitiligo (Fig. 11.19); depigmented  fundus appearance (‘sunset glow’ fundus - Fig. 11.20) and  depigmented limbal lesions (Sugiura sign) in pigmented,  especially Japanese, patients.   • Chronic recurrent phase is characterized by smouldering  anterior uveitis with exacerbations. Recurrent posterior  uveitis is much less common.   • Diagnostic criteria for VKH are set out in Table 11.8; in  complete VKH, criteria 1-5 must be present, in incomplete  VKH, criteria 1-3 and either 4 or 5 must be present, and in  probable VKH (isolated ocular disease), criteria 1-3 must be  present.   • Ocular complications include choroidal neovascularization,  subretinal fibrosis, preretinal and disc new vessels and  vitreous haemorrhage, cataract and glaucoma.   • Prognosis is very variable, and is partly dependent on  aggressive control in the early stages. Neurological and   5. Integumentary findings, not preceding onset of central  nervous system or ocular disease, such as alopecia,  poliosis and vitiligo    auditory manifestations tends to resolve but skin, lash and  hair changes usually persist.   Systemic manifestations should be investigated and managed by  an appropriate specialist.   • Lumbar puncture if diagnosis uncertain; CSF shows a  transient lymphocytic pleocytosis, and melanin-containing  macrophages.   • Ultrasonography shows diffuse choroidal thickening and  excludes posterior scleritis; UBM can be used to demonstrate  ciliary effusions.   • FA of the acute phase shows multifocal hyperfluorescent  dots at the level of the retinal pigment epithelium (RPE;   Fig. 11.21C) followed by subretinal pooling (Fig. 11.21D). The  chronic phase shows RPE window defects.   • ICGA during the acute phase of the disease shows regularly  distributed hypofluorescent spots, most of which remain  hypofluorescent during the late phase, when diffuse  hyperfluorescence over the posterior pole is also shown.  ICGA is useful for monitoring.   High dose (1-2 mg/kg/day) oral prednisolone, tapered over 3-6  months; this may be preceded by intravenous methylprednisolone  pulse therapy (500-1000 mg/day). Topical steroids and cyclople-  gics are used for anterior uveitis. Steroid-resistant patients may  require immunosuppressives; biological blockers such as inflixi¬  mab show promise.   Sympathetic ophthalmitis (SO) is a bilateral granulomatous panu¬  veitis occurring after penetrating trauma; uveal prolapse may have  been a feature of the trauma. Less frequently the condition occurs  following intraocular surgery, usually multiple vitreoretinal pro¬  cedures. Presentation in trauma-induced cases is between 2 weeks  and 3 months after initial injury in 65%. The incidence is probably  0.2-0.5% after injury and 0.01% following intraocular surgery.    Fig. 11.21 Imaging in ocular Vogt-Koyanagi-Harada syndrome. (A) FAF of the eye shown in Fig. 11.18 demonstrating multiple  exudative detachments; (B) OCT; (C) FA - multiple hyperfluorescent leaking spots in venous phase; (D) pooling of dye within  detached areas in late FA images   Infiltration of the choroid by lymphocytes and scattered  aggregations of epithelioid cells, many of which contain  fine granules of melanin; (B) Dalen-Fuchs nodule - a  granuloma situated between Bruch membrane and the  retinal pigment epithelium   Histopathology shows a diffuse lymphocytic infiltration of the  choroid. Scattered aggregates of epithelioid cells are seen, many of  which contain fine granules of melanin (Fig. 11.22A). Dalen-Fuchs  nodules, which also occur in Vogt-Koyanagi-Harada syndrome  (see above) are granulomas located between Bruch membrane and  the RPE (Fig. 11.22B).   • Symptoms. There is a history of causative trauma; the  exciting eye is frequently red and irritable (Fig. 11.23 A). The  sympathizing eye develops irritation, blurred vision,  photophobia and loss of accommodation.   • Anterior uveitis develops in both eyes; this may be mild or  severe and is usually granulomatous (Fig. 11.23B). The  severity of inflammation may be markedly asymmetrical.   • Fundus: multifocal choroidal infiltrates develop in the  midperiphery (Fig. 11.23C), with sub-RPE infiltrates  corresponding to Dalen-Fuchs nodules. Exudative retinal  detachment, vasculitis and optic disc swelling may all manifest.  As inflammation settles, residual chorioretinal scarring may  confer a ‘sunset glow’ appearance similar to VKH.    • Systemic manifestations similar to those in VKH can occur  but are uncommon.   • Prognosis depends on the severity and location of disease  and the response to treatment. With aggressive therapy 75%  of sympathizing eyes retain a visual acuity of better than  6/60. Long-term follow-up is mandatory because relapses  occur in 50% of cases, and may be delayed for several years.   • FA shows multiple foci of leakage at the level of the RPE,  with subretinal pooling in the presence of exudative retinal  detachment.   • ICGA shows hypofluorescent spots in active disease, which  resolve with treatment.   • Enucleation of a severely injured eye in the first week or so  following injury has historically been considered effective in  preventing or reducing the severity of SO, but there is some  evidence that little useful effect is exerted, particularly with  modern standards of surgical repair. It may be considered  for an injured eye with a hopeless visual prognosis.  Evisceration has conventionally been viewed as inadequate,  though recent evidence has raised the possibility of a  protective effect provided all uveal tissue is removed.   • Steroids are the basis of treatment. High dose oral  prednisolone is given for several months, and gradually  tapered according to response. Initiation with intravenous  methylprednisolone may be used in some cases.  Supplementary topical steroids and cycloplegics may be  given to target anterior uveitis, and peri- and intraocular  steroids, including slow-release intravitreal implants, may  facilitate reduced systemic treatment.   • Immunosuppressives such as azathioprine, ciclosporin and  methotrexate can be used in resistant cases or as steroid¬  sparing agents. Biological blockers (e.g. infliximab,  adalimumab) may be considered.   Lens-induced or phacogenic (previously phacoanaphylactic)  uveitis results from an immune response to lens proteins following  exposure due to incomplete cataract extraction, trauma or rarely  capsular degeneration in a mature cataract (Fig. 11.24). The most  commonly encountered modern scenario is that of retained lens  fragments following phacoemulsification, either in the posterior  segment after posterior capsular rupture or zonular dehiscence, or   Fig. 11.24 Lens-induced uveitis - exposed lens material  producing an inflammatory reaction   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann, 2001)   an overlooked piece of nucleus or soft lens matter settling in the  anterior chamber (see also Chapter 9). Differential diagnosis is  from bacterial endophthalmitis, which is usually more severe; in  doubtful cases management should be as for infection.   • Symptoms. Variable pain, photophobia, redness and  blurring, usually with a history of recent (complicated or  uncomplicated) cataract surgery and uncommonly of injury.   • Anterior uveitis is granulomatous and may be mild,  moderate or severe.   • Corneal oedema is common adjacent to an anterior  chamber lens fragment.   • Lens fragments may be visible in the anterior or posterior  segment.   • Vitritis of variable severity is usually present if lens  fragments lie within the vitreous cavity.   • Lens injury may be evident in cases associated with trauma.   • Complications include CMO, glaucoma, epiretinal  membrane and, rarely, more severe sequelae such as retinal  detachment and cyclitic membrane.   Treatment involves steroids, the route and intensity dependent on  clinical circumstances, with surgical removal of all lens material  from the anterior chamber or via pars plana vitrectomy as required.  Small lens fragments in the posterior segment can often be  managed conservatively and will absorb slowly over months.  Cycloplegia and IOP-lowering treatment are commonly indicated.  Penetrating or (uncommonly) blunt ocular injury should be  managed concomitantly as appropriate, including removal of the  damaged lens.   Sarcoidosis is a chronic disorder of unknown cause, manifesting  with non-caseating granulomatous inflammatory foci. It can affect  essentially any organ system, but the lungs and lymph nodes are  the most commonly involved. It more frequently (10:1) affects  patients of black than white ethnicity but is more common in  colder climates. It is one of the most common systemic associa¬  tions of uveitis.   • Presentation. Respiratory symptoms (cough, shortness of  breath on exertion) and constitutional symptoms (malaise,  arthralgia) each occur in about 50% of patients. Lofgren  syndrome is an acute presentation carrying a very good  prognosis, characterized by the triad of erythema nodosum  (see below), bilateral hilar lymphadenopathy (Fig. 11.25A) on  chest X-ray, and polyarthralgia, usually seen in women. A  minority of patients are asymptomatic (incidentally  abnormal chest X-ray). Diagnosis may be made as the result  of investigation of extrapulmonary inflammation such as  uveitis.   • Lung disease ranges from mild parenchymal infiltration to  severe pulmonary fibrosis.   • Skin lesions are seen in about 25% of patients and can  include erythema nodosum (tender erythematous plaques  typically involving the shins - Fig. 11.25B), lupus pernio  (indurated violaceous lesions involving exposed parts of the  body such as the nose, cheeks, fingers and ears - Fig. 11.25C)  and granulomatous papules or macules.   • Neurological disease is rare; meningitis and cranial nerve  palsies may occur. Pituitary involvement can lead to  hormonal abnormalities.    • Cardiac involvement is relatively uncommon (5%  clinically), but is critically important as it may lead to  arrhythmia and sudden death.   • Lymphadenopathy. Enlargement of superficial nodes is  sometimes the initial clinical manifestation.   Ocular inflammation occurs in 25-70% of sarcoid patients  depending on ethnicity; granulomatous anterior uveitis is the  most common manifestation. Blindness can occur if not ade¬  quately managed. AAU typically affects patients with acute-onset  sarcoidosis. CAU, typically granulomatous, tends to affect older  patients with chronic pulmonary disease. The International  Workshop on Ocular Sarcoidosis (IWOS), reporting in 2009,  identified seven key signs in the diagnosis of intraocular  sarcoidosis:   1. ‘Mutton fat’ KPs (Fig. 11.26A) and/or small granulomatous  KPs and/or iris nodules (Koeppe and/or Busacca - Fig.  11.26B).   4. Multiple chorioretinal peripheral lesions (active and/or  atrophic - Fig. 11.27). Choroidal lesions are uncommon and  vary in appearance: multiple small pale-yellow infiltrates,  sometimes with a punched-out appearance (Figs 11.27A and  B) are the commonest; they are often most numerous  inferiorly. Multiple large confluent infiltrates are less common  (Fig. 11.27C). Multifocal choroiditis (Fig. 11.27D) carries a  guarded visual prognosis even after resolution of activity, as a  result of secondary choroidal neovascularization associated  with macular or peripapillary chorioretinal scarring. Retinal  granulomas may also occur, seen as discrete small yellow-  white lesions (Fig. 11.27E).   Fig. 11.25 Sarcoidosis. (A) Bilateral hilar lymphadenopathy; (B) erythema nodosum; (C) lupus pernio   (Courtesy of MA Mir ; from Atlas of Clinical Diagnosis, Saunders 2003 - fig. C)   Fig. 11.26 Ocular sarcoidosis. (A) Very large granulomatous ‘mutton fat’ keratic precipitates; (B) large iris nodules; (C) nodular  involvement of the trabecular meshwork; (D) snowballs    5. Nodular and/or segmental periphlebitis (± ‘candle wax  drippings’) and/or retinal macroaneurysm in an inflamed  eye. Periphlebitis appears as yellowish or grey-white  perivenous sheathing. Perivenous exudates referred to as  ‘candle wax drippings’ (en taches de bougie) are typical of  severe sarcoid periphlebitis (Fig. 11.28A). Occlusive  periphlebitis (Fig. 11.28B) is uncommon, but peripheral retinal  neovascularization may develop secondary to retinal capillary  dropout. In black patients it may be mistaken for proliferative  sickle-cell retinopathy.   6. Optic disc nodule(s)/granuloma(s) (Fig. 11.29) and/or  solitary choroidal nodule. Solitary choroidal nodules are less  common than multiple lesions in sarcoidosis. Focal optic  nerve granulomas do not usually affect vision. Persistent disc  oedema is a frequent finding in patients with retinal or  vitreous involvement, and papilloedema due to CNS  involvement may occur in the absence of other ocular  manifestations.    8. Other ocular manifestations include conjunctival nodules  resembling those of follicular conjunctivitis, lacrimal  gland infiltration (Fig. 11.30) and dry eye, eyelid skin  nodules, orbital and scleral lesions. Complications are  those typically seen in idiopathic uveitis, including cataract,  glaucoma, posterior and peripheral anterior synechiae,  band keratopathy, vitreous haemorrhage, maculopathy  (cystoid macular oedema, epiretinal membrane,  choroidal neovascularization), retinal detachment and  phthisis.   In addition to the acquisition of histopathological evidence, IWOS  judged the following five investigations to be of significant value  in the diagnosis of ocular sarcoidosis in patients having a compat¬  ible uveitis:   1. Negative tuberculin skin test in a BCG-vaccinated patient  or in a patient having had a positive tuberculin skin test   (A) Small choroidal granulomata; (B) same eye as (A)  showing lesion with a punched-out appearance; (C) confluent  choroidal infiltration; (D) multifocal choroiditis; (E) multiple  small retinal granulomata    previously. A tuberculin skin test is negative in most  sarcoid patients; a strongly positive reaction to one  tuberculin unit makes a diagnosis of sarcoidosis highly  unlikely.    3. Chest X-ray showing bilateral hilar lymphadenopathy  (BHL). Chest radiography is abnormal in 90%.   5. Chest CT scan in patients with a negative chest X-ray result.   High-resolution CT scanning is of considerably greater value  than standard resolution imaging.   (Courtesy of P Morse - fig. A; C Pavesio - fig. B)   Fig. 11.29 Involvement of the optic nerve head in  sarcoidosis - granulomata and periphlebitis   (Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases,  Mosby 1997)   • Calcium and vitamin D levels may be abnormal depending  on disease pattern and level of activity.   • Bronchoalveolar lavage fluid (BALF) shows characteristic  changes; CD4/CD8 T cell ratios are a key indicator.   • Induced sputum analysis correlates strongly with BALF, and  is a noninvasive technique.   Four diagnostic levels were defined by the IWOS for ocular  sarcoidosis:   1. Definite ocular sarcoidosis: biopsy-supported diagnosis in  the presence of a compatible uveitis.   2. Presumed ocular sarcoidosis: biopsy not done but chest  X-ray shows BHL with a compatible uveitis.   Fibreoptic bronchoscopy with biopsy; histopathological  confirmation of sarcoidosis is almost always required before  starting treatment; the lung is a common site from which to  establish this in the presence of clinical or investigational  evidence of pulmonary disease, though a more easily  accessible superficial lesion should be chosen if available.  Thoracic endosonography (endobronchial or oesophageal)  with needle aspiration has been shown in a large trial to be a  more sensitive technique than bronchoscopic biopsy.  Miscellaneous biopsy sites include superficial lymph nodes  or skin lesions, conjunctival nodules and lacrimal glands (up  to 75% of enlarged glands are positive). If the eye is  involved, vitreous biopsy is very useful (e.g. CD4/CD8 ratio).  Other imaging modalities include MRI cardiac and CNS  imaging (MRI is less useful than CT for thoracic evaluation),    3. Probable ocular sarcoidosis: biopsy not done, no BHL on  chest X-ray but >3/7 of the intraocular signs above and >2/5  positive laboratory tests.   4. Possible ocular sarcoidosis: lung biopsy negative but >4/7  signs and >2/5 positive laboratory tests.   It is critical that alternative causes of uveitis are adequately  excluded by appropriate assessment and investigation.   Corticosteroids have conventionally been the major treatment  modality in ocular and systemic sarcoidosis, though alternative  immunosuppressives are being used more commonly, particularly  as steroid-sparing agents and in refractory disease. Treatment  should be initiated aggressively to prevent sight-threatening  complications.   • Posterior uveitis generally requires systemic steroids and  occasionally immunosuppressive agents such as  methotrexate, azathioprine, ciclosporin and tumour necrosis  factor (TNF) inhibitors (e.g. adalimumab).   • Peripheral retinal neovascularization can be treated with  scatter photocoagulation to ischaemic areas demonstrated  by FA.   • Cystoid macular oedema may respond to a topical NS AID.   • Cataract and glaucoma may require treatment;  inflammation should be suppressed prior to surgery,  preferably for at least 3 months in the case of cataract  surgery.   Behcet disease (BD) is an idiopathic, multisystem syndrome char¬  acterized by recurrent aphthous oral ulcers, genital ulceration and  uveitis. Vasculitis is a key pathogenetic component and may  involve small, medium and large veins and arteries. Mortality is  around 5% at 5-10 years, typically due to cardiovascular or CNS  complications. BD probably has an autoimmune basis, and may  be precipitated by exposure to an infectious agent with subsequent  cross-reaction. The disease typically affects patients from Turkey,  the Middle and Far East (the ancient ‘Silk Road’ route), with a  lower prevalence in Europe and North America. It is strongly  associated with HLA-B51; the ethnic groups with a higher preva¬  lence of BD also have a higher rate of HLA-B51 positivity. The peak  age of onset is the third decade; reported gender prevalence varies  with ethnicity.   The International Study Group for Behcet Disease (ISGBD),  reporting in 1990, established criteria for diagnosis: recurrent oral  ulceration (Fig. 11.31A) characterized by oral ulcers at least three  times in a 12-month period, plus at least two of genital ulceration,   (Courtesy of MA Mir, from Atlas of Clinical Diagnosis, Saunders 2003 - fig. B)    ocular inflammation, characteristic skin lesions (erythema  nodosum - see Fig. 11.25B, pseudofolliculitis, acneiform nodules,  papulopustular lesions) and a pathergy reaction: pustule 24-48  hours after a sterile needle prick (>95% specific, but often negative  in European and North American patients).   Presentation does not always conform to the criteria above.  Additional features include:   • Vascular lesions. Aneurysms, including pulmonary and  coronary, and venous thrombosis/thrombophlebitis  (Fig. 11.31B).   • Dermatographia (Fig. 11.31C), similar to the pathergy  reaction, indicates skin hypersensitivity and consists of the  formation of erythematous lines following stroking or  scratching.   • Neurological manifestations (5%) such as  meningoencephalitis of the brainstem, dural sinus  thrombosis and cerebral aneurysms.   Fig. 11.32 Ocular lesions in Behget disease. (A) Hypopyon in a  (D) end-stage disease   Ocular inflammation occurs in about 70%, and tends to be more  severe in men; it is the presenting manifestation in about 10%.  Signs are virtually always bilateral eventually. Relapsing/remitting  acute onset panuveitis with retinal vasculitis and often spontane¬  ous resolution even without treatment is the classical pattern of  eye involvement; retinal vascular disease (vasculitis and occlusion)  is the main cause of visual impairment.   • AAU, often bilateral, is typical. It is not granulomatous. A  transient mobile hypopyon in a relatively white eye (Fig.  11.32A) is characteristic.   • Vitritis may be severe; it is universal in eyes with active  posterior segment disease.   • Retinitis. Transient superficial white infiltrates (Fig. 11.32B)  that heal without scarring may be seen during acute systemic  disease. There may be deeper more diffuse retinitis similar in  appearance to viral inflammation. Exudative detachments  can also occur. Inflammatory deposits analogous to KPs may  be seen on the inferior peripheral retina.    • Retinal vasculitis - arteritis as well as phlebitis, in contrast  to pure venous involvement in sarcoidosis - can manifest  with sheathing, perivascular haemorrhages and occlusion  (Fig. 11.32C). Vascular leakage may give rise to diffuse retinal  oedema and CMO.   • Optic disc hyperaemia and oedema. Raised intracranial  pressure can also cause optic disc swelling and optic atrophy  in BD.   • Disc and retinal neovascularization may be seen as a  response to inflammation and ischaemia.   • Uncommon manifestations include conjunctivitis,  conjunctival ulcers, episcleritis, scleritis and ophthalmoplegia  from neurological involvement.   • End-stage disease is characterized by optic atrophy, retinal  atrophy and gliosis, and sheathing, attenuation and ghosting  of affected vessels (Fig. 11.32D); the vitreous tends to clear.  Other complications include posterior synechiae, cataract,  glaucoma and, uncommonly, retinal detachment and  phthisis. Severe visual loss in males of up to two-thirds of  patients at 10 years has been reported, but is probably much  lower with aggressive management; the rate in women is  about half that in men.   • Inflammatory markers (e.g. ESR, CRP, complement levels,  white cell count) may be elevated.   • Thrombophilia screening is appropriate in some patients to  exclude other causes of thrombosis.   • FA delineates ischaemic areas and aids detection of posterior  segment inflammation and monitoring of disease activity.   • Laser flare photometry of the anterior chamber correlates  well with FA in determining the level of inflammatory  activity.   • Superficial lesion biopsy, synovial fluid aspiration and  lumbar puncture may be used to help rule out alternative  diagnoses.   • Systemic imaging may include brain MRI/magnetic  resonance angiography (MRA), CT/computed tomography  angiography (CTA) and conventional angiography to identify  ischaemia.   • Topical steroids alone may be adequate if - rarely - there is  no trace of posterior segment involvement.   • Systemic steroids and azathioprine (2.5 mg/kg/day) in  combination are recommended for the initial management of  posterior uveitis in European League Against Rheumatism  (EULAR) 2008 BD guidelines. Steroids should be tapered only  slowly. Topical and/or regional steroids may also be used; there  may be a high rate of ocular hypertension with intravitreal  steroid injection. Azathioprine may have a role in prophylaxis.    • Ciclosporin (2-5 mg/kg/day) or infliximab, in combination  with azathioprine and systemic steroids, is recommended by  EULAR for severe eye disease (> 2 lines reduction in visual  acuity and/or retinal vasculitis or macular involvement); a  recent study recommended a single infliximab infusion as  initial treatment of posterior uveitis. Hypertension,  nephrotoxicity and neurotoxicity are concerns with  ciclosporin, which should be avoided in patients with CNS  involvement unless it is determined that severe eye disease  warrants the risk. Infliximab may lead to activation of  tuberculosis, and screening-positive patients should receive  prophylactic treatment (e.g. isoniazid). Intravitreal  administration is a novel alternative route of administration  for infliximab.   • Infliximab or adalimumab should be considered early for  vision-threatening Behcet disease (American Uveitis Society  recommendation).   • Interferon-alfa (6 million IU per day subcutaneously  initially, gradually tapered) with or without steroids is a  EULAR-recommended alternative to the ciclosporin/  infliximab/azathioprine/steroid regimen above for severe  disease; it should not be used in combination with  azathioprine (risk of myelosuppression).   Toxoplasmosis is caused by Toxoplasma gondii , an obligate intra¬  cellular protozoan. It is estimated to infest at least 10% of adults  in northern temperate countries and more than half of adults in  Mediterranean and tropical countries. The cat is the definitive  host, with intermediate hosts including mice, livestock, birds and  humans. Oocysts are excreted in cat faeces and then ingested by  intermediate hosts (Fig. 11.33), including via contaminated water  supplies. Cat litter disposal with subsequent transfer to food is a  well-known potential mode of infection in humans (though  indoor cats have a low rate of toxoplasmosis infestation). The  bradyzoite is an inactive stage lying dormant within cysts in  tissues such as the eye, brain and skeletal muscle, and consump¬  tion of undercooked meat (or eggs) from an intermediate host  can lead to infestation. Bradyzoite cysts (Fig. 11.34) can rupture  to release tachyzoites, the proliferating active form, stimulating  an inflammatory reaction. Conceptually it may be helpful to  think of an acute phase and a long-term chronic phase of infec¬  tion; during the latter new retinochoroidal scars may form  asymptomatically over the course of years or decades. A critical  mode of human infection is transplacental haematogenous  spread to the fetus in a pregnant woman with active (not inactive  latent) toxoplasmosis - this is usually primary infection in an  immunocompetent host but occasionally reactivation of latent  infection, the latter predominantly in the immunocompromised.    Occasionally infection may be transmitted via organ transplanta¬  tion or blood transfusion.   • Congenital toxoplasmosis. The mother is often symptom-  free or has only mild constitutional manifestations. The  severity of fetal involvement is related to the duration of  gestation at the time of maternal infection, tending to be  more severe in early pregnancy, when fetal death may result  (10% of all congenital toxoplasmosis). Neurological and  visceral involvement may be very severe, but many cases are    subclinical, especially in later pregnancy. Retinochoroiditis  may occur in over 75%, leaving scars that are commonly a  later incidental finding (Fig. 11.35).   • Postnatal childhood acquisition probably accounts for over  50% of cases of childhood toxoplasmosis; as with adults, in  immunocompetent patients this is usually subclinical.   Ocular lesions are probably common, but may not develop  for years after the initial infection.   • Acquired toxoplasmosis in immunocompetent adults is  subclinical in 80-90%. Cervical lymphadenopathy, fever,  malaise and pharyngitis are common features in  symptomatic patients, but more serious systemic  manifestations are rare. Early retinitis may occur in up to  20%.   acquired or result from reactivation of pre-existing disease.  As well as the constitutional symptoms occurring in the  immunocompetent, meningoencephalitis, pneumonitis,  retinochoroiditis and a range of other features can occur.   Toxoplasmosis constitutes 20-60% of all posterior uveitis. Reac¬  tivation at previously inactive cyst-containing scars is the rule in  the immunocompetent, although a minority represent new infec¬  tion. More than half of quiescent retinal lesions will have been  acquired from postnatal infection. Recurrent episodes of inflam¬  mation are common and occur when the cysts rupture and release  hundreds of tachyzoites into normal retinal cells. First   Fig. 11.35 Retinochoroidal scars in congenital  toxoplasmosis. (A) Macular lesion; (B) multiple peripheral  scars on wide-field imaging; (C) wide-field autofluorescence  image of the eye in (B)    presentation with symptomatic ocular infection occurs at an  average age of 29 years, perhaps due to decreasing specific immu¬  nity. Ocular involvement from congenital infection may only be  detected later in life with the incidental discovery of typical retino¬  choroidal scars, though occasionally macular or optic nerve  damage may impair vision in childhood. Pregnancy may provoke  the recurrence of ocular toxoplasmosis in the mother, during  which it may be resistant to treatment.   • Symptoms. Unilateral acute or subacute onset of floaters,  blurring and photophobia.   • A single inflammatory focus of fluffy white retinitis or  retinochoroiditis associated with a pigmented scar (‘satellite  lesion’) is typical (Fig. 11.36A). Lesions tend to involve the  posterior pole.   • De novo foci not associated with an old scar, and multiple  lesions (Fig. 11.36B) are relatively uncommon in the  immunocompetent but occur more frequently in the  immunocompromised.   • Extensive and fulminant retinal involvement is  generally confined to the immunocompromised, in whom  it may be bilateral and difficult to distinguish from viral  retinitis.   • Retinochoroiditis may be absent in the acute phase of  acquired disease, with activity consisting of anterior uveitis,  vitritis and retinal vasculitis; typical retinal scars may form  later.   is rare, and may be a marker of acutely acquired rather than  reactivated infection.   • Punctate outer retinal toxoplasmosis is an atypical  manifestation featuring clusters of small (25-75  diameter) grey-white lesions.   • Visual loss. Causes of permanently reduced vision (around  25% of eyes) include macular inflammatory lesions (Figs  11.37A and B) and oedema, optic nerve involvement (Figs  11.37C), vascular occlusion (Figs 11.38A and B), serous,  rhegmatogenous and tractional retinal detachment   (Figs 11.38C and D), and late secondary choroidal  neovascularization (Figs 11.38E and F).   • Healing in immunocompetent hosts usually occurs  spontaneously within 6-8 weeks, although vitreous opacities  take longer to clear. The inflammatory focus is replaced by a  sharply demarcated atrophic scar that develops a pigmented  border (Fig. 11.39).   • Recurrence. The average number of recurrent attacks per  patient is 2.7; within five years more than half of patients  may experience a further episode.   (Courtesy of S Chen - fig. A; C Pavesio - figs B and C)   (A) Macular involvement, at presentation and (B) following  treatment; (C) juxtapapillary lesion involving the optic nerve  head   Fig. 11.38 Uncommon complications of Toxoplasma retinitis. (A) Periarteritis resulting in branch retinal artery occlusion;  (B) FA shows extensive non-perfusion at the posterior pole; (C) serous macular detachment; (D) FA of (C) shows  hyperfluorescence due to pooling of dye; (E) choroidal neovascularization adjacent to an old scar; (F) FA of (E) shows  corresponding hyperfluorescence   (Courtesy of C Pavesio - figs A-D; P Gili - figs E and F)   Fig. 11.39 Progression of Toxoplasma retinitis. (A) Moderate  activity; (B) 3 months later, following antibiotic treatment   • Serology. Toxoplasma IgG antibodies are detectable in the  serum within 1-2 weeks of initial infection, and indicate  exposure to the organism at some point in the past,  providing circumstantial evidence to support clinical  suspicion. However, community seroprevalence is high - at  least a third of individuals in most communities. Positivity  to IgM antibodies usually means that infection has been  acquired within the last year, and so helps to distinguish  between acute (newly acquired) and chronic infection; it is a  critical test if newly acquired infection is suspected during  pregnancy. Occasionally IgM is positive due to persistence or  reactivation following earlier infection.   • PCR testing of intraocular fluid is variably sensitive  (16-67%) but highly specific and can be diagnostic in  clinically uncertain cases. Aqueous and vitreous probably  give similar yields.    • Ocular fluid antibody assessment. Calculating the ratio  (Goldmann-Witmer coefficient) of specific IgG in aqueous  humour to that in serum seems to be a reasonably sensitive  (48-90%) investigation.   • Imaging. Macular OCT will demonstrate any macular  oedema if vitritis is not preventative. B-scan ultrasonic  imaging can be used to exclude retinal detachment in the  presence of severe vitritis. FAF (see Fig. 11.35C) may facilitate  monitoring of inflammatory activity.   Evidence for the efficacy of current regimens is limited; eradica¬  tion of the parasite has not been demonstrated but parasite activity  and multiplication may be reduced, with a decrease in size of the  eventual retinochoroidal scar. The agents used have potential for  significant morbidity, and as spontaneous resolution generally  occurs, treatment is not administered in every case. Clear indica¬  tions include a sight-threatening lesion involving the macula, pap-  illomacular bundle, optic nerve head or a major blood vessel, for  severe vitritis and in the immunocompromised. Treatment of  congenital toxoplasmosis in neonates with antimicrobials for one  year may reduce the frequency of subsequent development of  retinochoroidal scars.   • Prednisolone (1 mg/kg) is given initially and tapered  according to clinical response, but should always be used in  conjunction with a specific anti -Toxoplasma agent, most  frequently pyrimethamine combined with sulfadiazine  (‘classic’ or ‘triple’ therapy, sometimes supplemented with  clindamycin). Some authorities start steroids only after  24-48 hours of antimicrobial therapy. Systemic steroids  should be avoided or used with extreme caution in  immunocompromised patients.   • Pyrimethamine is a folic acid antagonist that is believed to  be highly effective. It is administered as a loading dose of  75-100 mg for 1-2 days followed by 25-50 mg daily for 4  weeks in combination with oral folinic (not folic) acid 5 mg  three times a week to retard thrombocytopenia, leukopenia  and folate deficiency. Weekly blood counts should be  performed. In acquired immunodeficiency syndrome (AIDS)  pyrimethamine is avoided or used at a lower dosage because of  possible pre-existing bone marrow suppression and the  antagonistic effect of zidovudine when the drugs are combined.   • Sulfadiazine 1 g four times daily for 3-4 weeks is usually  given in combination with pyrimethamine. Side effects of  sulfonamides include renal stones, allergic reactions and  Stevens-Johnson syndrome.   • Intravitreal therapy with clindamycin (1 mg) and  dexamethasone (400 jag) may be as effective as triple therapy  in reactivated infection; two to three injections (two-weekly  intervals) may be required. It may be preferred in recurrent  infection in pregnancy, but would not generally be used in  isolation in the immunocompromised, and in newly  acquired (IgM-positive) infection systemic therapy has  apparently superior efficacy. Depot steroid intra- and  periocular preparations such as triamcinolone should   • Azithromycin 250-500 mg daily shows evidence of reducing  the rate of recurrence of retinochoroiditis and its use in  combination with pyrimethamine, folinic acid and  prednisolone is a promising newer regimen. Clarithromycin  may be a good alternative to azithromycin.   • Co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole  800 mg) twice daily in combination with prednisolone is a  lower-cost and better-tolerated option that might not be  quite as effective as classic therapy.   • Clindamycin 300 mg four times daily may be added to triple  therapy (see above) or used instead of pyrimethamine.  Pseudomembranous colitis is a potential adverse effect.   • Atovaquone theoretically attacks encysted bradyzoites, but  does not seem to prevent recurrence in vivo ; dosing is   • Topical steroid and mydriatic may be given for anterior  uveitis.   • Pregnancy. Treatment of recurrent ocular toxoplasmosis  during pregnancy should be chosen carefully and only  started if clearly necessary; management should be  multidisciplinary. Several of the drugs discussed above have  the potential to harm the fetus. Intravitreal therapy (see  above) for reactivated disease, or systemic treatment with  azithromycin, clindamycin and possibly prednisolone may  be appropriate. Specific treatment to prevent transmission to  the fetus is not generally given except in newly acquired  infection, when urgent specialist management is appropriate;  spiramycin alone or in combination is commonly chosen.   Toxocariasis is caused by infestation with a common intestinal  ascarid (roundworm) of dogs, Toxocara canis ; puppies are more  commonly infected than adult dogs, and are also more likely to  spread the organism. The feline variant - Toxocara cati - may also  be causative. Human infestation is by ingestion of soil or food  contaminated with ova shed in canine faeces; young children are  at particular risk from the soil of parks and playgrounds. Once  ingested, ova develop into larvae, which penetrate the intestinal  wall and travel to various organs such as the liver, lungs, skin,  brain and eyes, with resultant inflammation (Fig. 11.40).   • Visceral toxocariasis (VT), also known as visceral larva  migrans (VLM) is systemic infection of variable severity that  usually occurs in a child aged 2-7 years. Fever, abdominal  pain, pneumonitis, lymphadenopathy, hepatomegaly and  myocarditis are some of the possible features. Spontaneous   Fig. 11.40 Toxocara canis larva surrounded by an  inflammatory tissue reaction   (Courtesy of CA Hart and P Shears, from Color Atlas of Medical Microbiology,  Mosby 2004)    recovery is usual; death is very rare, and usually occurs in  individuals hypersensitive to parasitic antigens.   • Ocular toxocariasis (OT) (ocular larva migrans - OLM)  generally occurs independently of VLM, and is associated  with a lower parasitic load. It is typically unilateral, and in  around two-thirds causes some degree of permanent visual  impairment. In contrast to VT, it tends to occur in older  children and adults.   o Chronic endophthalmitis (Fig. 11.41) typically presents  with leukocoria, strabismus, floaters or unilateral visual  loss. Features may include anterior uveitis, vitritis,  chorioretinitis, papillitis and a fundus granuloma (see  below). A dense greyish-white exudate, similar to the  snowbanking seen in pars planitis, may involve the  peripheral retina and pars plana. Complications include  tractional retinal or ciliary body detachment with  hypotony leading to phthisis bulbi; the visual prognosis is  often poor.   inflammation (Fig. 11.42) classically presents in an older  child or adult with unilateral impaired vision or as an  incidental finding. A 1-2 disc diameter-sized round  yellow-white granuloma is present in the posterior  fundus or periphery. Vitreoretinal traction may lead to  complications due to macular distortion and/or retinal  detachment.   • Full blood count. Eosinophilia may be present, particularly  in VLM, and can become chronic.   Fig. 11.41 Chronic Toxocara endophthalmitis. (A) Leukocoria; (B) peripheral exudation and vitreoretinal traction bands;   (C) ultrasonography shows a vitreoretinal traction band; (D) a pathological specimen shows an inflammatory mass and  total retinal detachment   (Courtesy of N Rogers - figs A and C; S Lightman - fig. B; J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 - fig. D)   • Serology. Antibodies to Toxocara canis are detectable in only  about 50% of ocular cases. Positivity is common in the  general population (14% overall in the USA).   • Aqueous or vitreous sampling for eosinophilia, antibody  detection and PCR.   • Biopsy of a granuloma of the skin or elsewhere for larvae is  sometimes possible.   • Anthelmintic agents such as mebendazole and  thiabendazole can be considered in OT, noting that worm  death may promote inflammation.   Onchocerciasis, which affects the eyes and skin, is the second most  common cause of infectious blindness in the world. It is endemic  in areas of Africa and other regions, and disease is particularly   Fig. 11.42 Toxocara granuloma. (A) Juxtapapillary granuloma;  (B) peripheral granuloma with a vitreous band extending to  the disc   (Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases,  Mosby 1997 - fig. A)    severe in savanna regions, where in some areas more than 50%  of older adults are blind from the condition. Chronic onchocer¬  ciasis shortens lifespan by reducing resistance to other diseases.  The parasitic helminth Onchocerca volvulus is causative; the  vector is the Simulium blackfly, which breeds in fast-flowing  water, hence the colloquial term ‘river blindness’. Larvae are trans¬  mitted when the fly bites to obtain blood; they migrate to subcu¬  taneous sites to form onchocercomas, where microfilariae are  produced by adult worms (Fig. 11.44). Degenerating microfilariae  excite an intense inflammatory reaction accounting for most of  the clinical manifestations of the disease. The rickettsia Wolbachia  lives symbiotically in adult worms and microfilaria and is impor¬  tant for microfilarial production. Diagnosis is by skin-snip biopsy,    serology, tear or urine antigen detection (oncho-dipstick) and  PCR of lesion fluid.   • Systemic features are principally dermatological and include  pruritus, a maculopapular rash (onchodermatitis - Fig.  11.45A) involving the buttocks and extremities, and areas of  hypo- and hyperpigmentation on the shins (‘leopard skin’   - Fig. 11.45B); scratching of itchy areas leads to  lichenification. Onchocercomata are non-tender  subcutaneous nodules (Fig. 11.45C) that enclose 2-3 adult  worms. Severe lymphadenopathy can occur, with secondary  lymphoedema. Eosinophilia is typical.   • Live microfilariae may be seen in the cornea, vitreous and  suspended in the anterior chamber after the patient has   postured face-down for a few minutes followed by  immediate slit lamp examination.   • Anterior uveitis is an early feature. Pear-shaped pupillary  dilatation may be seen, and is due to posterior synechiae.   • Keratitis. Punctate keratitis (snowflake opacities) affects a  third of patients and consists of infiltrates surrounding dead  microfilariae; initial lesions are most commonly located   at 3 and 9 o’clock in the anterior third of the stroma  (Fig. 11.46A). Slowly progressing sclerosing keratitis may  eventually involve the entire cornea (Fig. 11.46B).   • Chorioretinitis is usually bilateral and predominantly  involves the temporal fundus, sparing the macula until late.  Widespread choroidal sclerosis and atrophy can ensue (Fig.  11.46C). A perpetuating autoimmune response is    hypothesized for progressive longer-term chorioretinopathy  that may persist after control of infection.   • Ivermectin (supplied in many countries by Merck at no  charge) kills microfilariae (but not adult worms) and is  given at least annually for many years. It has been effective  in substantially reducing transmission rates and morbidity,  and no recent new cases have been reported in many  communities. Ivermectin occasionally precipitates  inflammation, so prophylactic prednisolone may be  considered in patients with visible anterior chamber   Fig. 11.46 Ocular onchocerciasis. (A) Moderate and (B)  advanced corneal scarring; (C) choroidal pigment clumping  and chorioretinal atrophy    microfilariae. Ivermectin may cause toxic encephalopathy in  patients with Loa loa infection.   • Moxidectin is a newer drug that may be superior to  ivermectin.   • Doxycycline 100-200 mg per day for six weeks targets  Wolbachia , indirectly preventing microfilarial embryogenesis  and substantially reducing numbers for an extended period.  It also has some effect on adult worms, and may be a useful  adjunct to ivermectin or moxidectin.   • Suramin is effective against adult worms. It is given  intravenously.   Cysticercosis refers to infection by Cysticercus cellulosae , the larval  form of the pork tapeworm Taenia solium. Ingesting cysts of T.  solium in undercooked pork leads to intestinal tapeworm develop¬  ment (taeniasis); the infested human then sheds eggs that lead to  larval infection (cysticercosis) when ingested by the same or  another individual. Inflammation develops in response to antigens  released by dead organisms.   • Systemic disease may involve the lungs, muscle and CNS  (neurocysticercosis). MRI and CT imaging are effective at  demonstrating cysts; plain X-rays may show calcified cysts.  Serology and stool analysis are useful for diagnosis.   • Ocular features include cysts of the conjunctiva and  occasionally the orbit and eyelids. The anterior chamber  may show a free-floating cyst (Fig. 11.47A). Larvae entering  the subretinal space can cause exudative retinal detachment  (Fig. 11.47B); they can also pass into the vitreous where  released toxins can incite an intense vision-threatening  inflammatory reaction.   Systemic steroids to control inflammation are combined with sur¬  gical removal of the larvae from the anterior chamber, vitreous  and subretinal space. Anthelmintic agents such as albendazole  may be appropriate in systemic disease, but should be used with  caution under specialist guidance, and often with steroid  co- administration.   DUSN is a clinical syndrome due to the presence of a single  motile subretinal nematode such as Toxocara canis , Baylisascaris  procyonis and Ancylostoma caninum. Misdiagnosis (e.g. multifocal   choroiditis) is common as the worm is often small and may be  overlooked.   • Presentation is with insidious monocular visual decrease;  diagnosis is essentially clinical. Electroretinography (ERG) is  subnormal, even in early disease.   • Acute disease. Crops of grey-white outer retinal lesions  (Fig. 11.48A), vitritis, papillitis and retinal vasculitis.   • End-stage disease. Optic atrophy, retinal vascular  attenuation and diffuse RPE degeneration (Fig. 11.48B).   Photocoagulation (200 pm, 0.2-0.5 s, 150-300 mW) is the treat¬  ment of choice when a worm can be visualized (<50%); if neces¬  sary a slit beam or very light laser burns are first used to shepherd  (sometimes lure) the photosensitive nematode away from the  fovea. Systemic albendazole (400 mg for 30 days) or vitrectomy  may be appropriate in some cases. Steroid cover may be prudent  with all treatment modalities.   Human immunodeficiency virus infection/acquired immuno¬  deficiency syndrome (HIV/AIDS) is transmitted by unprotected  sexual intercourse (heterosexual contact overall globally but sex  between men in wealthier countries), via contaminated blood or  needles, and vertically from mother to child transplacentally,  during birth or breastfeeding. HIV depletes CD4 + T cells, which  are vital to the initiation of the immune response to pathogens.  Although there is currently no cure or vaccine, the progression of  disease can be slowed radically by combination drug therapy:  highly active antiretroviral therapy (HAART). Prophylaxis against  opportunistic infections may also be instituted.   (Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases,  Mosby 1997 - fig. A; C de A Garcia - fig. B)    Fig. 11.49 Examples of AIDS-defining clinical conditions. (A) Kaposi sarcoma; (B) HIV wasting syndrome   • Stages of infection: (1) a flu-like illness may occur 2-4 weeks  after infection, sometimes including a rash; (2) clinical  latency is a predominantly asymptomatic period of several  (average 8) years, sometimes with minor clinical features  such as persistent generalized lymphadenopathy; (3) AIDS  develops in about half of HIV-infected patients within 10  years and is defined as HIV infection with either a CD4 + T  count <200 cells/pl or the development of one or more  AIDS-defining conditions.   • AIDS-defining clinical conditions include particular  opportunistic infections such as respiratory or oesophageal  candidiasis, Pneumocystis jirovecii pneumonia,  cryptosporidiosis and cytomegalovirus retinitis, specific  tumours including Kaposi sarcoma (Fig. 11.49A) and certain  lymphomas, and other manifestations such as HIV wasting  syndrome (Fig. 11.49B) and progressive multifocal  leukoencephalopathy.   • Eyelid. Blepharitis, Kaposi sarcoma, multiple molluscum  lesions and herpes zoster ophthalmicus.   • Conjunctiva. Kaposi sarcoma, squamous cell carcinoma and  microvasculopathy (up to 80%).   • Cornea. Keratoconjunctivitis sicca and an increased  incidence of keratitis, e.g. herpes simplex and zoster, and  fungal.   • Anterior uveitis associated with ocular infections, or  (commonly) with drug toxicity, e.g. rifabutin, cidofovir.   • HIV-related retinal microangiopathy. Retinal  microangiopathy is the most frequent retinopathy in patients  with AIDS, developing in up to 70% of patients. It is  associated with a declining CD4 + count and higher plasma  HIV-RNA levels and is a marker for increased    cytomegalovirus (CMV) retinitis risk. Postulated causes  include immune complex deposition, HIV infection of the  retinal vascular endothelium, and abnormalities of flow. It  manifests with cotton-wool spots and/or retinal  haemorrhages (Fig. 11.50) and sometimes capillary  abnormalities such as microaneurysms. In contrast to CMV  retinitis, lesions are usually asymptomatic and almost  invariably disappear spontaneously after several weeks.   • Other viral retinitis: cytomegalovirus retinitis (most  common), progressive retinal necrosis, acute retinal necrosis.   • Neuro-ophthalmological. Usually secondary to meningitis  or encephalopathy due to an opportunistic infection (e.g.  toxoplasmosis, cryptococcosis, neurosyphilis) or neoplastic  process (e.g. CNS lymphoma).   Infection with cytomegalovirus (CMV), a herpesvirus, is very  common in the general population, causing no or minimal con¬  stitutional symptoms in most healthy individuals. CMV retinitis  is seen in patients immunocompromised from a variety of causes;  it is a common opportunistic ocular infection in patients with  AIDS, in whom it may represent reactivation of latent infection.  Without treatment, severe visual loss is essentially inevitable. Since  the advent of HAART the incidence and severity have declined,  though the prevalence remains high, partly due to increasing sur¬  vival rates in AIDS patients, in whom systemic steroid therapy may  be a risk factor. There is a very strong association with a low CD4 +  count.   Severe involvement of a range of organs including the lungs, CNS  and skin can occur in the immunocompromised.   • Presentation is with reduced vision from macular  involvement or with floaters from vitritis. One eye is usually  affected initially, progressing to both eyes in 50% of patients  if untreated. Indolent retinitis (see below) frequently starts  in the periphery without symptoms and progresses over  weeks.   • Anterior uveitis can occur but is usually mild with little  or no injection; it is considered separately later in this  chapter.   • Vitritis is typically mild, except in immune recovery (see  below).   • Retinitis. The characteristic appearance is of one or two  areas of dense white retinal infiltration associated  prominently with flame-shaped retinal haemorrhages  (‘pizza pie’ or ‘Margherita pizza’), beginning peripherally  (centrally in 10%) and extending along the course of the  vascular arcades. Peripheral areas tend to appear granular,  with fewer rounder haemorrhages and little vasculitis.  Indolent (more peripheral and less aggressive - Fig. 11.51A)  and fulminant (Fig. 11.51B) clinical patterns have been  distinguished.   • Optic neuritis (Fig. 11.51C) may result from direct spread or  from primary involvement.   • Retinal necrosis is evident in areas where active  inflammation has settled, leaving irregular pigmentation,  atrophy and holes frequently leading to retinal detachment  (Fig. 11.51D), a major cause of visual morbidity (up to 50%).   • Frosted branch angiitis (FBA) describes marked vascular  sheathing that occurs in about 6% (see Fig. 11.51D); this  appearance is seen in other conditions, and the term is also  used for a distinct idiopathic disorder (primary FBA).    • Immune recovery uveitis (IRU). This is a cause of limited  visual outcome in CMV retinitis, thought to be due to a  rejuvenated immune response against residual viral antigen  following immune reconstitution with HAART.  Manifestations can be severe, progressing to phthisis in some  cases.   • HAART is the mainstay of management, restoring the  patient’s innate ability to suppress CMV activity.  Discontinuation of antiviral treatment is considered when  the CD4 + count reaches >100-150 cells/pl   • Valganciclovir is a pro-drug of ganciclovir that is taken  orally and is as effective for both induction (900 mg twice  daily for up to 3 weeks) and maintenance (900 mg daily).  Neutropenia is a common side effect due to bone marrow  suppression, but can be effectively treated with filgrastim  (granulocyte colony-stimulating factor).   • Ganciclovir, foscarnet and cidofovir given intravenously  were formerly key therapeutic agents, but substantial side  effects have largely led to their relegation to reserve status.   • Ganciclovir slow-release intravitreal implant (Fig. 11.52) is  now less commonly used but still has utility in situations  such as intolerance of systemic treatment. It is as effective as  intravenous therapy, and the duration of efficacy is 8  months. Intravitreal injection of other agents such as  fomivirsen and cidofovir may occasionally be indicated.   • Vitrectomy with endolaser demarcation and silicone oil  tamponade is successful in around 75% of CMV-related  retinal detachments.   • Steroids may be required for IRU, though intravitreal and  systemic administration should be used with caution.   • Screening of patients with low CD4 counts: 3-monthly <  50/pi, 6-monthly 50-100/pl, yearly if >ioo/pl   Progressive retinal necrosis (PRN; also known as progressive - or  posterior - outer retinal necrosis, PORN) is a rare but devastating  necrotizing retinitis usually caused by varicella zoster virus (VZV);  other herpesviruses have been implicated. It occurs predominantly  in AIDS, but may be associated with other immunocompromised  states, particularly drug-induced. The prognosis is always  extremely guarded, with no perception of light the outcome in  more than half of affected eyes.   • Presentation is with rapidly progressive unilateral or  bilateral visual loss.   • Anterior uveitis and vitritis are minimal, in contrast to  CMV retinitis and ARN (see below).    Fig. 11.51 Cytomegalovirus retinitis. (A) Indolent retinitis with typical granular appearance; (B) fulminating disease;   (C) advanced disease involving the optic nerve head; (D) large posterior retinal tear with shallow localized detachment -  there is vascular sheathing reminiscent of frosted branch angiitis   o Early. Multifocal homogeneous yellow-white deep retinal  infiltrates. The macula may be involved at an early stage,  often giving a cherry-red spot (Fig. 11.53A).  o Established/middle. The signs typically spread rapidly  around the retina, with very extensive full-thickness  necrosis (Fig. 11.53B). Signs of vasculitis are absent or  mild, and significant haemorrhage is uncommon.   o Late. Scarring is plaque-like and characterized as ‘cracked  mud’. Rhegmatogenous retinal detachment (RRD) is very  common, as is optic atrophy.   Vitreous and/or aqueous PCR assay for viral DNA; antibody assay  is less effective.   Immune rescue with HAART together with aggressive antiviral  therapy, e.g. intravitreal and intravenous ganciclovir and foscar-  net. Vitreoretinal surgery for retinal detachment often yields poor  results.   Acute retinal necrosis (ARN) is a rare but devastating necrotizing  retinitis. It typically affects otherwise healthy individuals, but  tends to be caused by herpes simplex virus (HSV) in younger and  VZV in older patients; other herpesviruses are suspected. The  prognosis is relatively poor, with more than half of patients even¬  tually achieving only 6/60 as a result of retinal and optic nerve  ischaemia or RRD.   Fig. 11.52 Slow-release ganciclovir implant used in the  treatment of cytomegalovirus retinitis - there is an  associated localized lens opacity    • Systemic features. ARN has been reported following and  occurring simultaneously with HSV encephalitis and  herpetic skin infection.   • Ocular features. Presentation is initially unilateral with  blurred vision and floaters. Pain is usually a feature. The  American Uveitis Society defines criteria for diagnosis:   1. Prominent anterior uveitis and vitritis (panuveitis).  Episcleritis and scleritis may occur.   2. One or more discrete foci of peripheral retinal necrosis.  Deep yellow-white infiltrates with well-defined borders are  seen (Figs 11.54A, B and C). Retinal haemorrhages can  occur, but are generally less prominent than in CMV  retinitis. The acute lesions resolve after 6-12 weeks, leaving  behind necrotic retina with hyperpigmented borders.  Secondary RRD is a major cause of visual morbidity.   3. Circumferential spread of retinal involvement. Posterior  pole involvement is late. Optic neuritis is sometimes a  feature.   4. Occlusive retinal vasculitis including arteritis. Preretinal  neovascularization can develop and may lead to vitreous  haemorrhage.   • Aciclovir: intravenously (10 mg/kg every 8 hours) for 10-14  days and then orally 800 mg five times daily for 6-12 weeks.  This may hasten resolution of the acute retinal lesions and    dramatically reduces the risk of second eye involvement.  Long-term therapy is occasionally required.   • Oral valaciclovir or famciclovir may be substituted for oral  aciclovir, with similar outcomes but better tolerability.   • Systemic steroids may be started 24 hours after initiation of  antiviral therapy, especially in severe cases.   • Laser retinopexy around necrotic areas may be used to try  to prevent RRD but is controversial.   Fig. 11.53 Progressive retinal necrosis. (A) Early macular  involvement; (B) established disease resulting from  confluence of multiple foci - there is little or no  haemorrhage   (Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases,  Mosby 1997 - fig. A; B Bodaghi - fig. B)   Fig. 11.54 Acute retinal necrosis. (A) Peripheral infiltrates  with well-defined borders - there is vitreous haze, and a  few perivascular haemorrhages; (B) advanced disease  reaching the posterior pole; (C) full-thickness retinal  necrosis   (Courtesy of S Kheterpal - fig. A; C Barry - fig. B)   Anterior uveitis may occur with or without active corneal disease  (see Ch. 6). Patchy and occasionally sectoral iris atrophy that  includes the pigment epithelium (Fig. 11.55A) is common, as  is elevated IOP. The pupil may be larger than its fellow. As in  Fuchs uveitis syndrome, KPs may be fine, stellate and diffusely  distributed across the cornea, but can also be large and grouped.  There is often a past history of herpes simplex keratitis, cold  sores and sometimes genital herpes. Recurrent episodes of her¬  petic iritis involve the same eye in almost all patients. Distinguish¬  ing herpetic from cytomegalovirus iridocyclitis (see below) can be  difficult.   Fig. 11.55 (A) Iris atrophy in herpes simplex anterior uveitis;  (B) sectoral iris atrophy in herpes zoster anterior uveitis   Topical steroids (e.g. prednisolone acetate 1% four times daily)  and a topical cycloplegic, in concert with an oral antiviral (e.g.  aciclovir 400 mg five times a day; famciclovir or valaciclovir may  be superior). Steroids may be delayed and used with caution if  active epithelial disease is present, when a topical antiviral may be  added. Raised IOP is treated as necessary.   Anterior uveitis of variable severity occurs in around 50% of  patients with herpes zoster ophthalmicus (HZO), and is generally  of onset 1-3 weeks after the acute skin rash (occasionally in patients  with HZO without dermatitis - zoster sine herpete). Zoster-  associated iridocyclitis may be recurrent, when diagnosis is usually  straightforward due to a past history of ipsilateral HZO. As with  herpes simplex, signs may be of granulomatous inflammation,  sectoral iris atrophy is often present (Fig. 11.55B), corneal sensation  may be reduced and IOP raised. PCR analysis of aqueous is indi¬  cated exceptionally. Anterior segment inflammation can occur in  primary VZV infection (chicken pox), particularly in the immu¬  nocompromised; neuroretinitis is rare. Uveitis has been reported  following VZV vaccination.   Topical steroids and mydriatics, in addition to standard systemic  antiviral treatment of shingles. Systemic steroids are required  rarely (e.g. optic neuritis). All patients with HZO must be moni¬  tored by an ophthalmologist dependent on severity, e.g. up to  weekly for at least 6 weeks to detect occult ocular inflammation,  and subsequently possibly long-term to detect late complications.  Persistence or recurrence of anterior uveitis may respond to a  week-long course of aciclovir 800 mg five times a day, and long¬  term systemic antiviral prophylactic treatment may be considered  for repeated recurrence. VZV vaccination offers protection against  shingles. See also Chapter 6.   Cytomegalovirus (CMV) iridocyclitis in the immunocompetent is  now thought to be more common than previously realized, albeit  still less prevalent than HSV- and VZV-related inflammation. It  may be recurrent or chronic, and unilateral or bilateral. Elevated  IOP is very common, and CMV has been reported as a cause of  Posner-Schlossman (see Ch. 10) and Fuchs uveitis syndromes.  Little or no ciliary injection, very limited flare, few cells, corneal  endotheliitis, KP of a range of morphology and sectoral iris  atrophy have been reported. Posterior synechiae are rare. A key    diagnostic indicator, in some cases only, may be a failure to  respond to aciclovir and/or steroids; PCR and antibody assay of  an aqueous sample should be considered if there is clinical  suspicion.   Oral valganciclovir in proven infection, which sometimes requires  long-term continuation. IOP elevation may be persistent.   Rubella (German measles) is a common childhood infection, and  usually follows a benign and short-lived course. However, trans¬  placental transmission of virus to the fetus from an infected  mother can lead to congenital abnormalities of multiple organ  systems, with severity generally worse the earlier in gestation infec¬  tion occurs. Latent rubella virus may cause chronic anterior uveitis  relatively unresponsive to steroids, and has been implicated in the  causation of Fuchs uveitis syndrome. Reported ocular features of  congenital rubella include cataract, anterior uveitis, ‘salt and  pepper’ pigmentary retinopathy (Fig. 11.56), glaucoma and  microphthalmos.   Congenital infection with the measles virus can cause spontaneous  abortion or congenital systemic and ocular anomalies including  cataract and retinopathy. Infection acquired in childhood typically  features conjunctivitis and epithelial keratitis; occasionally retini¬  tis with macular and disc oedema can occur. Subacute sclerosing  panencephalitis (SSPE) is a late complication of measles infection,  manifesting with chronic progressive neurodegenerative and  usually fatal disease of childhood caused by the measles virus.  Posterior uveitis (Fig. 11.57) is common, and maybe the presenting  feature.   • Presentation. POHS is usually asymptomatic unless macular  choroidal neovascularization supervenes; signs may be  discovered at a routine eye examination.   • Classic triad: (i) multiple white atrophic chorioretinal ‘histo’  spots about 200 pan in diameter (Fig. 11.58A); (ii)  peripapillary atrophy (Fig. 11.58B); (iii) vitritis is absent.  Linear midperipheral scars (Fig. 11.58C) also occur (5%).   • Choroidal neovascularization (CNV) is a late manifestation  occurring in less than 5% of affected eyes. It is usually  associated with a pre-existing macular histo spot. Associated  subretinal fluid and haemorrhage lead to a fall in vision  (Fig. 11.59).   • Acute chorioretinitis is almost always asymptomatic and  rarely identified, but discrete oval-round whitish lesions  <400 jam in diameter that may develop into classic punched-  out histo spots have been described.   Smallpox vaccination using the vaccinia virus has been resumed  for some groups as a result of the perceived risk of bioterrorism.  Though rare, a range of anterior segment manifestations has been  described, both from autoinoculation in vaccines and in close  contacts.    Skin antigen testing was of limited utility and may have worsened   • Serological testing is helpful if positive, but is usually  negative in the absence of systemic mycosis.   without treatment 60% of eyes with CNV have a final visual acuity   • Amsler grid testing of the fellow eye at least weekly,  particularly if a macular histo spot is present (25% risk of  CNV). Any role for antioxidant supplements is undefined.   Histoplasma capsulatum infection occurs following inhalation of  the yeast form of this dimorphic fungus, and can lead to the sys¬  temic mycosis histoplasmosis - pulmonary involvement is the  most common feature. It is common in AIDS. POHS is relatively  common in areas of endemic histoplasmosis (e.g. the Mississippi  river valley in the USA), implicating H. capsulatum in its aetiology.  This is reinforced by data from skin antigen testing, but has not  been established with certainty and it is possible that other causa¬  tive factors, including alternative infective agents, maybe involved.  It is believed most likely that eye disease represents an immune-  mediated response to microbial antigen, rather than immediate  damage due to active infection.   The fungus Pneumocystis jirovecii , a pulmonary commensal, is a  major cause of mortality in uncontrolled AIDS. Systemic antimi¬  crobial prophylaxis has replaced pulmonary-only preventative  treatment with inhaled pentamidine, and along with immune  reconstitution has dramatically reduced the incidence of Pneumo¬  cystis choroiditis. Multiple slowly progressing deep round yellow-  orange lesions (Fig. 11.60), commonly bilateral, are characteristic.  There is minimal vitritis, and visual loss is often negligible.   Cryptococcus neoformans , a dimorphic yeast, enters the body  through inhalation, and can spread to the eye in the bloodstream  or from the CNS via the optic nerve. As with pneumocystosis,  cryptococcosis was formerly responsible for much morbidity, but   Fig. 11.58 Presumed ocular histoplasmosis syndrome. (A)  Peripheral ‘histo’ spots; (B) circumferential peripapillary  atrophy and ‘histo’ spots; (C) linear streaks    clinically significant infection is now much less common since the  advent of more effective therapy for AIDS. Ocular involvement  may occur directly (e.g. multifocal choroiditis - Fig. 11.61) with  vasculitis and exudate or more commonly indirectly with papil-  loedema and ocular motility dysfunction.   Candida (usually the commensal C. albicans) can be introduced  into the eye from the external environment by trauma or surgery  or can spread from fungal keratitis, but endogenous infection is  an important alternative route. Risk factors for metastatic spread  include intravenous drug abuse, a septic focus associated with an  indwelling catheter, chronic lung disease such as cystic fibrosis,  general debilitation and diabetes. It is relatively uncommon in  AIDS.   Fig. 11.59 Choroidal neovascularization in presumed ocular  histoplasmosis. (A) The fovea shows a focal area of  oedema and a few small haemorrhages, and a small histo  spot temporally; (B) FA arterial phase shows a choroidal  neovascular membrane just above the fovea   Fig. 11.60 Choroidal pneumocystosis. (A) Multifocal choroidal  lesions; (B) large coalescent lesion   • Presentation. Systemic candidiasis may already have been  diagnosed; up to a third of patients with untreated  candidaemia will develop ocular involvement. Peripheral  fundus lesions may cause little or no visual disturbance  while central lesions or severe vitritis will manifest earlier.  Progression is typically much slower than bacterial  endophthalmitis. Bilateral involvement is common.   • Anterior uveitis is uncommon or mild in early disease but  may become prominent later.   • Chorioretinitis: one or more small creamy white lesions  with overlying vitritis (Fig. 11.62C). Retinal necrosis (Fig.  11.62D) may lead to retinal detachment, with severe  proliferative vitreoretinopathy.   • Vitreous biopsy (preferably using a vitreous cutter rather  than a needle) to identify the organism (PCR and culture)  and identify sensitivities.   • Antifungal treatment. The agent should be chosen with  local microbiological specialist guidance. Infectious Diseases  Society of America guidelines suggest intravenous  amphotericin-B in combination with oral flucytosine, but  resistance is a concern. Voriconazole orally or intravenously  has a broad spectrum of antifungal action with low reported  resistance and high ocular penetration; adjunctive  intravitreal treatment may be given (100 pg in 0.1 ml), with  serial injections probably needed.   • Pars plana vitrectomy should be considered at an early  stage, especially for severe or unresponsive disease; as well as  providing a substantial culture specimen, it reduces fungal  and antigen load, facilitates therapeutic agent penetration  and clears the ocular media.    Fig. 11.62 Candida endophthalmitis. (A) Severe vitritis; (B) ‘cotton ball’ colonies; (C) focal chorioretinitis; (D) retinal necrosis   Aspergillus species are common environmental fungi, but cause  disease in humans less commonly than Candida. Spores undergo  airborne spread, and risk factors for infection include intravenous  drug abuse, chronic lung disease, organ transplantation, and  blood disorders; neutropenia may be of particular importance.  Iridocyclitis and vitritis are common. Yellowish retinal and sub-  retinal infiltrates tend towards macular involvement (Fig. 11.63) at  an earlier stage than Candida infection; the disease progresses  more rapidly, and the visual outcome is often worse. Occlusive  retinal vasculitis is common. Systemic assessment is critical; endo¬  carditis presents a particular risk. Investigation and treatment is  similar to that of Candida endophthalmitis.   Coccidioides immitis acquired by inhalation usually causes a mild  pulmonary infection, but wider systemic involvement can occur,    and reinfection can lead to chronic lung disease. Ocular features  include severe granulomatous anterior uveitis and multifocal  choroiditis. Investigation and treatment is similar to that of  Candida endophthalmitis.   Tuberculosis (TB) is a chronic granulomatous infection usually  caused in humans by Mycobacterium tuberculosis. TB is primarily  a pulmonary disease but may spread by the bloodstream to other  sites; ocular involvement commonly occurs without clinically  overt systemic disease. Immune deficiency is a risk factor, when  atypical mycobacteria such as M. avium may cause disease.   • Anterior uveitis is common and is usually granulomatous;  iris nodules may be present. Broad posterior synechiae may  be formed.   • Vitritis is very common, and may be secondary to anterior,  intermediate or posterior primary foci. Macular  complications include cystoid oedema and epiretinal  membrane formation.   • Choroidal granuloma (tubercle): focal elevated dome¬  shaped lesions (Fig. 11.64A) that may be unilateral or  bilateral and solitary or multiple; extensive infiltration may  occur in AIDS (Fig. 11.64B). A very large abscess-like  tubercle is termed a tuberculoma.   • Choroiditis independent of tubercles, typically multifocal  and in a centrifugally spreading serpiginous pattern  (serpiginoid), has increasingly been recognized (Fig. 11.65).  Choroiditis that tracks retinal vessels may have reasonably  specificity for TB.   • Retinal vasculitis is preferentially venous. Retinal  haemorrhages are common. Vascular occlusion with  extensive ischaemia (Fig. 11.66) and preretinal or disc  neovascularization can occur. It is hypothesized that at least  some cases of Eales disease (see Ch. 13) represent a  hypersensitivity reaction to TB.   • Other manifestations include reddish-brown eyelid nodules  (lupus vulgaris), conjunctivitis, phlyctenulosis, interstitial  keratitis, scleritis, exudative retinal detachment and optic  neuropathy including neuroretinitis.   The diagnosis is often clinical, taking into account evidence of  previous TB exposure and other negative investigations.   • Systemic assessment by an appropriate specialist. Newer  investigations include sputum testing with PCR and the  interferon-gamma release assay (IGRA) blood test; this is  approximately as sensitive as skin testing (80% in active   Fig. 11.64 Tuberculous choroiditis. (A) Choroidal granuloma;  (B) diffuse infiltration in a patient with AIDS    disease) but has the advantage of being independent of  previous BCG vaccination. HIV status must be determined.  Chest X-ray, CT, positron emission tomography (PET)/CT  are among other tests that may be considered.   • Ocular. Aqueous or vitreous sampling rarely yields  demonstrable (smear - acid-fast bacilli on Ziehl-Neelsen  staining - or culture - Lowenstein-Jensen medium)  mycobacteria; PCR is highly specific but of variable  sensitivity. OCT is useful for macular evaluation. Fluorescein  angiography may be helpful in establishing whether  choroiditis is active, as well as confirming preretinal  neovascularization and demonstrating ischaemia. FAF allows  activity staging, lesions becoming progressively  hypoautofluorescent with healing.   • Prolonged multi-drug therapy (often four initially) should  be prescribed and monitored by a specialist with experience  in systemic TB management. If ethambutol is used,   Fig. 11.65 Serpiginoid tuberculous choroiditis. (A) Clinical  appearance - a granuloma is seen superiorly; (B) FA shows  corresponding areas of hyper- and hypofluorescence   monitoring for optic neuropathy should take place; rifabutin  can cause anterior uveitis. Non-adherence to treatment is  common.   • Topical and systemic steroids may be used concomitantly  to reduce inflammation-induced damage, particularly in the  early weeks of treatment, when they may retard paradoxical  worsening of the fundus appearance.   • Laser may be applied to ischaemic retina to treat preretinal  neovascularization.   Syphilis is caused by the spirochaete bacterium Treponema palli¬  dum. In adults the disease is usually sexually acquired when organ¬  isms enter through a skin or mucous membrane abrasion;  transmission by kissing, blood transfusion or percutaneous injury  is rare. Transplacental infection of the fetus can also occur, when    the mother has become infected during or shortly before preg¬  nancy (congenital syphilis - see Ch. 6).   • Primary syphilis is characterized by a painless ulcer  (chancre), commonly on the genitalia or anus.   • Secondary syphilis consists of a maculopapular rash (Fig.  11.67A) and other systemic features.   • Tertiary syphilis occurs in about 40% of untreated cases  and is characterized by cardiovascular manifestations such  as aortitis, neurosyphilis and gummatous infiltration  (Fig. 11.67B) of bone and viscera.   • Anterior uveitis occurs in about 4% of patients with  secondary syphilis; it may be granulomatous or   Fig. 11.66 Occlusive tuberculous periphlebitis. (A) Superior  retinal branch occlusion; (B) FA shows extensive  hypofluorescence due to capillary non-perfusion   Fig. 11.67 Acquired syphilis. (A) Maculopapular rash in  secondary disease; (B) gummatous infiltration of the  tongue in tertiary disease   (Courtesy of RT Emond, PD Welsby and HA Rowland, from Colour Atlas of  Infectious Diseases, Mosby 2003 - fig. B)   11.68 A) are dilated iris capillaries that may develop into  yellowish nodules. IOP may be elevated.   • Chorioretinitis is often multifocal (Fig. 11.68B), bilateral and  associated with vitritis; exudative retinal detachment can  ensue.   • Acute syphilitic posterior placoid chorioretinopathy  (ASPPC) is characterized by large pale-yellowish subretinal  lesions in the posterior pole (Fig. 11.68C); it is thought to be  due to retinal pigment epithelial infection and occurs more  commonly in the immunocompromised.   • Other features include conjunctivitis, episcleritis and  scleritis, intermediate uveitis, glaucoma, cataract and  miscellaneous neuro-ophthalmic features related to CNS  involvement including Argyll Robertson pupils (see Ch. 19).   • Systemic assessment by an appropriate specialist, including  lumbar puncture to rule out neurosyphilis. HIV status  should be established.   • Aqueous and/or vitreous sampling for PCR is sometimes  indicated, such as when HIV positivity makes serology less  reliable.   This should be under the supervision of an infectious diseases  specialist, but generally consists of an extended course of parenteral  penicillin. Alternatives may be required, for instance in penicillin  allergy, but are less effective, and parallel confirmatory allergen  testing and desensitization may be considered. Topical and sys¬  temic steroids may be given in conjunction with antibiotics to  ameliorate inflammatory damage. The Jarisch-Herxheimer reac¬  tion is a systemic response to treponemal antigens released on  commencement of therapy, and may include progression of ocular  signs.   Lyme disease (borreliosis), like syphilis, is caused by a spirochaete.  The responsible organism, Borrelia burgdorferi , is transmitted  through tick bites; deer are important vectors (Fig. 11.69A). An  adult tick (Fig. 11.69B) can be distinguished from a head louse by  the tick having eight legs - it is an arachnid - and the louse six  (though larval ticks have only six). The disease is endemic in  regions of North America, Europe and Asia, but can be difficult  to diagnose. Several days after a bite an annular skin lesion, ery¬  thema chronicum migrans (Fig. 11.69C) forms at the site in  60-80%, often accompanied by constitutional symptoms (stage 1).   Fig. 11.68 Ocular syphilis. (A) Roseolae; (B) old multifocal chorioretinitis; (C) acute posterior placoid chorioretinitis;  (D) neuroretinitis   (Courtesy of J Salmon - fig. B; C de A Garcia - fig. C)    Neurological (e.g. cranial nerve palsies, meningitis), cardiac (4-8%  e.g. arrhythmia) and other manifestations may follow within a few  weeks. Late (stage 3) complications include chronic arthritis of  large joints, polyneuropathy and encephalopathy. Some patients  develop chronic symptoms that may not respond to antibiotics.   These are varied; they tend to occur in established stage 2 and stage  3 (late) disease.   • Uveitis is relatively uncommon but can be anterior  (granulomatous or non-granulomatous), intermediate (the  most common), or posterior including multifocal  choroiditis, vasculitis and neuroretinitis.   • Other manifestations include early (stage 1) transient  conjunctivitis, bilateral stromal keratitis, episcleritis (Fig.  11.70), scleritis, orbital myositis, optic neuritis, papilloedema  and ocular motor and facial nerve palsy (up to 25% of facial  nerve palsy in endemic areas).   Serology should be performed at least a month after infection;  false positives can occur. PCR of CSF or synovial fluid is per¬  formed in appropriate cases. Diagnosis relies on a combination of  clinical features and positive serology. Co-infection with other  tick-borne diseases is possible.   Treatment of early acute disease is highly effective and involves  oral doxycycline (not children or in pregnancy), amoxicillin or  erythromycin. Untreated, many patients with early or asympto¬  matic disease will experience no further problems. Patients with  established disease, including ocular, may require extended intra¬  venous penicillin or ceftriaxone. Keratitis and uveitis may need  steroid treatment; systemic steroids should not be given without  concomitant antibiotics. Appropriate personal protection (cloth¬  ing, insect repellent) should be adopted in endemic areas to reduce   Fig. 11.69 Lyme disease. (A) Transmission; (B) tick attached  to eyelid; (C) severe erythema chronicum migrans   (Courtesy of RT Emond, PD Welsby and HA Rowland, from Colour Atlas of  Infectious Diseases, Mosby 2003 - fig. C)   the risk of tick bite. A Lyme disease vaccine is available, but does  not offer complete or prolonged protection.   Brucellosis is caused by the Gram-negative bacteria Brucella  melitensis and B. abortus. It is usually transmitted from animals to    man through milk products or uncooked meat. A variety of con¬  stitutional and ocular (20%) features are reported, the latter  including chronic anterior and posterior uveitis, papilloedema  and retinal haemorrhages. Investigation should include serology  and blood culture. Treatment is with a combination of two anti¬  biotics, e.g. streptomycin and doxycycline, with adjunctive ster¬  oids if required. Patients with known brucellosis should undergo  ophthalmic examination.   Roth spots develop in about 1% of cases of bacteraemia, but no  frank ocular infection occurs in the great majority of cases. A wide  range of organisms can be responsible - Gram-positives predomi¬  nate in North America and Europe and Gram-negatives in eastern  Asian. Risk factors include debilitating disease of many types as  well as other factors such as intravenous drug abuse; spread can  occur from any potential focus such as an indwelling catheter or  septic joint. Patients are usually systemically unwell, and mortality  is relatively high - 5-10%. The prognosis is poorer than with  postoperative endophthalmitis.   Diagnosis is frequently delayed. The main distinction is from  endogenous fungal endophthalmitis.   • Signs are broadly similar to those of postoperative  endophthalmitis (see Chapter 9), though retinal infiltrates  may be an early feature, reflecting the route of infection  (Fig. 11.71).   The search for a septic focus (blood and urine cultures, septic  arthritis, endocarditis, lumbar puncture etc.) should be in col¬  laboration with an appropriate physician and involve a search.   • Systemic infection is treated with intravenous antibiotics  according to clinical suspicion and local microbiological  advice. Broad spectrum empirical treatment may be  necessary.   • Endophthalmitis is treated with intravitreal and an oral  fluoroquinolone; the place of systemic steroids is undefined.  Pars plana vitrectomy may improve prognosis in some  patients.   Cat-scratch disease (bartonellosis) is caused by Bartonella henselae,  a Gram-negative rod. Infection is usually mediated transmitted by  the scratch (or bite) of an apparently healthy cat, though feline  contact is not always described. One or more red papules at the  site of inoculation are followed by fever and regional lymphaden-  opathy (Fig. 11.72), though general symptoms are frequently  absent; severe systemic disease occasionally occurs. The visual  prognosis is usually reasonable.   The eyes are affected in 5-10%: neuroretinitis (see Ch. 19) is the  most common manifestation and consists of disc oedema with  macular exudate in a star conformation (see Fig. 19.12B); interme¬  diate uveitis, focal retinochoroiditis, vasculitis, and conjunctivitis  with a 2-4 mm conjunctival granuloma (Parinaud oculoglandular  syndrome) may also be seen. Both eyes are involved in a  minority.   Oral antibiotics, e.g. co-trimoxazole, azithromycin, rifampicin or  ciprofloxacin (avoided in children). Steroids have been used in  some cases. Treatment is not usually given for mild systemic  symptoms alone.   Leprosy (Hansen disease) is a chronic granulomatous infection  caused by Mycobacterium leprae and M. lepromatosis. The mode  of spread remains uncertain, though nasal secretions have been  implicated. Infection is thought to lead to a chronic immune  response that leads to the peripheral neuropathy that is the  primary pathogenetic mechanism. Genetic factors are probably  important - only 5% of the general population is thought to be  vulnerable to leprosy on substantial contact with the organism.   • Borderline (multibacillary). The most common form.  Similar to tuberculoid, but more numerous and extensive  lesions.   • Lepromatous (multibacillary). Widespread cutaneous  thickening with leonine facies (Fig. 11.73A), peripheral  plaques and nodules, upper respiratory tract involvement   Fig. 11.72 Cat-scratch disease - ulcerated papule on the  cheek caused by a cat scratch 2 weeks previously, with  enlargement of submandibular lymph nodes   (Courtesy of BJ Zitelli and HW Davis , from Atlas of Pediatric Physical  Diagnosis, Mosby 2002)   Fig. 11.73 Lepromatous leprosy. (A) Leonine facies; (B) loss  of digits due to sensory neuropathy   (Courtesy of RT Emond, PD Welsby and HA Rowland , from Colour Atlas of  Infectious Diseases, Mosby 2003 - fig. A; CD Forbes and WF Jackson, from  Color Atlas and Text of Clinical Medicine, Mosby 2003 - fig. B)    and peripheral nerve lesions facilitating trauma that may  result in shortening and loss of digits (Fig. 11.73B).   • Iris pearls (pathognomonic): usually under 0.5 mm in  diameter (Fig. 11.74A).   • Keratitis: thickened, beaded corneal nerves, punctate  subepithelial lesions, pannus and vascularization.    • Miosis and iris atrophy (Figs 11.74B and C) result from  impaired dilator pupillae innervation.   • Other features: episcleritis and scleritis, retinal pearls, uveal  effusion, cataract, glaucoma, decreased corneal sensation,  facial nerve palsy, eyelid deformities and phthisis bulbi.   Fig. 11.74 Lepromatous chronic anterior uveitis. (A) Iris  pearls; (B) miosis; (C) iris atrophy   Skin, and occasionally ocular, specimens show acid-fast bacilli.  The lepromin test distinguishes between tuberculoid and lepro-  matous leprosy.   • Systemic. Combination regimens of extended duration with  antibiotics such as dapsone, rifampicin and clofazimine.   • Ocular. Anterior uveitis is treated with steroids. Specific  complications are addressed as indicated.    The conditions described below are uncommon inflammatory  disorders principally involving the posterior segment. Their aetiol¬  ogy is unknown or incompletely understood. Other entities may  present with similar clinical manifestations, and it is critical to  exclude alternative diagnoses including infection and neoplasia.  The ‘white dot syndromes’ (Table 11.9) constitute a subgroup with  some features in common; there is variation between sources in  the list of conditions falling into this category.   MEWDS is an uncommon idiopathic disease typically occurring  in young adult females; 25-50% describe a preceding viral-like  illness. Subsequent progression to AZOOR (see below) has been  reported in some patients.   • Presentation. Common: painless monocular blurring  (6/9-6/60) and photopsia; less common: floaters, scotomata,  dyschromatopsia.   ill-defined deep grey-white patches sparing the fovea, which  has a characteristic orange granular appearance and a dulled  reflex (Figs 11.75A and B).   (Courtesy of P Gili - fig. A; Moorfields Eye Hospital - fig. B)   • Recovery occurs over weeks, often leaving subtle residual  signs. Recurrence occasionally (10%) occurs.   • Visual fields. The blind spot may be enlarged; may show  other scotomata.   • FAF. Hyperautofluorescent spots corresponding to the  macular lesions are visible during active inflammation; FAF  has been used to demonstrate subclinical lesions in patients  with only foveal granularity (Figs 11.76A and B).   • FA shows subtle early hyperfluorescence of the dots with late  staining (Fig. 11.76C); occasionally vessel wall and disc  staining may be seen.   • ICGA shows hypofluorescent spots (Fig. 11.76D) that are  often more numerous than visible clinically or on FA.   • ERG shows a transiently reduced a-wave amplitude.  Electrooculography (EOG) and visual evoked response  (VER) abnormalities may be present.   Fig. 11.76 Multiple evanescent white dot syndrome. (A) Resolving lesions superior and temporal to the fovea; (B) appearance  on fundus autofluorescence; (C) FA arteriovenous phase shows subtle hyperfluorescent spots; (D) ICGA   This is generally not required, except for rare cases complicated  by choroidal neovascularization.   AIBSE is a rare condition reported in young to middle-aged  women. Features include photopsia and decreased vision, with  blind spot enlargement and mild disc swelling. Recovery to normal  or near-normal without treatment is usual. Some authorities  believe that AIBSE is not distinct from MEWDS.   APMPPE is an uncommon idiopathic inflammatory disorder. It  affects young to middle-aged adults of both genders equally. There    is often a viral prodrome, and it is speculated to occur as a result  of cell-mediated immunity to viral antigen. Associated cerebral  vasculitis is relatively common and can cause stroke. Erythema  nodosum and other systemic manifestations of vasculitis have  been reported. The clinical picture of APMPPE can be mimicked  by other entities such as sarcoidosis and tuberculosis.   • Symptoms. Subacute moderate visual impairment; central/  paracentral scotomata; photopsia is frequent. The fellow eye  is affected within a few days or weeks. Headache and other  neurological symptoms are common and can commence  many months after ocular disease onset.   • Fundus. Multiple large deep yellow-white placoid lesions,  initially at the posterior pole (Fig. 11.77A). Within weeks the  majority fade, with residual RPE disturbance of varying  severity. Subretinal macular fluid may be seen. Vasculitis  and papillitis are rare.   • Prognosis. In 25% of patients recovery is to only 6/15 or  worse, with recurrence in up to 50%.    Fig. 11.77 (A) Acute posterior multifocal placoid pigment epitheliopathy; (B) FA early venous phase shows dense foci of  hypofluorescence; (C) FA late phase shows hyperfluorescence; (D) ICGA shows focal hypofluorescence   • HLA-B7 and HLA-DR.2 are associated in a substantial  proportion of patients.   • FA of active lesions shows early dense hypofluorescence and  late staining (Figs 11.77B and C).   • CNS imaging and lumbar puncture should be performed in  patients with neurological symptoms.   Steroids and possibly ciclosporin may be given for cerebral vascu¬  litis. Patients should be instructed to seek medical advice urgently   Serpiginous choroidopathy (choroiditis) is usually bilateral,  though asymmetrical. It typically occurs in middle age, affects men  more frequently than women, and is associated with HLA-B7. The  disease is generally recurrent over years, with a relatively  poor prognosis. TB uveitis can give a similar clinical picture  (‘serpiginoid’).   • Symptoms. Initially unilateral blurring of central vision,  scotoma or metamorphopsia.   • Fundus. Active lesions (Fig. 11.78A) are grey-white and may  remain active for several months before becoming scalloped  and atrophic. The disease typically starts around the optic   Fig. 11.78 Serpiginous choroidopathy. (A) Early active  disease; (B) extension around the macula in typical  snake-like fashion; (C) advanced scarring    disc and extends gradually (Fig. 11.78B), though a variant  starting at the central macula (5%) is recognized. Recurrence  is usually contiguous with or adjacent to existing areas,  eventually resulting in extensive chorioretinal atrophy (Fig.  11.78C).   • FA of active lesions shows early hypofluorescence and late  hyperfluorescence.   • ICGA of active lesions reveals marked hypofluorescence  throughout all phases of the angiogram.   Oral or intravenous steroids may control activity; a variety of  immunosuppressives and infliximab may be effective, alone or in  combination.   This refers to a rare entity showing features of both APMPPE and  serpiginous choroiditis, and is also referred to as ampiginous  choroiditis.   This rare condition features lesions similar to those of the  macular variant of serpiginous choroidopathy, but which gener¬  ally behave in a more benign fashion unless complicated by CNV  (common).   AMN is a rare self-limited condition that typically affects healthy  young adult females. The disease may affect one or both eyes and  may be preceded by a flu-like illness. Symptoms consist of  decreased vision and paracentral scotomata. Red-brown wedge-  shaped lesions are observed in a flower petal arrangement around  the centre of the macula (Fig. 11.79), corresponding to the  scotomata. FA is normal or shows faint hypofluorescence. Symp¬  toms and signs fade slowly over months, with visual recovery.   The acute zonal outer retinopathies (AZOR) are a group of rare  conditions characterized by acute onset of loss of one or more  zones of visual field, often temporal, in one or both eyes of young  or middle-aged females, some of whom have an antecedent viral-  like illness; photopsia and mild vitritis are frequent, and subtle  vasculitis is sometimes seen. The mechanism is undefined as yet.  Acute zonal occult outer retinopathy (AZOOR) is the most  common of the AZOR syndromes, and is characterized by minimal  fundoscopic signs early in the disease course; the other postulated   (Courtesy of A Agarwal, from Gass’ Atlas of Macular Diseases, Elsevier ;  2012)    members of the group have more evident findings. Field loss may  progress; in 50% stabilization occurs within 6 months but recovery  is infrequent. Later findings include RPE clumping and vascular  attenuation in the involved area (Fig. 11.80) and peripapillary  region, although the fundus may remain normal. OCT, FA, ICGA  and FAF may demonstrate abnormalities. ERG is important for  diagnosis, characteristically showing a-wave and b-wave ampli¬  tude reduction and delayed 30 Hz flicker - that is, cones tend to  be affected more than rods. EOG shows absence or severe   Fig. 11.80 Later retinal pigment epithelial changes in acute  zonal occult outer retinopathy    reduction of the light rise. Final visual acuity is 6/12 in at least one  eye in most cases. Recurrence is sometimes seen.   • Anterior uveitis and vitritis are usually absent or very mild.   • Fundus. Several small yellow-white macular spots with  fuzzy borders at the level of the inner choroid and retina  (Fig. 11.81A), sometimes with an overlying serous sensory  retinal detachment. These evolve into sharply demarcated  atrophic scars with little pigmentation, similar to the histo  spots of POHS.   • Prognosis. Guarded; central vision may be compromised by  a lesion at the fovea or, commonly, by CNV (up to 40%   FA shows early hyperfluorescence and late staining of lesions, and  demonstrates CNV (Figs 11.81C and D).   This is usually reserved for CNV, though steroids may be consid¬  ered for a foveal lesion.   MCP is an uncommon, usually bilateral but asymmetrical,  chronic/recurrent disease that typically affects young and middle-  aged adult females. Severity and prognosis are very variable. Along  with PIC and SFU (see below), it is sometimes termed  pseudo-POHS.   • Fundus. Multiple discrete, ovoid, yellowish-grey lesions  50-350 pm in diameter at the posterior pole and/or  periphery, sometimes with linear clusters and/or streaks.   Fig. 11.81 Punctate inner choroidopathy. (A) Active lesions - there is also a suspicion of choroidal neovascularization  immediately superior to the fovea; (B) the same eye as (A) 2 weeks later, showing clear choroidal neovascularization; (C) FA  arterial phase of a different eye shows several hyperfluorescent spots with hypofluorescent edges inferior to the fovea and  lacy hyperfluorescence at the fovea indicating choroidal neovascularization; (D) FA late phase of eye in (C) showing discrete  hyperfluorescent spots and intense hyperfluorescence at the fovea   (Courtesy of S Chen - figs A and B; M Westcott - figs C and D)    Inactive lesions have sharply defined margins and pigmented  borders resembling POHS (Fig. 11.82A). Peripapillary  atrophy may be seen. The course is prolonged with the  development of new lesions and recurrent inflammatory  episodes. CNV (Figs 11.82B and C) occurs in 25-35%, CMO  and subretinal fibrosis resembling SFU (see below) can  develop.   • Optic disc oedema and blind spot enlargement may be  present.   • Visual fields may show large defects not corresponding with  examination findings.    • ICGA shows hypofluorescent acute lesions which may not  be clinically apparent. Old lesions remain hypofluorescent  throughout.   Systemic and local steroids. Steroid-resistant patients require  immunosuppressive therapy. CNV is treated with steroids and  anti-VEGF agents.   SFU, also known as diffuse subretinal fibrosis, is an extremely rare  chronic condition. It typically affects myopic young women,   Fig. 11.83 Progressive subretinal fibrosis and uveitis  syndrome. (A) Early and (B) advanced disease    causing gradual blurring of vision in one then both eyes. Anterior  uveitis and vitritis accompanies subretinal mounds at the poste¬  rior pole and midperiphery (Fig. 11.83A) progressing to widespread  subretinal fibrosis (Fig. 11.83B). Steroids may be effective early in  the disease, but the prognosis is poor. Some experts view SFU as  part of a spectrum with MFC/MCP and PIC.    Fig. 11.82 Choroidal neovascularization in multifocal  choroiditis with uveitis. (A) Inactive lesions; (B) early venous  phase fluorescein angiogram showing variable hypo- and  hyperfluorescence of the lesions and lacy  hyperfluorescence at the fovea indicating choroidal  neovascularization; (C) late phase showing  hyperfluorescence at the fovea due to leakage from  choroidal neovascularization    Birdshot retinochoroidopathy is an uncommon idiopathic chronic  bilateral disease predominantly affecting middle-aged women.   • Symptoms. Insidious impairment of central vision  associated with photopsia and floaters.   Fig. 11.84 Birdshot chorioretinopathy. (A) Active stage; (B) inactive lesions; (C) late phase fluorescein angiogram shows disc  and vessel leakage, vessel wall staining and cystoid macular oedema; (D) early phase indocyanine green angiogram shows  numerous hypofluorescent lesions   (Courtesy of C Barry - figs A and B; P Gili - fig. C)   choroidal patches, less than one disc diameter in size, in the  posterior pole and midperiphery (Fig. 11.84A). The lesions  often appear to radiate outward from the disc but usually  spare the macula itself. Inactive lesions consist of well-  delineated atrophic spots (Fig. 11.84B). CMO, epiretinal  membrane and CNV may develop.    • Prognosis. About one-third of patients have an eventual  best visual acuity of less than 6/60.    • Autofluorescence will generally show more numerous  hypoautofluorescent lesions than are seen on examination.   • FA shows extensive vascular leakage, with disc and vessel  staining and CMO (Fig. 11.84C); lesions are initially  hypofluorescent with later staining.   • ICGA: lesions are more numerous; they are hypofluorescent  during the early and intermediate phases (Fig. 11.84D) and  isofluorescent later.   • ERG is normal in early disease but with time shows rod and  cone abnormalities.   Fig. 11.85 (A) Acute retinal pigment epitheliitis; (B) FA venous  phase shows corresponding focal hyperfluorescence   ARPE (Krill disease) is a rare, idiopathic, self-limited condition  of the RPE; it is unilateral in 75% of cases. Presentation is in  young adults with mild disturbance of central vision; 1-2 weeks  after the onset of symptoms the macula shows 2-4 discrete  clusters of subtle small (one-fourth disc diameter) grey spots at  the level of the RPE, surrounded by hypopigmented yellow haloes  (Fig. 11.85A). Over 6-12 weeks the lesions resolve and vision  returns to normal. Recurrences are uncommon. OCT shows  hyper-reflectivity at the photoreceptor outer segment layer. FA  may be normal, or the spots may show a hypofluorescent centre  with a hyperfluorescent halo (Fig. 11.85B). The EOG is subnormal.  Treatment is not required.   AIM (UAIM) is a rare, self-limited condition that is most fre¬  quently unilateral and may be preceded by a flu-like illness.  Patients are young adults who describe sudden marked reduction  in central vision. A viral prodrome is common, and associated  systemic infections have been noted. An irregularly yellow or grey  exudative retinal detachment is seen at the macula (Figs 11.86A and  B); small haemorrhages and papillitis maybe associated. Within a  few weeks the exudative changes resolve; a bull’s eye appearance  (Fig. 11.86C) may develop following resolution and can be associ¬  ated with persistent visual loss. OCT shows hyper-reflectivity at  the photoreceptor outer segment layer and RPE thickening; FAF  shows stippled hyperautofluorescence that becomes hypofluores¬  cent; FA shows early irregular mild hyperfluorescence at the  detachment, with subsequent intense staining (Fig. 11.86D). Treat¬  ment is not given.   Acute multifocal retinitis is a very rare self-limited condition that  may be preceded by a flu-like illness; it may be an atypical pres¬  entation of cat-scratch disease. It causes sudden onset mild visual  loss in young adults; multiple areas of retinitis are seen posterior  to the equator (Fig. 11.87), along with mild vitritis, disc oedema  and sometimes a macular star. Recovery occurs over 2-4 months.  Treatment as for cat-scratch disease may be considered.   SIC is a rare entity that presents with mild visual loss or is asymp¬  tomatic. A discrete post-equatorial dull-yellow choroidal elevation  with ill-defined margins is seen (Fig. 11.88); vitritis is present  during active disease. Contiguous subretinal fluid and a macular  star may be present. With healing the lesion develops a better-  defined margin with resolution of subretinal fluid and exudation.  Treatment of a vision-threatening lesion is with systemic  steroids.   Fig. 11.86 Acute idiopathic maculopathy. (A) and (B) Development of macular sensory retinal detachment over the course of  a month; (C) bull’s eye appearance after a further month; (D) FA showing hyperfluorescence of subretinal fluid   (Courtesy of J Donald Gass , from Stereoscopic Atlas of Macular Diseases,  Mosby 1997)   FBA describes a characteristic fundus picture, usually bilateral,  and may represent a specific entity (primary) or a common  pathway in response to multiple stimuli. Secondary FBA may be  associated with infectious retinitis, notably cytomegalovirus retin¬  itis, and other conditions such as lymphoma and leukaemia.  Primary (idiopathic) FBA is rare and typically affects children and  young adults, in whom presentation is with bilateral visual loss  (6/30 to PL), floaters and/or photopsia. There may be a viral pro¬  drome. Florid sheathing of retinal arterioles and venules is seen  (Fig. 11.89); anterior uveitis, vitritis and retinal oedema are  common. Treatment is with systemic steroids, though some  authorities believe the prognosis, which is usually good in the  primary form, is unaffected.   Idiopathic retinal vasculitis, aneurysms and neuroretinitis syn¬  drome is a rare entity that typically affects one or both eyes of  healthy young women. Fundus signs consist of arteritis and mul¬  tiple aneurysmal dilatations of arteriolar branches and on the optic  nerve head, together with anterior uveitis and vitritis.   Disc oedema and a macular star (neuroretinitis) are common.  Marked macular and circumpapillary exudative retinopathy can  develop (Fig. 11.90A); the vascular changes are demonstrated very   Fig. 11.90 Idiopathic retinal vasculitis, aneurysms and  neuroretinitis syndrome. (A) Circinate pattern of hard  exudates surrounding the disc. There is also venous  irregularity and obscuration of the optic nerve head; (B) FA  showing multiple aneurysms at arteriolar bifurcations and  marked variation in arteriolar calibre   (Courtesy of J Donald Gass , from Stereoscopic Atlas of Macular Diseases,  Mosby 1997 - fig. A; RF Spaide, from Diseases of the Retina and Vitreous,  WB Saunders 1999 - fig. B)   well on FA (Fig. 11.90B). Extensive peripheral capillary non-  perfusion may lead to preretinal neovascularization, and early  panretinal photocoagulation should be considered. Intravitreal  anti-VEGF treatment and steroids have been associated with good  results in some patients and may be given in combination.   BENIGN EPIBULBAR  TUMOURS 468  Conjunctival naevus 468  Conjunctival papilloma 468  Limbal dermoid 468  Dermolipoma 468  Pyogenic granuloma 471  Miscellaneous benign epibulbar  tumours 471  Benign melanosis 472   Primary acquired melanosis/conjunctival  melanocytic intra-epithelial  neoplasia 473  Conjunctival melanoma 474  Ocular surface squamous neoplasia 476  Lymphoproliferative lesions 477  Kaposi sarcoma 477   Iris naevus 477  Iris freckle (ephelis) 478  Brushfield spots 478  Lisch nodules 478   Choroidal naevus 484  Choroidal melanoma 487  Circumscribed choroidal  haemangioma 492  Diffuse choroidal haemangioma 494  Optic disc melanocytoma 494  Choroidal osteoma 495  Metastatic tumours 495   A conjunctival naevus is the most common melanocytic conjunc¬  tival tumour; the overall risk of malignant transformation is less  than 1%. Treatment by excision is usually for cosmesis, but some¬  times for irritation or a suspicion of malignancy. The histological  appearance is similar to that of cutaneous naevi, but as there is no  conjunctival dermis, subepithelial and stromal replace dermal in  the nomenclature:   • Compound naevi are characterized by the presence of  naevus cells at the epithelial-subepithelial junction and  within the subepithelial stroma, often with epithelial  inclusions such as cysts and goblet cells (Fig. 12.1A).   • Junctional naevi consist of nests of naevus cells at the  epithelial-subepithelial junction (Fig. 12.1B). They are  uncommon.   • Symptoms. The lesion is typically initially noticed in the first  or second decade.   o A solitary slightly or moderately elevated pigmented or  partially pigmented lesion of variable size, most frequently  juxtalimbal; over half contain small cysts (Figs 12.1C and D).  o Naevi are mobile over the underlying sclera,  o The extent of pigmentation is variable; absence is  relatively common (Fig. 12.1E).  o The plica, fornix and caruncle (Fig. 12.1F) are uncommon  locations.   o Naevi may become inflamed, especially in children and  adolescents, and this may be mistaken for malignant  change.   o An unusual site such as the palpebral or forniceal  conjunctiva.   Conjunctival papillomata are strongly associated with human  papillomavirus infection, especially types 6 and 11. Histopathologi-  cally they consist of a fibrovascular core covered by an irregular  proliferation of non-keratinized stratified squamous epithelium  containing goblet cells (Fig. 12.2A).   Lesions are sessile (wide base and flatfish profile - Figs 12.2B and  C) or pedunculated (frond-like - Fig. 12.2D), and are frequently    located in the juxtalimbal area, fornix or the caruncle. They are  usually solitary but may be multiple.   Large lesions may cause irritation, interfere with lid closure or  encroach onto the cornea.   Small lesions may resolve spontaneously. Large lesions are treated  by excision, sometimes with cryotherapy to the base and the sur¬  rounding area. Options for recurrences include subconjunctival  interferon alfa, carbon dioxide laser vaporization, topical mitomy¬  cin C and oral cimetidine.   A limbal dermoid is a choristoma (a mass of histologically normal  tissue in an abnormal location) consisting of a mass of collagenous  tissue containing dermal elements; it is covered by stratified squa¬  mous epithelium (Fig. 12.3A). Presentation is in early childhood,  with a smooth, yellowish, soft subconjunctival mass commonly  located at the inferotemporal limbus, often with protruding hair  (Fig. 12.3B). Lesions are occasionally very large and may virtually  encircle the limbus (Fig. 12.3C). Treatment is indicated for cosme¬  sis, chronic irritation, dellen formation and amblyopia from astig¬  matism or involvement of the visual axis. Small dermoids can  undergo simple excision, but lamellar keratosclerectomy may be  required for large lesions.   • Goldenhar syndrome (oculoauriculovertebral spectrum  - Fig. 12.3D) is usually sporadic.   o Systemic features include hypoplasia of the malar,  maxillary and mandibular regions, macrostomia and  microtia, preauricular and facial skin tags, hemivertebrae  (usually cervical), mental handicap, cardiac, renal and  central nervous system (CNS) anomalies,  o Ocular features, apart from dermoids, include upper lid  notching or coloboma, microphthalmos and disc  coloboma.   o Systemic features include warty or scaly cutaneous  lesions, infantile spasms, CNS anomalies and  developmental delay.   o Ocular features, apart from dermoids, include ptosis,  cloudy cornea, lid colobomas, fundus colobomas and  microphthalmos.   A dermolipoma is similar in composition to a solid dermoid but  also contains fatty tissue. Presentation tends to be in adult life as  a soft yellowish subconjunctival mass near the outer canthus (Fig.  12.4A). The surface is usually keratinized, and in common with a  dermoid, may exhibit hairs. Occasionally the lesion may extend  into the orbit or anteriorly towards the limbus. Treatment is gen¬  erally avoided due to the possibility of complications such as   Fig. 12.1 Conjunctival naevus. (A) Compound naevus histology - see text; (B) junctional naevus histology - see text;  (C) partially pigmented naevus; (D) cystic pigmented naevus; (E) non-pigmented naevus (F) caruncular location   (Courtesy of J Harry - fig. A; J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 - fig. B; S Chen - figs D and E)   Fig. 12.2 Conjunctival papilloma. (A) Histology - see text; (B) sessile papilloma; (C) sessile papilloma with feeder vessels;  (D) pedunculated papillomata   Fig. 12.3 Limbal dermoid. (A) Histology - see text; (B) typical lesion with protruding hair;   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 - fig. A; U Raina - fig. B)    scarring, ptosis, dry eye and ocular motility problems. In selected  cases, debulking the anterior portion may improve cosmesis with  lower risk. It is critical to distinguish a dermolipoma from a prom¬  inent lacrimal gland lobe and from orbital fat prolapse (Fig. 12.4B);  lymphoma can also present in a similar fashion.   A pyogenic granuloma is a fibrovascular proliferative response to  a conjunctival insult such as surgery or trauma, or in association  with a chalazion or foreign body incarceration. Histology shows  granulation tissue with both acute and chronic inflammatory cells  and a proliferation of small blood vessels; the term pyogenic gran¬  uloma is a misnomer as the lesion is neither pyogenic nor    granulomatous. Presentation is typically a few weeks after surgery  for chalazion, strabismus or enucleation, with a rapidly growing  dark pink fleshy conjunctival mass (Fig. 12.5A). Treatment with  topical steroids is often successful; resistant cases require excision.  The differential diagnosis includes suture granuloma, which can  often be large and mistaken for a malignant lesion (Fig. 12.5B) and  Tenon capsule granuloma or cyst.   • Epibulbar telangiectasia (Fig. 12.6A) may be associated with  Sturge-Weber syndrome.   (Courtesy of R Curtis - fig. A; Courtesy of S Chen - fig. B)    • Reactive pseudoepitheliomatous hyperplasia is a rapidly  growing white juxtalimbal hyperkeratotic nodule (Fig. 12.6B)  that develops secondary to irritation.   • Melanocytoma is a rare congenital lesion. It manifests as a  slowly enlarging black lump (Fig. 12.6C) that cannot be  moved freely over the globe.   Benign conjunctival epithelial melanosis (conjunctival hypermela¬  nosis) is a normal variant, more common in darker-skinned indi¬  viduals (over 90% of blacks, 5% of whites) due to the presence of  excess melanin within basal layer conjunctival epithelial melano¬  cytes. Melanocyte numbers are normal, that is, there is no melano-  cytic hyperplasia. It may have a protective effect against neoplasia.  Benign melanosis appears during the first few years of life, and  becomes static by early adulthood; both eyes are affected but  involvement may be asymmetrical. Areas of flat, patchy, brownish  pigmentation may be seen throughout the conjunctiva but are  often concentrated at the limbus (Fig. 12.7A) and around   Fig. 12.7 Epithelial (racial) melanosis. (A) Juxtalimbal  involvement; (B) at site of perforating vessel and nerve   perforating branches of vessels or nerves as they enter the sclera  (Fig. 12.7B). The pigmented epithelium moves freely over the  surface of the globe. A variant is seen in which small cysts are  present.   Approximately 75% of conjunctival melanomas (see below) arise  in areas of melanocytic hyperplasia. Recent trends in the descrip¬  tion of pigmented conjunctival lesions have led to controversy  relating to terminology. Some classifications have historically used  the term primary acquired melanosis (PAM) to encompass both    benign epithelial melanosis (see above) and melanocytosis/  melanocytic hyperplasia (with and without atypia), whilst others  have restricted its use to the latter category. To avoid this ambigu¬  ity, the term conjunctival melanocytic intra-epithelial neoplasia  (C-MIN) may be preferred for lesions exhibiting proliferation of  melanocytes, with PAM reserved for clinical description before a  histological diagnosis has been established. The differential diag¬  nosis includes conjunctival naevus, benign melanosis, congenital  ocular melanocytosis (see below), secondary pigmentation in  Addison disease and pigmented squamous cell carcinoma.   • PAM without cellular atypia or with mild atypia is a benign  intraepithelial proliferation of epithelial melanocytes (Fig.   • PAM with severe atypia can be regarded as melanoma in  situ that has a substantial chance of progression to invasive  melanoma over several years. The risk is higher the greater  the extent of the lesion, measured in clock hours. Severe  atypia is present in only a small minority of PAM.   • C-MIN is graded from o to 10 according to degree of atypia  and spread, o corresponding to an absence of any  melanocyte proliferation or atypia (i.e. melanosis only) and  5 to conjunctival melanoma in situ.   • Symptoms. A pigmented area is noticed on the surface of  one or both (10%) eyes at a median age of 56 years, usually  in a white individual.   o Uni- or multifocal flat areas of irregular golden-brown to  dark chocolate-coloured epithelial pigmentation, typically  involving the limbus and interpalpebral region (Figs 12.8B  and C). PAM sine pigmento has been reported,  o Because any part of the conjunctiva may be affected, it is  important to evert the eyelids (Fig. 12.8D); C-MIN may  also extend onto the cornea.   o Transformation to melanoma may be suggested by the  appearance of nodular areas.   • Investigation. Careful documentation with drawing and/or  photography of lesions undergoing observation is important.  Immunohistochemical analysis of biopsied lesions is  performed.   o Observation of small (less than one clock hour) lesions  may be appropriate; some advocate excision biopsy of  every lesion.   o Excision biopsy is generally preferred to incisional biopsy  if possible (see under conjunctival melanoma below for  surgical approach).   o Double freeze-thaw cryotherapy may be administered to  the excision site, and/or following histological  confirmation of C-MIN postoperative topical mitomycin  C, e.g. four cycles of 0.04% four times daily for 7 days  separated by 3-week intervals, with punctum plugs in situ  to reduce the risk of punctal stenosis and increase  drug-surface contact time.   Fig. 12.8 Primary acquired melanosis (PAM). (A) Histology shows intraepithelial proliferation of conjunctival epithelial  melanocytes; (B) small area of PAM; (C) more extensive PAM; (D) tarsal PAM associated with lentigo maligna of the eyelid   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 - fig. A; C Barry - fig. C; D Selva - fig. D)    o Amniotic membrane grafting may be necessary for large  excision sites.   o Larger lesions: mapping incisional biopsies can be  accompanied by cryotherapy to all pigmented areas or  topical mitomycin C as above,  o Long-term follow-up is mandatory in all cases,  o Corneal involvement: alcohol-mediated epitheliectomy  followed by topical mitomycin C.   Conjunctival melanoma is rare, accounting for about 2% of all  ocular malignancies. Around 75% arise from an area of PAM,  about 25% from a pre-existing junctional or compound naevus  and rarely de novo. Presentation is often in the sixth decade,  though patients with the rare dysplastic naevus syndrome develop  multiple melanomas at a considerably younger age. The differen¬  tial diagnosis includes naevus, ciliary body melanoma with  extraocular extension, melanocytoma and pigmented conjunctival  squamous carcinoma. The overall mortality is up to 19% at 5 years    and 30% at 10 years. Metastasis occurs in 20-30%; the main sites  are regional lymph nodes, lung, brain and liver. Factors associated  with a worse prognosis include caruncular, forniceal or lid margin  location and tumour thickness of 2 mm or more.   • Appearance. A black or grey vascularized nodule that may be  fixed to the episclera. The limbus is a common site, but a  melanoma may arise anywhere in the conjunctiva (Fig. 12.9A).  Association with PAM/C-MIN is very common (Fig. 12.9B).   • Amelanotic tumours may give rise to diagnostic difficulty  (Fig. 12.9C).   • B-scan ultrasonography may be helpful in characterization  of the lesion.   • Systemic screening consists of regular general examination,  liver function testing and ultrasound, chest X-ray and  possibly whole body positron emission tomography/  computed tomography (PET/CT) imaging where available.   • Histology shows melanomatous cellular atypia with invasion  of the subepithelial stroma (Fig. 12.9D).   Fig. 12.9 Conjunctival melanoma. (A) Conjunctival melanoma extending into the eyelid; (B) multifocal melanoma arising from  PAM; (C) amelanotic melanoma; (D) histology showing melanoma cells within the epithelium and subepithelial stroma   (Courtesy of C Barry - fig. A; J Harry - fig. D)    • Sentinel lymph node biopsy may be helpful in staging,  though its place has not yet been fully defined.   • Circumscribed lesions are treated by excision with a wide  margin. As tumour seeding can occur during excision,  contact with the tumour itself should be avoided and fresh  instruments used to close the conjunctival defect.   • Adjunctive radiotherapy is routinely administered by some  authorities, even if histology suggests that excision is  complete; cryotherapy to the bed and surrounding tissue is  an alternative. Proton beam radiotherapy can be applied if  the caruncle or fornix is involved.    • Diffuse melanoma associated with extensive PAM/C-MIN is  treated by excision of localized nodules with mitomycin C or  cryotherapy to the diffuse component.   • Orbital recurrences are treated by local resection and  radiotherapy. Exenteration may not improve survival and is  therefore reserved for patients with extensive and aggressive  disease when the eye cannot be preserved.   • The drug vemurafenib improves survival in patients with  metastatic disease when the BRAF V600E mutation is  present (50% of primary and metastatic conjunctival  melanomas).   • Multifocal disease, non-limbal tumour location, tumour  margin involvement and lack of adjunctive treatment are  associated with a greater likelihood of recurrence.   Ocular surface squamous neoplasia (OSSN) describes a spectrum  of benign, pre-malignant and malignant slowly progressive epithe¬  lial lesions of the conjunctiva and cornea. Older adults are usually  affected unless a predisposing systemic condition is present. Risk  factors include ultraviolet light exposure, a pale complexion,  ciclosporin, smoking, petroleum product exposure, acquired  immunodeficiency syndrome (AIDS) and xeroderma pigmento¬  sum. Human papilloma virus infection (especially type 16) has  been implicated in some cases. Metastatic disease is extremely rare.   • Symptoms. A visible mass in one eye, sometimes  accompanied by conjunctivitis-type symptoms.   • Signs are variable and clinical correlation with histological  severity is unreliable. Most tend to develop within the    interpalpebral fissure, particularly at the limbus, although  any part of the conjunctiva or cornea may be involved.   The lesion may appear fleshy, gelatinous, leukoplakic  or papillomatous, superficial or feeder vessels may  be prominent or the appearance may be avascular  (Figs 12.10A-C). Intraocular extension is  uncommon.   or anterior segment optical coherence tomography (OCT) to  estimate the depth of invasion, exfoliative cytology and  impression cytology.   • Histology shows the following spectrum; the first two are  sometimes termed conjunctival-corneal intraepithelial  neoplasia (CCIN):   o Conjunctival epithelial dysplasia. Dysplastic cells are  confined to the basal epithelial layers,  o Carcinoma in situ. Dysplastic cells involve the full  thickness of the epithelium.   O Squamous cell carcinoma. Invasion of the underlying  stroma (Fig. 12.10D).   Fig. 12.10 Ocular surface squamous neoplasia. (A) Relatively  small lesion; (B) larger gelatinous lesion stained with rose  Bengal; (C) leukoplakic lesion; (D) histology of squamous cell  carcinoma shows downward proliferation of irregular  dysplastic epithelium with infiltration of subepithelial tissue   (Courtesy of B Damato - fig. C; J Harry - fig. D)   • Excision with 2-4 mm margins and assessment for  completeness of clearance, often with intraoperative frozen  section, has been the conventional standard approach.  Complete histological excision is associated with recurrence  of 5-33%. Adjunctive measures reduce recurrence and  include cryotherapy, brachytherapy or topical  chemotherapy.   • Topical chemotherapy. Traditionally used as adjunctive  treatment, this may also be employed as a primary modality  to avoid the scarring and stem cell damage associated with  extensive excision, to reduce tumour size prior to excision,  or to treat recurrence. Agents include mitomycin C,  5-fluorouracil and interferon alfa-2b eye drop regimens; the  latter two tend to be better tolerated.   The most common conjunctival lymphoproliferative lesion is  reactive lymphoid hyperplasia, a proliferation of both B and T  cells with germinal follicle formation. Conjunctival lymphoma  may arise de novo , by extension from orbital lymphoma or associ¬  ated with systemic lymphoma at diagnosis (up to 30%). Most  conjunctival lymphomas are of B cell origin, arising from mucosa-  associated lymphoid tissue (MALT) and tending to be indolent.   • Symptoms. Painless swelling, redness or irritation; this is  often bilateral, when systemic disease is more likely. Other  possible symptoms include ptosis and diplopia.   • Signs. A slowly growing salmon-pink or flesh-coloured  mobile infiltrate is seen on the epibulbar surface or in the  fornices (Figs 12.nA and B). Rarely, a diffuse lesion may  mimic chronic conjunctivitis.   • Biopsy is taken to confirm diagnosis; the uninvolved eye  should also be biopsied (inferior fornix).   • Systemic disease is treated as indicated, when local  conjunctival measures may not be required.   • Other options include chemotherapy, excision of small  lesions with adjuvant treatment, cryotherapy and  intralesional injections of interferon alfa-2b or rituximab.   Kaposi sarcoma is a slowly growing tumour that is typically found  in patients with AIDS, but occasionally in the elderly and when  there is long-term immunosuppression. A vascular bright red or    purplish plaque or nodule is seen (Fig. 12.12), sometimes resem¬  bling (or associated with) conjunctival haemorrhage. Histology  reveals a proliferation of spindle-shaped cells, vascular channels  and inflammatory cells. If treatment is necessary, systemic AIDS  therapy should be optimized, with local radiotherapy, excision  and local or systemic chemotherapy as additional options.   Iris naevi consist of a proliferation of melanocytes in the superfi¬  cial iris stroma, and appear as a circumscribed solitary flat or vari¬  ably elevated pigmented lesion (Figs 12.13A-D). The normal iris  architecture is disrupted. A diffuse naevus characteristically occurs  in congenital ocular melanocytosis and in iris naevus (Cogan-  Reese) syndrome (see Ch. 10). The malignant transformation rate    examination, as iris naevus is a marker for all forms of uveal  melanoma.   Iris freckles (ephelides) are superficial lesions that are smaller than  naevi, with no elevation or distortion (Fig. 12.14A and see Fig.  12.13A), and show increased melanocyte pigmentation but with a  normal number of cells.   These are small whitish peripheral iris speckles arranged in a  concentric ring (Fig. 12.14B), occurring particularly in Down  syndrome though also as a normal finding in lighter irides.  They consist of a focal mildly hyperplastic focus surrounded by  a ring of hypoplasia and have no malignant potential (see also    is up to 8% over 15 years; risk factors include young age (under  40), inferior location, bleeding from the lesion, diffuse iris involve¬  ment, feathery margins and ectropion uveae. Observation should  be life-long and involve documentation by slit lamp examination  and photography. Review should also include serial fundus   These are small well-defined nodules (Figs 12.14C and D) found in  both eyes of virtually all patients with neurofibromatosis type 1  (see Ch. 19).   Fig. 12.13 Iris naevus. (A) Small lesion with mild ectropion uveae - freckles are also present; (B) larger naevus;  (C) suspicious naevus with prominent associated vessels; (D) anterior chamber angle naevus    Fig 12.14 (A) Iris freckles; (B) Brushfield spots; (C) and (D) Lisch nodules in irides of different colours   About 8% of uveal melanomas arise in the iris. The prognosis is  comparatively good - only about 5% of patients develop metasta¬  sis within 10 years of treatment. Conditions associated with or  predisposing to uveal melanomas include fair skin and lighter iris  colour, numerous and/or atypical (dysplastic) cutaneous naevi,  iris or choroidal naevi, congenital ocular and oculodermal melano-  cytosis (naevus of Ota) and uveal melanocytoma. Chronic sunlight  exposure and arc welding are environmental risk factors. Presenta¬  tion is typically in middle age, a decade earlier than ciliary body  and choroidal melanoma.   • Symptoms. Enlargement of a pre-existing naevus is typical,  noticed either by the patient or at a routine eye examination.  Signs indicative of malignant transformation include growth  (Fig. 12.15) and the development of prominent blood vessels  (see Fig. 12.13C).   o A pigmented (Fig. 12.16A) or non-pigmented (Fig. 12.16B)  nodule at least 3 mm in diameter and 1 mm thick,  typically located in the inferior half of the iris and often  associated with surface blood vessels,  o Pupillary distortion, ectropion uveae and occasionally  localized cataract may be seen, although these can also  occur with naevi.   o Growth is usually slow, with extension across the iris  surface.   extrascleral extension is rare (Fig. 12.16C).  o Complications include hyphaema, cataract and glaucoma.  Histology in the majority shows diffusely infiltrating spindle  cells (see below) of low-grade malignancy (Fig. 12.16D). A  minority contain an epithelioid cell component and can be  more aggressive.   Fine-needle aspiration biopsy may be employed prior to  major surgical intervention.   • Sector iridectomy for small tumours, and iridocyclectomy  for tumours invading the angle.   • Radiotherapy with a radioactive plaque (brachytherapy) or  external irradiation with a proton beam.   • Enucleation may be required for diffusely growing tumours,  if radiotherapy is not possible.   Metastasis to the iris (Figs 12.17A and B) is rare and is characterized   by one or more fast-growing white, pink or yellow masses that   Breast and lung cancer and melanoma of the skin are among the   • Juvenile xanthogranuloma is a rare idiopathic  granulomatous disease of early childhood that involves the  skin, muscle, stomach, salivary glands and other organs. Iris  involvement is characterized by a localized or diffuse yellow  lesion (Fig. 12.18A) that may be associated with spontaneous  hyphaema or, less commonly, anterior uveitis and glaucoma.  Treatment is with topical steroids.   • Leiomyoma is an extremely rare benign tumour arising  from smooth muscle. The appearance is similar to that of an  amelanotic melanoma (Fig. 12.18B).   • Melanocytoma is a darkly pigmented nodular mass with a  mossy, granular surface, most frequently occupying the  peripheral iris (Fig. 12.18C). It may undergo spontaneous  necrosis resulting in seeding of the iris stroma and chamber  angle, with elevation of intraocular pressure.   • Vascular tumours of various types have been described, the  most common being racemose haemangioma (arteriovenous  communication), typically seen as a large ectatic vessel and/  or bunch of grapes (Figs 12.18D and E).    Iris cysts are rare lesions. Anterior segment OCT and ultrasound  biomicroscopy are especially useful to differentiate some lesions  from ciliary body tumours.   O Three-quarters are in the peripheral iris, where they  appear as a smooth dome-shaped bulging (Fig. 12.19A)  best seen on gonioscopy (Fig. 12.19B). Mid-zone lesions  again appear as a bulge in the iris - the wall may be  manifest on pupillary dilatation. At the pupillary margin  (least common), cysts appear darkly pigmented and often  elongated.   o They may rarely dislodge to float freely in the anterior  chamber or vitreous (Fig. 12.19C).   o The vast majority are asymptomatic and innocuous.  Rarely, large cysts may obstruct vision and require  collapse with photocoagulation.   o Solitary unilateral structure with a smooth translucent  anterior wall lying on or within the iris (Fig. 12.19D).  Contained debris may be visible.    Fig. 12.16 Iris melanoma. (A) Typical iris melanoma; (B)  amelanotic tumour; (C) angle invasion and extrascleral  extension; (D) histology shows infiltration of the entire  thickness of the stroma   (Courtesy of C Barry - figs A and C; J Harry and G Misson, from Clinical  Ophthalmic Pathology, Butterworth-Heinemann 2001 - fig. D)    Fig. 12.17 Iris metastasis. (A) Metastasis from breast; (B) multiple small deposits   (Courtesy of P Saine - fig. A; B Damato - fig. B)   Fig. 12.18 (A) Juvenile iris xanthogranuloma; (B) leiomyoma; (C) melanocytoma; (D) racemose haemangioma; (E) supplying and  draining vessels for lesion in (D)   (Courtesy of BJ Zitelli and HW Davis, from Atlas of Pediatric Physical Diagnosis, Mosby 2002 - fig. A; B Damato - fig. B)   Fig. 12.19 Primary iris cysts. (A) Subtle dome-shaped elevation of the peripheral iris due to an epithelial cyst; (B) gonioscopy  of lesion in (A); (C) dislodged epithelial cyst in the angle; (D) very large stromal cyst   (Courtesy of Centre for Eye Health, Sydney - fig. A; J McAllister - fig. D)    o Most congenital cysts require treatment by aspiration or  surgical excision. Ethanol-induced sclerosis may avoid the  need for excision.   o Traumatic cysts (Fig. 12.20A) occur following deposition  of epithelial cells from the conjunctiva or cornea onto the  iris after penetrating or surgical trauma. They frequently  enlarge, leading to corneal oedema, anterior uveitis and  glaucoma.   o Extended use of long-acting miotics may be associated  with usually bilateral small, multiple cysts located along  the pupillary border (Fig. 12.20B). Their development can  be prevented by the concomitant use of topical  phenylephrine 2.5%.  o Parasitic cysts are extremely rare.   Ciliary body melanomas comprise around 12% of all uveal melano¬  mas. Risk factors are as for iris melanoma. Presentation is usually  in the sixth decade with visual symptoms, although occasionally  discovery is incidental; diagnosis may be delayed as the lesion is  easily missed. Distinction is principally from an iridociliary cyst  though uveal effusion syndrome may cause diagnostic difficulty  that can be resolved by imaging. Other ciliary body tumours are  extremely rare and include melanocytoma, medulloepithelioma,    Fig. 12.20 Secondary iris cysts. (A) Traumatic cyst;  (B) pupillary border cysts due to miotic therapy   (Courtesy of S Chen - fig. A; R Bates - fig. B)   o A large tumour may be visualized with pupillary  dilatation (Fig. 12.21 A).   O Erosion through the iris root may mimic iris melanoma,  extraocular extension through scleral vessels a  conjunctival melanoma (Fig. 12.21C).   o Displacement of the lens (Fig. 12.21D) may cause  astigmatism, subluxation or cataract.    o Biopsy involving excisional, incisional or fine-needle  aspiration techniques may be helpful in selected cases.  Genetic profiling may help to determine the likelihood of  metastasis (see choroidal melanoma),  o Investigation for systemic involvement, particularly  hepatic.   • Iridocyclectomy or sclerouvectomy for small or medium¬  sized tumours involving no more than one-third of the  angle. Complications include retinal detachment, vitreous  haemorrhage, cataract, lens subluxation, hypotony and  incomplete resection.   Medulloepithelioma (previously known as diktyoma) is a rare  embryonal neoplasm that arises from the inner layer of the optic  cup and can be benign or malignant. Presentation is usually in the  first decade with visual loss, pain, photophobia, leukocoria, or  proptosis in advanced cases. A white, pink, yellow or brown ciliary  body, retrolental or anterior chamber mass is seen (Figs 12.22A and  B). Enucleation may be required.   Choroidal naevi are present in 5-10% of Caucasians but are rare  in darker-skinned races. Growth occurs mainly during the pre¬  pubertal years and is extremely rare in adulthood. For this reason  clinically detectable growth should raise a suspicion of malig¬  nancy. The lifetime risk of malignant transformation is up to 1%  from tertiary centre data. Histologically, the tumour is composed  of a proliferation of spindle cell melanocytes within the choroid  (Fig. 12.23A). It is vital to identify features suggesting a greater  likelihood of malignancy; as with cutaneous melanoma, early  treatment is associated with a substantially lower risk of metasta¬  sis. An extended period without any change provides no guarantee  that progression will not occur in the future, as sudden enlarge¬  ment of naevi has been documented following many years of  stability.   • Symptoms. The great majority are asymptomatic and  detected on routine examination.   o Usually post-equatorial, oval or circular, brown to  slate-grey lesion with indistinct feathery margins (Figs  12.23B and C).   Fig. 12.21 Ciliary body melanoma. (A) Tumour seen on fundoscopy; (B) ‘sentinel’ vessels in the same quadrant as the  tumour; (C) extraocular extension; (D) pressure on the lens   (Courtesy of B Damato - fig. B; R Curtis - fig. D)   Fig. 12.22 Medulloepithelioma. (A) Cystic brown ciliary body mass; (B) anterior segment involvement   Fig. 12.23 Choroidal naevus. (A) Histology shows proliferation of melanocytes in the choroid, sparing the choriocapillaris; (B)  typical small flat naevus with feathery edges, overlying drusen and a subtle broad halo; (C) peripapillary naevus; (D) naevus  with overlying drusen and distinct halo; (E) and (F) overlying orange pigment    o A depigmented halo is very common (Fig. 12.23D).  o Amelanotic lesions can occur.   o The presence of overlying orange pigment (lipofuscin  - Figs 12.23E and F).    o Acoustic hollowness on ultrasonography (US),  o Symptoms such as photopsia, blurred vision.   O Thickness greater than 2 mm; diameter over 5 mm.  o Absence of drusen.   O Margin within 3 mm of the optic disc,  o The absence of a halo.   Fig 12.24 Imaging of choroidal naevi. (A) OCT; (B) and (C) colour photograph and fundus autofluorescence image of  peripapillary naevus showing dramatic hyperautofluorescence of subtle orange pigment; (D) B-scan ultrasonography   o OCT (Fig. 12.24A) is useful for measurement of lesion  thickness as well as the detection of subtle associated fluid  (a high-risk factor). Secondary retinal changes tend to be  more marked overlying a melanoma than a naevus.  o Fundus autofluorescence (FAF) (Fig. 12.24B and C) can  demonstrate subtle orange pigment that may not be  easily discernible clinically; naevi may have patchy  increased autofluorescence, but the appearance of intense  diffuse or even confluent hyperautofluorescence is a  useful diagnostic indicator of melanoma,  o Fluorescein angiography (FA) is not helpful in  distinguishing a melanoma from a naevus.  o Ultrasonography (US) (Fig. 12.24D) shows a localized flat  or slightly elevated lesion with high internal acoustic  reflectivity; a hollow acoustic appearance is a risk  factor for progression. Lesion thickness should be  measured.   • Baseline fundus photography and ultrasonography or OCT,  with indefinite regular review.   • Review interval is determined by level of suspicion:  o No suspicious features: 6 months until stability   established (e.g. one year), then annual review,  o One or two suspicious features: 4-6 months,  o Three or more suspicious features: consider referral for  ocular oncology subspecialist assessment.   • Growth. If growth is documented (Figs 12.25A and B) or  highly suspicious features are present, the lesion should  generally be regarded as a melanoma and managed  accordingly.    melanomas, but is still relatively uncommon. Predisposing factors  are as for iris melanoma (above). Presentation peaks at around the  age of 60 years. Histopathologically, spindle (Fig. 12.26A) and  epithelioid (Fig. 12.26B) cell types are seen, the former being  arranged in bundles and having a better prognosis; epithelioid  cells are larger and more pleomorphic with more frequent mitotic  figures. Tumour composition is commonly exclusively spindle cell  or a mixture of spindle and epithelioid. Lesions may penetrate  Bruch membrane and the retinal pigment epithelium (RPE) with  herniation into the subretinal space, classically assuming the shape  of a collar stud (Fig. 12.26C). Scleral channel and vortex vein inva¬  sion can lead to orbital spread. Metastasis is commonly to the liver,  bone and lung; only about 1-2% of patients have detectable metas-  tases at the time of presentation. Mortality is up to 50% at 10 years;  adverse prognostic factors include particular histological features   Fig. 12.26 Histology of choroidal melanoma. (A) Spindle  cells - tightly arranged fusiform cells with indistinct  cell membranes and slender or plump oval nuclei;   (B) epithelioid cells - large pleomorphic cells with distinct  cell membranes, large vesicular nuclei with prominent  nucleoli, and abundant cytoplasm; (C) penetration of Bruch  membrane in a ‘collar stud’ fashion   (Courtesy of J Harry - figs A and B; J Harry and G Misson, from Clinical  Ophthalmic Pathology, Butterworth-Heinemann 2001 - fig. C)    (e.g. large numbers of epithelioid cells, mitotic activity), larger  tumour dimensions, tumour genetic characteristics (e.g. somatic  mutations in the tumour suppressor gene BAPi , present in nearly  50% of uveal melanomas, imply a greater chance of metastasis),  extrascleral extension and anterior location.   • Symptoms are often absent, with a tumour detected by  chance on routine fundus examination; a range of visual  disturbance can occur depending on tumour characteristics.   o A solitary elevated subretinal grey-brown (Fig. 12.27A) or  rarely amelanotic (Fig. 12.27B) dome-shaped mass; diffuse  infiltration is uncommon.   o About 60% are located within 3 mm of the optic disc  (Fig. 12.27C) or fovea.   o Associated haemorrhage and subretinal fluid (Fig. 12.27E)  are common; the latter may become bullous (Fig. 12.27F),  and mask the underlying lesion,  o Other signs can include sentinel vessels (Fig. 12.28),  choroidal folds, inflammation, rubeosis iridis, secondary  glaucoma and cataract.   o A choroidal naevus usually exhibits numerous surface  drusen, without serous retinal detachment and little if  any orange pigment.   o Melanocytoma is deeply pigmented and usually located at  the optic disc.   o Congenital hypertrophy of the RPE is flat, is often  grey-black and has a well-defined margin with lacunae,  o Haemorrhage in the subretinal or suprachoroidal space,  for example from choroidal neovascularization or retinal  artery macroaneurysm.   o Metastatic cutaneous melanoma has a smooth surface, a  light brown colour, indistinct margins, extensive retinal  detachment and often a past history of malignancy.   o Circumscribed choroidal haemangioma is typically  posterior, pink, dome-shaped and has a smooth surface,  o Metastasis is often associated with exudative retinal  detachment.   o Posterior scleritis, which can present with a large elevated  lesion, but in contrast to melanoma pain is a common  feature.   o Large elevated choroidal neovascular lesion, which can be  eccentrically located, usually in the temporal pre-  equatorial region; typically associated with exudate and  fresh haemorrhage, both of which rarely accompany a  melanoma.   o Prominent vortex vein ampulla is characterized by a  small, smooth, brown, dome-shaped lesion, which  disappears with pressure on the eye.   • FA is of limited diagnostic value because there is no  pathognomonic pattern. The most common findings are an  intrinsic tumour (‘dual’) circulation (Fig. 12.29A), mottled  fluorescence during the arteriovenous phase and late diffuse  leakage and staining. FA may, however, be useful in the  differential diagnosis of simulating lesions.   • US is used to measure lesion dimensions and to detect  tumours through opaque media and exudative retinal  detachment; it may also demonstrate extraocular extension.  The characteristic findings are internal homogeneity with low  to medium reflectivity, choroidal excavation (Fig. 12.29B) and  orbital shadowing; a basal acoustically quiet zone referred to  as ‘acoustic hollowing’ is typical and is due to the greater  tissue homogeneity in this region. A ‘collar stud’ configuration  (Fig. 12.29C) is almost pathognomonic when present.   • FAF. Intense diffuse or confluent hyperautofluorescence, if  present, is a useful diagnostic indicator of melanoma.   • OCT measures dimensions and may demonstrate associated  subretinal fluid, often before clinically apparent. Secondary  retinal changes are often evident overlying the lesion.   • Indocyanine green angiography (ICGA) usually shows  hypofluorescence throughout the study and provides more  information than FA about the extent of the tumour, due to  lower interference from the RPE.   • Magnetic resonance imaging (MRI) (Fig. 12.29D) is useful  to demonstrate extraocular extension and may be of some  help in differential diagnosis.   • Biopsy is useful when the diagnosis cannot be established by  less invasive methods. It may be performed either with a fine  needle or using the 25-gauge vitrectomy system, the latter  providing a larger sample.   • Genetic tumour analysis is becoming increasingly important  in management, particularly with regard to prognosis;  metastasis occurs almost exclusively with certain genetic  profiles.   • Systemic investigation is directed principally towards  detecting metastatic spread, though it may also be used to  search for a primary tumour elsewhere if choroidal  metastasis is likely. Liver function testing and  ultrasonography are mainstays. Chest radiography rarely  shows lung secondaries in the absence of liver disease. The  comparative value of whole body PET/CT imaging is not  fully defined; it has greater sensitivity for detecting  metastatic disease, particularly extrahepatic lesions, but  involves a substantial ionizing radiation dose.   Treatment is performed to avoid the development of a painful and  unsightly eye whilst conserving as much useful vision as possible.  The extent to which ocular treatment influences survival is not yet  defined, though there is some evidence that in general the risk of  metastasis is lower with smaller earlier tumours. Management is  individualized based on the characteristics of the particular    Fig. 12.27 Choroidal melanoma. (A) Typical pigmented melanoma; (B) amelanotic lesion; (C) melanoma of the optic disc; (D)  overlying orange pigment; (E) associated haemorrhage and exudation; (F) extensive subretinal fluid with bullous detachment   (Courtesy of C Barry - figs A, C and E; B Damato - figs D and F)    tumour and the patient (e.g. general health, age, preferences, state  of fellow eye).   • Brachytherapy (episcleral plaque radiotherapy) may be used  for tumours less than 20 mm in basal diameter and up to  10 mm thick in which there is a reasonable chance of  salvaging vision. Survival is similar to that following  enucleation. A plaque is sutured to the sclera (Fig. 12.30A)  for several days according to dosage requirement; regression  begins about 1-2 months after treatment and continues over  several years, leaving a flat or dome-shaped pigmented scar  (Figs 12.30B and C). Complications include cataract,  papillopathy (with or without disc neovascularization) and  radiation retinopathy. Release of cytokines by the irradiated  tumour can also cause retinopathy and other complications  (‘toxic tumour syndrome’) that may need to be treated   Fig. 12.29 Imaging of choroidal melanoma. (A) FA early phase of a ‘collar stud’ tumour showing a ‘dual circulation’; (B)  B-scan of a dome-shaped tumour shows choroidal excavation; (C) B-scan of a ‘collar stud’ tumour; (D) Tl-weighted MRI  shows a choroidal melanoma (white arrow) and extraocular extension (black arrow)   (Courtesy of B Damato - figs A and B; S Milewski - fig. C; M Karolczak-Kulesza - fig. D)   (A) Placement of plaque; (B) amelanotic tumour prior  to treatment; (C) smaller pigmented lesion following  treatment   (Courtesy of S Chen - fig. A; C Barry - figs B and C)   • External beam radiotherapy. Fractionated irradiation with  charged particles such as protons achieves a high dose in the  tumour with relative sparing of adjacent tissues, and is used  for tumours unsuitable for brachytherapy either because of  large size or posterior location. Targeting is aided by  suturing radio-opaque tantalum markers to the sclera.  Regression is slower than with brachytherapy, but survival is  comparable. Intraocular complications are similar, but  extraocular complications such as loss of lashes, eyelid  depigmentation and keratitis may be seen.   • Stereotactic radiotherapy uses multiple collimated beams  from different directions, either concurrently or sequentially,  so that only the tumour receives a high dose of radiation. It  is relatively effective, though there may be a comparatively  high complication rate.   • Transpupillary thermotherapy (TTT) uses an infrared laser  beam to induce tumour cell death by hyperthermia rather  than coagulation. Indications include the treatment of a  small tumour when radiotherapy is inappropriate due to  poor general health. It can be used as an adjunct to  radiotherapy, particularly for vision-threatening exudation.  Tumour response is gradual, the lesion first becoming darker  and flatter, and eventually disappearing to leave bare sclera.  Complications include retinal traction, retinal tear formation  with rhegmatogenous detachment, vascular occlusion and  neovascularization. Local recurrence is common, especially if  the tumour is thick, amelanotic or involves the disc margin.   • Trans-scleral choroidectomy. This is a technically difficult  procedure that may be used for carefully selected tumours  that are too thick for radiotherapy but less than about   16 mm in diameter. Complications include retinal  detachment, hypotony, wound dehiscence and local tumour  recurrence.   • Enucleation. Indications include large tumour size, optic  disc invasion, extensive involvement of the ciliary body or  angle, irreversible loss of useful vision, and poor motivation  to keep the eye. It is essential to perform ophthalmoscopy  after surgical draping to ensure that the correct eye is  removed. Manipulation of the eye should be kept to a  minimum. Orbital recurrence is rare if there is no  extraocular tumour spread or if any such extension is  completely excised.   • Systemic chemotherapy has not been shown to be of  benefit in cases where there is no evidence of metastatic  spread.   Circumscribed choroidal haemangioma (CCH) consists of a mass  of varying-sized vascular channels within the choroid (Fig. 12.31A).  It is not associated with systemic disease. It may be dormant  throughout life or may give rise to symptoms, usually in early  adulthood, as a result of exudative retinal detachment. Slow  enlargement can occur over many years.   Fig. 12.31 Circumscribed choroidal haemangioma. (A) Histology (see text); (B) clinical appearance; (C) surface fibrous  metaplasia; (D) FA early phase shows hyperfluorescence; (E) ICGA shows early hyperfluorescence; (F) B-scan shows an  acoustically solid lesion with a sharp anterior surface and high internal reflectivity   (Courtesy of J Harry - fig. A; P Gili - figs B, D and E; B Damato - figs C and F)   o An oval orange mass at the posterior pole with indistinct  margins that blend with the surrounding choroid (Fig.  12.31B); median base diameter is 6 mm and median  thickness 3 mm.   o Subretinal fluid is usually present in symptomatic cases,  o Complications include surface fibrous metaplasia (Fig.  12.31C), cystoid retinal degeneration, RPE degeneration  and subretinal fibrosis.   • OCT. The overlying retina may be normal or show sub- and  intraretinal fluid, retinoschisis and atrophy.   • FA reveals early spotty hyperfluorescence (Fig. 12.31D) and  late diffuse but intense hyperfluorescence.   • ICGA provides useful diagnostic information, with strongly  hyperfluorescent tumour vessels evident in the arterial phase  (Fig. 12.31E), with diffuse hypofluorescence later.   • FAF. The lesion itself shows little or no intrinsic  autofluorescence. Associated overlying orange pigment and  (fresh) subretinal fluid show hyperautofluorescence, with  RPE hyperplasia and atrophy giving hypoautofluorescence.   • US shows an acoustically solid lesion (high internal  reflectivity) with a well-defined anterior surface (Fig. 12.31F).   • MRI. The tumour is iso- or hyperintense to the vitreous in  Ti-weighted images and isointense in T2-weighted images,  with marked enhancement by gadolinium.   The following may be used if vision is threatened. The superiority  of any particular approach has not been established.   • Photodynamic therapy (PDT) using the same parameters as  for choroidal neovascularization. Treatment may need to be  repeated after a few months if subretinal fluid persists.   • Photocoagulation using a conventional thermal laser or  micropulse treatment may be effective.   • Intravitreal anti-VEGF therapy typically reduces serous  retinal detachment and can be used in combination with  other modalities.   • Oral propranolol may be of benefit, particularly for  associated exudative retinal detachment, but does not seem  to consistently reduce tumour size.   Diffuse choroidal haemangioma usually affects over half of the  choroid and enlarges very slowly. It occurs almost exclusively in  patients with Sturge-Weber syndrome ipsilateral to the naevus  flammeus (see Ch. 1). The fundus has a diffuse deep red colour  that is most marked at the posterior pole (Fig. 12.32A). Localized  areas of thickening, simulating a circumscribed haemangioma,  may be present within the larger lesion. B-scan ultrasonography  shows diffuse choroidal thickening (Fig. 12.32B). Complications  include secondary retinal cystoid degeneration and exudative   Fig. 12.32 (A) Diffuse choroidal haemangioma; (B) B-scan  shows diffuse choroidal thickening    retinal detachment; neovascular glaucoma can ensue if exudative  detachment is not treated. Treatment of vision-threatening cases  involves PDT or low-dose radiotherapy.   Melanocytoma (magnocellular naevus) is a rare, distinctive, uni¬  lateral, heavily pigmented congenital hamartoma seen most fre¬  quently in the optic nerve head but that may arise anywhere in the  uvea. Histology shows large deeply pigmented polyhedral or  spindle cells with small nuclei. In contrast to choroidal melanoma,  melanocytomas are relatively more common in dark-skinned  individuals and have a female predominance. Most cases are  asymptomatic, the condition being detected on routine ophthal¬  moscopy (mean age 50 years). The tumour is generally stationary,  and treatment is not required except in the very rare event  of malignant transformation. Other complications include spon¬  taneous tumour necrosis, optic nerve compression and retinal  vein obstruction.   Fig. 12.33 Melanocytoma. (A) and (B) The same lesion at  baseline and 11 years later   • A dark brown or black, flat or slightly elevated lesion with  feathery edges that may extend over the edge of the disc  (Figs 12.33A and B).   • Occasionally a large tumour occupies most of the disc  surface and may lead to pigment dispersion into the vitreous.   • A relative afferent pupillary defect may be present, even if  visual acuity (VA) is good.   Choroidal osteoma is a rare benign ossifying tumour that has a    Both eyes are affected in about 10-20%. Histology shows mature  cancellous bone, with overlying RPE atrophy. Presentation is in  the second-third decades. Masquerading lesions include osseous  metaplasia in association with a choroidal haemangioma, and scle-  rochoroidal calcification, the latter characterized by multiple geo¬  graphical yellow-white fundus lesions that usually involve both  eyes of an older adult.   • Symptoms. Gradual visual impairment if the macula is  involved by the tumour itself, or occasionally more rapid  deterioration secondary to choroidal neovascularization.   o Initially orange, maturing lesions appear yellow-white;  they are flat or minimally elevated with well-defined,  scalloped margins near the disc or at the posterior pole  (Figs 12.34A-D).   o Spider-like fine vessels and bone-spicule RPE changes  may develop (Fig. 12.34B).   o Slow growth may occur over several years (Figs 12.34C  and D).   o The visual prognosis is poor if the lesion involves the fovea.   • OCT demonstrates overlying retinal changes, with enhanced  depth imaging showing a lattice pattern in calcified tumour  similar to the appearance of cancellous bone.   • FA manifests early, irregular, diffuse mottled  hyperfluorescence and late staining (Fig. 12.35A).   • FAF shows mainly isoautofluorescence in calcified areas and  hypoautofluorescence in decalcified regions.   • ICGA shows early hypofluorescence (Fig. 12.35B) and late  staining. The tumour appears larger than on clinical  examination.   • US shows a highly reflective anterior surface and orbital  shadowing (Fig. 12.35C).   • CT demonstrates a dense plaque-like opacity at the level of  the choroid (Fig. 12.35D).   The choroid is by far the most common (90%) site for uveal  metastases. The most frequent primary sites are the breast and  bronchus. A choroidal secondary may be the initial presentation  of a bronchial carcinoma, whereas a past history of breast cancer  is the rule in patients with breast secondaries. Other less common  primary sites include the gastrointestinal tract, kidney and skin  (melanoma). The prostate is an extremely rare primary site. Sur¬  vival is generally poor, with a median of 8-12 months.   • Symptoms. Visual impairment may occur due to macular  involvement by the lesion itself or associated exudative  retinal detachment. A minority are discovered  incidentally.    Fig. 12.34 Choroidal osteoma. (A) Large macular lesion; (B) overlying RPE changes; (C) and (D) growth over 5 years   yellowish slightly elevated placoid lesion with indistinct  margins, typically at the posterior pole and often  multifocal and bilateral (10-30% - Figs 12.36A and B);  overlying pigmentary changes are fairly common  (Fig. 12.36C).   o Melanoma secondaries are usually pigmented,  o Secondary exudative retinal detachment is frequent and  may occur in eyes with relatively small lesions.   • US may be useful in detection, particularly to demonstrate a  lesion underlying exudative retinal detachment. A placoid  tumour shows diffuse choroidal thickening; a larger  dome-shaped lesion shows moderately high internal acoustic  reflectivity (Fig. 12.36D).   • OCT shows overlying RPE thickening and photoreceptor  irregularity, with subretinal fluid when present. Enhanced   • FA shows early hypofluorescence and diffuse late staining,  but in contrast to choroidal melanoma a dual circulation is  not seen.   • ICGA usually shows hypofluorescence through the study  and may show additional deposits not evident on clinical  examination or FA.   • Biopsy by fine needle aspiration or using a 25-gauge  vitrectomy system may be appropriate when the primary site  is unknown.   • Systemic investigation is directed at locating the primary  tumour, if unknown, and other metastatic sites. The list  below is not exhaustive.    Fig. 12.35 Imaging of choroidal osteoma. (A) FA late phase shows mottled hyperfluorescence; (B) ICGA early phase shows  hypofluorescence; (C) B-scan shows a highly reflective anterior surface and orbital shadowing; (D) axial CT demonstrates  bilateral lesions with similar consistency to bone    o Liver function tests,  o Abdominal or whole body scans,  o Faecal occult blood,  o Urinalysis for red blood cells,  o Abdominal ultrasound,  o Whole-body imaging, e.g. PET/CT, MRI.   • Observation, if the patient is asymptomatic or receiving  systemic chemotherapy, which may also be beneficial for  choroidal metastases.   • Radiotherapy, either external beam or brachytherapy,  typically for solitary lesions.   • TTT is useful for small tumours with minimal subretinal  fluid.    • Anti-VEGF treatment may lead to regression of metastases  in some cases, as well as addressing secondary phenomena  such as subretinal fluid accumulation. It is probably more  effective in small early lesions.   Retinoblastoma is rare, occurring in up to 1:18 ooo live births, but  is the most common primary intraocular malignancy of childhood  and accounts for about 3% of all childhood cancers. After uveal   Fig. 12.36 Choroidal metastasis. (A) and (B) Bilateral multifocal metastases from a breast primary - regression in response  to systemic chemotherapy is beginning in the left eye; (C) overlying pigmentary stippling; (D) B-scan showing moderate  internal reflectivity   (Courtesy of C Barry - figs A and B; B Damato - fig. C)    melanoma, it is the second most common malignant intraocular  tumour. Survival rates are over 95% in specialized centres, with  preservation of vision in a majority of eyes, but are much lower in  the developing world. Tumours are composed of small basophilic  cells (retinoblasts) with large hyperchromatic nuclei and scanty  cytoplasm. Many retinoblastomas are undifferentiated but varying  degrees of differentiation are characterized by the formation of  structures known as rosettes (Flexner-Wintersteiner, Homer-  Wright and fleurettes - Fig. 12.37A). Growth (Fig. 12.37B) may be  endophytic (into the vitreous) with seeding of tumour cells  throughout the eye, or exophytic (into the subretinal space)  leading to retinal detachment, or mixed, or the retina may be dif¬  fusely infiltrated. Optic nerve invasion (Fig. 12.37C) may occur,  with spread of tumour along the subarachnoid space to the brain.  Metastatic spread is to regional nodes, lung, brain and bone.   The genetics of retinoblastoma are often highlighted as a paradigm  illustrating the genetic basis of cancer. The tumour suppressor  gene in which mutations predisposing to retinoblastoma occur is  RBi ; over 900 different mutations have been reported to date. The  size of a gene deletion tends to correlate with aggressive retino¬  blastoma behaviour. Mutations in RBi or associated genes in a  common pathway are also disrupted in many sporadic tumours.  Modifier genes for retinoblastoma have also been identified and  may constitute therapeutic targets.   • Heritable (hereditary, germline) retinoblastoma accounts for  40%. In heritable retinoblastoma one of the pair of alleles of  RBi is mutated in all the cells in the body. When a further  mutagenic event (‘second hit’ according to the ‘two-hit’   Fig. 12.37 Pathology of retinoblastoma. (A) well-differentiated  tumour showing abundant Flexner-Wintersteiner rosettes;  (B) whole eye section showing both endophytic and  exophytic growth; (C) transverse section of the cut end of  an optic nerve demonstrating an area of tumour infiltration    hypothesis proposed by Knudson) affects the second allele,  the cell may then undergo malignant transformation.   Because of the presence of the mutation in all cells, a large  majority of these children develop bilateral and multifocal  tumours. Heritable retinoblastoma patients also have a  predisposition to non-ocular cancers such as  pinealoblastoma (‘trilateral retinoblastoma’, which occurs in  up to 10%, usually before the age of 5), osteosarcomas, soft  tissue sarcomas and melanomas; each of these tends to occur  in a particular age group. The risk of a second malignancy is  about 6% but this increases five-fold if external beam  irradiation has been used to treat the original tumour, the  second tumour tending to arise within the irradiated field.   The tumour is unilateral, not transmissible and does not  predispose the patient to second non-ocular cancers. If a  patient has a solitary retinoblastoma and no positive family  history, this is almost certainly (but not conclusively)  non-heritable so that the risk in each sibling and the  patient’s offspring is about 1%. Ninety per cent of children  with unilateral retinoblastoma will have the non-hereditary  form.   • Screening of at-risk family members. Germline mutations  are autosomal dominant and so transmitted to 50%, but  because of incomplete penetrance only 40% of offspring will  be affected. Detection of mutations in RBi has approached  95% in recent years. Once identified in a particular child, the  same mutation can be sought in siblings, its presence  confirming their high-risk status. Siblings at risk of  retinoblastoma should be screened by prenatal  ultrasonography, by ophthalmoscopy soon after birth and  then regularly until the age of 4 or 5 years. Early diagnosis  correlates with a higher chance of preserving vision,  salvaging the eye and preserving life. If a child has heritable  retinoblastoma, the risk to siblings is 2% if the parents are  healthy, and 40% if a parent is affected. It is important that  all family members, including the parents, are examined for  the presence of retinoblastoma-associated eye lesions  (retinomas, calcified retinal scars, phthisis).   • Presentation is within the first year of life in bilateral cases  and around 2 years of age if the tumour is unilateral. Careful  enquiry about a family history of ocular tumours is critical,  o Leukocoria (white pupillary reflex) is the commonest   presentation (60%) and may first be noticed in family  photographs (Fig. 12.38A).   o Strabismus is the second most common (20%); fundus  examination is therefore mandatory in all cases of  childhood squint.   o Painful red eye with secondary glaucoma, which may  occasionally be associated with buphthalmos (Fig. 12.38B).  o Poor vision.   Fig. 12.38 Presentation of retinoblastoma. (A) Leukocoria; (B) secondary glaucoma and buphthalmos; (C) red eye due to  uveitis; (D) iris nodules and pseudohypopyon; (E) orbital inflammation; (F) orbital invasion   (Courtesy of C Barry - fig. A; N Rogers - fig. B; U Raina - fig. C)    o Routine examination of a patient known to be at risk,  o Orbital inflammation mimicking orbital or preseptal  cellulitis may occur with necrotic tumours (Fig. 12.38E).  o Orbital invasion or visible extraocular growth may occur  in neglected cases (Fig. 12.38F).  o Metastatic disease involving regional lymph nodes  and brain before the detection of ocular involvement is  rare.   o An intraretinal tumour is a homogeneous, dome-shaped  white lesion (Fig. 12.39A) that becomes irregular, often  with white flecks of calcification,  o An endophytic tumour projects into the vitreous as a  white mass that may ‘seed’ into the gel (Figs 12.39B).    O An exophytic tumour forms multilobular subretinal  white masses and causes overlying retinal detachment  (Figs 12.39C and D).   • Red reflex testing with a direct ophthalmoscope is a simple  screening test for leukocoria that is easily employed in the  community.   o General examination for congenital abnormalities of the  face and hands,  o Tonometry.   Fig. 12.39 Retinoblastoma. (A) Intraretinal tumour; (B) endophytic tumour with vitreous seeding; (C) mixed endophytic and  exophytic growth; (D) total retinal detachment; (E) B-scan shows echoes from calcification; (F) axial CT shows bilateral  tumours with calcification   (Courtesy of B Dixon-Romanowska - fig. B; L MacKeen - fig. C; K Nischal - fig. F)   o Ophthalmoscopy, documenting all findings with colour  drawings or photography,  o Cycloplegic refraction.   • US is used mainly to assess tumour size. It also detects  calcification (Fig. 12.39E) within the tumour and is helpful  in the exclusion of simulating lesions such as Coats  disease.   • Wide-field photography (portable if necessary) is useful  for both surveying and documentation, and offers particular  advantages in the management of retinoblastoma.   • CT also detects calcification (Fig. 12.39F) but entails a  significant dose of radiation so is avoided by many  practitioners. Plain X-rays may be used to detect calcification  in resource-poor regions.   • MRI does not detect calcification but is useful for optic  nerve evaluation, detection of extraocular extension and  pinealoblastoma, and to aid differentiation from simulating  conditions.   • Systemic assessment includes physical examination and  MRI scans of the orbit and skull as a minimum in high-risk  cases. If these indicate the presence of metastatic disease  then bone scans, bone marrow aspiration and lumbar  puncture are also performed.   • Genetic studies on tumour tissue and blood samples from  the patient and relatives.   The approach to management is collaborative between the oph¬  thalmologist, paediatric oncologist, ocular pathologist, geneticist,   • Chemotherapy is a mainstay of treatment in most cases, and  may be used in conjunction with local treatments (focal  consolidation - see below). Intravenous carboplatin,  etoposide and vincristine (CEV) are given in three to six  cycles according to the grade of retinoblastoma. Single -  (carboplatin alone) or dual-agent therapy has also given  favourable results in some circumstances, such as bridging  therapy to allow deferral of more aggressive measures.  Selective ophthalmic artery infusion has shown promising  outcomes and study is ongoing. Intravitreal melphalan  seems to be effective for vitreous seeding, though carries a  very small risk of extraocular dissemination. Sub-Tenon  carboplatin injection is now less commonly used given the  availability of effective alternatives. Chemoreduction may be  followed by focal treatment with cryotherapy or TTT to  consolidate tumour control.   • TTT achieves focal consolidation following chemotherapy,  or is sometimes used as an isolated treatment. Focal  techniques such as TTT and cryotherapy exert both a direct  effect and probably increase susceptibility to the effects of  chemotherapy.    • Cryotherapy using a triple freeze-thaw technique is useful  for pre-equatorial tumours without either deep invasion or  vitreous seeding.   • Brachytherapy using a radioactive plaque can be utilized for  an anterior tumour if there is no vitreous seeding, and in  other circumstances such as resistance to chemotherapy (Fig.  12.40).   • External beam radiotherapy is avoided if possible,  particularly in patients with heritable retinoblastoma because  of the risk of inducing a second malignancy; retinoblastoma  is highly radiation-sensitive, however. Adverse effects include  cataract, radiation neuropathy, radiation retinopathy and  hypoplasia of the bony orbit.   • Enucleation is generally indicated if there is neovascular  glaucoma, anterior chamber infiltration, optic nerve invasion  or if a tumour occupies more than half the vitreous volume.  It is also considered if chemoreduction fails and is useful for  diffuse retinoblastoma because of a poor visual prognosis  and a high risk of recurrence with other modalities.  Enucleation should be performed with minimal  manipulation and it is imperative to excise a section of optic  nerve to at least 10 mm.   O Adjuvant chemotherapy consisting of a 6-month course  of CEV is given subsequent to enucleation at some  centres if there is retrolaminar or massive choroidal  spread.   o External beam radiotherapy is indicated when there is  tumour extension to the cut end of the optic nerve at  enucleation, or extension through the sclera.   • Review. Careful review at frequent intervals is generally  required following treatment, in order to detect recurrence  or the development of a new tumour, particularly in  heritable disease.    Fig. 12.41 Persistent anterior fetal vasculature. (A) Leukocoria with secondary cataract; (B) retrolental mass with elongated  ciliary processes; (C) retrolental vessels and less dense fibrosis; (D) dense plaque with secondary lens changes   (Courtesy of S Chen - fig. A; Hospital for Sick Children, Toronto - fig. B; K Nischal - figs C and D)   • Persistent anterior fetal vasculature (persistent hyperplastic  primary vitreous - see also Ch. 17) is confined to the  anterior segment and often involves the lens.   o Presentation is with leukocoria (Fig. 12.41A) involving a  retrolental mass into which elongated ciliary processes are  inserted (Fig. 12.41B).   o The size and density of the retrolental fibrovascular tissue  is variable (Fig. 12.41C).   o Early lens and vitreoretinal surgery may preserve useful  vision in some cases.   • Persistent posterior fetal vasculature is confined to the  posterior segment and the lens is usually clear.   o Presentation is with leukocoria, strabismus or nystagmus,  o A dense fold of condensed vitreous and retina extends  from the optic disc to the ora serrata (Fig. 12.42).  o Treatment is not effective.   • Coats disease is almost always unilateral, more common in  boys and tends to present later than retinoblastoma (see Ch. 13).    • Retinopathy of prematurity, if advanced, may cause retinal  detachment and leukocoria. Diagnosis is usually  straightforward because of the history of prematurity and  low birth weight (see Ch. 13).   • Toxocariasis. Chronic Toxocara endophthalmitis (see Ch. 11)  may cause a cyclitic membrane and a white pupil. A  granuloma at the posterior pole may resemble an endophytic  retinoblastoma.   • Uveitis may mimic the diffuse infiltrating type of  retinoblastoma seen in older children. Conversely,  retinoblastoma may be mistaken for uveitis, endophthalmitis  or orbital cellulitis.   • Vitreoretinal dysplasia is caused by faulty differentiation of  the retina and vitreous that results in a detached dysplastic  retina forming a retrolental mass with leukocoria (Fig.   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann 2001 - fig. A)    anterior chamber and elongated ciliary processes. Dysplasia  may occur in isolation or in association with systemic  abnormalities:   o Norrie disease is an X-linked recessive disorder in which  affected males are blind at birth or early infancy. It is  caused by mutations in the NDP gene. Systemic features  include cochlear deafness and mental retardation.   condition that is lethal in utero for boys. Mutations have  been found in the NEMO gene. It is characterized by a  vesiculobullous rash on the trunk and extremities that  with time is replaced by linear pigmentation. Other  features include malformation of teeth, hair, nails, bones  and CNS.   o Walker-Warburg syndrome is an autosomal recessive  condition characterized by absence of cortical gyri and  cerebellar malformations that may be associated with  hydrocephalus and encephalocele. Neonatal death is  common and survivors suffer severe developmental  delay. Apart from vitreoretinal dysplasia other ocular  features include Peters anomaly, cataract, uveal  coloboma, microphthalmos and optic nerve hypoplasia.   o Retinoma (retinocytoma) is a variant of retinoblastoma  that generally exhibits benign behaviour but has a genetic  profile indicating premalignancy - rarely, a retinoma can  undergo late transformation into a rapidly growing  retinoblastoma. It manifests as a smooth whitish  dome-shaped lesion, which typically involutes  spontaneously to a calcified mass associated with RPE  alteration and chorioretinal atrophy (Fig. 12.44).  o Retinal astrocytoma, which may be multifocal and  bilateral (see below).   Astrocytoma (astrocytic hamartoma) of the retina and optic  nerve head is rare; it frequently does not threaten vision or require  treatment. Most are endophytic, protruding into the vitreous,  but exophytic subretinal tumours can occur. Astrocytomas  may be encountered as incidental solitary lesions in normal indi¬  viduals but are most frequently seen in tuberous sclerosis (see  below) and occasionally in association with neurofibromatosis  type 1 and retinitis pigmentosa. About 50% of patients with tuber¬  ous sclerosis have one or more astrocytomas, which may be  bilateral.   • Symptoms. Most tumours are asymptomatic and detected  on screening for tuberous sclerosis; isolated lesions  unassociated with known systemic disease are usually found  at a routine eye examination.   • Signs. A yellowish or white semitransparent plaque, nodule  or mulberry-like lesion, often semitransparent in its  periphery and calcified centrally (Fig. 12.45A).   • Lesions can be large (Fig. 12.45B) and/or have a cystic  component (Fig. 12.45C); growth with vision-threatening  complications can occur.   • OCT shows a granular hyper-reflective appearance of the  retinal layers with relative sparing of underlying RPE.    Fig. 12.45 Astrocytoma. (A) Yellowish mulberry-like lesion; (B) large diffuse lesion; (C) cystic variant; (D) FA showing staining   (J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 - fig. D)    • FAF findings depend on the individual lesion’s  characteristics; typically hyperautofluorescence is seen in  calcified areas with hypoautofluorescence elsewhere.   • FA shows a prominent superficial vascular network within  the tumour in the arterial phase followed by late leakage and  staining (Fig. 12.45D).   • Systemic assessment. With an isolated astrocytoma  discovered incidentally in an older patient, the likelihood of  the presence of forme fruste tuberous sclerosis is low.  However, the option of genetic testing and systemic  investigation may be offered.   Tuberous sclerosis (Bourneville disease) is an autosomal domi¬  nant phacomatosis characterized by the development of hamarto¬  mas in multiple organ systems from all primary germ layers. The  classic triad of epilepsy, mental retardation and adenoma sebaceum  is present in only a minority of patients, but is diagnostic. About  60% of cases are sporadic and 40% are autosomal dominant.   o Adenoma sebaceum, consisting of fibroangiomatous red  papules with a butterfly distribution around the nose and  cheeks (Fig. 12.46A), is universal,  o Ash leaf spots are hypopigmented macules on the trunk,  limbs and scalp (Fig. 12.46B). In infants with sparse skin  pigmentation they are best detected using ultraviolet  light, under which they fluoresce (Wood lamp),  o Shagreen patches consist of diffuse thickening over the  lumbar region.   o Subungual hamartomas (Fig. 12.46C).  o Skin tags (molluscum fibrosa pendulum),  o Cafe-au-lait spots.   o Intracranial paraventricular subependymal astrocytic  nodules and giant cell astrocytic hamartomas,  o Learning difficulties,  o Seizures.   • Ocular features apart from fundus astrocytomas include  patchy iris hypopigmentation and atypical iris colobomas.   Retinal capillary haemangioma is a rare sight-threatening tumour  that may occasionally occur in isolation, although about 50% of  patients with solitary lesions and virtually all patients with multi¬  ple lesions have von Hippel-Lindau disease (VHL - see below).   (Courtesy of K Nischal - fig. A; MA Mir ; from Atlas of Clinical Diagnosis,  Mosby 2003 - fig. B)    The prevalence of retinal tumours in VHL is approximately 60%.  Vascular endothelial growth factor (VEGF) is important in the  development of retinal lesions, which are composed of capillary-  like vascular channels between large foamy cells. The median age  at haemangioma diagnosis in patients with VHL is earlier (18  years) than in those without VHL (31 years).   • Symptoms. Tumours may be detected by screening of those  at risk or because of symptoms due to macular exudates or  retinal detachment.   o Early tumours appear as small red oval or round lesions  located between an arteriole and venule (Fig. 12.47A).  o A well-established tumour is seen as a round orange-red  mass, usually located in the superior or inferior temporal  periphery with dilatation and tortuosity of the supplying  artery and draining vein extending from the optic disc  (Fig. 12.47B).    o A juxtapapillary site is common (Figs 12.47C and  D); lesions are often on the temporal side of the  disc, so that leakage can rapidly threaten the  fovea.   o Fibrotic bands, which can progress to tractional or  rhegmatogenous retinal detachment,  o Vitreous haemorrhage, secondary glaucoma and phthisis  bulbi.   • FA shows early hyperfluorescence and late leakage  (Figs 12.48A and B).   Fig. 12.47 Retinal capillary haemangioma. (A) Two early tumours; (B) more advanced lesion; (C) optic disc lesion with  associated macular exudation; (D) very large optic disc lesion in von Hippel-Lindau syndrome   (Courtesy of B Damato - fig. B; C Barry - fig. C; S Chen - fig. D)   Fig. 12.48 FA of retinal capillary haemangioma. (A) Early  filling; (B) late leakage   (Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases,   • Observation is advised for asymptomatic juxtapapillary  haemangiomas without exudation, because these may  remain inactive for many years and because of the high risk  of iatrogenic visual loss. Early peripheral lesions are not  usually left untreated because they are relatively easy to  ablate.   • Laser photocoagulation of small lesions. After closing the  feeder vessels, the tumour is treated with low-energy, long  duration burns. Multiple sessions may be needed.    • Cryotherapy for larger peripheral lesions, especially those  with exudative retinal detachment. Vigorous treatment of a  large lesion may cause extensive but usually temporary  exudative retinal detachment.   • Vitreoretinal surgery may be required for non-absorbing  vitreous haemorrhage, epiretinal fibrosis or tractional retinal  detachment. If appropriate, the tumour may be destroyed by  endolaser photocoagulation or surgical removal.   • Other modalities include photodynamic therapy (PDT),  which avoids damage to adjacent tissues, and anti-VEGF  agents. These may be particularly appropriate for  juxtapapillary tumours, which are otherwise virtually  untreatable without visual loss.   It is caused by a mutation in the VHL tumour suppressor gene on   12.49A), spinal cord, medulla or pons affects about 25%  of patients with retinal tumours,  o Phaeochromocytoma.   o Cysts of the testes, kidneys, ovaries, lungs, liver and  pancreas.   o Polycythaemia, which may be the result of factors  released by a cerebellar or renal tumour,  o Endolymphatic sac tumours develop in the inner ear in  10%, with consequent hearing and balance difficulties.   • Screening is vital; it is impossible to predict which patients  with retinal haemangiomas will harbour systemic lesions.  Relatives should also be screened because of the dominant  inheritance pattern of the disease. The following screening  protocol should be regularly performed in patients with  established VHL and relatives at risk.   O Annual physical examination, retinal examination from  age 2 to 5 years (6-monthly from ages 10 to 30 years),  renal ultrasonography from age 15 years, 24-hour urine  collection for estimation of vanillyl mandelic acid and  catecholamine levels from age 2 to 5 years to detect  phaeochromocytoma.   o Audiometry should be performed if there are any hearing  or balance problems.   o Two-yearly abdominal and brain MRI scans from the age  of 15; if CNS lesions are symptom-free, treatment may  not be required.   o It is thought safe to discontinue screening at around age  60 years if no abnormality has been identified,  o Genetic testing is indicated in all patients with suspected  VHL and in first- and second-degree relatives. With  modern techniques the likelihood of finding a mutation  approaches 100%, and once a mutation has been    Fig. 12.49 Tumours in von Hippel-Lindau syndrome. (A) Axial  MRI shows a cerebellar haemangioma; (B) axial CT of the  abdomen shows a renal carcinoma   (Courtesy of CD Forbes and WF Jackson, from Atlas and Text of Clinical  Medicine, Mosby 2003 - fig. B)    identified in the proband (initial subject) its presence can  be confirmed or refuted in family members. Screening is  unnecessary if the mutation is absent.   Cavernous haemangioma of the retina and optic nerve head is a  rare unilateral congenital hamartoma. It is usually sporadic but    occasionally can be inherited as autosomal dominant with incom¬  plete penetrance in combination with lesions of the skin and CNS.  Mutations in several different genes have been implicated. His-  topathology shows multiple thin-walled dilated channels with  surface gliosis.   • Symptoms may occur secondary to vitreous haemorrhage.  More frequently the lesions are detected by chance.   o Because of sluggish flow of blood, the red cells may  sediment and separate from plasma, giving rise to  ‘menisci’ or fluid levels within the lesion,  o A lesion occasionally involves the optic nerve head (Fig.  12.50C).   • FA highlights the sedimentation of erythrocytes and shows  delayed filling in the venous phase and lack of leakage (Fig.  12.50E).   Rarely, vitrectomy may be necessary for non-absorbing vitreous  haemorrhage but photocoagulation should be avoided as it may  precipitate haemorrhage and enlargement of the tumour.   A congenital arteriovenous communication, the more severe  forms of which are often termed racemose haemangioma, is a rare  sporadic congenital malformation, with unilateral involvement in  single or multiple sites of the same eye, most commonly tempo¬  rally. Occasionally reported complications include haemorrhage,  exudation and vascular occlusion, though the vision is commonly  unaffected and the condition discovered at a routine examination.  A visual field defect may be present. Some patients may harbour  ipsilateral brain, facial bone and skin lesions (Wyburn-Mason syn¬  drome), particularly those with more severe retinal changes.   • Group 1 consists of an anastomosis with the interposition of  an abnormal capillary or arteriolar plexus. A congenital  retinal macrovessel is often present (Fig. 12.51A); this is an  aberrant blood vessel, often larger than normal and usually a  vein, located in the posterior pole; it may cross the fovea and  horizontal raphe. Areas of capillary non-perfusion and foveal  cysts may be seen. The anomaly is non-progressive and is  usually associated with good vision.   • Group 2. Direct arteriovenous communication, without an  intervening capillary bed. The intervening channels may be  intermediate or large in size (Fig. 12.51B).    Fig. 12.50 Cavernous haemangioma. (A) Small peripheral  lesion; (B) larger lesion showing fibrosis; (C) optic nerve  involvement; (D) OCT of lesion in (B) demonstrating  aneurysms; (E) FA shows fluid levels due to separation of  red cells (hypofluorescent) from plasma (hyperfluorescent)   (Courtesy of S Chen - figs B and D; J Donald M Gass, from Stereoscopic Atlas  of Macular Diseases, Mosby 1997 - fig. E)   Fig. 12.51 Congenital arteriovenous communication (racemose haemangioma spectrum). (A) Group 1 lesion - retinal  macrovessel; (B) group 2 - arteriovenous communication; (C) group 3 - typical racemose lesion with early sclerosis; (D) FA  shows hyperfluorescence but absence of leakage   (Courtesy of C Barry - fig. B; J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 - fig. C)   blood vessels that are often more numerous than normal,  with venules and arterioles having a similar appearance.   The changes extend from and are most evident in the  region of the optic disc. With time the dilatation and  tortuosity becomes more marked, and sclerosis may  be seen (Fig. 12.51C); no leakage is seen on FA  (Fig. 12.51D).   Retinal vasoproliferative tumour is a rare gliovascular lesion that  can be primary (80%) or secondary to conditions such as    intermediate uveitis, ocular trauma and retinitis pigmentosa.  Secondary lesions may be multiple and occasionally bilateral  depending on the underlying aetiology. Histology shows glial cells  and a network of fine capillaries with some larger dilated vessels.  Presentation is usually in the third-fifth decades, with blurring of  vision due to macular exudation. A reddish-yellow globular vas¬  cular mass (Fig. 12.52A) is seen, most frequently in the inferotem-  poral periphery; retinal vessels may be seen entering the lesion  posteriorly. Complications include subretinal exudation, exuda¬  tive retinal detachment (Fig. 12.52B), macular oedema and fibrosis,  and haemorrhage. Treatment with cryotherapy or brachytherapy  induces regression of the tumour and exudation but the visual  prognosis is guarded if there is maculopathy.   Lymphoma is a group of conditions characterized by neoplastic  proliferation of cells of the immune system typified by lymph-  adenopathy, constitutional symptoms and, occasionally, CNS  involvement. The main classification and ocular manifestations  are as follows:   • Hodgkin disease may cause anterior uveitis, vitritis and  multifocal fundus lesions resembling chorioretinitis.   • Non-Hodgkin lymphoma can manifest with conjunctival  involvement, orbital involvement, Mikulicz syndrome and  uveal infiltration.   • CNS B-cell lymphoma may be associated with intermediate  uveitis and sub-RPE infiltrates.    • Primary vitreoretinal lymphoma (PVRL) represents a  subset of primary central nervous system lymphoma  (PCNSL), a variant of extranodal non-Hodgkin lymphoma.  The PCNSL cells are large, pleomorphic B lymphocytes with  large multilobular nuclei, prominent nucleoli and scanty  cytoplasm. The tumour arises from within the brain, spinal  cord and leptomeninges, is aggressive and has a poor  prognosis. About 20% of patients with PCNSL have ocular  manifestations, which can precede or follow neurological  involvement. Most patients with PVRL subsequently develop  CNS symptoms, with a mean delay of 29 months. Most of  those affected are older adults.   • Primary uveal lymphoma is a rare entity, usually of B-cell  origin, that tends to follow an extended relatively benign  course and will not be considered further in this section   • Symptoms. Unilateral floaters, blurred vision, red eye or  photophobia. The symptoms frequently become bilateral  after a variable interval.   o Occasionally coalescence of sub-RPE deposits may  completely encircle the fundus,  o Other features include retinal vasculitis, vascular  occlusion, exudative retinal detachment and optic  atrophy.   important diagnostic indicator, since this is almost always  present in true uveitic vitritis.   • Symptoms. An intracranial mass may cause headache,  nausea, personality change, focal deficit or seizures;  leptomeningeal disease may cause neuropathy, and spinal  cord involvement may cause bilateral motor and sensory  deficits.   • Clinical neurological examination may demonstrate  abnormalities such as cranial nerve palsies, hemiparesis and  ataxia.   • OCT will confirm an absence of CMO in most cases, aiding  differentiation from vitritis, and may demonstrate subretinal  infiltrative lesions.   • US may show vitreous debris, elevated subretinal lesions,  retinal detachment and thickening of the optic nerve.   Fig. 12.53 Primary intraocular lymphoma. (A) Slit lamp photograph (retroillumination) showing vitreous cellular infiltrate;  (B) and (C) extensive subretinal infiltration with overlying mottling; (D) multifocal subretinal infiltrates without mottling   (Courtesy of A Singh, H Lewis, A Schachat and D Peereboom, from Clinical Ophthalmic Oncology, Saunders 2007 - fig. A; B Damato - fig. C)   • Immunohistochemistry based on cell-surface markers  allows identification of the lymphocytic proliferation, which  is of a B-cell type in most patients.   • MRI of head and spine with gadolinium contrast may detect  one or more intracranial tumours, diffuse meningeal or  periventricular lesions, and/or localized intradural spinal  masses; regular screening MRI scans of the CNS can be  performed.   • Lumbar puncture may demonstrate malignant cells in the  CSF in a minority of patients with abnormal MR imaging,  but a positive result avoids the need for brain or eye biopsy.   Treatment of both the eye and the brain is often indicated. Radio¬  therapy and chemotherapy are the mainstays, but an optimal algo¬  rithm has not been established. Treatment limited to the eye may    not improve survival, but local treatment may be preferable if  there is monocular disease and no evidence of involvement  elsewhere.   • Radiotherapy has long been the first-line treatment for  PVRL, but recurrence is common and complications such as  radiation retinopathy and cataract can occur. It now tends  to be reserved for some cases of bilateral disease but may be  associated with lower recurrence rates than chemotherapy  alone. It is better tolerated by younger patients.   • Intravitreal methotrexate is useful for recurrent disease, but  close monitoring is needed to detect ocular complications  and any recurrence.   • Systemic chemotherapy with a variety of agents such as  methotrexate can prolong survival in patients with CNS  disease. This can be given in combination with whole brain  irradiation but neurotoxicity is a problem. A variety of  methods have been developed to overcome the blood-brain  barrier. Systemic treatment is usually effective for ocular    disease and this is preferred to ocular radiotherapy in some  centres because in addition to avoiding radiation-induced  complications it may improve survival. Monotherapy for  primary intraocular lymphoma (PIOL) with ifosfamide or  trofosfamide has also been successful.   • Biologic agents involving specific anti-B cell monoclonal  antibodies (e.g. rituximab), may represent a useful  alternative, but are generally given intravitreally because of  poor penetration through the blood-brain barrier.   • A flat or minimally elevated dark-grey or black (Fig. 12.54A),  round, oval or larger scalloped-edged lesion with well-  defined margins, usually located near the equator or in the  peripheral fundus.   • A depigmented halo located just inside the margin (Fig.  12.54B), and depigmented lacunae (Fig. 12.54C) are common,  particularly as a lesion matures; some lesions may become  virtually totally depigmented.   • Median diameter is 4-5 mm but lesions can be much smaller  or very large, especially in the far periphery (Fig. 12.54D),  and may cause diagnostic difficulty unless the possibility of  CHRPE is borne in mind.   • Histopathology shows densely packed RPE cells replete with  large melanosomes - a combination of cellular hyperplasia  and hypertrophy.   • Although formerly regarded as following a consistently  stable course, a slight enlargement of the involved area over  time is very common, and the development of a presumed  adenomatous or adenocarcinomatous nodule arising within  the lesion (see below) occurs in around 2%. Long-term  review is therefore now advised.   • Solitary CHRPE does not have an association with increased  gastrointestinal malignancy risk.   • Multiple lesions, much smaller than those of solitary CHRPE  and without haloes or lacunae, orientated in a pattern  simulating animal footprints (‘bear-tracks’ - Fig. 12.55A),  often confined to one sector or quadrant of the fundus with  the smaller spots located more centrally.   • The characteristic clinical appearance and monocular  distribution serve to distinguish typical grouped CHRPE  from the atypical multifocal variant associated with an  increased risk of gastrointestinal malignancy (see below).   • Multiple oval, spindle, comma- or fishtail-shaped lesions of  very variable size associated with irregularly hypopigmented  margins and perilesional areas (Figs 12.56A and B).   • The lesions have a haphazard, not sectoral, distribution and  may be pigmented, depigmented or heterogeneous.   • To emphasize the distinction with the CHRPE variants that  are not associated with gastrointestinal malignancy, the  alternative term ‘retinal pigment epithelial hamartomas  associated with familial adenomatous polyposis’ (RPEH-  FAP) has been proposed.   o Familial adenomatous polyposis (FAP) is an autosomal  dominant (AD) condition characterized by adenomatous  polyps throughout the rectum and colon, which usually  start to develop in adolescence. It results from a germline  mutation in the gene APC; mutations falling within a  certain codon range in this gene are associated with the  presence of related CHRPE. Patients undergo regular  colonoscopic screening with polyp excision. If untreated,  virtually all patients with FAP develop carcinoma of the  colorectal region by the age of 50 years. As a result of the  dominant inheritance pattern, genetic testing and  intensive survey of at-risk family members is imperative.  Between 70 and 80% of patients with FAP have atypical  CHRPE lesions, which are present at birth,  o Gardner syndrome is characterized by FAP, osteomas of  the skull, mandible and long bones, and cutaneous soft  tissue tumours such as epidermoid cysts, lipomas and  fibromas.   condition characterized by FAP and tumours of the CNS,  particularly medulloblastoma and glioma.   Combined hamartoma of the retina and RPE is a rare lesion that  is probably congenital. It may be more common in males. It typi¬  cally occurs sporadically in normal individuals but sometimes in  association with a systemic disorder, particularly neurofibromato¬  sis type 2, which should be considered particularly in children or  if bilateral lesions are present. Histopathology shows thickening   Fig. 12.54 Solitary CHRPE. (A) Heavily pigmented lesion; (B) partially depigmented lesion with halo; (C) large lesion with  depigmented lacunae; (D) very large peripheral involvement    of the RPE and sensory retina with prominent glial and vascular   • Symptoms. The most common presentation is with  decreased vision or strabismus in early childhood, though  symptom onset in late childhood or early adulthood is also  frequent.   • VA is 6/60 or worse in 40-50%, usually secondary to  macular involvement.   o Slightly elevated deep grey or brown - sometimes orange,  yellow or green - pigmented lesion that blends into the  adjacent RPE at its margins (Fig. 12.57A).  o Superficial whitish epiretinal membrane (ERM)  formation with retinal wrinkling. Occasionally    vitreoretinal interface changes are marked (Fig. 12.57B),  sometimes with focal tractional retinal detachment,  o Tortuosity and prominence of overlying retinal vessels;   there may be evident feeder and draining vessels,  o The lesion is usually located at the posterior pole, often  in a juxtapapillary or macular site; peripheral lesions (Fig.  12.57C) are uncommon. Dragging of the disc or macula  may be present.   o Uncommon findings include secondary macular oedema,  exudation (Fig. 12.57D), choroidal and preretinal  neovascularization, retinoschisis and retinal detachment.   • OCT will demonstrate associated epiretinal membrane  formation; this has variously been reported as intrinsic to or  distinct from the main lesion.   • FA shows early hyperfluorescence of the vascular  abnormalities and blockage by pigment; the late phase may  show leakage.   (Courtesy of S Chen - fig. A; J Donald M Gass, from Stereoscopic Atlas of  Macular Diseases, Mosby 1997 - fig. B)   Congenital simple hamartoma of the RPE is a rare entity, usually  incidentally diagnosed in asymptomatic children and young  adults. It is typically a small (1.5 mm or less) jet-black nodular  lesion, with well-defined margins, that appears to involve the full  thickness of the retina and RPE and to protrude into the vitreous  cavity (Fig. 12.58). A feeding artery and draining vein are generally  seen. The lesion is typically located immediately adjacent to the  foveola. VA is usually normal, but is occasionally impaired as a  result of central foveal involvement or traction.   Adenoma of the RPE is an oval pigmented lesion that most com¬  monly arises in the peripheral fundus, sometimes from an area of  solitary CHRPE. Associated vitreous inflammatory cells and  retinal exudation are frequently present. Associated prominent  feeding and draining vessels may develop. The behaviour of an  adenocarcinoma is thought to be similar to that of an adenoma.  Most lesions are simply observed in the absence of vision-  threatening complications, as metastasis has not been reported.  Fine needle biopsy is sometimes required for diagnostic  clarification.   Rare cases have been reported of massively proliferating RPE cells  simulating a uveal melanoma, including by extraocular extension.  True malignant tumours of the RPE are extraordinarily rare.   Fig. 12.56 (A) Atypical CHRPE; (B) characteristic  depigmentation at one margin   Fig. 12.57 Combined hamartoma of the retina and retinal pigment epithelium. (A) lesion obscuring the optic disc; (B) lesion  with substantial preretinal glial component; (C) peripheral lesion; (D) larger peripapillary lesion with peripheral hard  exudates   (Courtesy of S Chen - fig. A; S Milewski - fig. B)    Paraneoplastic retinopathies are rare diseases that might be missed  or misdiagnosed by the unwary observer. Many of the patients  present with visual symptoms before the primary malignancy is  diagnosed. It is therefore important for clinicians to be familiar  with these syndromes in order to detect the underlying malig¬  nancy as early as possible.   Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a  very rare paraneoplastic syndrome occurring usually in patients  with systemic, often occult, malignancy. It is characterized by the  proliferation of benign melanocytes in the outer choroid often  manifesting with multiple naevus-like choroidal lesions (Fig.  12.59), but a variety of other anterior and posterior ocular segment    features have been reported, including red-grey subretinal patches,  rapid-onset cataract, episcleral and conjunctival lesions. Vision  can be severely diminished. The mechanism is uncertain, but a  circulating factor may be responsible in many cases. Detection of  an occult primary malignancy might enable early treatment to  enhance survival. Treatment of BDUMP itself is generally unre¬  warding - improvement with plasmapheresis has been reported  - although successful treatment of the underlying primary tumour  may be followed by regression of the BDUMP, but without  improvement in vision.   Cancer-associated retinopathy (CAR) is most frequently associ¬  ated with small cell bronchial carcinoma. Visual symptoms  precede the diagnosis of malignancy in half the cases, typically by  several months but sometimes several years. Subacute visual loss  occurs over weeks to months associated with photopsia; colour  impairment, glare, photosensitivity and central scotoma are  attributed to cone dysfunction. Night blindness, impaired dark  adaptation, ring scotoma and peripheral field loss occur due to  rod dysfunction. The fundus often appears normal on presenta¬  tion, but attenuated arterioles, optic disc pallor and mild RPE  changes develop as the disease progresses. The electroretinogram  (ERG) is abnormal at an early stage under both photopic and  scotopic conditions. As with BDUMP, CAR should prompt a thor¬  ough search for an underlying malignancy, though this is not  always found and the condition is then regarded as an autoim¬  mune retinopathy.   The presentation of melanoma-associated retinopathy (MAR)  differs from CAR in that the visual symptoms usually arise after,  rather than prior to, the diagnosis of cutaneous melanoma. There  may be concurrent vitiligo. Autoantibodies from MAR sera react  against bipolar cells in human retina; clinical and electrophysio-  logical data also implicate bipolar cells as the target in MAR.  Generally, symptoms and signs are less marked than in CAR. The  ERG shows marked reduction of dark-adapted and light-adapted  b-wave and preservation of a-wave (normal photoreceptor func¬  tion), characteristic of bipolar cell dysfunction. The prognosis for  vision is typically good.   Introduction 538  Risk factors 538  Systemic assessment 538  Branch retinal vein occlusion 539  Impending central retinal vein  occlusion 541   Non-ischaemic central retinal vein  occlusion 542  Ischaemic central retinal vein  occlusion 542   Hemiretinal vein occlusion 544  Treatment of the complications of  CRVO 544   Systemic assessment 550  Amaurosis fugax 551  Branch retinal artery occlusion 551  Central retinal artery occlusion 552  Cilioretinal artery occlusion 552  Treatment of acute retinal artery  occlusion 552   Sickling haemoglobinopathies 559  Anterior segment 560  Non-proliferative retinopathy 560  Proliferative retinopathy 560   • The central retinal artery, an end artery, enters the optic  nerve approximately 1 cm behind the globe. It is composed  of three anatomical layers:   o The intima, the innermost, is composed of a single layer  of endothelium resting on a collagenous zone,  o The internal elastic lamina separates the intima from the  media.   o The media consists mainly of smooth muscle,  o The adventitia is the outermost and is composed of loose  connective tissue.   • Retinal arterioles arise from the central retinal artery. Their  walls contain smooth muscle, but in contrast to arteries the  internal elastic lamina is discontinuous.   Retinal capillaries supply the inner two-thirds of the retina, with  the outer third being supplied by the choriocapillaris. The inner   Fig. 13.1 Normal retinal capillary bed. (A) Periarteriolar  capillary-free zone - flat preparation of Indian ink-injected  retina; (B) endothelial cells with elongated nuclei and  pericytes with rounded nuclei - trypsin digest preparation   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann 2001)    capillary network (plexus) is located in the ganglion cell layer, with  an outer plexus in the inner nuclear layer. Capillary-free zones are  present around arterioles (Fig. 13.lA) and at the fovea (foveal avas¬  cular zone - FAZ). Retinal capillaries are devoid of smooth muscle  and elastic tissue; their walls consist of the following (Fig. 13.1B):   • Endothelial cells form a single layer on the basement  membrane and are linked by tight junctions that form the  inner blood-retinal barrier.   • The basement membrane lies beneath the endothelial cells  with an outer basal lamina enclosing pericytes.   • Pericytes lie external to endothelial cells and have multiple  pseudopodial processes that envelop the capillaries. Pericytes  have contractile properties and are thought to participate in  autoregulation of the micro vascular circulation.   • Small venules are larger than capillaries but have a similar  structure.   • Larger venules contain smooth muscle and merge to form  veins.   • Veins contain a small amount of smooth muscle and elastic  tissue in their walls and are relatively distensible. Their  diameter gradually enlarges as they pass posteriorly towards  the central retinal vein.   o Recurrent styes,  o Xanthelasmata,  o Accelerated senile cataract,  o Neovascular glaucoma (NVG).  o Ocular motor nerve palsies,  o Reduced corneal sensitivity.   • Rare. Papillopathy, pupillary light-near dissociation,  Wolfram syndrome (progressive optic atrophy and multiple  neurological and systemic abnormalities), acute-onset  cataract, rhino-orbital mucormycosis.   The reported prevalence of diabetic retinopathy (DR) in diabetics  varies substantially between studies, even amongst contemporary  populations in the same country, but is probably around 40%. It  is more common in type 1 diabetes than in type 2 and sight-  threatening disease is present in up to 10%. Proliferative diabetic    retinopathy (PDR) affects 5-10% of the diabetic population; type  1 diabetics are at particular risk, with an incidence of up to 90%  after 30 years.   • Duration of diabetes is the most important risk factor. In  patients diagnosed with diabetes before the age of 30 years,  the incidence of DR after 10 years is 50%, and after 30 years  90%. DR rarely develops within 5 years of the onset of  diabetes or before puberty, but about 5% of type 2 diabetics  have DR at presentation. It appears that duration is a stronger  predictor for proliferative disease than for maculopathy.   • Poor control of diabetes. It has been shown that tight blood  glucose control, particularly when instituted early, can  prevent or delay the development or progression of DR.  However, a sudden improvement in control may be  associated with progression of retinopathy in the near term.  Type 1 diabetic patients appear to obtain greater benefit  from good control than type 2. Raised HbAic is associated  with an increased risk of proliferative disease.   • Pregnancy is sometimes associated with rapid progression of  DR. Predicating factors include greater pre-pregnancy  severity of retinopathy, poor pre-pregnancy control of  diabetes, control exerted too rapidly during the early stages  of pregnancy, and pre-eclampsia. The risk of progression is  related to the severity of DR in the first trimester. If  substantial DR is present, frequency of review should reflect  individual risk, and can be up to monthly. Diabetic macular  oedema usually resolves spontaneously after pregnancy and  need not be treated if it develops in later pregnancy.   • Hypertension, which is very common in patients with type 2  diabetes, should be rigorously controlled (<140/80 mmHg).  Tight control appears to be particularly beneficial in type 2  diabetics with maculopathy. Cardiovascular disease and  previous stroke are also predictive.   • Nephropathy, if severe, is associated with worsening of DR.  Conversely, treatment of renal disease (e.g. renal  transplantation) may be associated with improvement of  retinopathy and a better response to photocoagulation.   • Other risk factors include hyperlipidaemia, smoking,  cataract surgery, obesity and anaemia.   DR is predominantly a microangiopathy in which small blood  vessels are particularly vulnerable to damage from high glucose  levels. Direct hyperglycaemic effects on retinal cells are also likely  to play a role.   Many angiogenic stimulators and inhibitors have been identi¬  fied; vascular endothelial growth factor (VEGF) appears to be of  particular importance in the former category.   The classification used in the Early Treatment Diabetic Retinopa¬  thy Study (ETDRS - the modified Airlie House classification) is    widely used internationally. An abbreviated version is set out in  Table 13.1, in conjunction with management guidelines. The fol¬  lowing descriptive categories are also in widespread use in clinical  practice:   • Background diabetic retinopathy (BDR) is characterized by  microaneurysms, dot and blot haemorrhages and exudates.  These are generally the earliest signs of DR, and persist as  more advanced lesions appear.   • Diabetic maculopathy strictly refers to the presence of any  retinopathy at the macula, but is commonly reserved for  significant changes, particularly vision-threatening oedema  and ischaemia.   • Preproliferative diabetic retinopathy (PPDR) manifests  with cotton wool spots, venous changes, intraretinal  micro vascular anomalies (IRMA) and often deep retinal  haemorrhages. PPDR indicates progressive retinal ischaemia,  with a heightened risk of progression to retinal  neovascularization.   • PDR is characterized by neovascularization on or within one  disc diameter of the disc (NVD) and/or new vessels  elsewhere (NVE) in the fundus.   • Advanced diabetic eye disease is characterized by tractional  retinal detachment, significant persistent vitreous  haemorrhage and neovascular glaucoma.   Microaneurysms are localized outpouchings, mainly saccular, of  the capillary wall that may form either by focal dilatation of the  capillary wall where pericytes are absent, or by fusion of two arms  of a capillary loop (Fig. 13.2A). Most develop in the inner capillary  plexus (inner nuclear layer), frequently adjacent to areas of capil¬  lary non-perfusion (Fig. 13.2B). Foss of pericytes (Fig. 13.2C) may  also lead to endothelial cell proliferation with the formation of  ‘cellular’ microaneurysms (Fig. 13.2D). Microaneurysms may leak  plasma constituents into the retina as a result of breakdown in the  blood-retinal barrier, or may thrombose. They tend to be the  earliest sign of DR.   • Signs. Tiny red dots, often initially temporal to the fovea  (Fig. 13.3A); may be indistinguishable clinically from dot  haemorrhages.   • Fluorescein angiography (FA) allows differentiation  between dot haemorrhages and non-thrombosed  microaneurysms. Early frames show tiny hyperfluorescent  dots (Fig. 13.3B), typically more numerous than visible  clinically. Fate frames show diffuse hyperfluorescence due to  leakage.   • Retinal nerve fibre layer haemorrhages arise from the larger  superficial pre-capillary arterioles (Fig. 13.4A) and assume  their characteristic shape (Fig. 13.4B) because of the  architecture of the retinal nerve fibre layer.    Table 13.1 Abbreviated Early Treatment Diabetic Retinopathy Study (ETDRS) classification of diabetic retinopathy   Review range 6-12 months, depending on severity of  signs, stability, systemic factors, and patient’s personal  circumstances   Any or all of: microaneurysms, retinal haemorrhages,  exudates, cotton wool spots, up to the level of  moderate NPDR. No intraretinal microvascular  anomalies (IRMA) or significant beading   Proliferative diabetic retinopathy (PDR) in up to 26%,  high-risk PDR in up to 8% within a year   • Severe retinal haemorrhages (more than ETDRS  standard photograph 2A: about 20 medium-large per  quadrant) in 1-3 quadrants or mild IRMA   • Significant venous beading can be present in no more  than 1 quadrant   PDR in up to 50%, high-risk PDR in up to 15% within a  year   Treatment considered according to severity of signs,  stability, systemic factors, and patient’s personal  circumstances such as reliability of attendance for  review. If not treated, review in up to 2 months   New vessels on the disc (NVD) or new vessels elsewhere  (NVE), but extent insufficient to meet the high-risk  criteria   Should be performed immediately when possible, and  certainly same day if symptomatic presentation with  good retinal view   • New vessels on the disc (NVD) greater than ETDRS  standard photograph 10A (about y 3 disc area)   • Intraretinal haemorrhages arise from the venous end of  capillaries and are located in the compact middle layers of  the retina (see Fig. 13.4A) with a resultant red ‘dot/blot’  configuration (Fig. 13.4C).   • Deeper dark round haemorrhages (Fig. 13.4D) represent  haemorrhagic retinal infarcts and are located within the  middle retinal layers (see Fig. 13.4A). The extent of  involvement is a significant marker of the likelihood of  progression to PDR.    by chronic localized retinal oedema; they develop at the junction  of normal and oedematous retina. They are composed of lipopro¬  tein and lipid-filled macrophages located mainly within the outer  plexiform layer (Fig. 13.5A). Hyperlipidaemia may increase the  likelihood of exudate formation.   o Waxy yellow lesions (Fig. 13.5B) with relatively distinct  margins arranged in clumps and/or rings at the posterior  pole, often surrounding leaking microaneurysms,  o With time the number and size tend to increase (Fig.   13.5C), and the fovea may be involved,  o When leakage ceases, exudates absorb spontaneously over  a period of months, either into healthy surrounding  capillaries or by phagocytosis.   Fig. 13.2 Microaneurysms - histopathology. (A) Two arms of a capillary loop that may fuse to become a microaneurysm -  flat preparation of Indian ink-injected retina; (B) an area of capillary non-perfusion and adjacent microaneurysms - flat  preparation of Indian ink-injected retina; (C) eosinophilic (dark pink) degenerate pericytes - trypsin digest preparation;   (D) microaneurysm with endothelial cell proliferation (cellular microaneurysm) - trypsin digest preparation   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 - figs A and C; J Harry - figs B and D)   Fig. 13.3 Microaneurysms. (A) Microaneurysms and dot/blot haemorrhages at the posterior pole; (B) FA shows scattered  hyperfluorescent spots in the posterior fundus   Fig. 13.4 Retinal haemorrhages. (A) Histology shows blood lying diffusely in the retinal nerve fibre and ganglion cell layers  and as globules in the outer layers; (B) retinal nerve fibre layer (flame) haemorrhages; (C) dot and blot haemorrhages;   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 - fig. A)    o Chronic leakage leads to enlargement and the deposition  of crystalline cholesterol (Fig. 13.5D).   • FA will commonly show hypofluorescence only with large  dense exudates, as although background choroidal  fluorescence is masked, retinal capillary fluorescence is  generally preserved overlying the lesions (Fig 13.6).   Diabetic maculopathy (foveal oedema, exudates or ischaemia) is  the most common cause of visual impairment in diabetic patients,  particularly type 2. Diffuse retinal oedema is caused by extensive  capillary leakage, and localized oedema by focal leakage from  microaneurysms and dilated capillary segments. The fluid is ini¬  tially located between the outer plexiform and inner nuclear  layers; later it may also involve the inner plexiform and nerve fibre  layers, until eventually the entire thickness of the retina becomes    oedematous. With central accumulation of fluid the fovea assumes  a cystoid appearance - cystoid macular oedema (CMO) that is  readily detectable on optical coherence tomography (OCT) (Fig.  13.7A) and assumes a central flower petal pattern on FA (Fig.  13.7B).   • Focal maculopathy: well-circumscribed retinal thickening  associated with complete or incomplete rings of exudates  (Fig. 13.8A). FA shows late, focal hyperfluorescence due  to leakage, usually with good macular perfusion   • Diffuse maculopathy: diffuse retinal thickening, which may  be associated with cystoid changes; there are typically also  scattered microaneurysms and small haemorrhages (Fig.   13.9A). Landmarks may be obscured by oedema, which may  render localization of the fovea impossible. FA shows  mid- and late-phase diffuse hyperfluorescence (Fig. 13.9B),  and demonstrates CMO if present.    Fig. 13.5 Exudates. (A) Histology shows irregular eosinophilic deposits mainly in the outer plexiform layer; (B) small exudates  and microaneurysms; (C) more extensive exudates, some associated with microaneurysms; (D) exudates involving the  fovea, including central crystalline cholesterol deposition - focal laser has recently been applied superotemporal to the  fovea   (Courtesy of J Harry - fig. A; S Chen - figs C and D)    Fig. 13.6 FA of exudates. (A) Clinical appearance; (B) exudates not shown on FA   Fig. 13.7 Cystoid macular oedema. (A) OCT shows retinal  thickening and cystoid spaces; (B) FA shows leaking  microaneurysms and central diffuse hyperfluorescence with  a flower-petal configuration - same patient as Fig. 13.6   • Signs are variable and the macula may look relatively  normal despite reduced visual acuity. In other cases PPDR  may be present.   • FA shows capillary non-perfusion at the fovea (an enlarged  FAZ) and frequently other areas of capillary non-perfusion  (Fig. 13.10) at the posterior pole and periphery.   Clinically significant macular oedema (CSMO) is detected on  clinical examination as defined in the ETDRS (Fig. 13.11):   • Retinal thickening within 500 pm of the centre of the  macula (Fig. 13.11, upper left).   • Exudates within 500 pm of the centre of the macula, if  associated with retinal thickening; the thickening itself may  be outside the 500 pm (Fig. 13.11, upper right).   • Retinal thickening one disc area (1500 pm) or larger, any  part of which is within one disc diameter of the centre of the  macula (Fig. 13.11, lower centre).   Cotton wool spots are composed of accumulations of neuronal  debris within the nerve fibre layer. They result from ischaemic  disruption of nerve axons, the swollen ends of which are known  as cytoid bodies, seen on light microscopy as globular structures  in the nerve fibre layer (Fig. 13.12A). As cotton wool spots heal,  debris is removed by autolysis and phagocytosis.   • Signs. Small fluffy whitish superficial lesions that obscure  underlying blood vessels (Fig. 13.12B and C). They are  clinically evident only in the post-equatorial retina, where  the nerve fibre layer is of sufficient thickness to render them  visible.   Fig. 13.8 Focal diabetic maculopathy. (A) A ring of hard  exudates temporal to the macula; (B) FA late phase shows  focal area of hyperfluorescence due to leakage  corresponding to the centre of the exudate ring   Fig. 13.9 Diffuse diabetic maculopathy. (A) Dot and blot  haemorrhages - diffuse retinal thickening is present;  (B) late-phase FA shows extensive hyperfluorescence  at the posterior pole due to leakage    • FA shows focal hypofluorescence due to local ischaemia and  blockage of background choroidal fluorescence.   Venous anomalies seen in ischaemia consist of generalized dilata¬  tion and tortuosity, looping, beading (focal narrowing and dilata¬  tion) and sausage-like segmentation (Fig. 13.13). The extent of the  retinal area exhibiting venous changes correlates well with the  likelihood of developing proliferative disease.   Intraretinal microvascular abnormalities (IRMA) are arteriolar-  venular shunts that run from retinal arterioles to venules, thus  bypassing the capillary bed and are therefore often seen adjacent  to areas of marked capillary hypoperfusion (Fig. 13.14A).   Fig. 13.10 Ischaemic diabetic maculopathy. FA venous phase  shows hypofluorescence due to capillary non-perfusion at  the central macula and elsewhere    • Signs. Fine, irregular, red intraretinal lines that run from  arterioles to venules, without crossing major blood vessels  (Fig. 13.14B).   Subtle retinal arteriolar dilatation may be an early marker of  ischaemic dysfunction. When significant ischaemia is present  signs include peripheral narrowing, ‘silver wiring’ and oblitera¬  tion, similar to the late appearance following a branch retinal  artery occlusion.   Fig. 13.12 Cotton wool spots. (A) Histology shows cytoid Fig. 13.13 Venous changes. (A) Looping; (B) beading;   bodies in the retinal nerve fibre layer; (B) clinical (C) severe segmentation   (A) Histology shows arteriolar-venular shunt and a few  microaneurysms within a poorly perfused capillary bed -  flat preparation of Indian ink-injected retina; phase  contrast microscopy; (B) clinical appearance   It has been estimated that over one-quarter of the retina must be  non-perfused before PDR develops. Although preretinal new  vessels may arise anywhere in the retina, they are most commonly  seen at the posterior pole. Fibrous tissue, initially fine, gradually  develops in association as vessels increase in size.   • New vessels at the disc (NVD) describes neovascularization  on or within one disc diameter of the optic nerve head (Fig.   • New vessels elsewhere (NVE) describes neovascularization  further away from the disc (Fig. 13.16); it may be associated  with fibrosis if long-standing.   • New vessels on the iris (NVI - Fig. 13.17), also known as  rubeosis iridis, carry a high likelihood of progression to  neovascular glaucoma (see Ch. 10).    • FA (see Fig. 13.15C) highlights neovascularization during the  early phases of the angiogram and shows irregular expanding  hyperfluorescence during the later stages due to intense  leakage of dye from neovascular tissue. FA can be used to  confirm the presence of new vessels (NV) if the clinical  diagnosis is in doubt, and also delineates areas of ischaemic  retina that might be selectively targeted for laser treatment.   • Patient education is critical, including regarding the need to  comply with review and treatment schedules in order to  optimize visual outcomes.   • Other risk factors, particularly systemic hypertension  (especially type 2 diabetes) and hyperlipidaemia should be  controlled in conjunction with the patient’s diabetologist.   • Fenofibrate 200 mg daily has been shown to reduce the  progression of diabetic retinopathy in type 2 diabetics and  prescription should be considered; the decision is  independent of whether the patient already takes a statin.   • Smoking should be discontinued, though this has not been  definitively shown to affect retinopathy.   • Other modifiable factors such as anaemia and renal failure  should be addressed as necessary.   Until recently laser photocoagulation was the mainstay of treat¬  ment for DMO, reducing the risk of visual loss by 50% overall  compared with observation. The availability of newer treatment  modalities and increasing evidence for their efficacy has dramati¬  cally altered the approach to management over recent years.  However, options should always be discussed fully with the  patient. In particular, patients with good vision who otherwise  meet criteria for treatment might prefer observation once the risks  of various interventions are taken into account.   o Focal (Figs 13.18A and B). Diode or argon burns are  applied to leaking microaneurysms 500-3000 pm from  the foveola; spot size 50-100 pm, duration 0.05-0.1 s with  sufficient power to obtain a greyish reaction beneath the  microaneurysm.   o Grid (Figs 13.18C-F). Burns are applied to macular areas  of diffuse retinal thickening, treating no closer than  500 pm from the foveola and 500 pm from the optic disc  using a spot size of 50-100 pm and duration 0.05-0.1  second, with power adjusted to give a mild reaction. A  ‘modified’ grid includes focal treatment to foci of leakage,  usually microaneurysms.   • Subthreshold micropulse diode laser. This modality uses  very short (microsecond order) laser pulse duration  combined with a longer interval (e.g. 5% duty cycle)    Fig. 13.15 Disc new vessels. (A) Mild; (B) severe; (C) FA  shows leaking disc vessels, with extensive peripheral  capillary dropout and a small focus of leaking vessels  elsewhere   Fig. 13.16 New vessels elsewhere. (A) Mild; (B) severe;  (C) associated with fibrosis    allowing energy dissipation, minimizing collateral damage to  the retina and choroid whilst stimulating the retinal pigment  epithelium (RPE). Research to date indicates that similar  results are achieved to those of conventional thermal laser.   • Intravitreal anti-VEGF agents. Following substantial clinical  studies, intravitreal VEGF inhibitors (see also Ch. 14) have  been adopted as a critical element of the management of  diabetic maculopathy. Most current studies have looked at  ranibizumab or bevacizumab.   • Intravitreal triamcinolone. In pseudophakic eyes  intravitreal triamcinolone steroid injection followed by  prompt laser is comparable to ranibizumab with regard to  visual improvement and reducing retinal thickening.  However, there is a significant risk of an elevation of  intraocular pressure (IOP) and this must be monitored  carefully. No benefit above laser has consistently been shown  for phakic eyes, which have a substantially increased risk of  cataract. Sustained-release intravitreal steroid implants have  also demonstrated promising results.   • Pars plana vitrectomy (PPV - Fig. 13.19) may be indicated  when macular oedema is associated with tangential traction  from a thickened and taut posterior hyaloid (see Ch. 14   - vitreomacular traction syndrome). It has also been  suggested that some eyes without a taut posterior hyaloid  may also benefit from vitrectomy. Clinically, a taut  thickened posterior hyaloid is characterized by an increased  glistening of the pre-macular vitreous face. FA typically  shows diffuse leakage and prominent CMO, but OCT is  usually the definitive assessment. There are several other  indications for PPV in the management of diabetic eye  disease (see later).   o CSMO not involving the macular centre should be  treated with photocoagulation (see Fig. 13.18), or with  micropulse laser if available.   o CSMO involving the macular centre but with normal or  minimally affected vision, perhaps 6/9 or better, can    either undergo laser (micropulse may carry a lower risk  of foveolar damage) or be observed if leakage arises very  close to the fovea. If laser is performed, it is prudent to  treat no closer than 500 pm from the perceived macular  centre.   CSMO involving the macular centre and with reduced or  reducing vision (6/9-6/90) and significant foveolar  thickening on OCT should be considered for intravitreal  anti-VEGF treatment, with initial induction using  monthly injections for 3-6 months. An as-needed  approach can subsequently be adopted. It is possible that  combining anti-VEGF treatment with laser - probably  deferred until completion of the induction phase - offers  advantages, particularly in terms of reducing the  frequency of injections, and investigation is ongoing.  Pseudophakic eyes with CSMO involving the macular  centre and 6/9-6/90 vision should be considered for  either the regimen above or intravitreal preservative-free  triamcinolone followed soon afterwards by laser,  o Options in resistant cases include intravitreal steroid:  intravitreal triamcinolone - optimally preservative-free  - or a sustained-release intravitreal steroid implant. Pars  plana vitrectomy may be considered, particularly if  vitreomacular traction is present,  o Eyes with markedly reduced vision due to DMO generally  have a poor prognosis, and optimal management is not  determined. Depending on circumstances, observation or  any of the interventions discussed above may be  considered.   Scatter laser treatment (panretinal photocoagulation - Fig. 13.20)  continues to be the mainstay of PDR treatment, with intravitreal  anti-VEGF injection and other modalities remaining adjunctive.  The Diabetic Retinopathy Study (DRS) established the character¬  istics of high-risk proliferative disease and demonstrated the  benefit of panretinal photocoagulation (PRP); for instance, severe  NVD without haemorrhage carries a 26% risk of visual loss at 2  years that is reduced to 9% with PRP.   • Informed consent. Patients should be advised that PRP may  occasionally cause visual field defects of sufficient severity to  legally preclude driving a motor vehicle; they should also be  made aware that there is some risk to central vision, and  that night and colour vision may be affected.   • Co-existent DMO. If actual or imminent CSMO is also  present, laser for this should preferably be carried out prior  to PRP or at the same session; the intensity and amount of  PRP should be kept to the lowest level likely to be effective,  and may be spread over multiple sessions; adjunctive  intravitreal steroid or an anti-VEGF agent may improve the  outcome.   • Lens. A contact lens is used to provide a stable magnified  fundus view. A panfundoscopic lens is now generally  preferred to a three-mirror lens, as it is more difficult to  inadvertently photocoagulate the posterior pole through   Fig. 13.18 Laser for clinically significant macular oedema. (A) Prior to focal laser treatment; (B) immediately following focal  laser; (C) prior to modified macular grid laser treatment; (D) patient in (C) immediately post-grid laser; (E) appearance 2  months following a limited laser grid; (F) dense macular grid - the fovea is spared   (Courtesy of S Chen - figs A, B and F; R Bates - figs C-E)   Fig. 13.19 Pars plana vitrectomy including macular grid in diabetic maculopathy. (A) Preoperative appearance; (B) appearance  several weeks postoperatively; (C) and (D) pre- and postoperative macular OCT scans   Fig. 13.20 (A) Limited panretinal photocoagulation, with fresh retrohyaloid haemorrhage; (B) more extensive treatment;   (Courtesy of C Barry - fig. C; S Chen - fig. D)    the former. Some practitioners prefer to use a higher-  magnification/smaller area contact lens (e.g. Mainster®, Area  Centralis®) for the more posterior component of treatment.  It is essential to constantly bear in mind that an inverted and  laterally reversed image is seen.   • Anaesthesia. The amount of treatment it is possible to apply  during one session may be limited by patient discomfort;  this tends to be least at the posterior pole and greatest in the  periphery and over the horizontal neurovascular bundles. It  tends to worsen with successive sessions. Topical anaesthesia  is adequate in most patients, although sub-Tenon or  peribulbar anaesthesia can be administered if necessary.   o Spot size. A retinal burn diameter of 400 pm is usually  desired for PRP. The diameter selected at the user  interface to achieve this depends on the contact lens used  and the operator must be aware of the correction factor  for the particular lens chosen. As an approximation, with  panfundoscopic-type lenses the actual retinal spot  diameter is twice that selected on the laser user interface;  200 pm is typically selected for PRP, equating to a  400 pm actual retinal diameter once relative  magnification is factored in. With the Mainster and Area  Centralis, the retinal diameter equates closely to the  interface selection, so 400 pm may be selected,  o Duration depends on the type of laser: 0.05-0.1 s was  conventionally used with the argon laser, but newer lasers  allow much shorter pulses to be used and 0.01-0.05 s  (10-50 ms) is the currently recommended range.  Multispot strategies available on some machines utilize a  combination of short pulse duration (e.g. 20 ms), very  short intervals and pre-programmed delivery arrays to  facilitate the application of a large number of pulses in a  short period (see Fig. 13.20D). True micropulse PRP is  also under investigation and shows promising results.  Shorter pulse duration seems to require a greater total    number of burns for an adequate response, and may be  slower to achieve regression,  o Power should be sufficient to produce only a light  intensity burn.   o Spacing. Burns should be separated by 1-1.5 burn widths,  o Extent of treated area. The initial treatment session  should consist of 1500 burns in most cases, though more  may be applied if there is a risk of imminent sight loss  from vitreous haemorrhage. The more extensive the  treatment at a single session, the greater the likelihood of  complications. Reported figures vary, but 2500-3500  burns are likely to be required for regression of mild  PDR, 4000 for moderate PDR and 7000 for severe PDR.  The number of burns offers only approximate guidance,  as the effective extent of treatment is dependent on  numerous variables.   o Pattern of treatment. Treatment is generally restricted to  the area outside the temporal macular vascular arcades; it  is good practice to delineate a ‘barrier’ of laser burns  temporal to the macula early in the procedure to help to  reduce the risk of accidental macular damage. Many  practitioners leave two disc diameters untreated at the  nasal side of the disc, to preserve paracentral field. In very  severe PDR it is advisable to treat the inferior fundus first,  since any vitreous haemorrhage will gravitate interiorly  and obscure this area, precluding further treatment. Areas  of vitreoretinal traction should be avoided.   • Review is dependent on PDR severity and the requirement  for successive treatment applications; initial treatment should  be fractionated over 2-3 sessions. Once an adequate number  of burns have been applied review can be set for 4-6 weeks.   • Indicators of regression include blunting of vessel tips,  shrinking and disappearance of NV, often leaving ‘ghost’  vessels or fibrosis (Fig. 13.21), regression of IRMA, decreased  venous changes, absorption of retinal haemorrhages, disc  pallor. Contraction of regressing vessels or associated   Fig. 13.21 Treatment of proliferative diabetic retinopathy. (A) Severe proliferative disease; (B) 3 months later the new vessels  have regressed - there is residual fibrosis at the disc    induction of vitreous separation can precipitate vitreous  haemorrhage. Significant fibrous proliferation can lead to  tractional retinal detachment (see below). Patients should  remain under observation, as recurrence can occur with a  requirement for additional PRP.   Intravitreal anti-VEGF injection has an adjunctive role in the  treatment of PDR. Indication can include attempted resolution    of persistent vitreous haemorrhage (with prior B-scan ultrasono¬  graphy to exclude retinal detachment) with the aim of avoiding  vitrectomy, the initial treatment of rubeosis iridis (see below and  Ch. 10) whilst a response to PRP is realized, and possibly the rapid  control of very severe PDR to minimize the risk of haemorrhage.   Wide-field fluorescein angiography allows accurate delineation  of peripheral capillary non-perfusion (Fig. 13.22). Selective    Fig. 13.22 Wide-field FA showing widespread areas of capillary non-perfusion - the arrow indicates a well-defined example    treatment of these areas with scatter laser has been reported as  effectively leading to regression of NV whilst minimizing potential  complications.   Advanced diabetic eye disease is a serious vision-threatening com¬  plication of DR that occurs in patients in whom treatment has  been inadequate or unsuccessful. Occasionally, advanced disease  is evident at, or prompts, presentation.   • Haemorrhage may be preretinal (retrohyaloid), intragel or  both (Figs 13.23A and B). Intragel haemorrhages usually take  longer to clear than preretinal because the former are usually  more substantial. In some eyes, altered blood becomes  compacted on the posterior vitreous face to form an ‘ochre  membrane’. Ultrasonography is used in eyes with dense  vitreous haemorrhage to detect the possibility of associated  retinal detachment.   • Tractional retinal detachment (Fig. 13.23C) is caused by  progressive contraction of fibrovascular membranes over  areas of vitreoretinal attachment. Posterior vitreous  detachment in eyes with PDR is often incomplete due to the  strong adhesions between cortical vitreous and areas of  fibrovascular proliferation; haemorrhage often occurs at  these sites due to stress exerted on NV.   • Rubeosis iridis (iris neovascularization - NVI) may occur in  eyes with PDR, and if severe may lead to neovascular  glaucoma (see Ch. 10). NVI is particularly common in eyes  with severe retinal ischaemia or persistent retinal  detachment following unsuccessful pars plana vitrectomy.   Vitrectomy in diabetic retinopathy is typically combined with  extensive endolaser PRP. Visual results depend on the specific  indication for surgery and the severity of pre-existing disease.   • Severe persistent vitreous haemorrhage that precludes  adequate PRP is the most common indication. In the  absence of rubeosis iridis, vitrectomy has traditionally been  considered within 3 months of the initial vitreous  haemorrhage in type 1 diabetics and in most cases of  bilateral haemorrhage. However, the outcome may be better  with earlier surgery, and the availability of intravitreal  anti-VEGF therapy may further modify the approach.   • Progressive tractional RD threatening or involving the  macula must be treated without delay. However,  extramacular tractional detachments may be observed, since  they often remain stationary for prolonged periods.   • Premacular retrohyaloid haemorrhage (Fig 13.24A), if dense  and persistent should be considered for early vitrectomy  because, if untreated, the internal limiting membrane or  posterior hyaloid face may serve as a scaffold for subsequent  fibrovascular proliferation and consequent tractional   Fig. 13.23 Advanced diabetic eye disease. (A) Retrohyaloid and  small amount of intragel haemorrhage; (B) more substantial  intragel bleeding; (C) tractional retinal detachment   Fig. 13.24 Large premacular retrohyaloid haemorrhage.  (A) Before and (B, C) after Nd:YAG laser hyaloidotomy    macular detachment or macular epiretinal membrane  formation. Dispersion with YAG laser (hyaloidotomy) is  often successful (Figs 13.24B and C).   Diabetic papillopathy (diabetic papillitis) has been speculated to  be an uncommon variant of anterior ischaemic optic neuropathy,  though is more commonly bilateral and tends to exhibit more  diffuse disc swelling. The underlying pathogenesis is unclear but  it may be the result of small-vessel disease. It occurs mainly in  younger diabetics, and manifests with mild painless visual impair¬  ment that is unilateral in more than half of cases; bilateral disc  swelling mandates the exclusion of raised intracranial pressure.  Hyperaemic disc swelling is characteristic, and disc telangiectasia  occasionally mistaken for neovascularization is present in many  affected eyes (Fig. 13.25). Crowding of the fellow disc may be  present. Resolution occurs over several months, often leaving  mild disc pallor. Final visual acuity (VA) is 6/12 or better in 80%,  subject to the effect of coexisting diabetic retinopathy. Distinction  from retinal vein occlusion (RVO)-type papillophlebitis (see  below) rests on the presence of more extensive retinal haemor¬  rhages and venous congestion in the latter, but may not be    Fig. 13.26 Incidental finding of a single cotton wool spot -  no positive findings on systemic investigation. A degree of  vascular tortuosity may be an additional cardiovascular risk  indicator   possible. Intravitreal anti-VEGF agents and steroids via various  routes have been tried, with indeterminate benefit.    Up to 10% of individuals over the age of 40 without diabetes mel-  litus exhibit - usually very mild - retinopathic features such as  microaneurysms, dot and blot haemorrhages and cotton wool  spots (Fig. 13.26) that would be consistent with a diagnosis of  diabetic retinopathy. Assuming that an alternative ocular cause  such as RVO or idiopathic macular telangiectasia has been  excluded, this ‘non-diabetic’ retinopathy tends to be associated  with increased cerebro- and cardiovascular risk, and may be par¬  ticularly prevalent in patients with known or incipient hyperten¬  sion. There is evidence suggesting that it may be a marker of  pre-clinical diabetes in some patients; higher venular calibre may  also denote this. Appropriate management is undefined, though  evaluation and optimal management of systemic vascular risk  factors may be prudent. The signs commonly disappear spontane¬  ously, and this is more likely in those with lower levels of cardio¬  vascular risk.   Retinal vein thrombosis is strongly associated with age-related  local and systemic factors. Typically, in branch retinal vein occlu¬  sion (BRVO) arteriolosclerotic thickening of a branch retinal arte¬  riole is associated with compression of a venule at an arteriovenous  crossing point, exacerbated by sharing an adventitial sheath. This  leads to secondary changes that include endothelial cell loss, tur¬  bulent flow and thrombus formation. Similarly, the central retinal  vein and artery possess a common sheath at crossing points pos¬  terior to the lamina cribrosa so that atherosclerotic changes of the  artery may precipitate central retinal vein occlusion (CRVO).    Haematological pro-thrombotic factors are thought to be impor¬  tant in a minority, amplifying an atherosclerotic anatomical pre¬  disposition. Once venous occlusion has occurred, elevation of  venous and capillary pressure with stagnation of blood flow  ensues, resulting in retinal hypoxia, which in turn results in  damage to the capillary endothelial cells, extravasation of blood  constituents and liberation of mediators such as VEGF.   • Age is the most important factor; over 50% of cases occur in  patients older than 65.   • Hypertension is present in two-thirds or more of RVO  patients over the age of 50 years and in 25% of younger  patients. It is most prevalent in patients with BRVO.   • Hyperlipidaemia is present in one-third or more of patients,  irrespective of age.   • Diabetes mellitus is present in up to 15% of patients over 50  years of age overall. It is more prevalent in Asian and black  patients, but uncommon in younger patients.   • Glaucoma and probably ocular hypertension are associated  with a higher risk of CRVO and possibly BRVO.   • Oral contraceptive pill. In younger females the contraceptive  pill is the most common underlying association, and  probably should not be taken following RVO.   • Smoking. Current smoking may be associated with an  increased incidence of RVO, though studies have shown  inconsistent results.   • Uncommon. Dehydration, myeloproliferative disorders (e.g.  myeloma, polycythaemia), thrombophilia (e.g.  hyperhomocysteinaemia, antiphospholipid antibody  syndrome, factor V Feiden mutation), inflammatory disease  associated with occlusive periphlebitis (e.g. Behcet  syndrome, sarcoidosis, Wegener granulomatosis), orbital  disease and chronic renal failure.   The detection and management of associated systemic disease is  aimed principally at reducing the risk of future vascular occlusive  events, both ocular and systemic.   • Random total and high-density lipoprotein (HDL)  cholesterol. Additional lipid testing may be considered.   • Plasma protein electrophoresis. To detect dysproteinaemias  such as multiple myeloma.   • Other tests. Some authorities advocate routine investigation  for systemic end-organ damage related to the cardiovascular  risk factors commonly found in patients with RVO. This is    intended to help the prevention of further non-ocular  damage, as well as facilitating systemic management to  reduce the risk of recurrent ocular venous occlusion.  Research is conflicting, some studies suggesting that  cardio- and cerebrovascular mortality is not elevated above  that of the general population in patients with RVO and  others finding the converse.   o Urea, electrolytes and creatinine to detect renal disease  associated with hypertension; chronic renal failure is also  a rare cause of RVO.   o Thyroid function testing. There is a higher prevalence of  thyroid disease in RVO patients,  o Electrocardiography (ECG). Left ventricular hypertrophy  is associated with hypertension.   These tests might be considered in patients under the age of 50, in  bilateral RVO, patients with previous thromboses or a family  history of thrombosis, and some patients in whom investigation  for the common associations is negative. Evidence of a causative  link for many of these is limited.   • Plasma homocysteine level. To exclude  hyperhomocysteinaemia, for which there is reasonable  evidence of an increased RVO risk.   • ‘Thrombophilia screen’. By convention this refers to  heritable thrombophilias; tests might typically include  thrombin time, prothrombin time and activated partial  thromboplastin time, antithrombin functional assay, protein  C, protein S, activated protein C resistance, factor V Leiden  mutation, prothrombin G20210A mutation, lupus  anticoagulant and anticardiolipin antibody (IgG and IgM);  the last may be the most important of these.   • Autoantibodies. Rheumatoid factor, antinuclear antibody  (ANA), anti-DNA antibody, antineutrophil cytoplasmic  antibody (ANCA).   • Symptoms if the central macula is involved consist of the  sudden painless onset of blurred vision and metamorphopsia.  Peripheral occlusion may be asymptomatic.   • VA at presentation is very variable. Historically 50% of  untreated eyes retain 6/12 or better in the long term, but  about a quarter only achieve 6/60 or worse.    • Iris neovascularization (NVI) and neovascular glaucoma  (NVG) are much less common in BRVO - 2-3% at 3 years -  than in CRVO.   o Dilatation and tortuosity of the affected venous segment,  with flame-shaped and dot/blot haemorrhages,  principally in the retinal area drained by the thrombosed  vein though an occasional haemorrhage may be identified  elsewhere; cotton wool spots and retinal oedema may be  absent but are often prominent (Fig. 13.27A).  o The superotemporal quadrant is most commonly affected,  o The site of occlusion may be identifiable as an  arteriovenous crossing point,  o The acute features usually resolve within 6-12 months  leaving venous sheathing and sclerosis, and variable  persistent/recurrent haemorrhage (Fig. 13.27B); the  severity of residual signs is highly variable,  o Collateral vessels may form near areas of limited capillary  perfusion after weeks to months. They usually connect a  poorly functioning to a normally functioning segment of  the venous circulation, and typically appear as tortuous  or looping channels. They may cross the horizontal raphe  between the inferior and superior vascular arcades. The  appearance of collaterals is associated with a better  prognosis; ablation of collaterals should be avoided if  laser is performed.   o Chronic macular oedema is the most common cause of  persistent poor visual acuity after BRVO.  o Retinal neovascularization occurs in about 8% of eyes by  three years; the risk is much higher in eyes with more  than about 5 disc areas of non-perfusion on FA (over  one-third of eyes). NVE are more common than NVD.  NVE usually develop at the border of ischaemic retina  drained by an occluded vein; they typically appear within  6-12 months but may develop at any time,  o Recurrent vitreous and preretinal haemorrhage, and  occasionally tractional retinal detachment, can occur  secondary to neovascularization.   • FA demonstrates peripheral and macular ischaemia (capillary  non-perfusion, staining of vessel walls, vessel ‘pruning’   - small branches failing to fill - Fig. 13.27C), haemorrhage  and oedema (Fig. 13.27D) with collateral vessels commonly  forming in established cases (Fig. 13.27E). Venous filling is  delayed. In late or subtle cases FA may be diagnostic.   Laser was formerly the standard of treatment for macular oedema  in BRVO, but newer effective and relatively safe treatments are  now available. However, the optimal regimen has not been ascer¬  tained, with investigation ongoing as to whether pharmacological  treatments alone or in combination with laser, including novel  modalities such as micropulse, carry the best risk/outcome profile.   • Systemic assessment should be carried out as above, with  appropriate specialist referral when warranted.   (A) Acute - flame-shaped and blot haemorrhages,  cotton wool spots and venous tortuosity; (B) 6 months  later - venous sheathing, a few exudates and residual  haemorrhages, with collaterals at the temporal macular  edge; (C) early FA image of the acute occlusion principally  showing capillary non-perfusion with some blockage by  blood; (D) later image clearly demonstrates vessel wall  staining, pruning and non-perfusion; (E) FA of chronic BRVO  shows capillary non-perfusion, with tortuous superior-  inferior collaterals temporally   Fig. 13.28 Treatment of branch retinal vein occlusion. (A) Sector laser photocoagulation for neovascularization; (B) cystoid  macular oedema before and (C) 4 weeks after bevacizumab intravitreal injection    • Observation without intervention is usually indicated if  visual acuity is 6/9 or better, or slightly worse but improving.   • FA. At 3 months, if visual acuity is 6/12 or worse, FA was  conventionally performed to exclude substantial macular  ischaemia prior to grid laser, though this may not be  required before anti-VEGF treatment alone (see below).   • NVE or NVD are generally regarded as an indication for  sector photocoagulation, though some authorities withhold  treatment unless vitreous haemorrhage occurs because early  intervention does not appear to affect the visual outcome.  Burns of mild-moderate intensity, 400-500 pm actual  diameter, 0.05 s duration and spaced one burn width apart  are applied to the ischaemic area (Fig. 13.28A). FA can be  used to confirm dubious NV if necessary, and to  demonstrate ischaemic areas that might be specifically  targeted with laser. Laser may be combined with 4-6 weekly  intravitreal anti-VEGF injection.   • NVI is an indication for urgent sector PRP; secondary  glaucoma is likely to be less aggressive than in CRVO. See  Chapter 10 for the detailed management of NVG.   • Intravitreal anti-VEGF agents (Figs. 13.28B and C). These  have been widely adopted for the treatment of macular  oedema secondary to BRVO, and probably raise acuity more  than laser (see below). There is also no requirement to wait  for 3 months before commencing treatment. However,  repeated injections are required. Combining intravitreal  injections with laser may allow a reduction in the frequency  of injections, but the optimal regimen is yet to be defined.   • Intravitreal dexamethasone implant. This confers visual  improvement in BRVO substantially superior to observation  alone. The treatment can be repeated after 4-6 months.  Adverse effects include an increased glaucoma and cataract  risk. As with anti-VEGF therapy, it may be used alone or in  conjunction with laser.   • Macular laser. If visual acuity remains 6/12 or worse after  3-6 months due to macular oedema that is associated with    good central macular perfusion on FA, laser may be  considered: 20-100 mild burns of diameter 50-100 pm and  duration 0.01-0.05 s, concentrating on areas of leakage on  FA; pulses at the shorter end of the duration range seem to  inflict less damage to the retina whilst exerting an  approximately comparable therapeutic effect. Treatment  should not encroach within 0.5 disc diameters of the foveal  centre. Retinal haemorrhages and blood vessels - especially  collaterals - should not be treated. With the advent of  intravitreal treatments, the threshold for macular laser has  been raised, and it may be regarded as an adjunctive or  combination modality.   • Micropulse laser may be as effective as conventional  photocoagulation for macular oedema but inflicts  considerably less retinal damage. Its onset of action is slower.   • Intravitreal triamcinolone in a preservative-free preparation  is as effective as laser in eyes with macular oedema but has a  less sustained effect and a relatively high rate of cataract  formation and IOP elevation.   • Periocular steroid injection is less invasive than intravitreal,  but almost certainly less effective.   • Review in cases that do not require early intervention should  usually take place after 3 months and then at 3-6 monthly  intervals for up to 2 years, principally to detect  neovascularization.   Impending (partial) CRVO on average occurs in younger patients  than those developing more severe occlusion; the prognosis is  usually good but a proportion will deteriorate to ischaemic CRVO.  The distinction between ‘impending’ and mild non-ischaemic  CRVO (see below) is not clear, and may be artificial. Symptoms  may be absent or consist of only minor or transient blurring that  is characteristically worse on waking. On examination, there is  mild retinal venous dilatation and tortuosity, with relatively few   Fig. 13.29 Impending central retinal vein occlusion (A) before  and (B) after spontaneous resolution    small scattered dot and blot haemorrhages (Fig. 13.29); there may  be mild macular oedema. Fundus autofluorescence (FAF) may  reveal a fern-like perivenular appearance (see below), and FA gen¬  erally demonstrates an impaired retinal circulation. Treatment is  empirical, with lack of an established evidence base. Correcting  any predisposing systemic conditions, avoiding dehydration, and  lowering IOP to improve perfusion have been postulated.  Antiplatelet agents, other anticoagulant measures and haemodilu-  tion are of no proven benefit, but may be considered in some cases.    syndrome - see later) is more common than the ischaemic form.  Around a third will progress to ischaemic CRVO, often within  months.   • VA is impaired to a variable degree dependent on severity;  eyes with initially good VA tend to have a good prognosis  and vice versa; initial VA in the middle range (6/30-6/60) is  an unreliable predictor of outcome. VA worse than 6/60  commonly indicates that substantial ischaemia is present. In  cases that do not become ischaemic, vision returns to  normal or near normal in about 50%.   o Tortuosity and dilatation of all branches of the central  retinal vein, with dot, blot and flame haemorrhages to  a mild-moderate extent; cotton wool spots, optic disc  and macular oedema are common but generally mild  (Fig. 13.30A).   O Patchy (or perivenular) ischaemic retinal whitening  (PIRW) in a perivenular pattern at the posterior pole is  an early sign occurring in younger patients with non-  ischaemic CRVO (Fig. 13.30B).  o Most acute signs resolve over 6-12 months; later findings  are variable, depending on severity but may include:  persistent scattered retinal haemorrhages; venous  tortuosity, sheathing and sclerosis; epiretinal gliosis;  macular pigmentary and atrophic changes; peripheral and  optic disc collateral vessels (Fig. 13.30C).  o The main cause of poor vision is chronic macular  oedema and secondary atrophy,  o Disc collaterals (see Fig. 13.30C) are common following  CRVO, appearing as a small vascular loop on the optic  nerve head. They are also known as optociliary shunts or  retinochoroidal collaterals, and are thought to represent a  compensatory circulation in response to impaired nerve  perfusion; their development is believed to be associated  with a markedly decreased risk of neovascularization.  They can form in a range of conditions besides CRVO,  including chronic glaucoma and chronic optic nerve  compression.   • FAF in acute RVO may show a characteristic fern-like  perivenular hypoautofluorescence due to masking of  background signal by oedema; it corresponds to PIRW (see  above) but is more commonly identifiable.   • FA shows delayed arteriovenous transit time, masking by  haemorrhage, usually good retinal capillary perfusion and  some late leakage (Fig. 13.30D).   • OCT is useful in the assessment of CMO, which is often  mild in a non-ischaemic lesion (Fig. 13.30E).   Ischaemic CRVO is characterized by substantially decreased  retinal perfusion with capillary closure and retinal hypoxia.  Macular ischaemia and NVG are the major causes of visual  morbidity.   Fig. 13.30 Non-ischaemic central retinal vein occlusion (CRVO). (A) Acute - wide-field image showing venous tortuosity and  dilatation, with moderate flame haemorrhages and at least one cotton wool spot; (B) young patient with mild non-  ischaemic CRVO showing perivenular ischaemic retinal whitening (PIRW), particularly noticeable in the perifoveal region;   (C) non-acute - disc collaterals and a few residual retinal haemorrhages; (D) FA late phase in a recent onset case shows  masking by blood and staining of vessel walls but good capillary perfusion; (E) OCT showing mild cystoid macular oedema   (Courtesy of S Chen - figs A-C and E; Moorfields Eye Hospital - fig. D)   • Symptoms. Sudden and severe monocular painless visual  impairment. Occasionally presentation may be with pain,  redness and photophobia due to neovascular glaucoma, a  prior reduction in vision having passed unnoticed or been  ignored.   • VA is usually CF or worse; the visual prognosis is generally  extremely poor due to macular ischaemia.   • NVI. Rubeosis iridis (Fig. 13.31A) develops in about 50% of  eyes, usually between 2 and 4 months (‘hundred-day    glaucoma’), and there is a high risk of neovascular  glaucoma. The pupillary margin should be examined at each  review prior to pharmacological mydriasis.   • Gonioscopy. Angle neovascularization (Fig. 13.31B) may  occur in the absence of neovascularization at the pupillary  margin. Routine gonioscopy should therefore be performed  at each review, again prior to pupillary dilatation.   o Severe tortuosity and engorgement of all branches of the  central retinal vein. There are extensive deep blot and  flame-shaped haemorrhages involving the peripheral and  posterior retina and cotton wool spots are typically   Fig. 13.31 (A) Rubeosis iridis at the pupillary border; (B) neovascularization of an open angle   (Courtesy of E Michael van Buskirk, from Clinical Atlas of Glaucoma, tVB Saunders 1986 - fig. B)    prominent. There is usually optic disc swelling and  hyperaemia (Fig. 13.32A).   o Most acute signs resolve over 9-12 months. The macula  may develop atrophic retinal and RPE changes, RPE  hyperplasia, epiretinal membrane and chronic CMO.  Rarely, subretinal fibrosis resembling that associated with  exudative age-related macular degeneration may develop,  o Retinal neovascularization occurs in about 5% of eyes  - much less commonly than with BRVO, but severe  vitreous haemorrhage can occur, obscuring vision and  preventing retinal laser.   o Optic disc collaterals (opticociliary shunts - see under  non-ischaemic CRVO) are common and may protect the  eye from anterior and posterior segment  neovascularization; their development (Fig. 13.32B)  probably indicates a dramatic reduction in the risk of this  complication.   • FA shows a marked delay in arteriovenous transit time,  masking by retinal haemorrhages, extensive areas of capillary  non-perfusion and vessel wall staining and leakage (Figs  13.32C and D). The presence of more than 10 disc areas of  retinal capillary non-perfusion is associated with a  substantially increased risk of neovascularization.   • Electroretinogram (ERG) is depressed and the extent of this  has sometimes been used to assess neovascular risk.   Hemiretinal vein occlusion is regarded as a variant of CRVO by  some authorities and may be ischaemic or non-ischaemic. It is less  common than either BRVO or CRVO and involves occlusion of  the superior or inferior branch of the central retinal vein (CRV).  A hemispheric occlusion blocks a major branch of the CRV at or  near the optic disc. The less common hemicentral occlusion  involves one trunk of a dual-trunked CRV that has persisted in  the anterior part of the optic nerve head as a congenital variant.   Prognosis depends on the severity of retinal ischaemia, but  management has been less well studied than BRVO and CRVO.  Extensive retinal ischaemia implies a risk of neovascular glaucoma  and should be managed in the same way as ischaemic CRVO (see    below), otherwise management, particularly of macular oedema,  may be as for BRVO.   • Symptoms. A sudden onset altitudinal visual field defect  (Fig. 13.33A).   • NVI is more common than in BRVO but less than in  CRVO.   • Fundus shows the features of BRVO, involving the superior  or inferior retinal hemisphere (Fig. 13.33B). NVD may be  more common than in either CRVO or BRVO.   • FA shows masking by haemorrhages, hyperfluorescence due  to leakage and variable capillary non-perfusion (Fig. 13.33C).   The management of non-ischaemic CRVO is generally much less  aggressive than ischaemic CRVO, so it is important to distinguish  the two as far as possible.   • Systemic assessment as described above is essential, followed  by appropriate systemic management (discussed below).   • Treatment of macular oedema. Treatment is generally  indicated for VA worse than 6/9 and/or with significant  central macular thickening (e.g. >250 pm) on OCT, but is  unlikely to be of benefit if 6/120 or worse. Intravitreal  anti-VEGF agents or dexamethasone implant are the current  standard of care.   o Intravitreal anti-VEGF agents (e.g. ranibizumab 0.5 mg)  may initially be given monthly for 6 months and  subsequently less intensively, with typically a two- to  three-line gain in VA. As with age-related macular  degeneration, initial research suggests that aflibercept  may facilitate less frequent administration for an  equivalent effect.   o Intravitreal dexamethasone implant. The GENEVA trial  of a sustained-release biodegradable dexamethasone  intravitreal implant (Ozurdex®) showed substantial visual  and anatomical (Figs 13.34A-D) improvement over the  first 2 months following a single implantation, and    Fig. 13.32 Recent ischaemic central retinal vein occlusion. (A) Numerous cotton wool spots, flame and deep blot  haemorrhages; (B) opticociliary shunt; (C) FA of (A) shows extensive hypofluorescence due to capillary non-perfusion;  (D) wide-field FA showing extensive peripheral ischaemia   (Courtesy of S Chen - figs A, C and D; C Barry - fig. B)    Fixation Monitor: Gaze /Blind Spot  Fixation Target: Central  Fixation Losses: 3/11 xx  False POS Errors: 1 %    -i -i  0 - 2-1  -3 -1 -1 -1  -1 -e -4    -13 -2? -18 -13 -20  -21 -22 -22 -22  -33 -33 -26  ■32 -31   0 0  -1 0 -2  0-1-1 -3  -1 -5 -6 -3 -2    ■18 -20 -17 -18 -19  ■20 “21 -22 -21  -32 -32-25  ■31 -30   MD -13.67 dB P < 0.5%  PSD 12.26 dB P < 0.5%    Fig. 13.33 (A) Inferior altitudinal visual field defect due to a superior hemiretinal vein occlusion;   Fig. 13.33, Continued (B) inferior hemiretinal vein occlusion; (C) FA late phase shows extensive hypofluorescence due to  capillary non-perfusion, with mild perivascular hyperfluorescence   (Courtesy of S Chen - fig. A; C Barry - figs B and C)   Fig. 13.34 Treatment of central retinal vein occlusion (CRVO) complications. (A) CRVO before and (B) 6 months after  intravitreal dexamethasone implant; (C) and (D) corresponding macular OCT images;   Fig. 13.34, Continued (E) triamcinolone after intravitreal administration; (F) a radial optic neurotomy incision site is visible on  the nasal side of the optic nerve head; (G) panretinal photocoagulation    although this declined to baseline by 6 months the  treatment could then be repeated. As with triamcinolone,  there was a slightly higher rate of IOP elevation and  cataract. Administration within 90 days of CMO onset is  likely to be associated with a better outcome. Treatment  can be repeated after 4-6 months,  o Intravitreal triamcinolone (Fig. 13.34E). The SCORE study  showed an improvement of three or more lines of vision  at one year in over 25% of patients (versus 7% of  controls) treated with an average of two injections of  1 mg triamcinolone, using a preservative-free preparation  developed for intraocular use. There was a slightly higher  rate of IOP elevation and cataract than with observation,  o Laser photocoagulation. Although macular oedema is  anatomically improved, laser is typically not beneficial for  visual outcome, except in some younger patients.    o Investigational treatments include chorioretinal  anastomosis, vitrectomy with radial optic neurotomy  (Fig. 13.34F) and local recombinant tissue plasminogen  activator (rtPA) CRV infusion.   o Panretinal photocoagulation (PRP) should be performed  without delay in eyes with NVI or angle  neovascularization. This initially involves placing  1500-2000 burns of o.5-0.1 s duration, spaced one burn  width apart, with sufficient energy to produce a pale to  moderate reaction, avoiding areas of haemorrhage (Fig.  13.34G). Treatment may be fractionated, and further  photocoagulation is commonly required,  o Intravitreal anti-VEGF injections are commonly  administered adjunctively every 6 weeks until the eye  stabilizes, and lead to more rapid resolution of new    vessels than PRP alone. If intravitreal treatment is  administered first, a delay of a few days is probably  prudent to avoid contaminating the fresh injection site.  VEGF inhibitors are likely to be of lower value if  synechial angle closure is present,  o The management of NVG is discussed in Chapter 10.  o Vitreous haemorrhage may respond to intravitreal   anti-VEGF - research is limited - but definitive treatment  is with vitrectomy and endolaser.   ischaemic CRVO should be seen monthly for 6 months  with a view to the early detection of anterior segment  neovascularization. Prophylactic PRP is generally not  recommended even with marked ischaemia unless iris  new vessels develop, though may be considered in  patients unlikely to attend scheduled review. Subsequent  monitoring should usually be for up to 2 years to detect  significant ischaemia and macular oedema; once a disc  collateral has developed, the risk of neovascularization is  probably much lower.   o Non-ischaemic CRVO. In a clearly non-ischaemic  occlusion, initial follow-up should take place after 3  months. Structured arrangements for review of test  results should be in place. The patient should be  instructed to make contact if the vision deteriorates as  this may indicate the development of significant  ischaemia. Pain or redness, which may indicate  neovascular glaucoma and occasionally inflammation  without rubeosis, should also be reported. Subsequent  review is dependent on the clinical picture and any  treatment, with discharge from follow-up usually taking  place at 18-24 months.   • Control of systemic risk factors. Although there is no  conclusive evidence that vascular mortality is higher in RVO  patients, independently important cardiovascular risk factors  are very commonly identified during investigation following  RVO. Addressing these as appropriate is critical, and as well  as conferring systemic benefit this may also reduce the risk  of the recurrence of retinal vein occlusion. Smoking should  be strongly discouraged.   • Antiplatelet therapy. The role of aspirin or alternative  antiplatelet agents in reducing the risk of further retinal  venous occlusion is unclear and they are generally not  prescribed unless systemically indicated.   • Hormone replacement therapy (HRT). The risk of HRT  remains undefined. Most authorities would avoid  commencing oestrogen-containing HRT following RVO,  though depending on indication and other circumstances it  may be appropriate to continue if already taking this.  Appropriate expert advice should be obtained; the presence  of other thrombophilia risk factors is associated with a    substantially increased risk of systemic venous thrombosis in  conjunction with HRT.   • Oral contraceptive pill. This should probably be  discontinued following RVO.   • Others. A range of systemic treatment modalities (e.g.  isovolaemic haemodilution, plasmapheresis, recombinant  tissue plasminogen infusion) has been employed to try to  improve visual outcomes in RVO, but clear evidence for  benefit is lacking. Dehydration should be avoided.   Papillophlebitis is an uncommon poorly defined condition that  typically affects individuals under the age of 50 years who may  have a higher prevalence of hypertension and diabetes. Some or  all cases may simply be a variant of CRVO occurring in younger  people, though optic disc swelling or inflammation of the central  retinal vein have been speculated as the initiating event in at least  some instances. There is likely to be some diagnostic overlap with  diabetic papillopathy. Papillophlebitis typically causes only mild  to moderate reduction of vision with no RAPD, and has a gener¬  ally good prognosis. Disc oedema is the dominant finding, and  retinal haemorrhages and other signs such as cotton wool spots  are predominantly peripapillary and confined to the posterior pole  (Fig. 13.35). CMO may be present, and posterior or anterior  segment neovascularization have been reported occasionally in  concert with capillary non-perfusion on FA. It may be bilateral,  when raised intracranial pressure must be ruled out. Investigation  should probably be as for CRVO in a young individual; distinction  from diabetic papillopathy may be difficult. Treatment with intra¬  vitreal anti-VEGF or steroid has been reported.   The outer retina is supplied by the ciliary arteries via the chorio-  capillaris and the inner retina by the central retinal artery (CRA).    The ophthalmic artery gives rise to both the CRA - its first branch  - and the ciliary arteries; the latter also supply the anterior segment  via the rectus muscles. Atherosclerosis-related embolism and  thrombosis are thought to be responsible for the majority of cases  of retinal artery occlusion, but the proportion of cases due to each  of these is unknown. Inflammation in or around the vessel wall  (e.g. giant cell arteritis - GCA, systemic lupus erythematosus,  Wegener granulomatosis, polyarteritis nodosa), vasospasm (e.g.  migraine) and systemic hypotension contribute in a minority. The  origin of emboli is most commonly an atheromatous carotid  plaque; the ophthalmic artery is the first branch of the internal  carotid artery, so embolic material has an easy route to the eye.  Emboli can be refractile yellow-white cholesterol (Hollenhorst)  plaques (Fig. 13.36A), greyish elongated fibrin-platelet aggregates  (Fig. 13.36B), non-scintillating white calcific particles (Fig. 13.36C),  and rarely vegetations from bacterial endocarditis, cardiac myxo¬  matous material, fat and others. Thrombophilic disorders that  may be associated with retinal artery occlusion (one-third of  young patients) include hyperhomocysteinaemia, antiphospho¬  lipid antibody syndrome and inherited defects of various natural  anticoagulants. Sickling haemoglobinopathies and Susac syn¬  drome (retinocochleocerebral vasculopathy), a microangiopathy  characterized by the triad of retinal artery occlusion, sensorineural  deafness and encephalopathy, are other rare associations.   Following diagnosis and initial evaluation by an ophthalmologist  many elements of the assessment may be carried out by a specialist  stroke team. Urgent specialist vascular evaluation, typically within  24 hours, is rapidly becoming the standard of care following  a retinal arterial event, including amaurosis fugax; the risk of  a stroke is relatively high in the first few days after a transient  ischaemic attack (TIA). The detection of atrial fibrillation is of  particular importance as admission for anticoagulation may be  indicated.   Many or most patients will already be aware of vascular risk factors  and/or disease.   • Symptoms of GCA ( 1 - 2 % of central retinal artery  occlusion - CRAO) such as headache, jaw claudication,  scalp tenderness, limb girdle pain, weight loss and existing  polymyalgia rheumatica (see Ch. 19 ). GCA is extremely  unlikely under 55-60 years. It constitutes an ophthalmic  emergency.   • Pulse should be palpated to detect arrhythmia, particularly  atrial fibrillation.   • Carotid auscultation is of limited value as the absence of a  bruit does not exclude significant stenosis.   Fig. 13.36 Retinal emboli. (A) Hollenhorst plaque; (B) fibrin-  platelet emboli; (C) calcific embolus at the disc   (Courtesy of L Merin - fig. A; S Chen - fig. B; C Barry - fig. C)    • Other blood tests include FBC (platelets may be raised in  GCA), glucose, lipids, and urea and electrolytes, the latter to  exclude derangement including dehydration.   • Carotid duplex scanning is a non-invasive screening test  involving a combination of high-resolution real-time  ultrasonography with Doppler flow analysis. If significant  stenosis is present, surgical management may be considered.   The following additional tests can be considered on a targeted  basis in some patients, particularly if younger and with no known  cardiovascular risk factors, or there is an atypical clinical picture  (Fig. 13.37).   • Cranial magnetic resonance imaging (MRI) or computed  tomography (CT) may be indicated to rule out intracranial  or orbital pathology.   • Echocardiography. Usually performed in young patients or  if there is a specific indication such as a history of rheumatic  fever, known cardiac valvular disease, or intravenous drug  use.   o ‘Thrombophilia screen’. By convention refers to heritable  thrombophilias, which have predominantly been  implicated in venous rather than arterial thromboses,  o Plasma protein electrophoresis to detect dysproteinaemias  such as multiple myeloma.   o Thyroid function tests, especially if atrial fibrillation is  present; may be associated with dyslipidaemia.  o Autoantibodies. Rheumatoid factor, anticardiolipin  antibody, antinuclear antibody, anti-double stranded  DNA antibodies, principally looking for vasculitis in  younger patients,  o Syphilis serology,  o Blood cultures.   Amaurosis fugax is characterized by transient monocular loss of  vision, often described as a curtain coming down over the eye; the  absence of pain may be included in the definition. The Amaurosis  Fugax Study Group divided the causes into five categories (embolic,  hemodynamic, ocular, neurologic and idiopathic), but in clinical  practice it is typically used to refer to transient visual loss of  embolic origin. It is common for patients to be unaware of whether  transient unilateral visual loss affects one eye or the ipsilateral  hemifield of both, the latter indicating cerebral rather than more  anterior ischaemia. Embolic visual loss, which may be complete,  usually lasts a few minutes. Recovery is generally in the same  pattern as the loss, although usually more gradual. Frequency of   Fig. 13.37 (A) and (B) Multiple bilateral branch retinal artery  occlusions in polyarteritis nodosa    attacks may vary from several times a day to once every few  months. The attacks may sometimes be accompanied by an ipsi¬  lateral cerebral TIA, with contralateral neurological features.  Investigation and systemic management of embolic-pattern  amaurosis fugax is the same as that of retinal arterial occlusion  and should be undertaken similarly urgently due to the high risk  of stroke.   • Symptoms. Sudden and profound painless altitudinal or  sectoral visual field loss. Branch retinal artery occlusion    (BRAO) can sometimes go unnoticed, particularly if central  vision is spared.   • VA is variable. In patients where central vision is severely  compromised, the prognosis is commonly poor unless the  obstruction is relieved within a few hours (see below).   • Fundus signs may be subtle (Figs 13.38A, B and D).   o Cloudy white oedematous (ground glass) retina  corresponding to the area of ischaemia,  o One or more occluding emboli may be seen, especially at  bifurcation points.   o The affected artery is likely to remain attenuated.  Occasionally, recanalization may leave absent  ophthalmoscopic signs.   • FA shows delay in arterial filling and hypofluorescence of  the involved segment due to blockage of background  fluorescence by retinal swelling (Figs 13.38C and E).   • Review in 3 months is warranted to review the appearance  of the fundus, the visual fields, provide advice on prognosis  and confirm that systemic management has been carried out  appropriately.   • Symptoms. Sudden profound loss of vision, painless except  in GCA.   • VA is severely reduced except if a cilioretinal artery  supplying a critical macular area preserves central vision (see  below). Absence of light perception usually indicates either  GCA or ophthalmic artery occlusion. The prognosis is poor  in all cases unless recovery occurs in the first few hours.   • Fundus shows similar changes to BRAO but involving all  retinal quadrants (Fig. 13.39A).   o The orange reflex from the intact choroid stands out at  the thin foveola, in contrast to the surrounding pale  retina, giving rise to a ‘cherry-red spot’ appearance,  o The peripapillary retina may appear especially swollen  and opaque.   o An occasional small haemorrhage is not unusual,  o Emboli are visible in 20%, when Nd: YAG embolysis may  be considered (see below).   o In eyes with a cilioretinal artery part of the macula will  remain of normal colour (Fig. 13.39B).  o Retinal signs can sometimes be subtle; retinal oedema  may take several hours to develop,  o Over a few days to weeks the retinal cloudiness and    o Around 2% of eyes with CRAO develop retinal or disc  neovascularization.   o Rubeosis iridis may occur in up to about 1 in 5 eyes,  typically earlier than in CRVO (4-5 weeks compared with  3 months, though sometimes later), and along with very  poor vision may indicate ophthalmic artery occlusion.   • OCT may show a highly reflective embolic plaque within the  superficial optic nerve head.   • FA shows a variable delay in arterial filling and masking of  background choroidal fluorescence by retinal oedema. A  patent cilioretinal artery will fill during the early phase  (Fig. 13 - 39 D).   • Electroretinography may be helpful to establish the  diagnosis if in doubt, particularly to distinguish from optic  nerve disease, typically when signs are subtle; a diminished  b-wave is present.   • Review. The patient should be seen by an ophthalmologist  after 3-4 weeks and a minimum of twice subsequently at  monthly intervals in order to detect incipient  neovascularization, particularly of the anterior segment. In  this event, PRP should be performed as for ischaemic  CRVO, and intravitreal injection of VEGF inhibitor might  be considered. Appropriate systemic management is  critical.   A cilioretinal artery is present in 15-50% of eyes, providing the  central macula with a second arterial supply derived from the  posterior ciliary circulation. Its main importance is that when  present it may facilitate preservation of central vision following  central retinal artery occlusion, provided the fovea is supplied.   • Isolated. This (Figs 13.40A and B) is rare; it may occur in  young patients with an associated systemic vasculitis.   • Combined with CRVO. This (Fig. 13.40C) is not  uncommon; occlusion is transient and the prognosis is  better than in isolated cilioretinal artery occlusion.   • Combined with anterior ischaemic optic neuropathy (Fig.  13.40D), typically affects patients with GCA and carries a  very poor prognosis.   Retinal artery occlusion is an emergency because it causes irrevers¬  ible visual loss unless the retinal circulation is re-established prior  to the development of retinal infarction. Theoretically, timely dis-  lodgement of thrombus or emboli may ameliorate subsequent  visual loss. The following treatments may be tried in patients with  occlusions of less than 24-48 hours’ duration at presentation,  though evidence of benefit is limited. The number of measures  tried and the intensity of treatment should be tailored to the indi¬  vidual (more aggressive if lower duration of occlusion, good  general health, monocularity; more aggressive systemic treatment  may be avoided in the frail elderly); options, including the lack of   (B) superior branch retinal artery occlusion due an embolus  at the disc; (C) FA shows lack of arterial filling of the  involved artery and hypofluorescence of the involved  segment due to blockage of background fluorescence by  retinal swelling; (D) small macular branch artery occlusion;  (E) FA of (D)   (Courtesy of C Barry - figs B and C; S Chen - figs D and E)    Fig. 13.39 Central retinal artery occlusion (CRAO). (A) Recent CRAO with a ‘cherry-red spot’ at the macula; (B) CRAO with a  patent cilioretinal artery; (C) posterior pole appearance several months after onset; (D) FA shows blockage of background  fluorescence by retinal oedema but normal perfusion of a sector of retina in the eye in (B)   (Courtesy of S Chen - fig. A; L Merin - figs B and D)   Fig. 13.40 Cilioretinal artery occlusion. (A) Isolated; (B) FA of the eye in (A) shows hypofluorescence in the affected area due  to reduced filling and masking by retinal oedema;   Fig. 13.40, Continued (C) combined with central retinal vein occlusion; (D) combined with anterior ischaemic optic neuropathy    evidence for clear benefit and the risks, should be discussed before   • Adoption of a supine posture might improve ocular  perfusion and should always be implemented.   • Ocular massage using a three-mirror contact lens (allows  direct artery visualization). The aim is to mechanically  collapse the arterial lumen and cause prompt changes in  arterial flow, improving perfusion and potentially dislodging  an embolus or thrombus. One described method consists of  positive pressure for 10-15 seconds followed by release,  continued for 3-5 minutes. Self-massage through closed  eyelids can be continued by the patient.   • Anterior chamber paracentesis using a 27-gauge needle to  withdraw 0.1-0.2 ml of aqueous is controversial but has been  advocated by some authorities. Povidone-iodine 5% and  topical antibiotic are instilled a few minutes prior to the  procedure, with a short course of antibiotic afterwards. It  may be prudent for ocular massage to be avoided following  paracentesis.   • Topical apraclonidine 1 %, timolol 0 . 5 % and intravenous  acetazolamide 500 mg to achieve a more sustained lowering  of intraocular pressure.   • ‘Rebreathing’ into a paper bag in order to elevate blood  carbon dioxide and respiratory acidosis has been advocated,  as this may promote vasodilatation.   • Breathing a high oxygen ( 95 %) and carbon dioxide ( 5 %)  mixture, ‘carbogen’, has been advocated for a possible dual  effect of retarding ischaemia and vasodilatation.   • Hyperosmotic agents. Mannitol or glycerol have been used  for their possibly more rapid IOP-lowering effect as well as  increased intravascular volume.   • Transluminal Nd: YAG laser embolysis/embolectomy has  been advocated for BRAO or CRAO in which an occluding  embolus is visible; shots of o.5-1.0 mj or higher are applied    directly to the embolus using a fundus contact lens.  Embolectomy has been said to occur if the embolus is  ejected into the vitreous via a hole in the arteriole. The  number of shots described in reports is extremely variable.  The main complication is vitreous haemorrhage; pressure on  the globe may curtail bleeding.   • Thrombolysis. Extrapolating from successful treatment of  stroke and myocardial infarction, various strategies have  been used to deliver thrombolytic agents to the ophthalmic  artery, including local arterial (internal carotid and  ophthalmic) and intravenous infusion. A recent large trial of  local intra-arterial fibrinolysis with recombinant tissue  plasminogen activator (rtPA) showed no benefit over  conservative treatment that included isovolaemic  haemodilution, with a nearly 40% adverse reaction rate in  the rtPA group. It has been speculated that this may reflect  very early loss of retinal viability, and perhaps the resistance  to dissolution of embolic, versus thrombotic, obstruction.   The risk of stroke is relatively high in the first few days following  retinal artery occlusion or amaurosis fugax, and as discussed  above, ‘fast-track’ referral to a specialist stroke clinic is advisable.   • General risk factors as discussed above should be addressed  and smoking should be discontinued. Urgent referral to an  appropriate physician is mandatory for significant cardiac  arrhythmia.   • Antiplatelet therapy is commenced provided there are no  contraindications; an immediate loading dose of 600 mg  may be given; alternative/additional agents include  dipyridamole and clopidogrel. If fibrinolysis (see above) is  being considered, this should be discussed with a physician  prior to starting antiplatelet treatment.   • Oral anticoagulation (e.g. warfarin) may be prescribed for  some patients, particularly those with atrial fibrillation.   • Carotid endarterectomy may be indicated in patients with  symptomatic stenosis greater than 70%.   It is not uncommon to identify a retinal embolus on routine  examination of an asymptomatic older patient (Fig. 13.41). This  indicates a substantially increased risk of stroke and ischaemic  heart disease, and management should consist of evaluation and  treatment of risk factors discussed above. A higher threshold for  carotid surgery is appropriate.   Ocular ischaemic syndrome (OIS) results from chronic ocular  hypoperfusion secondary to severe (more than 90%) ipsilateral  atherosclerotic carotid stenosis. It typically affects older patients  and may be associated with diabetes, hypertension, cardio- and  cerebrovascular disease. The male: female ratio is about 2:1. Five-  year mortality is around 40%, most frequently from cardiac  disease. OIS, along with non-ischaemic CRVO, is sometimes  termed ‘venous stasis retinopathy’ but it may be prudent to avoid  this term.   OIS is unilateral in 80%. The signs are variable and may be subtle  such that the condition is missed or misdiagnosed.   • Symptoms. Gradual loss of vision over weeks or months  although occasionally loss may be sudden or intermittent  (amaurosis fugax). Ocular and periocular pain may also be  present (40%). Patients may notice unusually persistent  after-images, or worsening of vision with sudden exposure  to bright light (‘bright light amaurosis fugax’), with slow  adaptation. The prognosis for vision is often very poor,  though patients with better acuity at presentation are more    likely to retain this. About 25% will deteriorate to light  perception by the end of 1 year.   o Diffuse episcleral injection and corneal oedema,  o Aqueous flare with few cells (ischaemic pseudo-iritis).   O Iris atrophy with a mid-dilated, poorly reacting pupil,  o Rubeosis iridis is common, developing in up to 90%, and  often progresses to neovascular glaucoma; the IOP may  remain low due to poor ocular perfusion,  o Cataract in advanced cases.   o Venous dilatation, arteriolar narrowing, deep round and  flame haemorrhages and occasionally disc oedema (Fig.  13.42A) and cotton wool spots,  o Proliferative retinopathy with NVD and occasionally  NVE.   o Spontaneous arterial pulsation, most pronounced near  the optic disc, is present in most cases or may be easily  induced by exerting gentle pressure on the globe (digital  ophthalmodynamometry).  o Macular oedema can occur.   o In diabetic patients retinopathy may be more severe  ipsilateral to carotid stenosis.   • FA. Delayed choroidal filling and prolonged arteriovenous  transit is the major feature; non-perfusion, vessel wall  staining and retinal oedema may also be evident (Figs  13.42B-D).   • Carotid imaging may involve duplex ultrasonography,  digital subtraction angiography, MR or CT angiography.   • Anterior segment inflammation is treated with topical  steroid and a mydriatic as appropriate.   • Neovascular glaucoma is managed medically or surgically  (see Ch. 10).   • Proliferative retinopathy can be treated with PRP although  the outcome is considerably less certain than in proliferative  diabetic retinopathy. Intravitreal anti-VEGF agents may be  beneficial.   • Macular oedema may respond to intravitreal steroid or  anti-VEGF agents, or to carotid surgery.   • Carotid surgery. Endarterectomy or stenting may be  performed to reduce the risk of stroke; it may be beneficial  for proliferative retinopathy and neovascular glaucoma, and  may help to stabilize vision. Endarterectomy cannot be  performed where there is total obstruction, and in this  situation extracranial-intracranial arterial bypass surgery is  sometimes carried out. It should be noted that an increase in  ocular perfusion following surgery can sometimes be  associated with a rise in IOP and exacerbation of  neovascularization. Surgery tends to be of greater benefit  when performed before the onset of severe ocular ischaemia.   • Investigation and management of cardiovascular risk  factors in conjunction with the appropriate medical  specialists is essential. OIS is occasionally the only   Fig. 13.42 Ocular ischaemic syndrome. (A) Venous dilatation, arteriolar narrowing, a few scattered flame haemorrhages and  hard exudates, and disc oedema; (B) and (C) FA early phase shows delayed choroidal filling and prolonged arteriovenous  transit; (D) FA late phase shows disc and perivascular hyperfluorescence, with spotty hyperfluorescence at the posterior  pole due to leakage    manifestation of marked systemic vascular disease. Full  investigation should be carried out, broadly similar to that  for retinal arterial occlusion.   The primary response of the retinal arterioles to systemic hyper¬  tension is vasoconstriction; this is less marked in older individuals  due to involutional sclerosis conferring increased rigidity. Arterio-  losclerosis refers to hardening and loss of elasticity of small vessel  walls, manifested most obviously by arteriovenous (AV) nipping  (nicking) at crossing points; its presence makes it probable that  hypertension has been present for many years, even if the BP  is currently controlled. Mild AV changes may be seen in the  absence of hypertension. In sustained hypertension the inner  blood-retinal barrier is disrupted, increased vascular permeability  leading to flame-shaped retinal haemorrhages and oedema.    • Grade 2 . Focal arteriolar narrowing (Fig. 13.43B) and  arteriovenous nipping (Fig. 13.43C). A ‘copper wiring’  opacified appearance of arteriolar walls may be seen (Fig.  13.43D).   • Grade 3. Grade 2 plus retinal haemorrhages (dot, blot,  flame), exudates (chronic retinal oedema may result in the  deposition of hard exudates around the fovea as a ‘macular  star’ - Fig. 13.43E) and cotton wool spots.   • Grade 4 . Severe grade 3 plus optic disc swelling (Fig. 13.43F);  this is a marker of malignant hypertension.   o Reduced retinal arteriolar calibre (see Fig. 13.43A) is an  early pre-hypertensive sign and if identified should  prompt BP monitoring.   o Wider venular calibre is relatively specific for impaired  glucose metabolism.   o Low arteriolar calibre and high venular calibre are both  thought to be markers of preclinical cardiovascular  disease.   o Increased venular tortuosity (Fig 13.44A) can be  associated with chronic hypertension and pre¬  hypertension, though evidence on arteriolar tortuosity is   Fig. 13.43 Hypertensive retinopathy. (A) Generalized arteriolar attenuation; (B) focal arteriolar attenuation; (C) red-free  photograph showing arteriovenous nipping; (D) ‘copper wiring’; (E) grade 3 retinopathy with macular star; (F) grade 4  hypertensive retinopathy   Fig. 13.44 Vascular tortuosity. (A) Selective venous  tortuosity - the arterioles are unaffected; (B) mixed  arteriolar and venular tortuosity   conflicting - straightening of arterioles has been reported  in some studies. Numerous other causes of retinal  vascular tortuosity (Fig. 13.44B) have been described,  notably conditions associated with high and low vascular  flow.   Hypertensive choroidopathy is rare but may occur as the result of  an acute hypertensive crisis (accelerated hypertension) in young  adults.   • Elschnig spots are focal choroidal infarcts seen as small  black spots surrounded by yellow haloes (Fig. 13.45A).   • Siegrist streaks are flecks arranged linearly along choroidal  vessels (Fig. 13.45B), and are indicative of fibrinoid necrosis  associated with malignant hypertension.    • Exudative retinal detachment, sometimes bilateral, may  occur in acute severe hypertension such as that associated  with toxaemia of pregnancy.   Sickling haemoglobinopathies are caused by one or more abnor¬  mal haemoglobins that induce red blood cells to adopt an anoma¬  lous shape (Fig. 13.46) under conditions of physiological stress  such as hypoxia and acidosis, with resultant vascular occlusion.  Mutant haemoglobin variants S and C can be found in combina¬  tion with the normal adult haemoglobin A or, less commonly,   Fig. 13.46 Several sickle red cells and one nucleated red  cell in a peripheral smear of a patient with homozygous  (HbSS) sickle cell anaemia   with other mutant haemoglobin variants. Retinopathy can occur  in sickle cell disease (homozygous for mutant haemoglobin S, i.e.  SS), sickle cell C disease (SC - the most likely to develop severe  retinopathy) and sickle cell-thalassaemia disease (S-Thal). It is rare  in patients with sickle cell trait (SA - found in 10% of African-  Americans), unless there is other co-existing systemic disease such  as diabetes or an inflammatory disorder. Carbonic anhydrase  inhibitors (CAI) should be avoided in sickling disorders as they  can precipitate sickling and vascular occlusion.   • Conjunctiva. Dark red corkscrew- or comma-shaped vessels  that are typically transient.   • Iris. Patches of ischaemic atrophy, often extending from the  pupillary edge to the collarette, and occasionally rubeosis.   • Hyphaema may be spontaneous or follow minor trauma.  Careful IOP control (avoiding CAI) is critical to reduce the  risk of RVO in the presence of a hyphaema.   • Venous changes. Tortuosity (see Fig. 13.44) is very common  and is thought to be due to peripheral arteriovenous  shunting; RVO is uncommon, though is a risk with raised  IOP.   • Arteriolar changes. Occlusions can involve branch, central  or macular (Fig. 13.47A) vessels and if seen acutely may  benefit from measures such as 100% oxygen and exchange  transfusion. ‘Silver wiring’ of arterioles in the peripheral  retina signifies previously occluded vessels. Corkscrewing of  peripheral vessels may be seen.    through to become preretinal or subretinal. The initiating  event is thought to be a vascular occlusion. Salmon patches  resolve to leave schisis cavities containing retractile deposits,  ‘black sunbursts’ (see below) when the RPE is sufficiently  stimulated, or a combination lesion.   • Black sunbursts. Patches of peripheral RPE hyperplasia and  chorioretinal atrophy (Fig. 13.47C) that evolve from some  salmon patches; the extent and morphology of pigmentation  is variable, but an outer pale band is generally present.   • Macular (retinal) depression sign. An oval depression in the  temporal macular retina due to retinal thinning following  arteriolar occlusion, with irregularity of the light reflex.  Vascular anomalies such as microaneurysms, and epiretinal  membranes may occur.   • Angioid streaks (see Ch. 14) occur in up to 6%.   with no symptoms unless vitreous haemorrhage or retinal detach¬  ment occurs.   • Stage 3. ‘Sea fan’ neovascularization (Fig. 13.48B) develops at  the edge of perfused retina, usually with a single supplying  arteriole and a single draining venule. Disc  neovascularization may rarely occur.   • Stage 4 . Vitreous haemorrhage from the new vessels (Fig.  13.48C).   • Stage 5. Rhegmatogenous retinal detachment caused by a  retinal break associated with extensive fibrovascular  proliferation (Fig. 13.48D). Tractional detachment may also  occur.   • FA in stage 3 shows filling of sea fans and peripheral  capillary non-perfusion (Fig. 13.48E) followed by leakage  from the new vessels (Fig. 13.48F). Wide-held imaging is  especially suited to evaluation of this condition.   • Observation if vitreous haemorrhage has not occurred,  particularly in middle-aged and older patients. Many  neovascular complexes involute spontaneously (Fig. 13.49) as  a result of auto-infarction or hbrotic strangulation,  subsequently appearing as greyish fibrovascular lesions.   • Laser or cryotherapy ablation of peripheral non-perfused  retina is probably the optimal approach, though ablation of  neovascularization may also be used; ablation of feeder  vessels is now rarely performed due to a high incidence of  subsequent choroidal neovascularization.   • Vitreoretinal surgery may be required for tractional retinal  detachment and/or persistent vitreous haemorrhage.   Fig. 13.47 Non-proliterative sickle-cell retinopathy. (A) FA shows macular ischaemia; (B) preretinal haemorrhage (‘salmon  patch’); (C) RPE hyperplasia (‘black sunburst’) and preretinal haemorrhages; (D) retinal hole and an area of whitening  superiorly   (Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 - fig. B)    Caution is required as anterior segment ischaemia,  potentially severe, is very common following scleral explant  application.    Thalassaemias are common gene disorders in which a mutation  gives rise to abnormal haemoglobin with a consequent failure of  normal red blood cell maturation. Ocular involvement occurs in  patients with thalassaemia major and thalassaemia intermedia.  Changes are caused by the disease itself as well as treatment with  blood transfusions and iron chelating agents such as desferriox-  amine. A major mechanism is tissue deposition of iron (siderosis)  from the lysing of abnormal red cells. The ocular features  predominantly affect the posterior segment and are non¬  proliferative, though vitreous haemorrhage has been reported.  Visual dysfunction is rarely severe. Manifestations include cata¬  ract, a smooth featureless iris, vascular tortuosity, angioid streaks,    optic neuropathy and pigmentary retinal mottling, including  pattern dystrophy-like macular changes. The fundus appearance  may resemble that of pseudoxanthoma elasticum.   Retinopathy of prematurity (ROP) affects premature low birth-  weight infants; additional systemic illness is a risk factor. Early  exposure to high ambient oxygen concentrations has been  regarded as a key risk, but recent evidence questions its signifi¬  cance; it is likely that, in the early phase of ROP development,  vessel growth is retarded by hyperoxia but that subsequently  retinal hypoxia promotes anomalous vascularization. The retina  has no blood vessels until the fourth month of gestation, when  vascular complexes grow from optic disc hyaloid vessels towards   Fig. 13.48 Proliferative sickle cell retinopathy. (A) Peripheral arteriovenous anastomosis (mild neovascularization is also  present); (B) ‘sea fan’ neovascularization; (C) haemorrhage from the new vessels; (D) extensive fibrovascular proliferation;  (E) FA early phase shows filling of new vessels and extensive peripheral retinal capillary non-perfusion; (F) late phase  shows leakage from the new vessels   (Courtesy of K Nischal - fig. A; R Marsh - figs B-D)   Fig. 13.49 Proliferative sickle retinopathy - spontaneous  involution of a neovascular tuft    the periphery. The nasal retina is normally fully vascularized after  8 months of gestation, the temporal periphery at or by l month  after delivery. Vascular endothelial growth factor (VEGF) is  believed to play an important role in the vascularization process.   The clinical findings in ROP are described as below according to  the 2005 International Classification of Retinopathy of Prematu¬  rity (ICROP).   Concentric zones centred on the optic disc are described (Fig.  13.50).   • Zone I is bounded by an imaginary circle, the radius of  which is twice the distance from the disc to the centre of the  macula. With a 28 dioptre binocular indirect lens, only zone  I is seen if any part of the optic nerve head is visible.   • Zone II extends concentrically from the edge of zone I; its  radius extends from the centre of the disc to the nasal ora  serrata.   • Zone III consists of a residual temporal crescent anterior to  zone II.   This describes the abnormal vascular response at the junction of  immature avascular peripheral and vascularized posterior retina.  Staging for the eye as a whole is determined by the most severe  manifestation.   • Stage 1 (demarcation line) is a thin, flat, tortuous, grey-white  line running roughly parallel with the ora serrata. It is more  prominent in the temporal periphery. There is abnormal  branching or ‘arcading’ of vessels leading up to the line  (Fig. 13.51A).    • Stage 2 (ridge) arises in the region of the demarcation line,  has height and width, and extends above the plane of the  retina. Blood vessels enter the ridge and small isolated  neovascular tufts may be seen posterior to it (Fig. 13.51B).   • Stage 3 (extraretinal fibrovascular proliferation) extends  from the ridge into the vitreous. It is continuous with the  posterior aspect of the ridge, causing a ragged appearance as  the proliferation becomes more extensive (Fig. 13.51C). The  severity of stage 3 can be subdivided into mild, moderate  and severe depending on the extent of extraretinal fibrous  tissue infiltrating the vitreous. The highest incidence of this  stage is around the post-conceptual age of 35 weeks.   • Stage 4 (partial retinal detachment) is divided into  extrafoveal (stage 4A - Fig. 13.51D) and foveal (stage 4B).   The detachment is generally concave and circumferentially  orientated. In progressive cases the fibrous tissue continues  to contract and the detachment increases in height and  extends anteriorly and posteriorly.   • ‘Plus’ disease signifies a tendency to progression and is  characterized by dilatation and tortuosity of blood vessels  (Fig. 13.51E) involving at least two quadrants of the posterior  fundus. Other features include failure of the pupil to dilate  and vitreous haze. ‘Pre-plus’ disease is also described.   • Aggressive posterior (‘rush’ disease) is uncommon but if  untreated usually progresses to stage 5, sometimes within a  few days. It is characterized by its posterior location,  prominence of plus disease and ill-defined nature of the  retinopathy.   (A) Stage 1 - demarcation line; (B) stage 2 - ridge; (C) stage  3 - ridge with extraretinal vascular proliferation; (D) stage  4A - partial extrafoveal retinal detachment; (E) ‘plus’  disease   (Courtesy of L MacKeen - figs A, C and D; P Watts - fig. B)    improved by earlier intervention; the outcome after treatment  varies depending on severity of disease; 30% of high-risk zone I  ROP will have an unfavourable visual outcome.   • Type 1. Treatment is now recommended within 72 hours for  type 1 disease.   o Any ROP stage in zone I when accompanied by plus  disease.   o Stage 3 to any extent within zone I.  o Stage 2 or 3 in zone II, together with plus disease.   o Stage 1 or 2 in zone I without plus disease,  o Stage 3 ROP within zone II without plus disease.   Formal criteria vary, but babies born at or before 30-32 weeks  gestational age, or weighing 1500 g or less, should be screened for  ROP; severe illness in other premature babies may also prompt    screening. This may involve indirect ophthalmoscopy with a 28 D  lens or a 2.2 panfunduscopic Volk lens and scleral depression, or  a wide field retinal camera with careful oversight. Screening should  begin 4-7 weeks postnatally. Subsequent review is at 1-3 week  intervals, depending on the severity of the disease, continuing  until retinal vascularization reaches zone III. The pupils in a pre¬  mature infant can be dilated with 0.5% cyclopentolate and 2.5%  phenylephrine. Topical anaesthetic is instilled, and a neonatal  eyelid speculum used; monitoring, especially for apnoea, is  prudent during and 24-48 hours after examination. About 10% of  babies screened require treatment. Refractive error, strabismus  and amblyopia are more common in children with ROP, and  longer-term monitoring is required.   • Laser ablation of avascular peripheral retina (Fig. 13.52) has  largely replaced cryotherapy because visual and anatomical  outcomes are superior.   • Intravitreal anti-VEGF agents. Bevacizumab has been used  for the treatment of ROP, but an optimal regimen is yet to  be established. Zone I disease is more likely to respond than  zone II. Allowing retinal development to proceed normally  without the destruction integral to laser treatment is a  potential advantage. However, systemic complications and  long-term effects in this age group are undetermined.   • Pars plana vitrectomy for tractional retinal detachment not  involving the macula (stage 4A) can be performed  successfully with respect to anatomical (90% success) and  visual outcome. The visual outcome in stages 4B (e.g. 60%)  and 5 (e.g. 20%) is typically disappointing even with  successful anatomical reattachment.   About 20% of infants with active ROP develop cicatricial compli¬  cations, which range from innocuous to extremely severe. In  general, the more advanced or the more posterior the proliferative  disease at the time of involution, the worse the cicatricial sequelae.  Findings range from moderate temporal vitreoretinal fibrosis and  straightening of vascular arcades (Fig. 13.53A) with ‘dragging’ of  the macula and disc (Fig. 13.53B), progressing to retrolental fibro-  vascular tissue that can lead to falciform retinal fold formation  (Fig. 13.53C) and to retinal detachment (Fig. 13.53D), sometimes  total (Fig. 13.53E) and known as ‘retrolental fibroplasia’; the latter  term has been used synonymously with ROP in the past. Second¬  ary angle-closure glaucoma may develop due to progressive shal¬  lowing of the anterior chamber caused by forward displacement  of the iris-lens diaphragm with anterior synechiae formation.  Lensectomy and anterior vitrectomy may be tried, but the results  are generally poor.    A retinal artery macroaneurysm is a localized dilatation of a retinal  arteriole; it has a predilection for older hypertensive (75%) women.   (A) Head-mounted binocular indirect ophthalmoscopy laser  under general anaesthesia; (B) appearance immediately  following laser photocoagulation for type 1 disease   (Courtesy of S Chen - fig. A; P Watts - fig. B)   • Symptoms. Insidious impairment of vision due to leakage  involving the macula; sudden visual loss due to haemorrhage  is less common.   • Fundus. A saccular arteriolar dilatation is typical, often at a  bifurcation or an arteriovenous crossing on a temporal  vascular arcade. The aneurysm may enlarge to several times  the diameter of the vessel; there is associated retinal  haemorrhage in 50%.   o Chronic leakage. Persistent retinal oedema with exudate  formation (Fig. 13.54A) is common and may affect central  vision.   Fig. 13.53 Cicatricial retinopathy of prematurity. (A) Straightening of vascular arcades; (B) ‘dragging’ of the disc and macula;  (C) falciform retinal fold; (D) retrolental fibrovascular tissue and partial retinal detachment; (E) total retinal detachment    o Haemorrhage. Intra-, sub- (Fig. 13.54B) or preretinal  (Fig. 13.54C) bleeding, in association with which the  diagnosis may be overlooked. The prognosis for central  visual function in those with submacular haemorrhage is  generally poor.   o Spontaneous involution following thrombosis and  fibrosis is very common and may precede or follow the  development of leakage or haemorrhage.   • FA. Uniform filling of the macroaneurysm is typical (Fig.  i3-54D)> with late leakage. Incomplete filling is due to  thrombosis.   • OCT can demonstrate the lesion itself (Fig. 13.54E), but its  main use is to document and monitor macular oedema, and  less commonly subhyaloid haemorrhage (Fig. 13.54F).   Fig. 13.54 Retinal artery macroaneurysm. (A) Associated with exudate; (B) sub- (darker) and intraretinal (brighter red)  haemorrhage; (C) preretinal (retrohyaloid) haemorrhage; (D) FA early venous phase shows hyperfluorescence of the  microaneurysm, which is surrounded by hypofluorescence due to masking by blood - same lesion as (B); (E) OCT of  macroaneurysm with preretinal blood; (F) OCT of loculated subhyaloid haemorrhage    • Vascular risk factors should be checked, especially blood  pressure and serum lipids.   • Observation is indicated in eyes with good visual acuity in  which the macula is not threatened, and in those with mild  retinal haemorrhage without significant oedema. In many  cases macroaneurysms will spontaneously involute (Fig.  13.55), particularly following retinal or vitreous haemorrhage.   • Laser treatment (Figs 13.56A and B) may be considered if  oedema or exudates threaten or involve the fovea,  particularly if there is documented visual deterioration.  Burns may be applied to the lesion itself, the surrounding  area (to reduce the risk of arteriolar occlusion), or both;  subthreshold laser may be as effective as standard  photocoagulation. It may take several months for oedema  and exudate to fully absorb.   Fig. 13.56 Treatment of retinal artery macroaneurysm. (A) Hard exudates at the macula due to chronic leakage;   (B) immediately following laser application; (C) large preretinal haemorrhage overlying the macula; (D) following YAG laser  hyaloidotomy, showing blood dispersing into the vitreous    • Intravitreal bevacizumab closed 95% of macroaneurysms in  a case series, with resolution of macular oedema.   • YAG laser hyaloidotomy may be considered for a persistent  premacular haemorrhage in order to disperse the blood into  the vitreous cavity (Figs 13.56C and D), from where it may  be absorbed more quickly.   • Intravitreal gas injection with face-down positioning may  shift subretinal haemorrhage away from the macula.  Adjunctive intravitreal recombinant tissue plasminogen  activator (rtPA) may be used.    Retinal capillary telangiectasia is relatively common. Most cases  develop secondary to another retinal condition, typically involving  inflammation or vascular compromise; examples include diabetic  retinopathy and retinal venous occlusion. Primary retinal tel¬  angiectasia comprises a group of rare, idiopathic, congenital or  acquired retinal vascular anomalies characterized by dilatation  and tortuosity of retinal blood vessels, multiple aneurysms, vascu¬  lar leakage and the deposition of hard exudates. Retinal tel¬  angiectasis involves the capillary bed, although the arterioles and  venules may also be involved.   Coats disease is an idiopathic retinal telangiectasia that is generally  of onset in early childhood. It is associated with intraretinal and  subretinal exudation, and frequently exudative retinal detach¬  ment, without signs of vitreoretinal traction. About 75% of patients  are male and 95% have involvement of only one eye. Presentation  is most frequently in the first decade of life. Although it is not  clearly inherited, a genetic predisposition may be involved as at  least some patients have a somatic mutation in the NDP gene,  which is also mutated in Norrie disease. It is now considered that  Leber miliary aneurysms, previously regarded as a distinct condi¬  tion, represents a generally milder form of the same disease, pre¬  senting later, in a more localized pattern, and carrying a better  visual prognosis. Differential diagnosis from other causes of leu-  kocoria in children, particularly retinoblastoma, is important. The  prognosis is variable and dependent on the severity of involvement  at presentation; younger children frequently have a more aggres¬  sive clinical course.   o Telangiectasia and fusiform focal aneurysmal arteriolar  dilatations (Figs 13.57B and C), often initially in the  inferior and temporal quadrants between the equator and  ora serrata.   o Intra- and subretinal exudate (Fig. 13.57C), often affecting  areas remote from the vascular abnormalities, particularly  the macula. Progression to extensive exudative retinal  detachment (Fig. 13.57D) may occur.   • Complications include rubeosis iridis, glaucoma, uveitis,  cataract and phthisis bulbi.   • FA in mild cases shows early hyperfluorescence of  telangiectases and aneurysmal dilatations (Fig. 13.57E) and  late staining and leakage (Fig. 13.57F).   • OCT may be useful for the assessment of the macula in  cooperative older children.   • Observation in patients with mild, non-vision threatening  disease and in those with a comfortable eye with total retinal  detachment for whom there is no potential for restoration of  useful vision.   • Laser ablation of points of leakage should be considered if  progressive exudation is documented (Fig. 13.58). Multiple  repeated treatments over an extended term are commonly  required.   • Anti-VEGF therapy. Limited studies of anti-VEGF therapy  have been carried out, but initial results are promising,  including as an adjunct to laser. Long-term safety in  childhood remains undetermined.   • Intravitreal triamcinolone (2-4 mg) has been used with  good effect in eyes with total exudative retinal detachment.   • Cryotherapy, with a double freeze-thaw method, in eyes  with extensive exudation or subtotal retinal detachment  although this may result in marked reaction with increased  leakage. Therefore, laser photocoagulation is still the  preferred option if possible.   • Vitreoretinal surgery may be considered in eyes with  significant tractional preretinal fibrosis or total exudative  detachment; There is a poor visual prognosis but successful  retinal re-attachment may prevent the development of  neovascular glaucoma.   • Enucleation may be required in painful eyes with  neovascular glaucoma.   Eales disease is an idiopathic occlusive peripheral periphlebitis. It  is rare in Caucasians but is an important cause of visual morbidity  in young males from the Indian subcontinent. It is characterized  by three overlapping stages: inflammatory, occlusive and retinal  neovascular, and is diagnosed principally by clinical examination.  The visual prognosis is good in the majority of cases. Tubercular   Fig. 13.57 Coats disease. (A) Leukocoria; (B) retinal telangiectasia and aneurysmal arteriolar changes; (C) progressively more  extensive vascular abnormalities and exudation; (D) extensive exudative retinal detachment; (E) FA early phase of eye in (C)  demonstrating telangiectasis and aneurysmal dilatations; (F) late-phase FA showing leakage    protein hypersensitivity may be important in the aetiology, but  evidence is conflicting; some patients may have tubercular  vasculitis.   • Symptoms. Floaters or sudden visual reduction due to  vitreous haemorrhage.   superficial retinal haemorrhages and sometimes cotton  wool spots. Pigmented chorioretinal scars may be seen.    Fig. 13.59 Eales disease. (A) Peripheral vascular sheathing  and occlusion; (B) peripheral neovascularization;   O Peripheral capillary non-perfusion; microaneurysms,  tortuosity, vascular shunts and neovascularization (Fig.  !3-59B) with recurrent vitreous haemorrhage (one-third  of eyes - Fig. 13.59C) may develop at the junction of  perfused and non-perfused retina. Disc new vessels can    sometimes develop. The vitreous haemorrhage tends to  be limited and to absorb over weeks, but can persist in  some cases.   o Macular involvement with the same changes can occur  but is rare; macular oedema can develop.   • Complications include tractional retinal detachment,  macular epiretinal membrane, neovascular glaucoma and  cataract.   • FA will identify vasculitis and areas of non-perfusion;  wide-held imaging is especially helpful.   • Investigation should be performed to rule out other causes  of vasculitis (e.g. sarcoidosis, tuberculosis) and peripheral  retinal neovascularization (e.g. haemoglobinopathies).   • Steroids. Periocular, systemic, topical, and intravitreal  steroids seem to be helpful in the inflammatory stage.   • Antitubercular treatment. This is strongly advocated by  some authorities but is controversial. It may be considered  in selected patients in combination with steroids, either to  avoid reactivation of prior tubercular infection (e.g. strongly  positive skin test, QuantiFERON®) or possibly when severe  ocular inflammatory signs are present.   • Scatter photocoagulation or cryotherapy of non-perfused  retina to reduce the neovascular stimulus.   • Intravitreal VEGF inhibitors may be helpful but research is  ongoing.   • Vitrectomy for persistent vitreous haemorrhage, tractional  detachment and macular epiretinal membrane.    Radiation retinopathy may develop following treatment of  intraocular tumours by plaque therapy (brachytherapy) or exter¬  nal beam irradiation of sinus, orbital or nasopharyngeal malignan¬  cies. It is characterized by delayed retinal micro vascular changes  with endothelial cell loss, capillary occlusion and microaneurysm  formation. Affected patients may also develop cataract and kerat¬  opathy (Fig. 13.60). There is some evidence that it is more likely  to occur in genetically predisposed individuals. The interval  between exposure and disease is variable and unpredictable,  although commonly between 6 months and 3 years. There is a  direct relationship with radiation dose.   o Retinal oedema, exudate, cotton wool spots and  haemorrhages (Figs 13.61D and E).  o Papillopathy (Fig. 13.61F); radiation optic neuropathy  may occur but is less common as the nerve seems to be  less sensitive than retinal vessels,  o Proliferative retinopathy.   • Treatment is frequently unsatisfactory. Options include  laser, steroids and intravitreal anti-VEGF agents.    • Prognosis depends on the severity of involvement. Poor  prognostic features include papillopathy and proliferative  retinopathy, which may result in vitreous haemorrhage and  tractional retinal detachment.    Purtscher retinopathy may follow severe trauma, especially chest  compressive and head injury, and involves occlusion and ischae¬  mia associated with microvascular damage, and is thought to  result from embolism and in some cases vascular occlusion by  other mechanisms such as complement-mediated white blood cell  aggregation. When it results from causes other than trauma (e.g.  fat or amniotic fluid embolism, acute pancreatitis, pre-eclampsia,  systemic vasculitides) it is sometimes referred to as ‘Purtscher-like’  retinopathy. Presentation is with sudden bilateral visual reduction,  typically to 6/60 or less. Multiple unilateral or bilateral superficial  white retinal patches - capillary bed infarcts known as Purtscher  flecken - resembling large cotton wool spots (Fig. 13.62) are seen,  often associated with superficial peripapillary haemorrhages,  typical cotton wool spots and disc swelling. Elevated complement  5a levels may be diagnostic where there is no history of trauma.  The acute fundus changes usually resolve within a few weeks, but  only a small proportion will regain normal vision. Treatment of  the underlying cause is not always possible.    The Valsalva manoeuvre consists of forcible exhalation against a  closed glottis, thereby creating a sudden increase in intrathoracic  and intra-abdominal pressure (e.g. weight-lifting, blowing up bal¬  loons). The associated sudden rise in venous pressure may rupture  perifoveal capillaries leading to pre-macular haemorrhage of  varying severity (Fig. 13.63); vitreous haemorrhage may also occur.  Treatment is with observation, or YAG laser membranotomy in  some cases.    Fig. 13.61 Radiation retinopathy. (A) Red-free photograph and (B) FA of aneurysmal and telangiectatic lesions associated with  retinal capillary non-perfusion and leakage with exudation; (C) more severe retinal capillary non-perfusion and  microvascular abnormalities; (D) microvascular abnormalities, cotton wool spots and haemorrhages; (E) severe macular  involvement; (F) papillopathy following treatment of a choroidal melanoma    Lipaemia retinalis is a rare condition characterized by creamy-  white discoloration of retinal blood vessels (Fig. 13.64) in some  patients with hypertriglyceridaemia; in mild examples only  peripheral vessels are affected, but in extreme cases the fundus  takes on a salmon colour. The visualization of high levels of chy-  lomycrons in blood vessels accounts for the fundus appearance.  Visual acuity is usually normal but electroretinogram amplitude  may be decreased.   The leukaemias are malignancies of haematopoietic stem cells  involving abnormal proliferation of white blood cells. The acute   Fig. 13.63 Valsalva retinopathy. (A) Acute presentation; (B) macular OCT; (C) case in (A) 5 months later; (D) severe case   (Courtesy of S Chen - figs A-C; J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 - fig. D)    leukaemias are characterized by the replacement of bone marrow  with immature (blast) cells. Chronic leukaemias are associated, at  least initially, with well-differentiated (mature) leukocytes and  occur almost exclusively in adults. The four major variants of  leukaemia are:   • Acute lymphocytic (lymphoblastic) predominantly affects  children, in whom there is around a 90% 5-year survival  rate.   • Acute myeloid (myeloblastic) is most frequently seen in  older adults.   • Chronic lymphocytic has a very chronic course, and many  patients die from unrelated disease.   • Chronic myelocytic has a progressive clinical course and  often a less favourable prognosis.   Ocular involvement is more commonly seen in the acute than the  chronic forms and virtually any ocular structure may be involved.  Primary leukaemic infiltration is fairly rare. Secondary changes  such as those associated with anaemia, thrombocytopenia, hyper¬  viscosity and opportunistic infections are more common and  include intraocular bleeding, infection and vascular occlusion.   o Retinal haemorrhages and cotton wool spots are common  (Fig. 13.65).   o Roth spots are retinal haemorrhages with white centres  (Fig. 13.66), the whitish element thought to be composed  of coagulated fibrin in most cases. They occur in acute  leukaemias, and in a range of other conditions such as  bacteraemia (classically subacute bacterial endocarditis),  diabetes, hypertension and anaemia,  o Peripheral retinal neovascularization is an occasional  feature of chronic myeloid leukaemia (Fig. 13.67A).   Fig. 13.65 Retinal haemorrhages in leukaemia. (A) Numerous  flame haemorrhages with cotton wool spots and Roth  spots; (B) premacular bleed; (C) large retrohyaloid  haemorrhage - a separate white cell layer is evident   (Courtesy of C Barry - fig. A; S Chen - figs B and C)    Fig. 13.66 Roth spots. (A) Typical appearance; (B) large lesion; (C) macular lesion in acute myeloid leukaemia; (D) OCT of  lesion in (C)   (A) Peripheral retinal neovascularization in chronic myeloid  leukaemia; (B) leukaemic chorioretinal deposit; (C) ‘leopard  skin’ appearance due to choroidal infiltration in chronic  leukaemia    o Retinal and choroidal infiltrates may occur, most  commonly posterior to the equator (Fig. 13.67B), and  may masquerade as posterior uveitides; in chronic  leukaemia they may give rise to a ‘leopard skin’  appearance (Fig. 13.67C).   The anaemias are a group of disorders characterized by a decrease  in the number of circulating red blood cells or in the amount of  haemoglobin in each cell, or both. Retinal changes in anaemia are  usually innocuous and rarely of diagnostic importance.   o Retinal venous tortuosity is related to the severity of  anaemia but may occur in isolation.    o Dot, blot and flame haemorrhages, cotton wool spots and  Roth spots (see Fig. 13.66) are more common with  co-existing thrombocytopenia.   • Polycythaemia is caused by the neoplastic proliferation of  erythrocytes with increased bone marrow activity and  hyperviscosity.   • Waldenstrom macroglobulinaemia is a malignant  lymphoproliferative disorder with monoclonal IgM  production, which most frequently affects elderly men.   • Ocular features include retinal haemorrhages and venous  changes (Fig. 13.69), and occasionally retinal vein occlusion  and conjunctival telangiectasia.   Symptoms 581  Visual acuity 582  Contrast sensitivity 584  Near visual acuity 584  Amsler grid 585  Pupils 585  Colour vision 586  Plus lens test 586   Microperimetry 586  Fundus fluorescein angiography 587  Indocyanine green angiography 593  Optical coherence tomography 597  Fundus autofluorescence 598  Wide-field imaging 598   Retinal pigment epithelial tear 608  Choroidal neovascularization (CNV) 609  Haemorrhagic AMD 615   Type 1: aneurysmal telangiectasia 627  Type 2: perifoveal telangiectasia 627  Occlusive telangiectasia 630   The macula (Fig. 14.1A) is a round area at the posterior pole, lying  inside the temporal vascular arcades. It measures between 5 and  6 mm in diameter, and subserves the central 15-20° of the visual  field. Histologically, it shows more than one layer of ganglion cells,  in contrast to the single ganglion cell layer of the peripheral retina.  The inner layers of the macula contain the yellow xanthophyll  carotenoid pigments lutein and zeaxanthin in far higher concen¬  tration than the peripheral retina (hence the full name ‘macula  lutea’ - yellow plaque).    • The fovea is a depression in the retinal surface at the centre  of the macula (Figs 14.1B and C), with a diameter of 1.5 mm  - about the same as the optic disc.   • The foveola forms the central floor of the fovea and has a  diameter of 0.35 mm (see Fig. 14.1C). It is the thinnest part  of the retina and is devoid of ganglion cells, consisting only  of a high density of cone photoreceptors and their nuclei  (Fig. 14.2), together with Muller cells.   • The umbo is a depression in the very centre of the foveola  (see Fig. 14.1C) which corresponds to the foveolar light reflex  (see Fig. 14.1A), loss of which may be an early sign of  damage.   • The foveal avascular zone (FAZ - see Fig. 14.1C), a central  area containing no blood vessels but surrounded by a   Fig. 14.1 Anatomical landmarks. (A) Normal foveolar (almost punctate central reflex) and macular (band-like reflex encircling  the fovea) light reflexes; (B) OCT showing the foveal depression; (C) fluorescein angiogram - fovea (yellow circle),  approximate extent of the foveal avascular zone (red circle), foveola (lilac circle), umbo (central white spot)    Fig. 14.2 Cross-section of the fovea (RPE = retinal pigment epithelium)    continuous network of capillaries, is located within the fovea  but extends beyond the foveola. The exact diameter varies  with age and in disease, and its limits can be determined with  accuracy only by fluorescein angiography (average o.6 mm).   o The retinal pigment epithelium (RPE) is composed of a  single layer of cells that are hexagonal in cross-section.  The cells consist of an outer non-pigmented basal  element containing the nucleus, and an inner pigmented  apical section containing abundant melanosomes.  o The cell base is in contact with Bruch membrane, and  at the cell apices multiple thread-like villous processes  extend between the outer segments of the  photoreceptors.   o At the posterior pole, particularly at the fovea, RPE cells  are taller and thinner, more regular in shape and contain  more numerous and larger melanosomes than in the  periphery.   o RPE cells and intervening tight junctional complexes  (zonula occludentes) constitute the outer blood-retinal  barrier, preventing extracellular fluid leaking into the  subretinal space from the choriocapillaris, and actively  pumping ions and water out of the subretinal space,  o Its integrity, and that of the Bruch membrane, is  important for continued adhesion between the two,  thought to be due to a combination of osmotic and  hydrostatic forces, possibly with the aid of  hemidesmosomal attachments,  o Facilitation of photoreceptor turnover by the  phagocytosis and lysosomal degradation of outer  segments following shedding.    o Preservation of an optimal retinal milieu. Maintenance of  the outer blood-retinal barrier is a key factor, as are the  inward transport of metabolites (mainly small molecules  such as amino acids and glucose) and the outward  transport of metabolic waste products,  o Storage, metabolism and transport of vitamin A in the  visual cycle.   • Structure. The Bruch membrane separates the RPE from the  choriocapillaris and on electron microscopy consists of five  distinct elements:   o The basal lamina of the RPE.  o An inner collagenous layer,  o A thicker band of elastic fibres,  o An outer collagenous layer.   o The basal lamina of the inner layer of the choriocapillaris.   • Function. The RPE utilizes Bruch membrane as a route for  the transport of metabolic waste products out of the retinal  environment. Changes in its structure are thought to be  important in the pathogenesis of many macular disorders   - for example, intact Bruch membrane may be important in  the suppression of choroidal neovascularization (CNV).   • Blurred vision and difficulty with close work may be an  early symptom. Onset can be rapid in some conditions, such  as CNV.    • A positive scotoma, in which patients complain of  something obstructing central vision, is a symptom of more  severe disease. This is in contrast to optic neuropathy, which  typically causes a missing area in the visual field (negative  scotoma).   • Metamorphopsia (distortion of perceived images) is a  common symptom that is virtually never present in optic  neuropathy.   • Micropsia (decrease in image size) is caused by spreading  apart of foveal cones, and is less common.   • Macropsia (increase in image size) is due to crowding  together of foveal cones, and is uncommon.   • Colour discrimination may be disturbed, but is generally less  evident than in even relatively mild optic neuropathy.   • Difficulties related to dark adaptation, such as poor vision  in dim light and persistence of after-images, may occur.   Distance visual acuity (VA) is directly related to the minimum  angle of separation (subtended at the nodal point of the eye)  between two objects that allow them to be perceived as distinct.  In practice, it is most commonly carried out using a Snellen chart,  which utilizes black letters or symbols (optotypes) of a range of  sizes set on a white chart (Fig. 14.3), with the subject reading the  chart from a standard distance. Distance VA is usually first meas¬  ured using a patient’s refractive correction, generally their own  glasses or contact lenses. For completeness, an unaided acuity may  also be recorded. The eye reported as having worse vision should  be tested first, with the other eye occluded. It is important to push   • Normal monocular VA equates to 6/6 (metric notation;  20/20 in non-metric ‘English’ notation) on Snellen testing.  Normal corrected VA in young adults is often superior to  6 / 6 .   • Best-corrected VA (BCVA) denotes the level achieved with  optimal refractive correction.   • Pinhole VA: a pinhole (PH) aperture compensates for the  effect of refractive errors, and consists of an opaque occluder  perforated by one or more holes of about 1 mm diameter  (Fig. 14.4). However, PH acuity in patients with macular  disease and posterior lens opacities may be worse than with  spectacle correction. If the VA is less than 6/6 Snellen  equivalent, testing is repeated using a pinhole aperture.   • Binocular VA is usually superior to the better monocular  VA of each eye, at least where both eyes have roughly equal  vision.   • Counts (or counting) fingers (CF) denotes that the patient  is able to tell how many fingers the examiner is holding up  at a specified distance (Fig. 14.5), usually 1 metre.   • Hand movements (HM) is the ability to distinguish whether  the examiner’s hand is moving when held just in front of the  patient.   • Perception of light (PL): the patient can discern only light  (e.g. pen torch), but no shapes or movement. Careful  occlusion of a fellow seeing eye is necessary. If poor vision is  due only to dense media opacity such as cataract, the patient  should readily be able to determine the direction from which  the light is being projected (Fig. 14.6).   LogMAR charts address many of the deficiencies of the Snellen  chart (Table 14.1), and are the standard means of VA measurement  in research and increasingly in clinical practice.   • LogMAR is an acronym for the base-10 logarithm of the  minimum angle of resolution, and refers to the ability to  resolve the elements of an optotype. Thus, if a letter on the  6/6 (20/20) equivalent line subtends 5' of arc, and each limb   Equal numbers of letters  on low and higher acuity  lines increases accuracy  at lower VA   Fig. 14.6 Notation for the projection of light test (right eye);  the patient cannot detect light directed from the superior  and temporal quadrants    of the letter has an angular width of T, an MAR of T is  needed for resolution. For the 6/12 (20/40) line, the MAR is  2', and for the 6/60 (20/200) line it is io'.   • The logMAR score is simply the base-10 log of the MAR, so  as the log of the MAR value of T is zero, 6/6 is equivalent to  logMAR 0.00. The log of the 6/60 MAR of io' is 1, so 6/60 is  equivalent to logMAR 1.00. The log of the 6/12 MAR of 2' is  0.301, giving a logMAR score of 0.30. Scores better than 6/6  have a negative value.   • As letter size changes by 0.1 logMAR units per row and there  are five letters in each row, each letter can be assigned a  score of 0.02. The final score can therefore take account of  every letter that has been read correctly and the test should  continue until half of the letters on a line are read  incorrectly.   • The Bailey-Lovie chart (Fig. 14.7).  o Used at 6 m testing distance.   o Each line of the chart comprises five letters and the   spacing between each letter and each row is related to the  width and the height of the letters. A 6/6 letter is 5' in  height by 4' in width.    o The distance between two adjacent letters on the same  row is equal to the width of a letter from the same row,  and the distance between two adjacent rows is the same  as the height of a letter from the lower of the two rows,  o Snellen VA values and logMAR VA are listed to the right  and left of the rows respectively.   • Other charts are available that are calibrated for 4 m. The  Early Treatment Diabetic Retinopathy Study (ETDRS) charts  utilize balanced rows comprising Sloan optotypes, developed  to confer equivalent legibility between individual letters and  rows. ETDRS letters are square, based on a 5 x 5 grid, i.e. 5'  x 5' for the 6/6 equivalent letters at 6 m.   • Computer charts are available that present the various  forms of test chart on display screens, including other means  of assessment such as contrast sensitivity (see below).   • Principles. Contrast sensitivity is a measure of the ability of  the visual system to distinguish an object against its  background. A target must be sufficiently large to be seen,  but must also be of high enough contrast with its  background; a light grey letter will be less well seen against a  white background than a black letter. Contrast sensitivity  represents a different aspect of visual function to that tested  by the spatial resolution tests described above, which all use  high-contrast optotypes.   o Many conditions reduce both contrast sensitivity and  visual acuity, but under some circumstances (e.g.  amblyopia, optic neuropathy, some cataracts, and    higher-order aberrations), visual function measured by  contrast sensitivity can be reduced whilst VA is preserved,  o Hence, if patients with good VA complain of visual  symptoms (typically evident in low illumination),  contrast sensitivity testing may be a useful way of  objectively demonstrating a functional deficit. Despite its  advantages, it has not been widely adopted in clinical  practice.   • The Pelli-Robson contrast sensitivity letter chart is viewed  at 1 metre and consists of rows of letters of equal size (spatial  frequency of 1 cycle per degree) but with decreasing contrast  of 0.15 log units for groups of three letters (Fig. 14.8). The  patient reads down the rows of letters until the lowest-  resolvable group of three is reached.   • Sinusoidal (sine wave) gratings require the test subject to  view a sequence of increasingly lower contrast gratings.   Near vision testing can be a sensitive indicator of the presence of  macular disease. A range of near vision charts (including logMAR  and ETDRS versions) or a test-type book can be used. The book  or chart is held at a comfortable reading distance and this is meas¬  ured and noted. The patient wears any necessary distance correc¬  tion together with a presbyopia correction if applicable (usually  their own reading spectacles). The smallest type legible is recorded  for each eye individually and then using both eyes together.   Fig. 14.9 Amsler grid superimposed on the macula; the  central fixation dot of the grid probably does not coincide  with the foveal anatomical centre in this image   The Amsler grid evaluates the 20° of the visual field centred on  fixation (Fig. 14.9). It is principally useful in screening for and  monitoring macular disease, but will also demonstrate central  visual field defects originating elsewhere. Patients with a substan¬  tial risk of CNV should be provided with an Amsler grid for  regular use at home.   There are seven charts, each consisting of a 10 cm outer square  (Figs 14.10 and 14.11).   • Chart 1 consists of a white grid on a black background, the  outer grid enclosing 400 smaller 5 mm squares. When  viewed at about one-third of a metre, each small square  subtends an angle of i°.   • Chart 2 is similar to chart 1 but has diagonal lines that aid  fixation for patients with a central scotoma.   • Chart 3 is identical to chart 1 but has red squares. The  red-on-black design aims to stimulate long wavelength  foveal cones. It is used to detect subtle colour scotomas and  desaturation in toxic maculopathy, optic neuropathy and  chiasmal lesions.   • Chart 4 consists only of random dots and is used mainly to  distinguish scotomas from metamorphopsia, as there is no  form to be distorted.   • Chart 5 consists of horizontal lines and is designed to detect  metamorphopsia along specific meridians. It is of particular  use in the evaluation of patients describing difficulty reading.   • Chart 6 is similar to chart 5 but has a white background and  the central lines are closer together, enabling more detailed  evaluation.    • Chart 7 includes a fine central grid, each square subtending  an angle of a half degree, and is more sensitive.   The pupils should not be dilated, and in order to avoid a photo¬  stress effect the eyes should not yet have been examined on the slit  lamp. A presbyopic refractive correction should be worn if appro¬  priate. The chart should be well illuminated and held at a comfort¬  able reading distance, optimally around 33 cm.   2. The patient is asked to look directly at the central dot with  the uncovered eye, to keep looking at this, and to report any  distortion or waviness of the lines on the grid.   3. Reminding the patient to maintain fixation on the central  dot, he or she is asked if there are blurred areas or blank spots  anywhere on the grid. Patients with macular disease often  report that the lines are wavy whereas those with optic  neuropathy tend to remark that some of the lines are missing  or faint but not distorted.   4. The patient is asked if he or she can see all four corners and  all four sides of the square - a missing corner or border  should raise the possibility of causes other than macular  disease, such as glaucomatous field defects or retinitis  pigmentosa.   The patient may be provided with a recording sheet and pen and  asked to draw any anomalies (Fig. 14.12).   The pupillary reactions to light are usually normal in eyes with  macular disease, although extensive pathology such as a large area  of CNV can give a relative afferent pupillary defect (RAPD). In    Fig. 14.12 Stylized Amsler recording sheet shows wavy lines  indicating metamorphopsia, and a dense scotoma   Colour vision is commonly affected only in proportion to the  decrease in visual acuity in macular disease, again in contrast to  optic neuropathy where subtle colour desaturation is an early sign.  Inherited retinal dystrophies such as cone dystrophy are an  exception.   A temporary hypermetropic shift may occur in some conditions  due to an elevation of the sensory retina - the classic example is  central serous chorioretinopathy (CSR). A +1.00 dioptre lens will  demonstrate the phenomenon.   This is a newer investigative technique that has hitherto been used  principally in research but may increasingly be incorporated into  clinical practice. It measures sensitivity at finely spaced central    retinal loci, including in patients with poor fixation, and uses a  tracking system based on image registration to facilitate serial  monitoring, allowing detection of subtle change.   • Fluorescence is the property of certain molecules to emit  light of a longer wavelength when stimulated by light of a  shorter wavelength. The excitation peak for fluorescein is  about 490 nm (in the blue part of the spectrum) - the  wavelength of maximal absorption of light energy by  fluorescein. Stimulated molecules will emit yellow-green  light of about 530 nm (Fig. 14.13).   • Fluorescein (sodium fluorescein) is an orange water-soluble  dye that, when injected intravenously, remains largely  intravascular (>70% bound to serum proteins). It is excreted  in the urine over 24-36 hours.   • FA involves photographic surveillance of the passage of  fluorescein through the retinal and choroidal circulations  following intravenous injection.   • Outer blood-retinal barrier. The major choroidal vessels  are impermeable to both bound and free fluorescein.  However, the walls of the choriocapillaris contain  fenestrations through which unbound molecules escape into  the extravascular space, crossing Bruch membrane but on  reaching the RPE are blocked by intercellular complexes  termed tight junctions or zonula occludentes (Fig. 14.14).   • Inner blood-retinal barrier is composed principally of the  tight junctions between retinal capillary endothelial cells,  across which neither bound nor free fluorescein can pass;  the basement membrane and pericytes play only a minor  role in this regard (Fig. 14.15A). Disruption of the inner   Fig. 14.14 The outer blood-retinal barrier (Z.O. = zonula  occludentes; B.M. = Bruch membrane)    blood-retinal barrier permits leakage of both bound and free  fluorescein into the extravascular space (Fig. 14.15B).   o Cobalt blue excitation filter. Incident white light from the  camera is filtered so that blue light enters the eye, exciting  the fluorescein molecules in the retinal and choroidal  circulations.   o Yellow-green barrier filter blocks any blue light reflected  from the eye, allowing only yellow-green emitted light to  pass.   Fig. 14.15 Inner blood-retinal barrier. (A) Intact; (B) disrupted  (E = endothelial cell; B.M. = basement membrane; P =  pericyte)    • Image capture in modern digital cameras uses a charge-  coupled device (CCD). Digital imaging permits immediate  picture availability, easy storage and access, image  manipulation and enhancement. Modern devices also  typically require a lower concentration of injected  fluorescein to obtain high-quality images, with a  correspondingly substantially lower incidence of adverse  effects.   o Fluorescein allergy is an absolute contraindication, and a  history of a severe reaction to any allergen is a strong  relative contraindication. Preventative anti-allergy  pre-treatment may be helpful in some cases,  o Other relative contraindications include renal failure (a  lower fluorescein dose is used), pregnancy, moderate-  severe asthma and significant cardiac disease,  o Allergy to iodine-containing media or seafood is not a  clear contraindication to FA or to indocyanine green  angiography (ICGA).   Facilities must be in place to address possible adverse events. This  includes adequate staffing, a resuscitation trolley that includes  drugs for the treatment of anaphylaxis, a couch (or reclining chair)  and a receiver in case of vomiting; significant nausea and vomit¬  ing, and probably other adverse reactions, are now much less  common with the lower fluorescein concentrations required by  modern digital cameras.   • Adequate pharmacological mydriasis is important to obtain  high-quality images; media opacity such as cataract may  reduce picture quality.   • The procedure is explained and formal consent taken. It is  important to mention common and serious adverse effects    (Table 14.2), particularly the invariable skin and urine  staining. As noted above, adverse effects are generally now  much less common.   • The patient should be seated comfortably in front of the  fundus camera, and colour photographs, red-free (green  incident light, to enhance red detail) and autofluorescence  images taken as indicated.   • An intravenous cannula is inserted; a standard cannula is  often preferred rather than a less secure ‘butterfly’ winged  infusion set. After cannulation, the line should be flushed  with normal saline to check patency and exclude  extravasation.   • Fluorescein, usually 5 ml of a 10% solution, is drawn up into  a syringe and injected over the course of 5-10 seconds,  taking care not to rupture the cannulated vein (Fig. 14.17).   • Oral administration at a dose of 30 mg/kg is an alternative if  venous access cannot be obtained or is refused; a 5 ml vial of  10% (100 mg/ml) sodium fluorescein contains 500 mg, and   Extravasation of injected dye, giving a painful local  reaction (treat with cold compress)   Vasovagal episode or syncope (usually due to anxiety  but sometimes to ischaemic heart disease)  Anaphylactic and anaphylactoid reactions (1:2000  angiograms)   • Images are taken at 1-2 second intervals initially to capture  the critical early transit phases, beginning 5-10 seconds after  injection, tapering frequency through subsequent phases.   • With monocular pathology, control pictures of the opposite  eye should be taken, usually after the initial transit phase has  been photographed in the index eye.   • If appropriate, images may be captured as late as 10-20  minutes.   • Stereo images may be helpful to demonstrate elevation, and  are usually taken by manually repositioning the camera  sideways or by using a special device (a stereo separator) to  adjust the image; these are actually ‘pseudostereo’, true  stereo requiring simultaneous image capture from different  angles.   Fluorescein enters the eye through the ophthalmic artery, passing  into the choroidal circulation through the short posterior ciliary  arteries and into the retinal circulation through the central retinal  artery (Fig. 14.18); the choroidal circulation fills about 1 second  before the retinal. Precise details of the choroidal circulation are  typically not discernible, mainly because of rapid leakage of free  fluorescein from the choriocapillaris; melanin in the RPE cells also  blocks choroidal fluorescence. The angiogram consists of the fol¬  lowing overlapping phases:   • The choroidal (pre-arterial) phase typically occurs 9-15  seconds after dye injection - longer in patients with poor  general circulation - and is characterized by patchy lobular  filling of the choroid due to leakage of free fluorescein from  the fenestrated choriocapillaris. A cilioretinal artery, if  present, will fill at this time because it is derived from the  posterior ciliary circulation (Fig. 14.19A).   • The arterial phase starts about a second after the onset of  choroidal fluorescence, and shows retinal arteriolar filling  and the continuation of choroidal filling (Fig. 14.19B).    • The arteriovenous (capillary) phase shows complete filling  of the arteries and capillaries with early laminar flow in the  veins in which the dye appears to line the venous wall  leaving an axial hypofluorescent strip (Fig. 14.19C). This  phenomenon reflects initial drainage from posterior pole  capillaries filling the venous margins, as well as the small-  vessel velocity profile, with faster plasma flow adjacent to  vessel walls where cellular concentration is lower.   • The venous phase. Laminar venous flow (Fig. 14.19D)  progresses to complete filling (Fig. 14.19E), with late venous  phase featuring reducing arterial fluorescence. Maximal  perifoveal capillary filling is reached at around 20-25 seconds  in patients with normal cardiovascular function, and the first  pass of fluorescein circulation is generally completed by  approximately 30 seconds.   • The late (recirculation) phase demonstrates the effects of  continuous recirculation, dilution and elimination of the  dye. With each succeeding wave, the intensity of  fluorescence becomes weaker although the disc shows  staining (Fig. 14.19F). Fluorescein is absent from the retinal  vasculature after about 10 minutes.   • The dark appearance of the fovea (Fig. 14.20A) is caused by  three factors (Fig. 14.20B):   o Absence of blood vessels in the FAZ.  o Blockage of background choroidal fluorescence due to  the high density of xanthophyll at the fovea,  o Blockage of background choroidal fluorescence by the  RPE cells at the fovea, which are larger and contain  more melanin and lipofuscin than elsewhere in the  retina.   • Autofluorescent compounds absorb blue light and emit  yellow-green light in a similar fashion to fluorescein, but  much more weakly. Autofluorescence can be detected on  standard fundus photography with the excitation and barrier  filters both in place; some modern digital cameras have   Fig. 14.19 Normal fluorescein angiogram. (A) Choroidal phase shows patchy choroidal filling as well as filling of a cilioretinal  artery; (B) arterial phase shows filling of the choroid and retinal arteries; (C) arteriovenous (capillary) phase shows  complete arterial filling and early laminar venous flow; (D) early venous phase shows marked laminar venous flow;   (E) mid-venous phase shows almost complete venous filling; (F) late (recirculation) phase shows weaker fluorescence with  staining of the optic disc   Fig. 14.20 (A) Dark appearance of the fovea on FA; (B) anatomical causative factors (see text)    enhanced autofluorescence detection capability, though  imaging is most effective with scanning laser  ophthalmoscopy. Autofluorescent lesions classically include  optic nerve head drusen (Fig. 14.21) and astrocytic  hamartoma, but with increased availability of    high-sensitivity imaging, patterns associated with a wide  range of posterior segment pathology have been  characterized.   • Pseudofluorescence (false fluorescence) refers to non-  fluorescent reflected light visible prior to fluorescein  injection; this passes through the filters due to the overlap of  wavelengths passing through the excitation then the barrier  filters. It is more evident when filters are wearing out.   • Increased fluorescence may be caused by (a) enhanced  visualization of normal fluorescein density, or (b) an  increase in fluorescein content of tissues.   • A window defect is caused by atrophy or absence of the RPE  as in atrophic age-related macular degeneration (Fig.   14.22A), a full-thickness macular hole, RPE tears and some  drusen. This results in unmasking of normal background  choroidal fluorescence, characterized by very early  hyperfluorescence that increases in intensity and then fades  without changing size or shape (Figs 14.22B and C).   • Pooling in an anatomical space occurs due to breakdown of  the outer blood-retinal barrier (RPE tight junctions):   o In the subretinal space, e.g. CSR (Fig. 14.23A). This is  characterized by early hyperfluorescence, which, as the   Fig. 14.22 Flyperfluorescence caused by window defects associated with dry age-related macular degeneration    Fig. 14.23 Hyperfluorescence caused by pooling of dye in the  subretinal space in central serous chorioretinopathy    responsible leak tends to be only small (Fig. 14.23B),  slowly increases in intensity and area, the maximum  extent remaining relatively well defined (Fig. 14.23C).  o In the sub-RPE space, as in pigment epithelial    early hyperfluorescence (Fig. 14.24B) that increases in  intensity but not in size (Fig. 14.24C).   • Leakage of dye is characterized by fairly early  hyperfluorescence, increasing with time in both area and  intensity. It occurs as a result of breakdown of the inner  blood-retinal barrier due to:   o Dysfunction or loss of existing vascular endothelial tight  junctions as in background diabetic retinopathy (DR),  retinal vein occlusion (RVO), cystoid macular oedema  (CMO - Fig. 14.25A) and papilloedema.  o Primary absence of vascular endothelial tight junctions as  in CNV, proliferative diabetic retinopathy (Fig. 14.25B),  tumours and some vascular anomalies such as Coats  disease.   • Staining is a late phenomenon consisting of the prolonged  retention of dye in entities such as drusen, fibrous tissue,  exposed sclera and the normal optic disc (see Fig. 14.19F),  and is seen in the later phases of the angiogram,  particularly after the dye has left the choroidal and  retinal circulations.   Reduction or absence of fluorescence may be due to: (a) optical  obstruction (masking or blockage) of normal fluorescein density  (Fig. 14.26) or (b) inadequate perfusion of tissue (filling defect).   • Masking of retinal fluorescence. Preretinal lesions such as  blood will block all fluorescence (Fig. 14.27).   • Masking of background choroidal fluorescence allows  persistence of fluorescence from superficial retinal vessels:  o Deeper retinal lesions, e.g. intraretinal haemorrhages,   o Subretinal or sub-RPE lesions, e.g. blood (Fig. 14.28).  o Increased density of the RPE, e.g. congenital hypertrophy  (Fig. 14.29).   o Vascular occlusion, which may involve the retinal  arteries, veins or capillaries (capillary drop-out - Fig.   14.30A), or the choroidal circulation. FA is sometimes  used to demonstrate optic nerve head filling defects as in  anterior ischaemic optic neuropathy,  o Loss of the vascular bed as in myopic degeneration and  choroideremia (Fig. 14.30B).   A fluorescein angiogram should be interpreted methodically to  optimize diagnostic accuracy.   1. Clinical findings, including the patient’s age and gender,  should be noted before assessing the images.   2. Note whether images of right, left or both eyes have been  taken.   3. Comment on any colour and red-free images and on any  pre-injection demonstration of pseudo- or autofluorescence.    Fig. 14.25 Causes of hyperfluorescence due to leakage. (A) Cystoid macular oedema; (B) proliferative diabetic retinopathy  showing leakage from extensive vessels on the inferior macular arcade   (Courtesy of P Gili - fig. A; S Chen - fig. B)    4 . Looking at the post-injection images, indicate whether the  overall timing of filling, especially arm-to-eye transit time, is  normal.   5. Briefly scan through the sequence of images in time order for  each eye in turn, initially concentrating on the eye with the    greatest number of shots as this is likely to be the one about  which there is greater concern. On the first review, look for  any characteristic major diagnostic, especially  pathognomonic, features; examples might include a lacy  filling pattern or a ‘smokestack’ (see later).   6. Go through the run for each eye in greater detail, noting the  evolution of any major features found on the first scan and  then providing a description of any other findings using the  methodical consideration of the causes of hyper- and  hypofluorescence set out above.   • Advantages over FA. Whilst FA is an excellent method of  studying the retinal circulation, it is of limited use in  delineating the choroidal vasculature, due principally to  masking by the RPE. In contrast, the near-infrared light  utilized in indocyanine green angiography (ICGA)  penetrates ocular pigments such as melanin and xanthophyll,   Fig. 14.27 Hypofluorescence - masking of all signal, including from retinal vessels, by preretinal haemorrhage  (ILM = internal limiting membrane)   Fig. 14.28 Hypofluorescence - blockage by sub- and  intraretinal haemorrhage, showing persistence of signal  from retinal vessels   Fig. 14.29 Hypofluorescence caused by blockage of  background fluorescence by congenital hypertrophy of the  retinal pigment epithelium    as well as exudate and thin layers of subretinal blood,  making this technique eminently suitable. An additional  factor is that about 98% of ICG molecules bind to serum  protein (mainly albumin), considerably higher than the  binding of fluorescein; therefore, as choriocapillaris  fenestrations are impermeable to larger protein molecules,  most ICG is retained within choroidal vessels. Infrared light  is also scattered less than visible light, making ICGA superior  to FA in eyes with media opacity.   • Image capture. ICG fluorescence is only i/25th that of  fluorescein so modern digital ICGA uses high-sensitivity  videoangiographic image capture by means of an  appropriately adapted camera. Both the excitation (805 nm)  and emission (835 nm) filters are set at infrared wavelengths  (Fig. 14.31). Alternatively, scanning laser ophthalmoscopy  (SLO) systems provide high contrast images, with less  scattering of light and fast image acquisition rates facilitating  high quality ICG video.   • The technique is similar to that of FA, but with an increased  emphasis on the acquisition of later images (up to about 45  minutes) than with FA. A dose of 25-50 mg in 1-2 ml water  for injection is used.   • Phases of ICGA: (i) early - up to 60 seconds post-injection;  (ii) early mid-phase - 1-3 minutes; (iii) late mid-phase -  3-15 minutes; and (iv) late phase - 15-45 minutes (Fig. 14.32).   • Nausea, vomiting and urticaria are uncommon, but  anaphylaxis probably occurs with approximately equal  incidence to FA.   • Serious reactions are exceptionally rare. ICG contains iodide  and so should not be given to patients allergic to iodine or   Fig. 14.32 Normal indocyanine green angiogram. (A) Early phase (up to 60 seconds post-injection) showing prominent  choroidal arteries and poor early perfusion of the ‘choroidal watershed’ zone adjacent to the disc; (B) early mid-phase  (1-3 minutes) showing greater prominence of choroidal veins as well as retinal vessels; (C) late mid-phase (3-15 minutes)  showing fading of choroidal vessels but retinal vessels are still visible; diffuse tissue staining is also present; (D) late  phase (15-45 minutes) showing hypofluorescent choroidal vessels and gradual fading of diffuse hyperfluorescence   • ICG A is relatively contraindicated in liver disease (excretion  is hepatic), and as with FA in patients with a history of a  severe reaction to any allergen, moderate or severe asthma  and significant cardiac disease. Its safety in pregnancy has  not been established.   Examples of pathological images are shown under the discussion  of individual conditions where relevant.   o A window defect similar to those seen with FA.  o Leakage from retinal or choroidal vessels (Fig. 14.33), the  optic nerve head or the RPE; this gives rise to tissue  staining or to pooling.   o Abnormal retinal or choroidal vessels with an anomalous F'S-14.33 ICGA image showing hyperfluorescence due to  morphology (see Fig. 14.33) and/or exhibiting greater P 0 ^ 5 and leaka S e in Polypoidal choroidal vasculopathy   Fig. 14.34 OCT imaging. (A) Anterior chamber angle; (B) spectral-domain image of the macula: ELM = external limiting  membrane; GCL = ganglion cell layer; INL = inner nuclear layer; IPL = inner plexiform layer; IS/OS = photoreceptor  inner-segment/outer-segment junction; NFL = nerve fibre layer; ONL = outer nuclear layer; OPL = outer plexiform layer;  RPE = retinal pigment epithelium   o Blockage (masking) of fluorescence. Pigment and blood  are self-evident causes, but fibrosis, infiltrate, exudate and  serous fluid also block fluorescence. A particular  phenomenon to note is that in contrast to its FA  appearance, a pigment epithelial detachment appears  predominantly hypofluorescent on ICGA.  o Filling defect due to obstruction or loss of choroidal or  retinal circulation.   • Polypoidal choroidal vasculopathy (PCV): ICGA is far  superior to FA for the imaging of PCV (see Fig. 14.33).   Conventional FA remains the primary method of  assessment, but ICGA can be a useful adjunct, particularly if  PCV is suspected.   • Chronic central serous chorioretinopathy in which it is  often difficult to interpret areas of leakage on FA. However,  ICGA shows choroidal leakage and the presence of dilated  choroidal vessels. Previously unidentified lesions elsewhere  in the fundus are also frequently visible using ICGA.   • Posterior uveitis. ICGA can provide useful information  beyond that available from FA in relation to diagnosis and  the extent of disease involvement.    • Choroidal tumours may be imaged effectively but ICGA is  inferior to clinical assessment for diagnosis.   • Breaks in Bruch membrane such as lacquer cracks and  angioid streaks are more effectively defined on ICGA than  on FA.   Optical coherence tomography (OCT) is a non-invasive, non-  contact imaging system providing high resolution cross-sectional  images of the posterior segment. Imaging of the anterior segment  (AS-OCT - Fig. 14.34A) has also been increasingly adopted. OCT  is analogous to B-scan ultrasonography but uses near-infrared  light interferometry rather than sound waves, with images created  by the analysis of interference between reflected reference waves  and those reflected by tissue. Most instruments in current use  employ spectral/Fourier domain technology, in which the  mechanical movement required for image acquisition in older  ‘time domain’ machines has been eliminated and the information  for each point on the A-scan is collected simultaneously, speeding  data collection and improving resolution. Promising newer  modalities include swept-source (SS) OCT that can acquire images    at a much higher rate and with extremely high retinal element  resolution and better imaging depth; choroidal definition is  improving rapidly. So-called adaptive optics allows correction of  higher-order optical aberrations to greatly improve resolution,  and wide-field, intraoperative, functional and Doppler (blood  flow measurement) OCT applications may all have clinical utility  in the future.   • Macula. The diagnosis and monitoring of macular pathology  has been revolutionized by the advent of OCT imaging, e.g.  AMD, diabetic maculopathy, macular hole, epiretinal  membrane and vitreomacular traction, CSR and retinal  venous occlusion.   • Glaucoma. The widespread availability of OCT in  ophthalmology suites for the assessment of medical retinal  disease has contributed to its increased adoption as an  adjunct to clinical and perimetric assessment in the  management of glaucoma.   • Anterior segment OCT has an expanding range of clinical  applications such as suspected angle-closure glaucoma and  corneal analysis (pachymetry, pre- and post-corneal  refractive procedures, diagnosis and monitoring).   High reflectivity structures can be depicted in a pseudo-colour  image as red, intermediate as green-yellow and low reflectivity as  blue-black. Fine retinal structures such as the external limiting  membrane and ganglion cell layer can be defined (Fig. 14.34B).  Detailed quantitative information on retinal thickness can be dis¬  played numerically and in false-colour topographical maps; three-  dimensional images can be constructed and different retinal layers  studied in relief (Fig. 14.35).   Imaging of fundus autofluorescence (FAF) using an enhanced  fundus camera or scanning laser ophthalmoscopy permits visuali¬  zation of accumulated lipofuscin in the retinal pigment epithe¬  lium. The scope of its place in the clinical management of macular  degeneration and other conditions has not yet been clearly defined.  It can be useful, for instance, to demonstrate more extensive  macular disease than is visible clinically, in order either to deter¬  mine the cause of unexplained poor visual acuity or to establish  the reason for substantial visual symptoms despite good measured  acuity. There is speculation that it may have greater utility in the  future in the management of dry AMD once effective therapies  become available. A key finding may be that FAF in patients with  geographic atrophy (see below) shows distinct areas of autofluo¬  rescence at the leading edges of lesions that seems to precede  retinal demise (Fig. 14.36); hyperautofluorescence is thought to  commonly indicate retinal pigment epithelial stress. Autofluores¬  cence is discussed further under ‘Fluorescein angiography’ above.   Several wide-field (also referred to as ultrawide-field) high resolu¬  tion imaging devices are now available. These are able to capture  views of up to about 80% of the area of the retina in a single image;  some have the facility of imaging FAF and FA (Fig. 14.37 and see  especially Ch. 16), and can provide extremely useful additional  information.   Age-related macular degeneration (AMD) is a degenerative disor¬  der affecting the macula. It is characterized by the presence of  specific clinical findings, including drusen and RPE changes, in the  absence of another disorder. Later stages of the disease are associ¬  ated with impairment of vision.   • Conventionally, AMD has been divided into two main types:  o Dry (non-exudative, non-neovascular) AMD is the most   common form, comprising around 90% of diagnosed  disease. Geographic atrophy (GA) is the advanced stage  of dry AMD; it has been authoritatively suggested that  the term ‘dry AMD’ be used only to describe GA rather  than earlier stages of AMD.   o Wet (exudative, neovascular) AMD is much less common  than dry, but is associated with more rapid progression to  advanced sight loss. The main manifestations are CNV  and PED, though in recent years at least two additional  conditions, retinal angiomatous proliferation (RAP) and  polypoidal choroidal vasculopathy (PCV), have been  included under the umbrella of neovascular AMD by  many authorities.   • A recent expert consensus committee has provided a  clinical classification of AMD (Table 14.3).   • AMD is the most common cause of irreversible visual loss in  industrialized countries. In the USA, it is responsible for  around 54% of severe sight loss (better eye worse than 6/60)  in Caucasian, 14% in Hispanic and 4% in black individuals.  The prevalence increases with age and symptoms are rare in  patients under 50 years of age.   • In the UK, significant visual impairment (binocularly 6/18 or  worse) from AMD affects about 4% of the population aged  over 75 years and 14% of those over 90, with 1.6% over 75  having binocular acuity of less than 6/60.   • Patients with late AMD in one eye, or even moderate vision  loss due to non-advanced AMD in one eye, have about a  50% chance of developing advanced AMD in the fellow eye  within 5 years.    Fig. 14.35 OCT printout showing cross-sectional views, retinal thickness measurement and different retinal layers in a  three-dimensional reconstruction in a patient with a macular epiretinal membrane and consequent loss of the foveal  depression   AMD is multifactorial in aetiology, and is thought to involve a  complex interaction between polygenic, lifestyle and environmen¬  tal factors.   • Race. Late AMD is more common in white individuals than  those of other races.   Definition, based on presence of  lesions within two disc diameters  of the fovea in either eye    Pigmentary abnormalities: any definite hyper- or hypopigmentary  abnormalities associated with medium or large drusen but not due to other  known disease.   The size of drusen can be estimated by comparison with the approximately  125 pm diameter of a retinal vein at the optic disc margin.    • Heredity. Family history is important; the risk of AMD is up  to three times as high if a first-degree relative has the disease.  Variants in many genes have been implicated in AMD risk  and protection such as the complement factor H gene CFH ,  which helps to protect cells from complement-mediated  damage, with several times the risk of AMD for homozygotes  with a particular single nucleotide polymorphism (SNP), and   Fig. 14.37 Wide-field imaging. (A) Colour image of peripheral drusen; (B) FA in central serous chorioretinopathy   the ARMS2 gene on chromosome 10. Genes related to lipid  metabolism are also thought to be important.   • Hypertension and other cardiovascular risk factors are likely  to be associated.   • Dietary factors. High fat intake and obesity may promote  AMD, with high antioxidant intake having a protective effect  in some groups (see below).   • Aspirin may increase the risk of neovascular AMD. Though  the evidence is limited, if an individual at high risk requires  an antiplatelet agent it may be sensible to consider an  alternative to aspirin.   • Other factors such as cataract surgery, blue iris colour, high  sunlight exposure and female gender are suspected, but their  influence remains less certain.   Drusen (singular: druse) are extracellular deposits located at the  interface between the RPE and Bruch membrane (Fig. 14.38A). The  material of which they are composed has a broad range of con¬  stituents, and is thought to be derived from immune-mediated  and metabolic processes in the RPE. Their precise role in the  pathogenesis of AMD is unclear, but is positively associated with  the size of lesions and the presence or absence of associated pig¬  mentary abnormalities. Age-related drusen are rare prior to the  age of 40, but are common by the sixth decade. The distribution  is highly variable, and they may be confined to the fovea, may  encircle it or form a band around the macular periphery. They  may also be seen in the peripheral and mid-peripheral fundus (see  Ch. 16).   There is a strong association between the size of drusen (Fig.  14.38B-E) and the risk of developing late AMD over a 5-year  period.   • Small drusen (drupelets), sometimes termed ‘hard’ drusen,  are typically well-defined white-yellow and by definition  measure <63 pm - less than half the width of a retinal  vein at the optic disc margin - in diameter. Their presence  as the only finding probably carries little increased risk   • Intermediate drusen are fairly well-defined yellow-white  focal deposits at the level of the RPE measuring between  63 pm and 125 pm. Without accompanying pigmentary  abnormalities, they carry only a very small risk of  progression to late AMD over 5 years, but this increases to  over 10% if pigmentary abnormalities are present in both  eyes.   • Large drusen are less well delineated yellow-white deep  retinal lesions measuring over 125 pm in diameter; the term    ‘soft’ drusen (see Fig. 14.38B) is sometimes used  synonymously. As they enlarge and become more numerous  (see Figs 14.38C and D), they may coalesce giving a localized  elevation of the RPE, a ‘drusenoid RPE detachment’ - see  below. The presence of large drusen in both eyes is  associated with a 13% risk of progression to late AMD over 5  years, but with accompanying bilateral pigmentary  abnormalities this rises to about 50%.   • Pigmentary abnormalities. Hyper- and hypopigmentation  (see Fig. 14.38E) not due to other retinal disease is associated  with a significantly higher likelihood of progression to late  AMD with visual loss.   Medium-sized and large drusen are seen as hyper-reflective irreg¬  ular nodules beneath the RPE, located on or within the Bruch  membrane (Fig 14.38F).   FA findings depend on the state of the overlying RPE and on the  affinity of the drusen for fluorescein. Hyperfluorescence can be  caused by a window defect due to atrophy of the overlying RPE,  or by late staining. Hypofluorescent drusen masking background  fluorescence are hydrophobic, with a high lipid content, and tend  not to stain.   A number of conditions feature lesions similar to age-related  drusen, and at least some may have a similar pathophysiological  basis.   • Doyne honeycomb retinal dystrophy (malattia leventinese,  autosomal dominant radial drusen) is an uncommon  condition in which fairly characteristic drusen (Fig. 14.39A)  appear during the second or third decades (see Ch. 15);   the genetic basis has been established for the majority  of cases.   • Cuticular drusen, also known as grouped early adult-onset  or basal laminar drusen (not to be confused with basal  laminar deposit and basal linear deposit in AMD - see dry  AMD below), tend to be seen in relatively young adults. The  lesions consist of small (25-75 flm) yellowish nodules (Fig.  14.39B) that tend to cluster and increase in number with  time and can progress to serous PED. FA characteristically  gives a ‘stars in the sky’ appearance (Fig. 14.39C). The  condition has been linked to a variant of the CFH gene.   • Type 2 membranoproliferative glomerulonephritis is a  chronic renal disease that occurs in older children and  adults. A minority of patients develop bilateral diffuse  drusen-like lesions. The CFH gene has again been  implicated.   Fig. 14.38 Drusen. (A) Histopathology shows homogeneous eosinophilic deposits lying between the retinal pigment  epithelium (RPE) and the inner collagenous layer of Bruch membrane; (B) mixed small, intermediate and large drusen;  (C) initial image; and (D) same eye 4 years later showing increase in number and size of drusen; (E) drusen with  associated pigmentary abnormalities; (F) OCT showing nodules associated with the RPE   (Courtesy of J Harry - fig. A; S Chen - figs B-E)   (Courtesy of S Chen - fig. A; C Barry - figs B and C)   There is substantial evidence, notably from the Age-Related Eye  Disease Study (AREDS, now known as AREDSi) and the follow-up  AREDS2, that taking high-dose antioxidant vitamins and minerals  on a regular basis can decrease the risk of the development of  advanced AMD in individuals with certain dry AMD features. The  recommendation was made in AREDSi that individuals aged over  55 should undergo examination for the following high-risk char¬  acteristics, and if one or more are present should consider anti¬  oxidant supplementation:   In AREDSi the reduction in risk of progression to advanced AMD  at 10 years was in the order of 25-30% for those with the more  advanced of these signs at baseline who took supplements; sup¬  plements did not discernibly reduce progression in those with  early or no AMD at baseline.   The regimen used in AREDSi consisted of vitamin C, vitamin E,  the beta-carotene form of vitamin A, and 80 mg daily of zinc  (with copper to prevent zinc-induced copper deficiency). How¬  ever, high zinc doses are potentially associated with genitourinary  tract problems, and there are data suggesting that 25 mg of  zinc may be the maximal level that is absorbed. Beta-carotene  almost certainly increases the incidence of lung cancer in current  and former smokers. AREDS2 looked at adjusting the beta-  carotene and zinc components, and also whether additional  or alternative supplements could enhance outcomes. AREDS2  found:   • The carotenoids lutein and zeaxanthin are a safe alternative  to beta-carotene, and are probably superior (possible 18%  reduction in risk of advanced AMD above that conferred by  the AREDSi regimen).   • Lutein and zeaxanthin supplementation added to the  original AREDSi regimen was only associated with a  statistically significantly reduced (26%) risk of AMD in  patients in whom the dietary intake of these was not already  high (self-described and blood testing); there was evidence  that competition for absorption between different  carotenoids may have prevented the demonstration of  superiority in other patients. This group also showed a  one-third reduction in the likelihood of cataract surgery.   • Adding omega-3 fatty acids to the regimen did not seem to  enhance outcomes.   • Lowering the zinc dose did not lead to a statistically  significant prognostic worsening, and is likely to be  associated with a lower incidence of side-effects such as  gastrointestinal and urinary problems.    • Recommended daily supplementation based on AREDS2:  o Vitamin E (400 IU).   o Vitamin C (500 mg),  o Lutein (10 mg),  o Zeaxanthin (2 mg).   o Zinc (25-80 mg; the lower dose may be equally effective).  O Copper (2 mg; this may not be required with the lower  zinc dose).   • A liberal green leafy vegetable intake confers a lower risk of  AMD, and for individuals with a strong family history of  AMD and those with early AMD who do not meet the  AREDS criteria, this may be a prudent lifestyle choice.   • Protective measures against exposure to excessive sunlight  should be considered.   • Some authorities consider that evidence still supports the  regular consumption of oily fish.   • Symptoms consist of gradual impairment of vision over  months or years. Both eyes are usually affected, but often  asymmetrically. Vision may fluctuate, and is often better in  bright light.   o Focal hyper- and/or hypopigmentation of the RPE (Fig.  14.40A and B).   o Sharply circumscribed areas of RPE atrophy associated  with variable loss of the retina and choriocapillaris (Fig.  14.40C).   o Enlargement of atrophic areas, within which larger  choroidal vessels may become visible and pre-existing  drusen disappear (GA - Fig. 14.40D). Visual acuity may  be severely impaired if the fovea is involved. Rarely, CNV  may develop in an area of GA.  o Drusenoid RPE detachment (see below).   o Loss of RPE and morphological alterations of the  overlying retina of increasing severity are seen in GA,  including increased hyper-reflectivity initially in the outer  retinal layers and eventual photoreceptor loss,  o Outer retinal tubulations may be seen; these are thought  to consist of degenerating photoreceptors aggregated into  tubular structures that appear as roundish hyporeflective  spaces (Fig. 14.40E), often around the margin of GA.  o Outer retinal corrugations. This recently described  phenomenon is an undulating hyper-reflective layer on    OCT thought to correspond to the histological finding of  basal laminar deposit, a layer that accumulates between  the RPE and the RPE basement membrane (the inner  layer of the Bruch membrane) in AMD. Basal linear  deposit is a distinct finding consisting of membranous  debris laid down between the RPE basement membrane  and the inner collagenous layer of the Bruch membrane  that may progress focally to form drusen.   • FA of atrophic areas shows a window defect due to  unmasking of background choroidal fluorescence (see Fig.  14.22), if the underlying choriocapillaris is still intact.   o Antioxidant supplementation if indicated,  o Risk factors should be addressed, e.g. smoking, ocular  sun protection, cardiovascular, dietary.   • An Amsler grid should be provided for home use, with  advice to self-test on a regular basis, perhaps weekly, and to  seek professional advice urgently in the event of any change,  when imaging (e.g. OCT, FA) should be performed to rule  out progression to neovascular AMD. This might be of  increased importance following cataract surgery.   • Provision of low vision aids and, for patients with significant  visual loss, certification as visually impaired if available as  this may facilitate access to social and financial support.   o Miniature intraocular telescope implantation may  provide benefit in selected cases,  o Retinal translocation surgery has had limited success,  o Visual prostheses of various types are under investigation,  but are likely to be adopted for severe retinal dystrophies  initially.   • Potential new therapies. An extensive range of therapies  shows promise for the treatment of dry AMD. Examples are:  O Lampalizumab, a complement-inhibiting monoclonal   antibody injected intravitreally on a monthly basis  reduced progression of GA by 44%.  o Visual cycle modulation: ameliorating the formation of  cytotoxic products by reducing the rate of vitamin A  processing; clinical trials (e.g. fenretinide, emixustat) are  under way.   reduction in their extent, but does not seem to reduce the  risk of progression to AMD. A newer modality using  extremely short (nanosecond range) pulses of non-  thermal laser energy may have a rejuvenating effect on  the RPE and Bruch membrane,  o Saffron (20 mg/day); preliminary evidence suggests a  neuroprotective effect.   o Others include subretinal stem cell transplantation, and  intravitreal injection of a range of drugs including ciliary  neurotrophic factor, steroid inserts and neuroprotective  drugs including brimonidine.   Fig. 14.40 Age-related macular degeneration without neovascularization. (A) Drusen and mild pigmentary changes; (B) same  eye as (A) 4 years later with moderate retinal atrophy and pigmentary abnormalities; (C) small and intermediate drusen  with geographic atrophy; (D) substantial geographic atrophy and pigmentary abnormalities; (E) OCT- outer retinal tubulations   Pigment epithelial detachment (PED) from the inner collagenous  layer of Bruch membrane is caused by disruption of the physio¬  logical forces maintaining adhesion. The basic mechanism is  thought to be the reduction of hydraulic conductivity of a thick¬  ened and dysfunctional Bruch membrane, thus impeding move¬  ment of fluid from the RPE towards the choroid. Immune-mediated  processes may also be important. The different types are discussed  below.   o An orange dome-shaped elevation with sharply delineated  edges, often with a paler margin of subretinal fluid (Fig.  14.41A). Multiple lesions may occur,  o An associated pigment band may indicate chronicity.  o Associated blood, lipid exudation, chorioretinal folds  or irregular subretinal fluid may indicate underlying  CNV.   Fig. 14.41 Detachment of the retinal pigment epithelium (RPE). (A) Clinical appearance; (B) FA shows hyperfluorescence;   (C) ICGA shows hypofluorescence with a faint ring of surrounding hyperfluorescence; (D) OCT shows separation of the RPE  from Bruch membrane;   Fig. 14.41, Continued (E) gradual resolution of a pigment epithelial detachment with sequential monthly injections of  bevacizumab   (Courtesy of P Gili - figs A and B; A Bolton - fig. C; S Chen - fig. E)    o If no drusen are seen, polypoidal choroidal vasculopathy  (PCV - see below) should be suspected.   • FA: a well demarcated oval area of hyperfluorescent pooling  (Fig. 14.41B) that increases in intensity but not in area with  time; an indentation (notch) may signify CNV.   • ICGA: an oval hypofluorescent area with a surrounding  hyperfluorescent ring (Fig. 14.41C). Occult CNV (focal hot  spot or diffuse plaque) is detected in over 90%.   • OCT shows separation of the RPE from the Bruch  membrane by an optically empty area (Fig. 14.41D). CNV  may be indicated by a notch between the main elevation and  a second small mound.   o Patients aged over 60 have a worse prognosis (6/60 or  less), but speed of deterioration varies,  o Resolution leaving GA with visual loss (spontaneous  resolution with relative preservation of vision is more  common in younger patients),  o RPE tear formation (see below) or haemorrhage from  CNV can occur, with sudden visual loss,  o Up to a third of eyes develop clinical CNV within  2 years, but the proportion is much higher  angiographically.   o Observation may be appropriate in clinically stable  patients without readily detectable CNV, especially those  younger than 60.   o Intravitreal injection of vascular endothelial growth  factor (VEGF) inhibitor may stabilize or improve vision    (Fig. 14.41E), and should be considered particularly when  there is associated CNV; however, there is a 5-20% risk  of RPE tear.   o Combining photodynamic therapy (PDT) with  intravitreal anti-VEGF or intravitreal triamcinolone  injection (IVTA) can also be effective, though the RPE  tear risk persists.   • Signs. The PED is much more irregular in outline and  elevation than serous PED.   • OCT. Less uniform than a serous PED; both fluid and  fibrous proliferation are shown, the latter as irregular  scattered reflections.   • FA shows markedly irregular granular (stippled)  hyperfluorescence, with uneven filling of the PED, leakage  and late staining.   • Signs. Shallow elevated pale areas with irregular scalloped  edges (Fig. 14.42A).   • FA. Early diffuse hypofluorescence with patchy relatively  faint early hyperfluorescence, progressing to moderate  irregular late staining (Fig. 14.42B).   o Blood may break through into the subretinal space,  assuming a more diffuse outline and a lighter red colour.   • Management of large haemorrhagic lesions is described  below under ‘Haemorrhagic AMD’, but the prognosis for  central vision is generally poor. CNV associated with a small  haemorrhagic PED can be managed conventionally.  Management of PCV is discussed separately.    Fig. 14.42 Drusenoid detachment of the retinal pigment  epithelium. (A) Clinical appearance; (B) FA late phase shows  moderate hyperfluorescence due to staining   An RPE tear may occur at the junction of attached and detached   • Signs. A crescent-shaped pale area of RPE dehiscence is  seen, next to a darker area corresponding to the retracted  and folded flap (Figs 14.44A and B).   • OCT. Loss of the normal dome shape of the RPE layer in the  PED, with hyper-reflectivity of the folded RPE (Figs 14.44C  and D).   • FA late phase shows hypofluorescence over the flap due to  the thickened folded RPE, with adjacent hyperfluorescence,  initially over the exposed choriocapillaris where the RPE   is absent and later due to scleral staining. The two areas  are often separated by a sharply defined border  (Fig. 14.44E).   • The prognosis in subfoveal tears is poor. Good VA is usually  maintained if the fovea is spared.   • OCT shows homogeneous hyper-reflectivity within the PED,  in contrast to optically empty serous PED. There is  commonly no subretinal fluid.   • Natural course. The outlook is usually better than other  forms of PED, with only gradual visual loss, though  probably around 75% still progress to develop GA and 25%  CNV by 10 years from diagnosis. Long-term stability is  common: at 3 years, only about one-third will have GA or  CNV.   • Management. Observation in most cases, with no evidence  to support the efficacy of any intervention.    Fig. 14.43 Haemorrhagic detachment of the retinal pigment  epithelium (RPE); subretinal blood is present in the lighter  red areas and sub-RPE blood in the darker red areas    Virtually every haemorrhagic PED has underlying CNV or poly¬  poidal choroidal vasculopathy (PCV): the latter should always be  considered if no drusen are present.   Choroidal neovascularization (CNV) consists of a blood vessel  complex that extends through Bruch membrane from the chori-  ocapillaris into the sub-RPE (type 1) or subretinal (type 2) space.  It occurs in many different disorders, usually when Bruch mem¬  brane and/or RPE function has been compromised by a degenera¬  tive, inflammatory, traumatic or neoplastic process. AMD is the  most common causative association, followed by myopic degen¬  eration. The present discussion relates to CNV arising de novo as  the primary lesion in neovascular AMD, but CNV may also  develop secondary to retinal angiomatous proliferation and  polypoidal choroidal vasculopathy (RAP and PCV - see below),  both of which are considered by many practitioners to themselves  be variants of neovascular AMD. The prognosis of untreated  CNV is generally poor, with ‘hand movements’ VA a common  outcome. Understanding of aetiopathogenesis has improved  over recent years; the promotion and inhibition of blood vessel  growth by cytokines is important, particularly vascular endothelial  growth factor (VEGF), which binds to endothelial cell receptors,  promoting proliferation and vascular leakage. The inhibitory  mediators pigment epithelium-derived factor (PEDF) and com¬  plement factor H (CFH) are also thought to play key roles. Sup¬  plementary endothelial progenitor cells are thought to be recruited  from systemic reservoirs, enhancing growth of the new vessel  complex.   • Symptoms. Acute or subacute painless blurring of vision,  usually with metamorphopsia. Haemorrhage may give a  positive scotoma.   o The CNV itself may be identifiable as a grey-green or  pinkish-yellow lesion (Fig. 14.45A).  o Associated medium-large drusen are a typical finding in  the same or fellow eye.   o Haemorrhage (Fig. 14.45C) is common, e.g. subretinal,  preretinal/retrohyaloid, vitreous,  o There may be an associated serous, fibrovascular  drusenoid or haemorrhagic PED.  o Retinal and subretinal cicatrization (‘disciform’ scar) in  an evolved or treated lesion (Fig. 14.45D).   FA was previously used to diagnose CNV and to plan and monitor  the response to laser photocoagulation or PDT. Current indica¬  tions include:   • Diagnosis of CNV prior to committing to anti-VEGF  treatment; FA should usually be performed urgently on the  basis of clinical suspicion.    • As an adjunct to diagnosis of an alternative form of  neovascular AMD such as PCV and RAP.   Terminology used to describe CNV on FA is derived from the  Macular Photocoagulation Study (MPS):   • Classic CNV (20%) fills with dye in a well-defined ‘lacy’  pattern during early transit (Fig. 14.46A), subsequently  leaking into the subretinal space over 1-2 minutes (Fig.  14.46B), with late staining of fibrous tissue (Fig. 14.46C).  Most CNV is subfoveal, extrafoveal being defined as   >200 jam from the centre of the foveal avascular zone on FA.   • Occult CNV (80%) is used to describe CNV when its limits  cannot be fully defined on FA (Fig. 14.47). Variants are  fibrovascular PED (see above) and ‘late leakage of an  undetermined source’ (FEUS).   • Predominantly or minimally classic CNV is present when  the classic element is greater or less than 50% of the total  lesion respectively.   • Increased sensitivity in the detection of CNV, e.g. if  low-density haemorrhage, fluid or pigment preclude  adequate FA visualization.   • The distinction of CNV from other conditions that may  have a similar presentation, particularly PCV, RAP and CSR.   • The delineation of occult CNV may still have utility for  combined modality treatment, and for patients who refuse  intravitreal therapy.   OCT is critical in quantitative monitoring of the response to CNV  treatment. It has to date been of limited assistance in the diagnosis  of CNV, though ongoing technological refinements are likely to  lead to increasing utility. Typically, CNV is shown as a thickening  and fragmentation of the RPE and choriocapillaris. Subretinal and  sub-RPE fluid, blood and scarring are demonstrated (Fig. 14.49).  Outer retinal tubulations (see Fig. 14.40E) may be present, often  in a branching pseudodendritic conformation.   • Principles. Inhibitors of VEGF block its interaction with  receptors on the endothelial cell surface and so retard or  reverse vessel growth. They have become the predominant  means of treatment for CNV, dramatically improving the  visual prognosis. Intravitreal injection is the standard  method of administration, notable risks including retinal  detachment, damage to the lens, RPE tears and  endophthalmitis. Sustained elevation of intraocular pressure  (IOP) and sterile uveitis may also occur. Systemically, there   Fig. 14.44 Retinal pigment epithelium (RPE) tear. (A) Pigment epithelial detachment prior to tear; (B) pale area denuded of  RPE with an adjacent darker area consisting of rolled-up RPE following a tear; (C) OCT prior to tear; (D) OCT following a  tear shows corrugation of the elevated RPE and hyper-reflectivity of the rolled-up region;    Fig. 14.44, Continued (E) FA late phase of a different eye shows relative hypofluorescence of the folded flap with adjacent  hyperfluorescence where the RPE is absent   (Courtesy of S Chen - figs A-D; C Barry - fig. E)   Fig. 14.45 Signs in choroidal neovascularization (CNV). (A) CNV visible as a grey-green subfoveal area; (B) extensive lipid  deposition; (C) haemorrhage - intra- and subretinal; (D) ‘disciform’ scarring    Fig. 14.46 FA of classic subfoveal choroidal neovascularization  - the eye in Fig. 14.45A. (A) FA early venous phase - ‘lacy’  hyperfluorescent pattern; (B) late venous phase - more  intense hyperfluorescence with leakage and staining;   Fig. 14.47 FA of occult choroidal neovascularization. (A) Specks of blood at the fovea; (B-D) FA shows diffuse  hyperfluorescence but the limits of the membrane cannot be defined    Fig. 14.48 ICGA of choroidal neovascularization (CNV). (A) Blood and fluid at the macula surrounded by hard exudates;  (B-D) shows a small area of increasing hyperfluorescence (‘hot spot’) from underlying CNV   Fig. 14.49 OCT. (A) Choroidal neovascularization and  subretinal fluid; (B) long-established lesion with secondary  atrophic retinal changes    is a suspicion of a slightly increased incidence of stroke. All  available anti-VEGF agents seem to have potential for  benefit in a range of vascular eye diseases.   • Indications. All CNV subtypes respond to anti-VEGF  therapy, but benefit is only likely in the presence of active  disease; the presence of a mature fibrotic disciform scar with  little or no fluid makes treatment extremely unlikely to be  useful. Evidence for active CNV includes fluid or  haemorrhage, leakage on FA, an enlarging CNV membrane,  or deteriorating vision judged likely to be due to CNV  activity. An eye with almost any level of vision may benefit,  although better VA at the outset is associated with a better  final VA and patients with only ‘hand movements’ should be  assessed on an individual basis. It is likely that anti-VEGF  agents have a reduced duration of action in vitrectomized  eyes.   • Aflibercept (Eylea®) is a recombinant fusion protein that  binds to VEGF-A, VEGF-B and placental growth factor  (P 1 GF). After becoming commercially available, it was  adopted rapidly into clinical practice, principally because the  recommended maintenance regimen consists of one  injection every 2 months in contrast to the monthly  injections recommended with ranibizumab and bevacizumab  (see below), though in some patients dosing is required  more frequently than every 2 months. The standard dose is   2 mg in 0.05 ml; an induction course of three injections is  given at monthly intervals.   • Ranibizumab (Lucentis®). Ranibizumab is a humanized  monoclonal antibody fragment developed specifically for use  in the eye, though is derived from the same parent mouse  antibody as bevacizumab (see next). It non-selectively binds    and inhibits ah isoforms of VEGF-A. The usual dose is  0.5 mg in 0.05 ml. Three main treatment strategies are  adopted in AMD:   O Regular monthly injection is the regimen adopted in  initial major trials. Overall, around 95% of patients  maintain vision regardless of lesion type, and 35-40%  significantly improved, most markedly during the first  3 months. This regimen seems to offer a marginally  better visual outcome, but may be associated with  progression to geographic atrophy of slightly greater  severity than less intensive administration and the  long-term implications of this remain undetermined.  There is a suggestion that systemic adverse events may,  counterintuitively, be less common with regular monthly  injections than discontinuous schedules.   O Three initial monthly injections followed by monthly  review with re-injection when deterioration occurs as  assessed by VA (e.g. loss of 5 letters or more) and OCT  (e.g. retinal thickness increase of 100 pan or more),  o ‘Treat and extend’ entails administering three initial  injections at monthly intervals and then gradually  increasing the period between injections until  deterioration is evident. If possible a tailored interval is  determined for each patient.   • Bevacizumab (Avastin®). In contrast to ranibizumab,  bevacizumab is a complete antibody originally developed to  target blood vessel growth in metastatic cancer deposits. Its  use for AMD and other indications is ‘off label’; it is very  much cheaper than ranibizumab and aflibercept. Clinical  trial results suggest that it is approximately comparable to  ranibizumab in efficacy and safety, though some assessments  have suggested that the risk of serious systemic adverse  events is marginally higher with bevacizumab than  ranibizumab. Treatment strategies in AMD are similar to  those used for ranibizumab. The dose of bevacizumab is  usually 1.25 mg/0.05 ml.   • Pegaptanib (Macugen®). Pegaptanib sodium was the first  anti-VEGF agent approved by regulatory authorities for  ocular treatment; the results are similar to outcomes with  PDT, and its use is now extremely limited.   • Technique of intravitreal injection. Various protocols are in  use; a typical approach is set out in Table 14.4; this applies to  ant-VEGF injection - there are slight differences for  intravitreal steroid administration.   Patients can return to normal activity after 24 hours, but should  be warned to seek advice urgently should they experience any  deterioration in their vision or symptoms of inflammation.   Verteporfin is a light-activated compound preferentially taken up  by dividing cells including neovascular tissue. It is infused intra¬  venously and then activated by diode laser to cause thrombosis.  The main indication was previously subfoveal predominantly  classic CNV with visual acuity of 6/60 or better. Severe adverse  effects are rare. With the advent of anti-VEGF treatment, PDT is   • The procedure and its risks should be explained to the patient and appropriate consent obtained.   • The indication and the eye to be treated should be checked and the eye marked.   • It should be confirmed that anterior and posterior segment examination (including IOP) has been carried out recently  to exclude contraindications.   • Confirmation should be obtained that a syringe of the drug to be injected is available.   • Bilateral injections are optimally administered at separate sessions to minimize risk, but if necessary different  instruments and drug batches should be used.   • Povidone-iodine 5% (chlorhexidine if allergic to iodine) is applied to the ocular surface and at least 3 minutes allowed  prior to injection.   • Subconjunctival lidocaine 1% or 2% may be used to supplement the topical agent. Some practitioners prefer  lidocaine gel, though concerns have been expressed regarding the possibility of microorganism retention within this.   • Hands are washed using a standard surgical procedure, and sterile gloves donned.   • The periocular skin, eyelids and lashes are cleaned with 5-10% povidone iodine.   • As for other forms of intraocular surgery, a sterile periocular drape may be advisable.   • The sterile pouch containing a pre-prepared syringe is opened, or a sterile syringe is used to draw up the appropriate  volume of drug from a vial of ready-prepared drug. A needle (typically 30-gauge, 0.5 inch) on the syringe is primed to  expel any air.   • The patient is instructed to look away from the injection site - this is most commonly inferotemporal because of  ease of access, though any quadrant can be used; the 3 and 9 o’clock positions are avoided because of the risk of  neurovascular damage.   • A gauge is used to identify an injection site 3.5-4.0 mm posterior to the limbus (pars plana).   • Forceps can be used to stabilize the eye, and if wished to apply anterior traction to the conjunctiva so that the  conjunctival hole does not overlie the scleral track.   • The needle is advanced perpendicularly through the sclera towards the centre of the eyeball, and the required  volume of drug (usually 0.05 ml) injected into the vitreous cavity. Some practitioners make an attempt to ‘step’ the  needle track.   • It has become usual practice not to use post-injection antibiotics as there is a suggestion that serial use may  increase the rate of infection by promoting bacterial resistance.   • Elevated IOP can occlude the central retinal artery, and it is important routinely to ensure this remains perfused  after the procedure by checking the patient’s vision (subjectively is adequate), directly visualizing the artery, or  optimally by checking the IOP (particularly in glaucoma patients). If occlusion occurs, urgent paracentesis should be  carried out; simply lying down may restore blood flow.   • A clear plastic eye shield may be used until the local anaesthetic has worn off, and during sleep for the first night or  two, but practice varies.    now rarely used for CNV, but combination therapy (see below)  and refusal of intravitreal treatment remain indications. Reduced-  intensity regimens have been used with good effect in CSR.   Although anti-VEGF therapy has revolutionized the management  of CNV, further investigation is attempting to achieve outcomes  that are better still, particularly a reduction in the frequency of  intravitreal injections. To date, regimens that include the combi¬  nation of PDT with anti-VEGF treatment have not been shown to  be superior to anti-VEGF treatment alone, but investigation is  ongoing, including parallel inhibition of anti-VEGF agents with  inhibition of other cytokines and with low-intensity macular  radiotherapy. Sustained-release anti-VEGF systems, and gene  therapy utilizing adenoviral vectors to facilitate the production of  cytokines within the eye, are other avenues of potential therapeutic  advantage.   Thermal argon or diode laser ablation of CNV is now rarely used,  though may still be suitable for the treatment of small classic  extrafoveal membranes well away from the macular centre, and  possibly some cases of PCV and RAP.   The visual prognosis for most eyes with extensive subretinal or  sub-RPE haemorrhage is relatively poor. Clinical trials assessing  surgical drainage of extensive subretinal or sub-RPE haemorrhage  with CNV excision did not show any significant improvement in  prognosis, and rhegmatogenous retinal detachment was frequent.  However, results superior to the untreated course have been  reported for intravitreal anti-VEGF injection alone, and liquefac¬  tion of blood by intravitreal (or subretinal, requiring vitrectomy)  recombinant tissue plasminogen activator (rtPA) and pneumatic   displacement may be appropriate for large or thick haemorrhage.  If the patient takes a coumarin anticoagulant, liaison with the  prescribing physician is worthwhile to assess if this could reason¬  ably be stopped - there is an association with massive macular  haemorrhage. Antiplatelet drugs do not usually require discon¬  tinuation, though aspirin may be associated with a greater risk of  CNV than other agents. Alternative pathology (e.g. PCV, macro¬  aneurysm) that may be associated with extensive haemorrhage  should always be considered.    Retinal angiomatous proliferation (RAP) maybe a variant of neo-  vascular AMD in which the major component of the neovascular  complex is initially located within the retina. The process may  originate within the deep retinal capillary plexus or within the  choroid, in the latter case with the early formation of a retinal-  choroidal anastomosis (RCA) without underlying type 1 CNV; the  term ‘type 3 neovascularization’ has been suggested. The disease  is frequently bilateral and symmetrical, and is probably substan¬  tially underdiagnosed; it may constitute 10-20% of neovascular  AMD in Caucasians.   • Presentation is similar to that of CNV but PED and exudate  are more frequent. Haemorrhages are also more common  and tend to be superficial and multiple.   • Stage 1: Intraretinal neovascularization (IRN). Dilated  telangiectatic retinal vessels and small angiomatous lesions,  typically accompanied by intra-, sub- and preretinal  haemorrhage, oedema and exudate (Fig. 14.50A).   • Stage 2: Sub retinal neovascularization (SRN) extends into  the subretinal space associated with increasing oedema and  exudate. A serous PED may be present.   • Stage 3: CNV. Perfusion is principally via the choroid, with  RCA formation. CNV is clearly evident clinically or  angiographically; a disciform scar will often form.   • OCT demonstrates neovascularization as a hyper-reflective  area. Other features depend on the stage.   • FA is usually similar to occult or minimally classic CNV  (Fig. 14.50B), but may show focal intraretinal  hyperfluorescence.   • ICGA is diagnostic in most cases, showing a hot spot in mid  and/or late frames (Fig. 14.50C), and frequently a perfusing  retinal arteriole and draining venule (‘hairpin loop’ when  linked).   Anti-VEGF therapy shows encouraging results; favourable out¬  comes in combination with PDT have been reported. Fimited  success has been reported for other modalities, including PDT  alone and photocoagulation of feeder vessels, though the latter  may be used in resistant cases.    Fig. 14.50 Retinal angiomatous proliferation. (A) Macular  drusen and a small intraretinal haemorrhage at the  macula; (B) FA early venous phase shows faint  hyperfluorescence from a small frond of intraretinal  neovascularization; (C) ICGA late phase shows  hyperfluorescence of the frond (‘hot spot’)   Polypoidal choroidal vasculopathy (PCV), like RAP, is believed by  many to be a variant of neovascular AMD. It is characterized by a  branching vascular network of inner choroidal vessels with mul¬  tiple terminal aneurysmal protuberances that appear to be the  source of bleeding and exudation. It is more common in patients  of African and East Asian ethnic origin than in whites and more  common in women than men (5:1). The disease is often bilateral  but tends to be asymmetrical. Overall, it is relatively common, and  the presence of prominent haemorrhage should lead to the con¬  sideration of PCV, particularly if there is an absence of drusen and  the patient is relatively young and Asian or black.   • Presentation is usually in late middle age with the sudden  onset of unilateral visual impairment.   o Terminal swellings are frequently visible as reddish-  orange nodules beneath the RPE in the peripapillary or  macular area (Fig. 14.51A), and less commonly the  periphery.   o Deterioration can be slow with intermittent bleeding and  leakage, resulting in macular damage and visual loss; up  to 50% may have a favourable outlook, with eventual  spontaneous resolution of exudation and haemorrhage.   o Hyperfluorescent nodules and a network of large  choroidal vessels with surrounding hypofluorescence  appear in the early phase. The polyp-like swellings rapidly  begin to leak (see Fig. 14.33 - same eye as Fig. 14.51A).  o The previously darker surrounding region becomes  hyperfluorescent by the late phase,  o A cluster of grape-like lesions may carry a higher risk of  severe visual loss.   The favourable prognosis without treatment in a significant pro¬  portion of cases should be borne in mind, and asymptomatic  polyps may be observed.   • Anti-VEGF agents appear to be less effective than in typical  CNV, but may suppress leakage and bleeding.   • Combination anti-VEGF and PDT may be superior to  anti-VEGF treatment alone; PDT may lead to regression of  polyps and putatively an extended treatment effect, but  carries an additional complication risk.   • baser photocoagulation of feeder vessels or polyps may be  effective in selected cases.    Fig. 14.51 Polypoidal choroidal vasculopathy. (A) Reddish-  orange nodular terminal swellings with leakage;    Peripheral exudative haemorrhagic chorioretinopathy (PEHCR)  is an uncommon disorder affecting predominantly older women.  It typically manifests with peripheral retinal haemorrhage, exuda¬  tion and PED associated with CNV. It is bilateral in a substantial  minority. The visual prognosis is often good, but the macula may  be involved by extensive disease. The aetiology is unknown,  though it may be a form of neovascular AMD; at least a proportion  of cases share characteristics with polypoidal choroidal vasculopa¬  thy. Treatment for sight-threatening disease generally consists of  intravitreal anti-VEGF injection.    Idiopathic CNV is an uncommon condition that affects patients  under the age of 50 years and is usually unilateral. The diagnosis  is one of exclusion of other possible associations of CNV in  younger patients, such as angioid streaks, high myopia and  chorioretinal inflammatory conditions such as presumed ocular  histoplasmosis. The condition carries a better visual prognosis  than that associated with AMD and in some cases spontaneous  resolution may occur. Treatment is typically with an anti-VEGF  agent.   An epiretinal membrane (ERM) is a sheet-like fibrocellular struc¬  ture that develops on or above the surface of the retina. Prolifera¬  tion of the cellular component and contraction of the membrane  leads to visual symptoms, primarily due to retinal wrinkling,  obstruction and localized elevation with or without pseudocyst  formation and CMO.   o No apparent cause, such as previous retinal detachment,  surgery, trauma or inflammation,  o Residual vitreous tissue remains on the retinal surface  following cortical separation in around 50% of eyes, with  subsequent proliferation. The predominant cellular  constituent is glial cells, probably derived from the  indigenous posterior hyaloid membrane (PHM) cell  population (laminocytes). ERM development can occur  at any stage of posterior vitreous detachment (PVD); it is  now believed that the process of PVD from initiation to  completion often extends over the course of years,  o About 10% are bilateral,  o Tend to be milder than secondary ERMs.   o Occur following retinal detachment surgery (most  frequent cause of secondary ERM), retinal break,  panretinal photocoagulation, retinal cryotherapy, retinal  vascular disease, inflammation and trauma,  o Binocularity is dependent on whether both eyes are  affected by the causative factors,  o Cell type more varied; pigment cells are prominent -  thought to be derived from the RPE.   o VA is highly variable, depending on severity,  o An irregular translucent sheen (cellophane maculopathy)  is present in early ERM, often best detected using green  (red-free) light (Fig. 14.52A).  o As the membrane thickens and contracts it becomes  more obvious (macular pucker) and typically causes mild  distortion of blood vessels (Fig. 14.52B).  o Advanced ERM may give severe distortion of blood  vessels, marked retinal wrinkling and striae and may  obscure underlying structures (Fig. 14.52C).  o Associated findings may include macular pseudohole  (Fig. 14.52D), CMO, retinal telangiectasia and small  haemorrhages.   • OCT shows a highly reflective surface layer associated with  retinal thickening (Fig. 14.52E). Disruption of the inner-  segment/outer-segment junction may be associated with a  worse visual outcome following surgery. OCT is also useful  to exclude significant vitreomacular traction (see later).   • FA has been superseded by OCT for routine assessment of  ERM, but highlights vascular tortuosity and demonstrates  any leakage. It is sometimes indicated to investigate the  cause of an ERM, such as a prior retinal vein occlusion.   • Observation if the membrane is mild and non-progressive.  Spontaneous resolution of visual symptoms sometimes  occurs, typically due to separation of the ERM from the  retina as a previously incomplete PVD completes. CMO or  tractional detachment may require fairly prompt surgery to  minimize secondary degenerative change.   • Surgical removal of the membrane via vitrectomy to  facilitate peeling usually improves or eliminates distortion  (the main benefit), with an improvement in visual acuity of  at least two lines in around 75% or more; in about a quarter  VA is unchanged, and around 2% get worse. The surgical  complications are principally those of vitrectomy. Removal  of the internal limiting membrane (ILM) in concert with  ERM peeling may be beneficial but remains controversial.  Visual improvement commonly does not occur for several  months postoperatively. Recurrence is rare.   Full-thickness macular hole (FTMH) is a relatively common cause  of central visual loss, with a prevalence of approximately 3:1000;  onset is most common in females aged 60-70. The risk of fellow  eye involvement at 5 years is around 10%. The role of vitreomacu¬  lar traction (VMT - see below) in the aetiology of macular hole  has increasingly been defined over recent years; a new OCT-based  classification has been published by the International    Fig. 14.52 Macular epiretinal membrane. (A) Translucent  membrane seen with red-free light; (B) more obvious  membrane; (C) advanced membrane; (D) macular pseudohole -  same eye as (C), 3 years earlier; (E) OCT shows high  reflectivity anterior to the retina, foveal thickening, and  vitreomacular traction   (Courtesy of L Merin - fig. A; S Chen - figs B-D)    Vitreomacular Traction Study (IVTS) Group with the intention  of replacing the older Gass clinical classification; both systems are  discussed below, and vitreomacular traction is considered at  greater length as a separate topic later in the chapter. Other causes  of full-thickness macular hole include high myopia, which can lead  to macular retinal detachment, and blunt ocular trauma. Lesions  that may sometimes have a similar appearance include macular  pseudohole and lamellar hole (see ‘Vitreoretinal traction’).   • Symptoms. Presentation of a full-thickness dehiscence may  be with impairment of central vision in one eye, or as a  relatively asymptomatic deterioration, first noticed when the  fellow eye is occluded or at a routine sight test. Symptoms  are absent or mild prior to the development of a full-  thickness lesion; metamorphopsia may be present.   o Stage o macular hole (IVTS: vitreomacular adhesion  - VMA) was a term proposed originally to denote the  OCT finding of oblique foveal vitreoretinal traction  before the appearance of clinical changes.   o Stage la: ‘Impending’ macular hole (IVTS: vitreomacular  traction - VMT) appears as flattening of the foveal  depression with an underlying yellow spot. Pathologically,  the inner retinal layers detach from the underlying  photoreceptor layer, often with the formation of a  cyst-like schisis cavity. The differential diagnosis of a  foveal yellow spot includes adult vitelliform macular  dystrophy, solar and laser pointer retinopathy, and CMO.   o Stage lb: Occult macular hole (IVTS: vitreomacular  traction - VMT) is seen as a yellow ring (Fig. 14.53A).  With loss of structural support, the photoreceptor  layer commonly undergoes centrifugal displacement  (Fig. 14.54B).   o Stage 2: Small full-thickness hole (IVTS: small or medium  FTMH with VMT) consists of a full-thickness hole less  than 400 pm in diameter (Fig. 14.53B and see Fig. 14.56B)  at its narrowest point; the defect may be central, slightly  eccentric or crescent-shaped. A dehiscence is present in  the inner retina with persistent vitreofoveolar adhesion  (Fig. 14.54C).   o Stage 3: Full-size macular hole (IVTS: medium or large  FTMH with VMT). A full-thickness hole greater than  400 pm in diameter, with a red base in which yellow-  white dots may be seen. A surrounding grey cuff of  subretinal fluid is usually present (Figs 14.53C and  14.54D), and an overlying retinal operculum (sometimes  called a pseudo-operculum) may be visible. Visual acuity  is commonly reduced to 6/60, but is occasionally better,  particularly with eccentric fixation. Opercula (Fig. 14.54E)  consist primarily of glial tissue and condensed vitreous  cortex, though 40% contain photoreceptor elements. By  definition, there is persistent parafoveal attachment of the  vitreous cortex.   o Stage 4: Full-size macular hole with complete PVD  (IVTS: small, medium or large FTMH without VMT).   The clinical appearance is indistinguishable from stage 3.  The posterior vitreous is completely detached, often  suggested (but not confirmed) by the presence of a Weiss  ring. A significant proportion of idiopathic macular holes  have an associated ERM.   o Spontaneously resolved macular hole. Macular holes may  heal spontaneously, often resuming a near-normal or  even normal clinical and OCT appearance. A tiny outer    Fig. 14.53 Macular hole. (A) Occult - stage lb; (B) small  full-thickness - stage 2; (C) full-size - stage 3   (Courtesy of J Donald M Gass , from Stereoscopic Atlas of Macular Diseases,  Mosby 1997 - fig. A; S Milenkov - fig. B; S Chen - fig. C)    Fig. 14.54 High resolution OCT of full-thickness macular hole (FTMH). (A) Normal; (B) stage lb - vitreomacular traction  - shows attachment of the posterior hyaloid to the fovea, separation of a small portion of the sensory retina from the  RPE in the foveolar region and intraretinal cystic changes; (C) eccentric stage 2 - small FTMH with vitreomacular traction  (VMT) - shows attachment of the vitreous to the lid of the hole and cystic change; (D) stage 3 - medium or large FTMH  with VMT - with intraretinal cystic spaces; (E) stage 4 - large FTMH with no VMT - shows a full-thickness macular hole  with intraretinal cystic spaces and an overlying operculum (sometimes termed a pseudo-operculum); (F) stage 4 after  surgical closure, showing outer retinal disturbance (ELM = external limiting membrane; GCL = ganglion cell layer; INL =  inner nuclear layer; IPL = inner plexiform layer; IS/OS = photoreceptor inner-segment/outer-segment junction; NFL = nerve  fibre layer; ONL = outer nuclear layer; OPL = outer plexiform layer; RPE = retinal pigment epithelium)    retinal - often inner-segment/outer-segment junction  - or other subfoveolar defect may persist after  spontaneous or surgical closure (Fig. 14.54F and see  Fig. 14.56D); solar retinopathy commonly gives a similar  appearance, as does scarring from several other  conditions where the foveal centre is a focus of  damage.   • Amsler grid testing will usually show non-specific central  distortion rather than a scotoma.   • The Watzke-Allen test is performed by projecting a narrow  slit beam over the centre of the hole vertically and  horizontally, preferably using a fundus contact lens. A  patient with a macular hole will report that the beam is  thinned or broken. Patients with other pathology usually see  a distorted beam of uniform thickness.   • OCT is extremely useful in diagnosis and staging (see  Fig. 14.54).    • FAF shows a markedly hyperfluorescent foveolar spot in  stages 3 and 4, and punctate fluorescence in stage 2.   • FA in a full-thickness hole shows an early well-defined  window defect (Fig. 14.55A) due to xanthophyll displacement  and RPE atrophy. Late frames may show the surrounding  sub retinal fluid as a hyperfluorescent halo (Fig. 14.55B).   • Observation. About 50% of stage 1 holes resolve following  spontaneous vitreofoveolar separation, so these are managed  conservatively. About 10% of full-thickness holes also close  spontaneously, sometimes with marked visual improvement;  spontaneous resolution is more common with smaller  FTMH. Treatment is not usually given for spontaneously  healed holes, though vitrectomy with ERM peeling is  sometimes indicated.   • Pharmacological vitreolysis with ocriplasmin is a newer  treatment that may be suitable for small earlier-stage holes.   Fig. 14.55 FA of stage 4 macular hole. (A) Early-phase  window defect with early surrounding pooling;    • Surgery may be considered in stage 2 or greater holes and  for some lamellar holes. Superior results are usually achieved  in smaller lesions present for under 6 months, but  substantial visual improvement has been reported in  long-standing cases.   o Operative treatment consists of vitrectomy, together with  (i) peeling of the ILM facilitated by vital dye staining, (ii)  relief of vitreomacular traction by either induction of a  total PVD if not already present or removal of the  perifoveal vitreous, and (iii) gas tamponade; the need for  extended face-down positioning has been questioned,  o The hole is closed in up to ioo% of cases and visual  improvement occurs over the course of months in  80-90% of eyes, with a final visual acuity of 6/12 or better  in approximately 65%. Worsening of visual acuity occurs  in up to 10% of eyes. Mild residual abnormality on OCT  such as a defect in the inner-segment/outer-segment  junction or other disturbance adjacent to the RPE (see  Figs 14.54F and 14.56D) is common, and may also provide    a diagnostic indicator of a spontaneously healed macular  hole or microhole.   o Complications are essentially those of vitrectomy and the  adjunctive procedures.   Macular microhole refers to a small (<150 pm) full-thickness  foveal retinal defect that in the current classification of vitreoreti-  nal interface pathology (see below) is synonymous with a small  full-thickness macular hole. Symptoms are often minimal and  may consist of mild central blurring, metamorphopsia (distor¬  tion) or disturbed reading vision. Visual acuity is typically impaired  less than with a larger FTMH, and the abnormality may not be  noticed immediately. The full-thickness defect typically heals  within a few weeks, and by the time of initial examination only  a well-demarcated red spot (Fig. 14.56A) rather than a visibly  full-thickness defect may be present. OCT demonstrates the  defect, either full-thickness (Fig. 14.56B), or more commonly by  the time of presentation involving only the outer retinal layers  (Fig. 14.56C). A microhole (or healed larger macular hole - see  Fig. 14.54F) may be represented by only a tiny focal defect in the  inner-segment/outer-segment layer (Fig. 14.56D), a similar appear¬  ance to which can occur in other conditions such as solar  retinopathy.   Physiological PVD (see Ch. 16) usually proceeds gradually over an  extended period to encompass complete separation from the  macula and optic nerve head: complete PVD. If adhesion of the  gel persists at the central macula, an anomalous PVD is present  and can precede a range of macular conditions. An expert panel,  the International Vitreomacular Traction Study Group, recently  published a classification of vitreomacular interface disease based  principally on OCT appearance in order to unify previously dis¬  parate terminology.   • Vitreomacular adhesion (VMA) refers to residual  attachment of the vitreous within a 3 mm radius of the  central macula in the presence of perifoveal vitreous  separation; in most cases it constitutes a stage in a dynamic  process of PVD so may not incur pathological sequelae.  There is no distortion of the foveal contour or any  secondary retinal changes. Focal VMA involves an area of  attachment of <1500 pm diameter, broad VMA >1500 pm.   • Vitreomacular traction (VMT) is defined as the presence of  retinal changes on OCT with evident perifoveal (within   3 mm) PVD. Distortion of the foveal surface contour and/or  other structural retinal changes may be present (Figs 14.57A  and B). Focal (Fig. 14.57C) and broad types are defined as for  VMA. Concurrent VMT is associated with other macular  disease, e.g. AMD, RVO, DR. Isolated VMT is unassociated  with other macular disease.   Fig. 14.56 Macular microhole (small full-thickness macular hole). (A) Small red foveal lesion; (B) full-thickness sensory retinal  defect on OCT; (C) OCT showing outer retinal defect - a full-thickness defect was documented 3 weeks earlier in this eye,  and a small operculum can be seen; (D) tiny focal inner/outer segment junction deficit   (Courtesy of M Lai, S Bressler, J Haller ; from American Journal of Ophthalmology, 141:210-12 - fig. C)    • Full-thickness macular hole (FTMH). A foveal lesion  featuring interruption of all retinal layers from the internal  limiting membrane to the RPE (see above). FTMH can be  small (<250 pm), medium (>250 to <400 pm) or large  (>400 pm). Other considerations include (i) the status of the  vitreous (with or without VMT) and (ii) the presence of an  identifiable cause such as trauma.   • Lamellar macular hole. This is a partial-thickness defect of  the inner retina at the fovea but maintenance of an intact  photoreceptor layer. Its pathogenesis is incompletely defined,  but may develop from anomalous PVD, sometimes  following a foveal pseudocyst, or represent abortive FTMH  formation in some patients. Classically, lamellar hole was  described as a sequel to CMO.   • Macular pseudohole. This lesion mimics the clinical  appearance of a FTMH, but is caused by distortion of the  perifoveal retina into heaped edges by ERM, without any  loss of retinal tissue, and near-normal foveal thickness; there  is a central defect in the membrane. VMT may be present.    • Epiretinal membrane (ERM). ERM is independent of the  IVTS classification, but a majority of eyes with broad VTS  have an associated ERM. Vitreous remnants on the retinal  surface following PVD provide a mechanism for the  development of idiopathic ERM.   • Symptoms in VMT include decreased vision,  metamorphopsia, photopsia and micropsia, but are usually  milder in lamellar holes and pseudoholes, and absent in VMA.   • Signs in VMT may include retinal surface thickening,  wrinkling and distortion (Fig. 14.57D), foveal pseudocyst,  CMO, macular schisis or detachment, and capillary leakage;  the limit of the attached gel may be visible as a whitish band  or reflex. Visible changes may be subtle. Both lamellar holes  and pseudoholes can appear as a discrete reddish oval or  round foveal spot.   Fig. 14.57 Vitreomacular traction (VMT). (A) and (B) show an  OCT of the same eye, in which the foveal contour is  flattened and the foveal surface slightly elevated above the  surrounding retina; (C) OCT of focal VMT; (D) VMT with  retinal surface thickening and wrinkling and an associated  epiretinal membrane - the area of vitreous attachment is  demarcated by a whitish line that extends around the optic  disc as well as the macula   • Observation. Spontaneous separation occurs in a proportion  of patients with VMT, and is probably more likely in  milder cases; published figures vary. Observation is  appropriate in patients with VMA and in many cases   • Pharmacological vitreolysis. Intravitreal injection of  ocriplasmin, a recombinant form of human plasmin, releases  VMT in over 25% of eyes, and may close macular holes  where VMT is present (40% versus 10% with placebo).  Results are generally inferior to vitrectomy. Smaller areas of  VMT and smaller macular holes have better outcomes; the  presence of ERM is a poorer prognostic indicator for  ocriplasmin treatment. Diffuse retinal dysfunction of  uncertain mechanism, including substantially decreased  acuity, has been reported as a rare side effect.   • Pars plana vitrectomy with peeling of the adherent area and  any associated ERM usually gives good results in VMT. The  benefit of vitrectomy for lamellar and pseudoholes is less  clear-cut, but is probably greater if significant ERM is  present.   Central serous chorioretinopathy (CSR) is an idiopathic disorder  characterized by a localized serous detachment of the sensory  retina at the macula secondary to leakage from the choriocapillaris  through one or more hyperpermeable RPE sites. CSR typically  affects one eye of a young or middle-aged Caucasian man; women  with CSR tend to be older. Imperfectly defined risk factors include  steroid administration (including intravitreal), Cushing syn¬  drome, Helicobacter pylori infection, pregnancy, psychological  stress and sleep apnoea syndrome.   o VA is typically 6/9-6/18, but may improve with a weak  convex lens due to acquired hypermetropia from retinal  elevation.   o Round or oval detachment of the sensory retina at the  macula (Fig. 14.58 A).   o The subretinal fluid may be clear (particularly in early  lesions) or turbid; precipitates may be present on the  posterior retinal surface (see Fig. 14.60 A),  o One or more depigmented RPE foci (often small PEDs)  of variable size may be visible within the neurosensory  detachment; small patches of RPE atrophy (Fig. 14.58B)  and hyperplasia elsewhere in the posterior pole may   Fig. 14.58 Central serous chorioretinopathy (CSR). (A) Serous retinal and underlying pigment epithelial detachment; (B) small  patches of pigmentary abnormality in a patient with resolving foveal CSR; (C) FAF of the same eye as (B) showing scarring  from additional subclinical lesions; (D) chronic lesions, the inferior with a gravitational tract; (E) same eye as (C) on  wide-field autofluorescence imaging; (F) OCT of the eye in (A) shows separation of the sensory retina from the retinal  pigment epithelium and a smaller underlying pigment epithelial detachment    indicate the site of previous lesions, and are typically seen  easily on FAF imaging (Fig. 14.58C).  o Chronic lesions may be associated with substantial  underlying atrophic change (Fig. 14.58D); fluid can  sometimes track downwards in a gravity-dependent  fashion (gravitational tract), best shown on FAF imaging  (Fig. 14.58E), and can occasionally progress to bullous  CSR (see below).   congenital pit as the cause of a neurosensory detachment  (see Ch. 19).   O Spontaneous resolution within 3-6 months, with return  to near-normal or normal vision, occurs in around 80%;  recurrence is seen in up to 50%.  o A substantial minority follow a chronic course lasting  more than 12 months. Prolonged detachment is  associated with gradual photoreceptor and RPE   Fig. 14.59 FA of central serous chorioretinopathy. (A) and (B) ‘    degeneration and permanently reduced vision; multiple  recurrent attacks may also give a similar clinical picture,  o CMO, CNV or RPE tears develop in a small minority.   • Bullous CSR is characterized by large single or multiple  serous retinal and RPE detachments.   Other findings may include one or more smaller RPE  detachments (Fig. 14.58F), precipitates on the posterior  surface of detached retina, and thickened choroid.  Degenerative changes may be seen in chronic or recurrent  cases.   commonly, forms a vertical column (‘smokestack’ - Figs  14.59C and D) followed by diffusion throughout the  detached area. An underlying PED may be demonstrated.  Multiple focal leaks or diffuse areas of leakage can be  evident, particularly in chronic or recurrent disease.   • FAF shows a focal decrease in fundus autofluorescence at  the leakage site, and at sites of old lesions (see Figs 14.58C  and E). A gravitational tract is sometimes seen.   • ICGA. The early phase may show dilated or compromised  choroidal vessels at the posterior pole, and the mid-stage  areas of hyperfluorescence due to choroidal  hyperpermeability. Subclinical foci are commonly visible.   • Observation is appropriate in many cases. All treatment  modalities can be associated with RPE tear formation; this  can also occur spontaneously.   • Corticosteroid treatment should be discontinued if possible,  particularly in chronic, recurrent or severe cases.   • Laser. Micropulse diode laser to the RPE site of leakage has  shown good results (Figs 14.60A and B) in several studies,  and is associated with significantly less retinal damage on  OCT than conventional photocoagulation.   • PDT at 30-50% of the dose used for CNV in conjunction  with 50% light intensity typically leads to complete  resolution, including in severe chronic cases, and is  associated with a considerably lower incidence of significant  choroidal ischaemia than higher-intensity regimens.   • Intravitreal anti-VEGF agents show some promise and may  be used in conjunction with other treatments.   • Others. Case reports show benefit with a variety of agents  including aspirin, beta-blockers, mifepristone and  eplerenone, but controlled assessment is limited to date.   Fig. 14.60 Micropulse laser treatment of central serous  chorioretinopathy. (A) Prior to treatment; (B) after successful  treatment    Idiopathic macular telangiectasia (IMT, MacTel) is a condition of  unknown pathogenesis. It may be more common than previously  believed and can be confused with DR, prior RVO and other  causes of macular vascular changes. A family history is present in  a small proportion of cases.   This may be closely related to Coats disease, or more specifically  the milder form of Coats previously known as Leber miliary aneu¬  rysms; it generally involves only one eye, and both the peripheral  retina and macula can be affected. Patients are typically middle-  aged males.   • Symptoms. Mild to moderate blurring of vision in one eye.   o Telangiectasia and microaneurysms; early signs may be  subtle and more readily detected on red-free photography  (Fig. 14.61A).   o Larger aneurysms form as the condition progresses,  o Macular oedema, including cystoid changes,  o Chronic leakage and lipid deposition (Fig. 14.61B).   • OCT demonstrates retinal thickening, CMO and localized  exudative retinal detachment.   • FA shows telangiectasia and multiple capillary, venular and  arteriolar aneurysms (Figs 14.61C and D) with late leakage  and CMO (Fig. 14.61E). There is minimal non-perfusion.   • Treatment is with laser to points and areas of leakage, but  can be technically difficult depending on the proximity of  changes to the foveola. Intravitreal VEGF inhibitors may be  effective.   This bilateral form is more common than type 1, and usually has  a worse visual prognosis. Males and females are equally affected;  onset is in middle age. In contrast to type 1, findings are generally  limited to the perifoveal area. Degeneration of Muller cells is  thought to be an important pathogenic mechanism.   • Symptoms. Blurring in one or both eyes. Distortion may be  a feature.   o Greyish loss of parafoveol retinal transparency extending  up to one disc diameter from the foveola, initially  temporal to (Fig. 14.62A) and later surrounding the  fovea.   o Parafoveal telangiectasia may not be visible clinically but  can often be demonstrated more readily by red-free  photography. Right-angled venules (Fig. 14.62C) are  characteristic. The abnormal vessels can proliferate to  subretinal neovascularization distinct from CNV but  similar to retinal angiomatous proliferation - the  proliferative stage of the condition.   Fig. 14.61 Idiopathic macular telangiectasia type 1 - aneurysmal telangiectasia. (A) Early disease - red-free image;   (B) aneurysms and telangiectasis surrounded by a ring of exudate; (C) FA of eye in (A) showing microaneurysms; (D) FA  early phase of the eye in (B) shows telangiectasis temporal to the fovea; (E) FA late phase of eye in (B) and (D) showing  leakage   Fig. 14.62 Idiopathic macular telangiectasia type 2 - perifoveal. (A) Loss of temporal parafoveal transparency; (B) macular  crystals and early telangiectasis; (C) telangiectasis with small parafoveal right-angled venules; (D) pigment plaques;   (E) pseudocystic perifoveal spaces on OCT; (F) inner lamellar subfoveal cyst    o Foveal atrophy may simulate a lamellar hole,  o Small RPE plaques (Fig. 14.62D) develop in many  patients, often associated with the right-angled venules,  o Aneurysms are uncommon but have been reported; lipid  deposition does not tend to be a feature,  o Visual acuity generally does not deteriorate to less  than 6/60 unless CNV supervenes, although CNV in    this condition tends to carry a better prognosis than  in AMD.   • OCT findings are a key aid to diagnosis. The formation of  hyporeflective inner retinal spaces of variable size (Fig.  14.62E), morphologically distinct from those seen in CMO,  is characteristic in moderate though not early disease; an  inner lamellar cyst that enlarges with progressive disease is    commonly seen underlying the fovea (Fig. 14.62F). Thinning  and disruption of the photoreceptor layers is also very  common, and may occur early. Pigment clumps are shown  as intraretinal hyper-reflective plaques with posterior  shadowing. Foveal thinning is common, but diffuse  parafoveal retinal thickening is variably present. Hyper-  reflective inner retinal dots corresponding to telangiectatic  vessels are seen early on in many patients.   • FAF changes occur early in the disease course, and may  precede clinically detectable signs. Central foveal  hyperautofluorescence is a common early finding; this  gradually increases in extent but in more advanced disease  an area of well-demarcated central hypoautofluorescence  develops. Retinal crystals and pigment clumping give  hypoautofluorescence. Irregular central and peripheral areas  of increased signal surrounding patches of decreased signal  may be seen.   • FA in early disease shows bilateral perifoveal telangiectasia  with early leakage from the abnormal vessels progressing to  diffuse leakage, though without CMO. The cystoid spaces  identifiable on OCT do not hyperfluoresce on FA. FA is also  used to confirm CNV.   • Macular pigment optical density (MPOD) imaging shows a  possibly pathognomonic pattern of oval reduction in density  corresponding to the late distribution of hyperfluorescence  on FA. MPOD is preserved from 6° outwards.   • Treatment. Intravitreal anti-VEGF agents decrease leakage  on FA in the non-proliferative stage but are probably not  helpful visually. They are likely to be useful in the  proliferative stage, especially for CNV.   This extremely rare condition presents in late middle age and  carries a poor visual prognosis. The manifestations relate to capil¬  lary occlusion rather than telangiectasia: progressive occlusion of  parafoveal capillaries with marked aneurysmal dilatation of termi¬  nal capillaries.   Cystoid macular oedema (CMO) results from the accumulation  of fluid in the outer plexiform and inner nuclear layers of the  retina with the formation of tiny cyst-like cavities (Fig. 14.63).  Fluid may initially accumulate intracellularly in Muller cells, with  subsequent rupture. Coalescence of smaller cavities may occur  over time with subsequent progression to a foveal lamellar hole  with irreversible impairment of central vision. CMO is a non¬  specific manifestation of any type of macular oedema. Causes  include:   • Ocular surgery and laser, e.g. phacoemulsification,  panretinal photocoagulation and miscellaneous other  procedures.   Fig 14.63 Histology of cystoid macular oedema shows cystic  spaces in the outer plexiform and inner nuclear layer   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology,  Butterworth-Heinemann 2001)   • Inflammation, e.g. intermediate uveitis, severe or chronic  uveitis of any kind.   o Loss of the foveal depression, thickening of the retina and  multiple cystoid areas in the sensory retina (Fig. 14.64A),  best seen with red-free light using a fundus contact lens  (Fig. 14.64B).   o Optic disc swelling is sometimes present,  o A lamellar hole may be visible,  o Features of associated disease.   • FA. A petaloid pattern is seen due to dye accumulation  in microcystic spaces in the outer plexiform layer  (Fig. 14.64C).   • OCT shows retinal thickening with cystic hyporeflective  spaces, and loss of the foveal depression (Fig. 14.64D). A  lamellar hole may be demonstrated in advanced cases.    Microcystic changes of the inner nuclear layer distinct from classic  CMO can occur in eyes with optic neuritis and some other forms  of optic neuropathy. It is believed to be caused by retrograde  degeneration of the inner retinal layers that manifests with  impaired fluid resorption.   Fig. 14.64 (A) Cystoid macular oedema; (B) red-free image; (C) FA late phase shows a ‘flower petal’ pattern of  hyperfluorescence; (D) OCT shows hyporeflective spaces within the retina, macular thickening and loss of the foveal  depression   (Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 - fig. A; P Gili - fig. B; S Chen - fig. C)   Myopia is the result of complex hereditary and environmental  factors; there is strong evidence for a causative association with  long-term intensive near visual activity, particularly reading. A  refractive error of more than -6 dioptres constitutes a common  definition of high myopia, in which axial length is usually greater  than 26 mm; it affects over 2% of an adult Western European or  American population and may be as high as io% in East Asians.  Pathological or degenerative myopia is characterized by progres¬  sive anteroposterior elongation of the scleral envelope associated  with a range of secondary ocular changes, principally thought to  relate to mechanical stretching of the involved tissues. It is a    significant cause of legal blindness, with maculopathy the most  common cause of visual loss. Various techniques such as scleral  buckling and patching have been used to try to stem the progres¬  sion of myopia or reinforce extremely thinned areas, but remain  controversial. Table 14.5 lists systemic associations of myopia.   Down syndrome  Stickler syndrome  Marfan syndrome  Prematurity  Noonan syndrome  Ehlers-Danlos syndrome  Pierre-Robin syndrome   • A pale tessellated (tigroid) appearance is due to diffuse  attenuation of the RPE with visibility of large choroidal  vessels (Fig. 14.65A).    • Focal chorioretinal atrophy is characterized by patchy  visibility of choroidal vessels, and often sclera (Fig. 14.65B).   • Anomalous optic nerve head. This may appear unusually  small, large or anomalous with a ‘tilted’ conformation (Fig.  14.65C). Peripapillary chorioretinal atrophy is very common,    Fig. 14.65 High myopia. (A) Tessellated fundus; (B) focal chorioretinal atrophy and tilted disc; (C) tilted disc; (D) lacquer  cracks; (E) ‘coin’ haemorrhage; (F) Fuchs spot    most commonly as a temporal crescent of thinned or absent  RPE.   • Acquired optic disc pit formation is not uncommon, and is  thought to be due to expansion of the peripapillary region as  the eye enlarges over time.   • Lacquer cracks are ruptures in the RPE-Bruch membrane-  choriocapillaris complex characterized by fine irregular  yellow lines criss-crossing at the posterior pole (Fig. 14.65D)  in around 5% of highly myopic eyes and can be complicated  by CNV.   • A Fuchs spot (Fig. 14.65F) is a raised, circular, pigmented  lesion at the macula developing after a subretinal  haemorrhage has absorbed.    • A staphyloma is a peripapillary or macular ectasia of the  posterior sclera (Figs 14.66A and B) due to focal thinning  and expansion present in about a third of eyes with  pathological myopia. Associations include macular hole  formation and ‘dome-shaped macula’, an overlying anterior  bulge typically involving the retina, RPE and inner choroid  best shown on OCT (Fig. 14.66C); it may be complicated by  a foveal detachment.   • (Peripapillary) intrachoroidal cavitation, formerly  described as peripapillary detachment of pathological  myopia (PDPM), may occur adjacent to the nerve,  commonly inferiorly. Clinically, it may be evident as a small  yellowish-orange peripapillary area typically inferior to the  disc (Fig. 14.66D); it can generally be identified on OCT  (Figs 14.66E and F). Visual field defects are common and  frequently mimic glaucoma.    Fig. 14.66 High myopia. (A) axial CT shows a left posterior staphyloma; (B) staphyloma on OCT; (C) dome-shaped macula;  (D) intrachoroidal cavitation (ICC) - orange peripapillary area inferior to the disc;   Fig. 14.66, Continued (E) OCT appearance of ICC; (F) central line indicates the plane of the image in (E); (G) shallow retinal  detachment confined to the posterior pole, caused by a myopia-related macular hole   (Courtesy of S Chen - figs B-F; M Khairallah - fig. G)    • Rhegmatogenous retinal detachment (RD) is much more  common in high myopia, the pathogenesis including  increased frequency of PVD, lattice degeneration,  asymptomatic atrophic holes, myopic macular holes (see  below) and occasionally giant retinal tears.   o 10% of highly myopic eyes develop CNV.  o The prognosis is better in younger patients with myopia-  related CNV than in AMD.   o Anti-VEGF therapy is generally the treatment of choice; a  lower injection frequency may be needed than for AMD  but RD risk is higher.   • Macular retinoschisis (foveoschisis) and macular retinal  detachment without macular hole formation may occur in  highly myopic eyes with posterior staphyloma, probably as a  result of vitreous traction. Some cases are associated with  intrachoroidal cavitation (see above). Retinoschisis maybe  mistaken clinically for CMO, and is better characterized by  OCT than biomicroscopy.    • Macular hole may occur spontaneously or after relatively  mild trauma, and is associated with the development of  rhegmatogenous retinal detachment much more commonly  than age-related idiopathic macular hole (Fig. 14.66G).  Myopic macular retinoschisis and myopic macular hole may  be part of the same pathological process. Vitrectomy may be  effective for both, but the best surgical technique remains  undefined.   • Peripapillary detachment is an innocuous yellow-orange  elevation of the RPE and sensory retina at the inferior  border of the myopic conus (anomalous optic nerve head  complex).   • Glaucoma. There is an increased prevalence of primary  open-angle glaucoma, pigmentary glaucoma and steroid  responsiveness.   • Amblyopia is uncommon but may develop when there is a  significant difference in myopia between the two eyes.   • Dislocation of the lens (natural or artificial) is a rare but  well-recognized risk.   • Pseudoxanthoma elasticum (PXE), a hereditary disorder of  connective tissue in which there is progressive calcification,  fragmentation and degeneration of elastic fibres in the skin,  eye and cardiovascular system, is by far the most common  association of angioid streaks (Gronblad-Strandberg  syndrome). Patients develop a ‘plucked chicken’ appearance  of the skin, most commonly on the neck, axillae and  antecubital fossae. Approximately 85% of patients develop  ocular involvement of variable severity, usually after the  second decade of life.   • Ehlers-Danlos syndrome is a rare, usually autosomal  dominant, disorder of collagen. There are 11 subtypes but  only type 6 (ocular sclerotic) is associated with ocular  features.   • Paget disease is a chronic, progressive metabolic bone  disease characterized by excessive and disorganized  resorption and formation of bone. Angioid streaks occur  in only about 2%; it is thought that calcium binds to the  elastin of Bruch membrane, imparting brittleness and  fragility.   • Haemoglobinopathies occasionally associated with angioid  streaks are numerous, including sickle-cell trait and disease  and thalassaemias; in these the brittle Bruch membrane is  thought to be due to iron deposition.   o Grey or dark red linear lesions with irregular serrated  edges that intercommunicate in a ring-like fashion  around the optic disc and radiate outwards from the  peripapillary area (Fig. 14.67A). The streaks tend to  increase in width and extent slowly over time,  o ‘Peau d’orange’ (orange skin), also known as leopard  skin, mottled yellowish speckling (Figs 14.67B and C) is  common, particularly in cases associated with PXE.  o Optic disc drusen are frequently (up to 25%) associated  (Fig. 14.67D).   o Scleral depression is relatively contraindicated in these  eyes, due to the risk of further damage to the Bruch  membrane leading to new angioid streaks or choroidal  rupture.    • Complications. Though angioid streaks are typically  asymptomatic at first, visual impairment occurs eventually  in over 70% of patients.   o CNV is by far the most common cause of visual loss,  o Choroidal rupture may occur following relatively trivial  trauma (Fig. 14.67E).  o Foveal involvement by a streak.   • FA shows hyperfluorescent window defects due to RPE  atrophy overlying the streaks, associated with variable  associated hypofluorescence corresponding to RPE  hyperplasia. FA is generally indicated only if CNV is  suspected.   • FAF. Streaks are autofluorescent; they are often more  extensive than clinically, which may confirm the diagnosis in  subtle cases (Fig. 14.67F); peau d’orange is shown.   Following systemic investigation where appropriate, usually via  referral to an appropriate physician, observation is the approach  in most cases. Patients should be warned against participating in  contact sports and advised to use protective spectacles when neces¬  sary. CNV should usually be treated with intravitreal anti-VEGF  agents, but commonly recurs or develops at a new site.   Choroidal folds are parallel grooves or striae involving the inner  choroid, Bruch membrane, the RPE and sometimes the retina  (chorioretinal folds). They are likely to develop in association with  any process that induces sufficient compressive stress within the  choroid, Bruch membrane and retina. Primary mechanisms  include choroidal congestion and scleral compression, and occa¬  sionally tissue contraction. Choroidal folds should be distin¬  guished from retinal folds, which have a different pathogenesis  (usually ERM). Causes include:   • Idiopathic (‘congenital’) folds may be present in healthy,  often hypermetropic, individuals in whom visual acuity is  typically unaffected. The folds are usually bilateral. A  syndrome of idiopathic acquired hypermetropia with  choroidal folds has been described - in these patients  elevated intracranial pressure should always be excluded  even without evident papilloedema (see next) although a  constricted scleral canal causing optic disc congestion has  been proposed as an alternative mechanism in some patients.   • Papilloedema. Choroidal folds may occur in patients with  chronically elevated intracranial pressure, when they may be  associated with reduction of visual acuity that may be  permanent.   • Orbital disease such as retrobulbar tumours and thyroid  ophthalmopathy may cause choroidal folds associated with  impaired vision.    Fig. 14.67 Angioid streaks. (A) Advanced angioid streaks; (B) subtle angioid streaks around the optic disc, with ‘peau  d’orange’ at the temporal macula; (C) angioid streaks with more marked peau d’orange; (D) angioid streaks and optic disc  drusen; (E) subretinal haemorrhage caused by a traumatic choroidal rupture; (F) FAF imaging of the eye in (B), showing  more extensive changes than evident clinically, including demonstration of the peau d’orange   (Courtesy of P Saine - fig. A; S Chen - figs C-E)    • Ocular disease such as choroidal tumours, inflammation  such as posterior scleritis, scleral buckling for retinal  detachment, and hypotony.   • Symptoms. The effect on vision is variable and dependent  on the cause; many patients are asymptomatic.   o Parallel lines, grooves or striae typically located at the  posterior pole. The folds are usually horizontally  orientated (Fig. 14.68A).   Fig. 14.68 Choroidal folds (A) Wide-field photograph; (B) OCT  appearance; (C) FAF    o The crest (elevated portion) of a fold is yellow and less  pigmented as a result of stretching and thinning of the RPE  and the trough is darker due to compression of the RPE.  o Clinical examination should be directed towards the  exclusion of optic disc swelling, as well as other ocular or  orbital pathology.   • OCT allows differentiation between choroidal, chorioretinal  and retinal folds (Fig. 14.68B).   • FAF effectively demonstrates the folds (Fig. 14.68C) and may  show associated atrophy; if this is marked the appearance  can be mistaken for angioid streaks.   • FA shows hyperfluorescent crests as a result of increased  background choroidal fluorescence showing through the  stretched and thinned RPE and hypofluorescent troughs due  to blockage of choroidal fluorescence by the compressed and  thickened RPE.   • Supplementary imaging. Ultrasound, computed  tomography (CT) or magnetic resonance (MR) scanning of  the orbits or brain may be indicated. In elevated intracranial  pressure or acquired hypermetropia with choroidal folds, an  enlarged perineural space may be noted on B-scanning and  MR of the optic nerves.   Maculopathy is common in eyes developing hypotony, defined as  IOP less than 5 mmHg. The most common cause is excessive  drainage following glaucoma filtration surgery, for which adjunc¬  tive antimetabolites confer a higher risk; other causes include  trauma (cyclodialysis cleft, penetrating injury), chronic uveitis (by  directly impairing ciliary body function and by tractional ciliary  body detachment due to cyclitic membrane) and retinal detach¬  ment. Systemic causes of hypotony (usually bilateral) include  dehydration, hyperglycaemia in uncontrolled diabetes, uraemia  and treatment with hyperosmotic agents or carbonic anhydrase  inhibitors. The development of secondary choroidal effusion may  act to perpetuate the hypotony. With time the hypotonous process  can itself lead to further damage, including sclerosis and atrophy  of ciliary processes. Prolonged severe hypotony may lead to  phthisis bulbi and loss of the eye. Treatment to restore normal  IOP is directed according to cause.   • VA is variably affected; delayed normalization of IOP may  result in permanent visual impairment, though substantial  improvement has been reported following reversal of  hypotony after several years.   • Fine retinal folds radiating outwards from the foveola,  which may also show CMO (Fig. 14.69).   • Chorioretinal folds may radiate outwards in branching  fashion from the optic disc; these are due to scleral collapse  with resultant chorioretinal redundancy.    Fig. 14.69 Hypotony maculopathy showing cystoid macular  oedema and retinal folds    • Miscellaneous. A variety of other features may be present,  related both to aetiology and secondary effects of hypotony,  including a shallow anterior chamber, choroidal effusion,  cataract, corneal decompensation, optic disc oedema, uveitis,  wound leak or an unexpected filtering bleb adjacent to a  wound (e.g. following cataract surgery), cyclodialysis cleft on  gonioscopy, and retinal detachment.   • Ultrasound biomicroscopy may show a cyclitic membrane  or cyclodialysis cleft if there is clinical reason to suspect this.    • Pathogenesis. Retinal injury results from photochemical  effects of solar radiation after directly or indirectly viewing  the sun (eclipse retinopathy).   • Presentation is within a few hours of exposure with  impairment of central vision and a small central scotoma.   o VA is variable according to severity,  o A small yellow or red foveolar spot (Fig. 14.70A) that  fades within a few weeks.   o The spot evolves to a sharply defined foveolar defect with  irregular borders (Fig. 14.70B), or a lamellar hole.   • OCT shows foveal thinning with a focal hyporeflective area,  the depth of which correlates with the extent of visual acuity  loss but which generally includes the photoreceptor inner  and outer segments (see Fig. 14.56C for similar appearance).   • Prognosis is good in most cases with improvement of visual  acuity to normal or near-normal levels within 6 months; in a  minority, significantly reduced vision persists.    Focal choroidal excavation (FCE) is a recently described relatively  common condition in which one or more areas of macular choroi¬  dal excavation are detected in one or both eyes of a patient,  typically middle-aged and possibly more commonly Eastern   Fig. 14.70 Solar maculopathy. (A) Yellow foveolar spot; (B) foveolar defect   Fig. 14.71 Focal choroidal excavation. (A) OCT of conforming type; (B) OCT of nonconforming type   (Courtesy of J Chen and R Gupta, from Canadian Journal of Ophthalmology, 2012; 47: e56-8)    Asian, without a history of ocular disease known to produce  choroidal thinning. Vision is variably affected, and may be com¬  promised by complications such as CNV, CSR and PCV. Over-  lying pigment epithelial disturbance or small yellowish-white  deposits, sometimes vitelliform, are often seen clinically. On    OCT, in ‘conforming’ FCE the overlying RPE and inner-segment/  outer-segment junction follow the outwards indentation of the  excavation (Fig. 14.71A); in contrast, in ‘nonconforming’ FCE the  photoreceptor layers are disrupted and appear to be separated  from the RPE (Fig. 14.71B).   INVESTIGATION 642  Electroretinography 642  Electro-oculography 644  Dark adaptometry 644  Colour vision testing 645   Retinitis pigmentosa 646  Atypical retinitis pigmentosa 650  Cone dystrophy 652  Stargardt disease/fundus  flavimaculatus 654  Bietti crystalline corneoretinal  dystrophy 654  Alport syndrome 658  Familial benign fleck retina 658  Congenital stationary night  blindness 658  Congenital monochromatism  (achromatopsia) 660   Best vitelliform macular dystrophy 660  Multifocal vitelliform lesions without Best  disease 661   North Carolina macular dystrophy 663  Familial dominant drusen 664  Sorsby pseudoinflammatory  dystrophy 664  Concentric annular macular  dystrophy 664   Central areolar choroidal dystrophy 664  Dominant cystoid macular oedema 665  Sjogren-Larsson syndrome 665  Familial internal limiting membrane  dystrophy 666   VITREORETINOPATHIES 669  Juvenile X-linked retinoschisis 669  Stickler syndrome 672  Wagner syndrome 673  Familial exudative vitreoretinopathy 674    Enhanced S-cone syndrome and  Goldmann-Favre syndrome 674  Snowflake vitreoretinal  degeneration 675  Autosomal dominant neovascular  inflammatory vitreoretinopathy 677  Autosomal dominant  vitreoretinochoroidopathy 677  Kniest dysplasia 678   The hereditary fundus dystrophies are a group of disorders that com¬  monly exert their major effect on the retinal pigment epithelium  (RPE)-photoreceptor complex and the choriocapillaris to cause a  range of visual impairment; the most common group of dystrophies  is retinitis pigmentosa. Some dystrophies manifest in early child¬  hood, others do not present until later in life. Isolated dystrophies  have features confined to the eye, whilst syndromic dystrophies are  part of a wider disease process that also affects tissues elsewhere in  the body. Treatments such as gene therapy are being actively inves¬  tigated, but are unlikely to be available imminently.   • The rods are the most numerous (120 million) and are of  the densest concentration in the mid-peripheral retina. They  are most sensitive in dim illumination and are responsible  for night, motion sense and peripheral vision. If rod  dysfunction occurs earlier or is more severe than cone  dysfunction, it will result in poor night vision (nyctalopia)  and peripheral field loss, the former usually occurring first.   • The cones are far fewer in number (6 million) and are  concentrated at the fovea. They are most sensitive in bright  light, and mediate day vision, colour vision, central and fine  vision. Cone dysfunction therefore results in poor central  vision, impairment of colour vision (dyschromatopsia) and  occasionally problems with day vision (hemeralopia).   Most dystrophies are inherited, but sometimes a new mutation  (allelic variant) can occur in an individual, and can subsequently  be passed to future generations.   • Autosomal dominant (AD) dystrophies often exhibit  variable expressivity, and tend to have a later onset and  milder course than recessive disorders.   • Recessive dystrophies may be autosomal (AR) or X-linked  (XLR). They generally have an earlier onset and a more  severe course than AD conditions. In some cases female  carriers of XLR conditions show characteristic fundus  findings.   • X-linked dominant (XLD) conditions are very rare; they are  typically lethal in boys (e.g. Aicardi syndrome).   • Mitochondrial DNA is inherited solely via the maternal line;  retinal dystrophies associated with mitochondrial DNA  variants are extremely rare and occur as part of a wider  systemic disease. A maternal carrier will usually possess a  mixture of mitochondria, only some of which contain the  dysfunctional gene, and the presence and severity of a  resultant dystrophy in offspring depends on the proportion  of faulty mitochondria inherited.   • Digenic conditions are due to the combined effect of  mutations in two different genes.   As well as division by inheritance pattern, dystrophies can be  considered as generalized, in which the clinical effects involve the  entire fundus (rod-cone or cone-rod, depending on which pho¬  toreceptor type is predominantly dysfunctional), or central (local,  macular) in which only the macula is affected. They can also be  classified according to the element that is the focus of the patho¬  logical process (e.g. photoreceptors, RPE or choroid), and by  whether they are stationary (non-progressive) or progressive.   The electroretinogram (ERG) measures retinal electrical activity;  when stimulated by light of adequate intensity, ionic flow - prin¬  cipally sodium and potassium - is induced in or out of cells such  that a potential is generated. The recording is made between an  active electrode either in contact with the cornea or a skin elec¬  trode placed just below the lower eyelid margin, and a reference  electrode on the forehead. The potential between the two elec¬  trodes is then amplified and displayed (Fig. 15.1). The normal ERG  is predominantly biphasic (Fig. 15.2):   • The a-wave is an initial fast corneal-negative deflection  generated by the photoreceptors.   • The b-wave is a subsequent slower positive large amplitude  deflection. Although it is generated from Muller and bipolar  cells, it is directly dependent on functional photoreceptors   o Rod responses are elicited with a very dim flash of white  or blue light, resulting in a large b-wave and a small or  non-recordable a-wave.   o Combined rod and cone responses are elicited with a very  bright white flash, resulting in a prominent a-wave and  b-wave.   o Oscillatory potentials are elicited by using a bright flash  and changing the recording parameters. The oscillatory  wavelets occur on the ascending limb of the b-wave and  are generated by cells in the inner retina.   o Cone responses are elicited with a single bright flash,  resulting in an a- and a b-wave with subsequent small  oscillations.   o Cone flicker is used to isolate cones by using a flickering  light stimulus at a frequency of 30 Hz to which rods  cannot respond. It provides a measure of the amplitude  and implicit time of the cone b-wave. Cone responses can  be elicited in normal eyes up to 50 Hz, after which point  individual responses are no longer recordable (‘critical  flicker fusion’).    and its magnitude makes it a convenient measure of  photoreceptor integrity. Its amplitude is measured from the  a-wave trough to the b-wave peak. It consists of b-i and b-2  subcomponents; the former probably represents both rod  and cone activity and the latter mainly cone activity, and it  is possible to distinguish rod and cone responses with  appropriate techniques. The b-wave is enhanced with dark  adaptation and increased light stimulus.   • The c-wave is a third (negative) deflection generated by the  RPE and photoreceptors.   • Latency is the interval to the commencement of the a-wave  after the stimulus is applied.   • Implicit time is the interval from the stimulus to the b-wave  peak.   Electroretinography is used for the diagnosis of a range of different  retinal disorders on the basis of characteristic patterns of change,  as well as monitoring of disease progress in dystrophies and other  conditions such as some forms of uveitis (e.g. birdshot retino-  choroidopathy) and drug toxicity (e.g. hydroxychloroquine).   A standard full-field ERG consists of five recordings (Fig. 15.3)  taken during diffuse stimulation of the entire retinal area, and is  used to assess generalized retinal disorders but may not detect  localized pathology. The first three are elicited after 30 minutes of  dark adaptation (scotopic), and the last two after 10 minutes of  adaptation to moderately bright diffuse illumination (photopic).  It may be difficult to dark-adapt children for 30 minutes and  therefore dim light (mesopic) conditions can be utilized to evoke  predominantly rod-mediated responses to low-intensity white or  blue light stimuli.    Multifocal ERG is a method of producing topographical maps of  retinal function (Fig. 15.4). The stimulus is scaled for variation  in photoreceptor density across the retina. At the fovea, where  the density of receptors is high, a lesser stimulus is employed  than in the periphery where receptor density is lower. As with    conventional ERG, many types of measurements can be made.  Both the amplitude and timing of the troughs and peaks can be  measured and reported and the information can be summarized  in the form of a three-dimensional plot which resembles the hill  of vision. The technique can be used for almost any disorder that  affects retinal function.   A similar stimulus to that used in visual evoked potentials (see Ch.  19), pattern reversal, is used to target ganglion cell function, typi¬  cally in order to detect subtle optic neuropathy.   The electro-oculogram (EOG) measures the standing potential  between the electrically positive cornea and the electrically nega¬  tive back of the eye (Fig. 15.5). It reflects the activity of the RPE  and the photoreceptors. This means that an eye blinded by disease  proximal to the photoreceptors will have a normal EOG. In  general, diffuse or widespread disease of the RPE is needed to  significantly affect the response. As there is much variation in EOG  amplitude in normal subjects, the result is calculated by dividing  the maximal height of the potential in the light (‘light peak’) by  the minimal height of the potential in the dark (‘dark trough’).  This is expressed as a ratio (Arden ratio) or as a percentage. The  normal value is greater than 1.85 or 185%.   Dark adaptation (DA) is the phenomenon by which the visual  system adapts to decreased illumination, and evaluation of this is  particularly useful in the investigation of nyctalopia. The retina is  exposed to an intense light for a time sufficient to bleach 25% or  more of the rhodopsin in the retina. Following this, normal rods  are insensitive to light and cones respond only to very bright  stimuli. Subsequent recovery of light sensitivity can be monitored  by placing the subject in the dark and periodically presenting spots  of light of varying intensity in the visual field and asking the    subject if they are perceived. The threshold at which the subject  just perceives a light is recorded, the flashes repeated at regular  intervals and the increased sensitivity of the eye to light plotted:  the sensitivity curve (Fig. 15.6).   • The cone branch of the curve represents the initial 5-10  minutes of darkness during which cone sensitivity rapidly  improves. The rod photoreceptors are also recovering, but  more slowly during this time.   • The ‘rod-cone’ break normally occurs after 7-10 minutes  when cones achieve their maximum sensitivity, and the rods  become perceptibly more sensitive than cones.   • The rod branch of the curve is slower and represents the  continuation of improvement of rod sensitivity. After 15-30    minutes, the fully dark-adapted rods allow the subject to  perceive a spot of light over 100 times dimmer than would  be possible with cones alone. If the flashes are focused onto  the foveola (where rods are absent), only a rapid segment  corresponding to cone adaptation is recorded.   Dyschromatopsia may develop in dystrophies prior to the impair¬  ment of other visual parameters; assessment of colour vision is also  useful in the evaluation of optic nerve disease and in determining  the presence of a congenitally anomalous colour defect. Colour  vision depends on three populations of retinal cones, each with a  specific peak sensitivity; blue (tritan) at 414-424 nm, green (deu-  teran) at 522-539 nm and red (protan) at 549-570 nm. Normal  colour perception requires all these primary colours to match  those within the spectrum. Any given cone pigment may be defi¬  cient (e.g. protanomaly - red weakness) or entirely absent (e.g.  protanopia - red blindness). Trichromats possess all three types  of cones (although not necessarily functioning perfectly), while  absence of one or two types of cones renders an individual a  dichromat or monochromat, respectively. Most individuals with  congenital colour defects are anomalous trichromats and use  abnormal proportions of the three primary colours to match those  in the light spectrum. Those with red-green deficiency caused by  abnormality of red-sensitive cones are protanomalous, those with  abnormality of green-sensitive cones are deuteranomalous and  those with blue-green deficiency caused by abnormality of blue-  sensitive cones are tritanomalous. Acquired macular disease tends  to produce blue-yellow defects, and optic nerve lesions red-green  defects.   • The Ishihara test is designed to screen for congenital protan  and deuteran defects, but is simple to use and widely  available and so in practice is frequently used to screen for  colour vision deficit of any type. It consists of a test plate  followed by 16 plates, each with a matrix of dots arranged to  show a central shape or number that the subject is asked to  identify (Fig. 15.7A). A colour-deficient person will only be  able to identify some of the figures. Inability to identify the  test plate (provided visual acuity is sufficient) indicates  non-organic visual loss.   • The Hardy-Rand-Rittler test is similar to the Ishihara,  but can detect all three congenital colour defects   • The City University test consists of 10 plates, each  containing a central colour and four peripheral colours (Fig.  15.7C) from which the subject is asked to choose the closest  match.   • The Farnsworth-Munsell 100-hue test is a sensitive but  longer test for both congenital and acquired colour defects.  Despite the name, it consists of 85 caps of different hues in   Fig. 15.7 Colour vision tests. (A) Ishihara; (B) Hardy-Rand-  Rittler; (C) City University; (D) Farnsworth-Munsell 100-hue  test   four racks (Fig. 15.7D); the subject is asked to rearrange  randomized caps in order of colour progression, and the  findings are recorded on a circular chart. Each of the three  forms of dichromatism is characterized by failure in a  specific meridian of the chart (Fig. 15.8).   Fig. 15.8 Farnsworth-Munsell test results of colour  deficiencies. (A) Protan; (B) deuteran; (C) tritan   Retinitis pigmentosa (RP), or pigmentary retinal dystrophy,  denotes a clinically and genetically diverse group of inherited  diffuse retinal degenerative diseases initially predominantly affect¬  ing the rod photoreceptors, with later degeneration of cones (rod-  cone dystrophy). It is the most common hereditary fundus  dystrophy, with a prevalence of approximately 1:5000. The age of  onset, rate of progression, eventual visual loss and associated  ocular features are frequently related to the mode of inheritance;  RP may occur as a sporadic (simplex) disorder, or be inherited  in an AD, AR or XLR pattern. Many cases are due to allelic  variation (mutation) of the rhodopsin gene. XLR is the least  common but most severe form, and may result in complete  blindness by the third or fourth decades, generally due to loss of  function of a specific protein. AR disease can also be severe, and  like XLR is commonly due to loss of function in a particular  pathway. Sporadic cases may have a more favourable prognosis,  with retention of central vision until the sixth decade or later.  AD disease generally has the best prognosis. In 20-30% of cases,  RP, often atypical (see below), is associated with a systemic  disorder (syndromic RP); these conditions are usually of AR or  mitochondrial inheritance. A similar clinical picture can be given  by drug toxicity (see Ch. 20). Around 5% of RP belongs to the  very early-onset severe type grouped together as Leber congenital  amaurosis (see separate topic).   • Symptoms. Nyctalopia and dark adaptation difficulties are  frequently presenting symptoms, but peripheral visual  problems may be noticed; reduced central vision tends to be  a later feature but can be involved earlier, including by  complications such as cataract. Photopsia (flashing lights) is  not uncommon. There may be a family history of RP, and a  pedigree should be prepared.   o Visual acuity (VA) may be normal; contrast sensitivity is  affected at an earlier stage than VA.  o Bilateral mid-peripheral intraretinal perivascular  ‘bone-spicule’ pigmentary changes and RPE atrophy  associated with arteriolar narrowing (Figs 15.9A and B).  o There is a gradual increase in density of the pigment with  anterior and posterior spread, and a tessellated fundus  appearance develops due to unmasking of large choroidal  vessels (Fig. 15.9C).   Fig. 15.9 Progression of retinitis pigmentosa. (A) and (B) relatively early changes; (C) advanced changes - wide-field image;  (D) end-stage disease   (Courtesy of P Saine - fig. A; S Chen - figs B and C)    o The macula may show atrophy, epiretinal membrane  (ERM) formation and cystoid macular oedema (CMO).   o Optic disc drusen occur more frequently in patients with  RP.   o Female carriers of the XLR form may have normal fundi  or show a golden-metallic (‘tapetaP) reflex at the macula  (Fig. 15.10A) and/or small peripheral patches of bone-  spicule pigmentation (Fig. 15.10B).   • Complications include posterior subcapsular cataract  (common in all forms of RP), open-angle glaucoma (3%),  keratoconus (uncommon) and posterior vitreous  detachment. Occasionally seen are intermediate uveitis and a  Coats-like disease with lipid deposition in the peripheral  retina and exudative retinal detachment.   • Investigation. Investigation for mimicking infectious  conditions (e.g. syphilis) is sometimes warranted.   o Full-field ERG is a sensitive diagnostic test. In early  disease it shows reduced scotopic rod and combined    responses (Fig. 15.11); photopic responses reduce with  progression, and eventually the ERG becomes  extinguished. Multifocal ERG may provide more specific  information.   o DA is prolonged; it may be useful in equivocal early  cases.   o Perimetry initially demonstrates small mid-peripheral  scotomata that gradually coalesce, and may deteriorate to  leave a tiny island of residual central vision (Fig. 15.12)  that may subsequently be extinguished. Microperimetry  (see Ch. 14), when available, is useful for central visual  assessment.   o Genetic analysis may identify the particular mutation  responsible in an individual patient and facilitate genetic  counseling, including the risk of transmission to  offspring. It may also inform a decision on vitamin A  supplementation.   Fig. 15.10 Findings in carriers of X-linked retinitis  pigmentosa. (A) ‘Tapetal’ reflex at the macula; (B) mild  peripheral pigmentary changes   (Courtesy of D Taylor and CS Hoyt, from Pediatric Ophthalmology and  Strabismus, Elsevier Saunders 2005 - fig. A)   • Regular follow-up (e.g. annual) is essential to detect  treatable vision-threatening complications, provide support  and maintain contact in case of therapeutic innovation.   • No specific treatment is yet commercially available, but  modalities such as gene therapy and retinal prostheses show  promise for the future.   • Low-vision aid provision, rehabilitation and social service  access when appropriate.   • Sunglasses, ‘nanometer-controlled’ to block wavelengths up  to about 550 nm, and with side-shielding, should be worn  outdoors, and other light-protective strategies adopted.   Fig. 15.11 ERG in early retinitis pigmentosa shows reduced  scotopic rod and combined responses    Indoor amber spectacles blocking to 511-527 nm may  improve contrast sensitivity and comfort.   • CMO in RP may respond to oral acetazolamide, and  sometimes topical carbonic anhydrase inhibitors.   • High-dose vitamin A supplementation (e.g. palmitate 15 000  units per day) probably has a marginal benefit, but caution  may be advisable in light of potential adverse effects, notably  the increased risk of lung cancer flagged by the Age-Related  Eye Disease Study (AREDS) in smokers taking beta-  carotene (see Ch. 14), hepatotoxicity in susceptible subjects  and worsening retinal function in some genetic subtypes of  RP; it should be avoided in pregnancy or planned pregnancy.  If supplementation is used, visual function should be  carefully monitored during the early months of treatment,  and regular vitamin A blood levels and liver function testing  must be performed. Lutein, possibly with zeaxanthin, may be  safer alternatives and the AREDS doses may be taken.  Patients with mutations in gene RHOi may be more likely to  benefit, but it should probably be avoided in patients with  ABCA4 mutations (see ‘Stargardt disease’). Vitamin  deficiencies should probably be addressed in all patients,  though with caution, again particularly with ABCA4 mutations.   • Several other drugs (e.g. calcium-channel blockers) have  shown potential benefits but their efficacy and safety in RP  have not been fully ascertained.   • Potentially (even mildly) retinotoxic medications should be  avoided or used with caution. Candidates include erectile  dysfunction drugs, isotretinoin and other retinoids,    Fixation Monitor; Gaze/Blind Spot  Fixation Target: Central  Fixation Losses: 0/14  False PCS Errors: 0%    phenothiazines, hydroxychloroquine, tamoxifen and  vigabatrin. Potentially neurotoxic drugs (see Ch. 20) should  also be used with caution.   The term ‘atypical RP’ has conventionally been used to group  together heterogeneous disorders clinically having features in  common with typical pigmentary retinal dystrophy. The precise  conditions included within this category vary between authors.   • Usher syndrome (AR, genetically heterogeneous) accounts  for about 5% of all cases of profound deafness in children,  and about half of all cases of combined deafness and  blindness. There are three major types, ranging from type I  (75%)) which features profound congenital sensorineural  deafness and severe RP with an extinguished ERG in the first  decade, to type III (2%), with progressive hearing loss,  vestibular dysfunction and relatively late-onset pigmentary  retinopathy. Systemic features are widely variable and can   • Kearns-Sayre syndrome (mitochondrial inheritance) is  characterized by chronic progressive external  ophthalmoplegia with ptosis (Fig. 15.13A) associated with  other systemic problems, described in Ch. 19. The fundus  usually has a salt and pepper appearance most striking at the  macula; less frequent findings are typical RP or choroidal  atrophy similar to choroideremia.   • Bassen-Kornzweig syndrome or abetalipoproteinaemia  (AR) is a condition in which fat and fat-soluble vitamin (A,  D, E, K) absorption is dysfunctional. There is a failure to  thrive in infancy, with the development of severe  spinocerebellar ataxia. A blood film shows ‘thorny’ red cells  (acanthocytosis - Fig. 15.13B). The fundus exhibits scattered  white dots followed by RP-like changes developing towards  the end of the first decade; there may also be ptosis,  ophthalmoplegia, strabismus and nystagmus. Vitamin  supplementation and a low-fat diet are implemented.   • Refsum disease (AR) consists of genetically and clinically  distinct infantile and adult forms. Phytanic acid accumulates  throughout the body, with substantial and varied skin (Fig.  15.13C), neurological and visceral features. Retinal changes  may be similar to RP or take on a salt and pepper   Fig. 15.13 Selected systemic associations of retinitis pigmentosa. (A) Ptosis in Kearns-Sayre syndrome; (B) acanthocytosis  in Bassen-Kornzweig syndrome; (C) ichthyosis in adult Refsum disease; (D) polydactyly in Bardet-Biedl syndrome   appearance, and there may be other ocular features such as  cataract and optic atrophy. A low phytanic acid diet can  retard progression.   • Bardet-Biedl syndrome (genetically heterogeneous) can  encompass a range of systemic abnormalities including  polydactyly (Fig. 15.13D) and mental handicap. There is  typically a bull’s-eye maculopathy due to cone-rod  dystrophy and less frequently typical RP, RP sine pigmento  and retinitis punctata albescens. Almost 80% have severe  changes by the age of 20 years.   RP sine pigmento is characterized by an absence or paucity of  pigment accumulation (Fig. 15.14A), which may subsequently  appear with time. Functional manifestations are similar to  typical RP.   Retinitis punctata albescens (AR or AD) is characterized by scat¬  tered whitish-yellow spots, most numerous at the equator, usually  sparing the macula, and associated with arteriolar attenuation  (Fig. 15.14B). They are similar to the spots in fundus albipunctatus,  and there is speculation and some genetic supporting evidence  that the two clinical presentations are variants of the same disor¬  der; the relative natural history of the two is yet to be completely  defined. Nyctalopia and progressive field loss occur, in contrast to  the benign prognosis believed to pertain in fundus albipunctatus,  and the retinal findings may come to resemble those of retinitis  pigmentosa.   Sector (sectoral) RP (AD) is characterized by involvement of infe¬  rior quadrants only (Fig. 15.14C). Progression is slow, and many  cases are apparently stationary. Unilateral RP can also occur.   Leber congenital amaurosis (AR, genetically heterogeneous) is a  severe rod-cone dystrophy that is the commonest genetically  defined cause of visual impairment in children. The ERG is usually  non-recordable even in early cases. Systemic associations include  mental handicap, deafness, epilepsy, central nervous system and renal  anomalies, skeletal malformations and endocrine dysfunction.   • Presentation is with blindness at birth or early infancy,  associated with roving eye movements or nystagmus, and  photoaversion.   o Absent or diminished pupillary light reflexes,  o The fundi may be normal in early life apart from mild  arteriolar narrowing.   (Fig. 15.15A), salt and pepper changes, and less frequently  yellow flecks.   o Severe macular pigmentation (Fig. 15.15B) or coloboma-  like atrophy (Fig. 15.15C).   Fig. 15.14 Atypical retinitis pigmentosa. (A) Sine pigmento ;  (B) retinitis punctata albescens; (C) sectoral    O Pigmentary retinopathy, optic atrophy and severe  arteriolar narrowing in later childhood,  o Oculodigital syndrome: constant rubbing of the eyes may  cause orbital fat atrophy with enophthalmos (Fig. 15.15D),  and subsequent keratoconus or keratoglobus.   Fig. 15.15 Leber congenital amaurosis. (A) Mild pigmentary retinopathy; (B) macular pigmentation and optic disc drusen;  (C) coloboma-like macular atrophy; (D) oculodigital syndrome   (Courtesy of A Moore - figs A-C; N Rogers - fig. D)   • Treatment should generally be as for retinitis pigmentosa;  gene therapy offers some hope for the future.   Pigmented paravenous chorioretinal atrophy (predominantly AD)  is usually asymptomatic and non-progressive. The ERG is normal.  Paravenous bone-spicule pigmentation (Fig. 15.16) is seen, together  with sharply outlined zones of chorioretinal atrophy that follow  the course of the major retinal veins; changes may also encircle the  optic disc. The optic disc and vascular calibre are usually normal.    Cone dystrophies are in most cases actually cone-rod dystrophies,  with cones being affected earlier and more severely than the rods.   early adulthood, with impairment of central vision rather than the  nyctalopia of rod-cone dystrophy. The prognosis is commonly  poor, with an eventual visual acuity of 6/60 or worse.   • Symptoms. Gradual bilateral impairment of central and  colour vision, which may be followed by photophobia.   • Signs. The features may evolve through the stages below,  o The macula may be virtually normal or show non-specific   central pigmentary changes (Fig. 15.17A) or atrophy,  o A bull’s-eye maculopathy (Figs 15.17B and C) is classically  described but is not universal; causes of a bull’s-eye  appearance are given in Table 15.1.    Chloroquine maculopathy  Advanced Stargardt disease  Cone and cone-rod dystrophy  Fenestrated sheen macular dystrophy  Benign concentric annular macular dystrophy  Clofazimine retinopathy   Fig. 15.17 Cone dystrophy. (A) Early pigment mottling; (B) and (C) bull’s-eye macular appearances - a choroidal naevus is also  present in (C); (D) central macular atrophy   o Fundus autofluorescence (FAF) is often the key  diagnostic test, showing various annular patterns  concentric with the fovea (Figs 15.18A-C).  o ERG: photopic responses are subnormal or   non-recordable and flicker fusion frequency is reduced,  but rod responses are preserved until late (Fig. 15.18D).  o EOG is normal to subnormal.   o DA: the cone segment is abnormal; the rod segment is  initially normal, but may become subnormal later,  o Colour vision: severe deuteron-tritan defect out of  proportion to visual acuity,  o Fluorescein angiography (FA) shows a round   There is no specific treatment for cone dystrophies, but lutein,  zeaxanthin and omega-3 fatty acids have been prescribed in some  cases. General measures (e.g. minimizing phototoxicity) as for  rod-cone dystrophies should be considered where applicable.   Stargardt disease (juvenile macular dystrophy) and fundus flavi¬  maculatus (FFM) are regarded as variants of the same disease, and  together constitute the most common macular dystrophy. The  condition is characterized by the accumulation of lipofuscin  within the RPE. Three types are recognized: STGDi (AR) is the  most common, and is usually caused by mutation in the gene  ABCA4; STGD3 (AD) and STGD4 (AD) are uncommon, and are  related to different genes. Presentation is typically in childhood or  adolescence, but sometimes later. The prognosis for the macu-  lopathy is poor; once visual acuity drops below 6/12 it tends to  worsen rapidly before stabilizing at about 6/6o. Patients with flecks  only in the early stages have a relatively good prognosis and may  remain asymptomatic for many years until the development of  macular disease.   • Symptoms. Gradual impairment of central vision that may  be out of proportion to examination findings; malingering  may be suspected. There may also be complaints of reduced  colour vision and impairment of dark adaptation.   (Fig. 15.19B) or ‘beaten-bronze’ appearance (Fig. 15.19C) and  subsequently to geographic atrophy (Fig. 15.19D) that may    tend to a bull’s-eye configuration (see Fig. 15.19C). A small  proportion develop choroidal neovascularization (CNV).  o Numerous yellow-white round, oval or pisciform   (fish-shaped) lesions at the level of the RPE; these may be  confined to the posterior pole (Fig. 15.19E) or extend to  the mid-periphery.   o New lesions develop as older ones become ill-defined and  atrophic.   o OCT will demonstrate flecks (Fig. 15.20A) and atrophy,  o FAF shows a characteristic appearance with   hyperautofluorescent flecks (Fig. 15.20B) and macular  hypoautofluorescence (Fig. 15.20C), and may be key to  the diagnosis in early cases,  o Visual fields show central loss (Fig. 15.20D), and   microperimetry can accurately document progression,  o ERG: Photopic is normal to subnormal, scotopic may be  normal.   o FA: The classic feature is a ‘dark choroid’ due to masking  of background choroidal fluorescence by diffuse RPE  abnormality; the macula shows mixed hyper- and  hypofluorescence (Fig. 15.20E). Fresh flecks show early  hypofluorescence due to blockage, and late  hyperfluorescence due to staining; old flecks show RPE  window defects (Fig. 15.20F).  o Indocyanine green angiography (ICGA) shows   • General measures should be considered as for retinitis  pigmentosa; protection from excessive high energy light  exposure may be particularly important.   • Vitamin A supplementation is avoided as it may accelerate  lipofuscin accumulation.   • Gene therapy and stem cell trials have been initiated and  show promising results.   Bietti dystrophy (AR, CYP4VZ gene) is characterized by deposi¬  tion of crystals in the retina and the superficial peripheral cornea.  It is much more common in East Asians, particularly Chinese,  than other ethnicities. The mechanism may be linked to an error  in systemic lipid metabolism. The rate of progression is variable;  specific treatment is not currently available.   • Presentation. Young adults with slowly progressive visual  loss constitute the typical case.   o Superficial peripheral corneal crystals,  o Numerous fine yellow-white crystals scattered throughout  the posterior fundus (Fig. 15.21A) are followed by localized  atrophy of the RPE and choriocapillaris at the macula.   Fig. 15.18 Investigation in cone dystrophy. (A) FAF - patient  in Fig. 15.17B; (B) patient in Fig. 15.17C; (C) patient in  Fig. 15.17D; (D) ERG - reduced photopic responses and  flicker fusion frequency; (E) wide-field fluorescein angiogram   (Courtesy of C Barry - fig. C; S Chen - fig. E)   Fig. 15.19 Stargardt disease/fundus flavimaculatus. (A) Non-specific macular mottling; (B) ‘snail slime’ maculopathy  surrounded by flecks; (C) quasi bull’s-eye maculopathy surrounded by flecks - note the ‘beaten-bronze’ paramacular  appearance; (D) geographic atrophy; (E) posterior pole flecks; (F) posterior pole flecks - wide-field image   (Courtesy of S Chen - figs A, C, D, E and F)    Fig. 15.20 Imaging in Stargardt disease/fundus  flavimaculatus. (A) OCT showing RPE/deep retinal deposit;   (B) wide-field fundus autofluorescence (FAF) image of the eye  in Fig. 15.19E showing flecks; (C) FAF showing macular  hypoautofluorescence and surrounding flecks; (D) central  visual field loss; (E) FA showing macular mottling and  midperipheral ‘dark choroid’; (F) FA showing hyperfluorescent  spots   (Courtesy of S Chen - figs A, B, C and D; A Bolton - fig. F)   Fig. 15.21 Bietti corneoretinal crystalline dystrophy. (A)  Wide-field image showing crystalline deposits; (B) OCT  showing deposits and macular changes; (C) FA showing  characteristic hypofluorescent patches    o Diffuse atrophy of the choriocapillaris subsequently  develops, with a decrease in size and number of the  crystals.   o There is gradual confluence and expansion of the  atrophic areas into the periphery, leading to diffuse  chorioretinal atrophy in end-stage disease.   hypofluorescent patches corresponding to choriocapillaris  loss, with intact overlying retinal vessels (Fig. 15.21C); the  patches become confluent over time.   Alport syndrome (predominantly XLR) is caused by mutations in  several different genes, all of which encode particular forms of type  IV collagen, a major basement membrane component. It is char¬  acterized by chronic renal failure, often associated with sen¬  sorineural deafness. There are scattered yellowish punctate flecks  in the perimacular area (Fig. 15.22A), which are often subtle (Fig.  15.22B) and larger peripheral flecks, some of which may become  confluent (Fig. 15.22C). The ERG is normal, and the prognosis for  vision is excellent. Anterior lenticonus and posterior polymor¬  phous corneal dystrophy may occasionally be seen.   Familial benign fleck retina (benign flecked retina syndrome) is a  very rare AR disorder. It is asymptomatic, so usually discovered  by chance. Numerous diffusely distributed yellow-white polymor¬  phous lesions spare the fovea and extend to the far periphery (Fig.  15.23). The flecks autofluoresce, and are probably composed of  lipofuscin. The ERG is normal, and the prognosis excellent.   Congenital stationary night blindness (CSNB) refers to a group of  disorders characterized by infantile-onset nyctalopia but non-  progressive retinal dysfunction. The fundus appearance may be  normal or abnormal.   CSNB with a normal fundus appearance is sometimes classified  into type 1 (complete) and type 2 (incomplete) forms that are  generally due to mutations in different genes. The former is char¬  acterized by a complete absence of rod pathway function and  essentially normal cone function clinically and on ERG, the latter  by impairment of both rod and cone function. Mutations in  numerous genes have been implicated, with XLR, AD and AR  inheritance patterns; the AD form is usually associated with  normal visual acuity, but many AR and XLR patients have poor  vision with nystagmus, and often significant myopia.   • Oguchi disease (AR). The fundus has an unusual golden-  yellow colour in the light-adapted state (Fig. 15.24A), which    Fig. 15.22 Alport syndrome. (A) Perimacular flecks; (B) subtle  flecks; (C) peripheral flecks    Fig. 15.24 Mizuo phenomenon in Oguchi disease. (A) In the  light-adapted state; (B) in the dark-adapted state   (Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases,  Mosby 1997)    becomes normal after prolonged dark adaptation (Mizuo or  Mizuo-Nakamura phenomenon - Fig 15.24B). Rod function  is absent after 30 minutes of dark adaptation but recovers to  a near-normal level after a long period of dark adaptation.   • Fundus albipunctatus is an AR or AD condition that may  be the same entity as retinitis punctata albescens (see  earlier); they can both be caused by mutation in the RLBPi  gene. The fundus shows a multitude of subtle, tiny yellow-  white spots at the posterior pole (Fig. 15.25A), sparing the  fovea - sometimes the macula - and extending to the  periphery. In contrast to retinitis punctata albescens, the  retinal blood vessels, optic disc, peripheral fields and visual  acuity are believed to remain normal, though the natural  history is not yet absolutely defined. Fluorescein angiography   Fig. 15.25 Fundus albipunctatus. (A) Clinical appearance;  (B) FA shows mottled hyperfluorescence    shows mottled hyperfluorescence, indicating depigmentation  of the RPE (Fig. 15.25B). The ERG is variably abnormal; both  cones and rods may be affected.   This is a group of congenital disorders in which colours cannot be  perceived and visual acuity is reduced, particularly in brightly  illuminated environments (hemeralopia).   In rod monochromatism (AR) visual acuity is poor, typically  6/60; there is congenital nystagmus and photophobia. Colour  vision is totally absent, all colours appearing as shades of grey. The  macula usually appears normal but may be hypoplastic. The pho-  topic (cone) ERG is abnormal and the scotopic may also be  subnormal.   Blue cone monochromatism (XLR) features only slightly subnor¬  mal acuity at 6/6—6/9, but colour vision is completely absent.  Nystagmus and photophobia are not typical features. There is a  normal macula.   The ERG is normal except for the absence of cone responses to  red and white light.   Best vitelliform macular dystrophy (early- or juvenile-onset vitel¬  liform macular dystrophy) is the second most common macular  dystrophy, after Star gar dt disease. It is due to allelic variation in  the BESTi gene. Inheritance is AD with variable penetrance and  expressivity. The prognosis is usually reasonably good until middle  age, after which visual acuity declines in one or both eyes due to  CNV, scarring or geographic atrophy.   o Pre-vitelliform is characterized by a subnormal EOG in  an asymptomatic infant or child with a normal fundus,  o Vitelliform develops in infancy or early childhood and  does not usually impair vision. A round, sharply  delineated (‘sunny side up egg yolk’) macular lesion  between half a disc and two disc diameters in size  develops within the RPE (Fig. 15.26A); the size of the    Fig. 15.26 Best dystrophy. (A) Vitelliform stage; (B) pseudohypopyon; (C) vitelliruptive stage; (D) OCT shows abnormal material  within and anterior to the RPE    lesions and stage of development in the two eyes may be  asymmetrical, and sometimes only one eye is involved  initially. Occasionally the condition may be extramacular  and multiple.   o Pseudohypopyon may occur when part of the lesion  regresses (Fig. 15.26B), often at puberty.   o Vitelliruptive: the lesion breaks up and visual acuity  drops (Fig. 15.26C).   o Atrophic in which all pigment has disappeared leaving an  atrophic area of RPE.   hyperautofluorescent (see Fig. 15.28C); hypoautofluorescent  areas supervene in the later atrophic stages.   o OCT shows material beneath, above and within the RPE  (Fig. 15.26D).    o EOG is severely subnormal during all stages (Arden index  less than 1.5), and is also abnormal in carriers with  clinically normal fundi.   Occasionally multifocal vitelliform lesions (Fig. 15.27), identical to  those in Best dystrophy but distributed around the macular vas¬  cular arcades and optic disc, may become manifest in adult life  and give rise to diagnostic problems. However, in these patients  the EOG is normal and the family history is negative. Occasionally  genetically confirmed Best dystrophy may present with multifocal  lesions. The relationship between multifocal vitelliform lesions,  juvenile vitelliform (Best) dystrophy and adult-onset vitelliform  macular dystrophy is incompletely defined, though some cases of  each are associated with mutations in the same genes.   Adult-onset vitelliform macular (foveomacular) dystrophy  (AOVMD) is sometimes classified with juvenile-onset vitelliform  macular dystrophy, but they are generally considered distinct enti¬  ties; AOVMD may be a form of pattern dystrophy of the RPE (see  next), and at least one family has been described with a combina¬  tion of AOVMD and other pattern dystrophies. In contrast to  juvenile Best disease, the foveal lesions are typically smaller,  present later and generally do not evolve in a similar fashion. A  minority of cases are caused by mutation in the PRPH2 ( RDS ) or  the BESTi gene.   • Symptoms. Often the condition is discovered by chance, but  may present in late middle or old age with decreased central  vision. The prognosis is very variable, though often the  vision is reduced by one or more lines by presentation and  mild deterioration occurs subsequently.   • Signs. A round or oval slightly elevated yellowish subfoveal  deposit (Fig. 15.28A), generally smaller than the lesions of  Best disease, is seen in one or both eyes. There may be  central pigmentation, and numerous associated drusen   are present in some cases. The material may persist,  absorb, or break up and disperse at a late stage, leaving  atrophy of very variable severity; choroidal  neovascularization sometimes supervenes.   o OCT shows hyper-reflective material associated with the  RPE, similar to Best disease (see Fig. 15.26D).  o FAF imaging shows intense hyperautofluorescence  corresponding to the deposited material, which is  typically much more obvious than on clinical  examination (Fig. 15.28B and C); if atrophy supervenes,  there is hypoautofluorescence.  o FA shows central hypofluorescence surrounded by a  small irregular hyperfluorescent ring.   Fig. 15.28 (A) Adult-onset macular vitelliform dystrophy;  (B) smaller lesion; (C) fundus autofluorescence image  of the eye in (B) - the lesion is much more obvious   Pattern (patterned) dystrophy of the RPE encompasses several  clinical appearances associated with the accumulation of lipofus-  cin at the level of the RPE and manifesting with yellow, whitish,  grey or pigmented deposits at the macula in a variety of morpholo¬  gies. All the described entities tend to have characteristics in  common including typically AD (occasionally AR) inheritance, a  slow course leading to mild to moderate foveal atrophy, and a  normal ERG but occasionally an abnormal EOG. Symptoms often  begin in early adulthood or later. The different clinical pictures are  believed in many cases to represent variable expression of a single  disorder, particularly as different forms of pattern dystrophy can  affect siblings with the same mutation and even the two eyes in  the same patient. Notably, a pattern dystrophy-like appearance  can occur in response to a range of pathogenic stimuli.   • Butterfly-shaped: foveal yellow and melanin pigmentation,  commonly in a spoke-like or butterfly wing-like  conformation (Fig. 15.29A); drusen- or Stargardt-like flecks  may be associated with any pattern dystrophy (Fig. 15.29B).  FA shows central and radiating hypofluorescence with  surrounding hyperfluorescence (Fig. 15.29C). More than one  gene has been implicated.   • Reticular (Sjogren): a network of pigmented lines at the  posterior pole.   • Multifocal pattern dystrophy simulating fundus  flavimaculatus: multiple, widely scattered, irregular yellow  lesions; they may be similar to those seen in fundus  flavimaculatus (Fig. 15.30A). FA shows hyperfluorescence of  the flecks; the choroid is not dark (Fig. 15.30B).   • Macroreticular (spider-shaped): initially pigment granules  are seen at the fovea; reticular pigmentation develops that  spreads to the periphery (Fig. 15.31).   North Carolina macular dystrophy is a rare non-progressive con¬  dition. It was first described in families living in the mountains of  North Carolina and subsequently in many unrelated families in  other parts of the world. Inheritance is AD with complete pene¬  trance but highly variable expressivity.   • Grade 1 is characterized by yellow-white, drusen-like  peripheral (Fig. 15.32A) and macular deposits that develop  during the first decade but may remain asymptomatic  throughout life.   • Grade 2 is characterized by deep, confluent macular deposits  (Fig. 15.32B). The long-term visual prognosis is guarded  because some patients develop neovascular maculopathy  (Fig. 15.32C) and subretinal scarring.   • Grade 3 is characterized by coloboma-like atrophic macular  lesions (Fig. 15.32D) associated with variable impairment of  visual acuity.   Fig. 15.29 Butterfly-shaped pattern dystrophy of the RPE.  (A) Spokes of yellowish material and pigment radiating  from the foveola; (B) associated with flecks; (C) FA of the  eye in (A) showing central and spoke-like radiating  hypofluorescence with surrounding hyperfluorescence   Fig. 15.30 (A) Multifocal pattern dystrophy simulating fundus  flavimaculatus; (B) FA shows hyperfluorescence but the  choroid is not dark   Familial dominant drusen (Doyne honeycomb choroiditis, malat-  tia leventinese) is thought to represent an early-onset variant of  age-related macular degeneration. Inheritance is AD with variable  expressivity; mutations in the gene EFEMPi are responsible.  Asymptomatic yellow-white, elongated, radially orientated drusen  develop in the second decade; they may involve the disc margin  and extend nasal to the disc (Fig. 15.33A). With age the lesions  become increasingly dense and acquire a honeycomb pattern    (Fig. 15.33B). Visual symptoms may occur in the fourth to fifth  decades due to RPE degeneration, geographic atrophy or occa¬  sionally CNV. The ERG is normal, but the EOG is subnormal in  patients with advanced disease.   Sorsby pseudoinflammatory (hereditary haemorrhagic) macular  dystrophy is a rare disorder that results in bilateral visual loss,  typically in late middle age. Inheritance is AD with full penetrance  but variable expressivity; allelic variation in the gene TIMP3 is  responsible. Early presentation may be in the third decade with  nyctalopia, when confluent yellow-white drusen-like deposits  may be seen along the arcades, nasal to the disc and in the mid¬  periphery (Fig. 15.34A), or in the fifth decade with sudden visual  loss due to exudative maculopathy secondary to CNV (Fig. 15.34B)  and subretinal scarring (Fig. 15.34C). Peripheral chorioretinal  atrophy may occur by the seventh decade and result in loss of  ambulatory vision. The ERG is initially normal but may be sub¬  normal in later disease.   The prognosis is good in the majority of cases of (benign) concen¬  tric annular macular dystrophy, an AD disorder, although a  minority develop progressive loss of acuity and nyctalopia. Pres¬  entation is in adult life with mild impairment of central vision;  bull’s-eye maculopathy is associated with slight vascular attenua¬  tion but a normal disc. A paracentral ring scotoma is present on  visual field testing. FA shows an annular RPE window defect.   Central areolar choroidal dystrophy, also termed central choroidal  sclerosis, is a genetically heterogeneous (types 1-3 are described)  but typically AD condition presenting in the third or fourth   (Courtesy of RF Spaide, from Diseases of the Retina and Vitreous, WB  Saunders 1999)    Fig. 15.32 North Carolina macular dystrophy. (A) Peripheral flecks; (B) confluent macular flecks; (C) early neovascular  maculopathy; (D) coloboma-like macular lesion    decades with gradual impairment of central vision. Non-specific  foveal granularity progresses to well-circumscribed RPE atrophy  and loss of the choriocapillaris (Fig. 15.35A), and subsequently  slowly expanding geographic atrophy with prominence of large  choroidal vessels (Figs 15.35B and C). The prognosis is poor.   Bilateral cystoid macular oedema (AD) commonly presents in  adolescence with gradual impairment of central vision; treatment  tends to be ineffective and geographic atrophy inevitably ensues.   Sjogren-Larsson syndrome (AR) is a neurocutaneous disorder  secondary to defective enzyme (fatty aldehyde dehydrogenase)  activity, and is characterized by congenital ichthyosis and neuro¬  logical problems. Presentation is with photophobia and poor  vision, and glistening yellow-white crystalline deposits develop at  the macula (Fig. 15.36), appearing during the first two years of life.  Visual evoked potential testing is abnormal. Pigmentary retino¬  pathy (50%), cataract and colobomatous microphthalmos may  also occur.   Fig. 15.33 Familial dominant drusen. (A) Typical earlier  radially orientated lesions extending nasal to the disc;  (B) high-density drusen with RPE degeneration   Presentation of this AD condition may be in middle age with  reduced central vision; a glistening inner retinal surface is evident  at the posterior pole (Fig. 15.37). The prognosis is poor.   Maternally inherited diabetes and deafness (MIDD) constitutes  around 1% of all cases of diabetes, with inheritance via mitochon¬  drial DNA. A majority of patients develop progressive dystrophic  macular changes (Fig. 15.38), but vision is not usually affected.  Some patients have other ocular features, such as pigmentary  retinopathy and ptosis.   Fig. 15.34 Sorsby pseudoinflammatory macular dystrophy.  (A) Confluent flecks nasal to the disc; (B) exudative  maculopathy; (C) scarring in end-stage disease   (Courtesy of D Taylor and C S Hoyt , from Pediatric Ophthalmology and  Strabismus, Elsevier Saunders 2005)   Choroideremia (tapetochoroidal dystrophy) is a progressive  diffuse degeneration of the choroid, RPE and photoreceptors.  Inheritance is XLR, so that males are predominantly affected.  However, it is important to identify female carriers as 50% of their  sons will develop choroideremia and 50% of their daughters will  be carriers. The prognosis is very poor; although most patients  retain useful vision until the sixth decade, very severe visual loss    Fig. 15.35 Progression of central areolar choroidal dystrophy.  (A) Early; (B) intermediate; (C) end-stage   (Courtesy of J Donald M Gass , from Stereoscopic Atlas of Macular Diseases,  Mosby 1997)   Fig. 15.38 Macular changes in maternally inherited diabetes  and deafness. (A) Initial appearance; (B) 6 years later    occurs thereafter. The gene responsible is CHM ; a contiguous  extended gene deletion leads to associated deafness and mental  handicap.   • Symptoms. Nyctalopia, often beginning in adolescence, is  followed some years later by reduced peripheral and central  vision; clinically problematic disease occurs almost  exclusively in males, but if present in females a number of  genetic mechanisms can be responsible.   atrophy and mottling (Fig. 15.39A); acuity, fields and ERG  are usually normal.   o Males initially exhibit mid-peripheral RPE abnormalities  that may, on cursory examination, resemble RP. Over  time, atrophy of the RPE and choroid spreads  peripherally and centrally (Fig. 15.39B). The end-stage  appearance consists of isolated choroidal vessels coursing    over bare sclera, retinal vascular attenuation and optic  atrophy. In contrast to primary retinal dystrophies, the  fovea is spared until late (Fig. 15.39C).   o FA shows filling of the retinal and large choroidal vessels  but not of the choriocapillaris. The intact fovea is  hypofluorescent and is surrounded by hyperfluorescence  due to an extensive window defect (Fig. 15.39D).   • Treatment. Early clinical trials of specific gene therapy for  choroideremia, involving the introduction of functional  copies of the faulty gene into the eye, have produced  promising results.   Gyrate atrophy (AR) is caused by a mutation in the gene (OAT)  encoding the main ornithine degradation enzyme, ornithine ami¬  notransferase. Deficiency of the enzyme leads to elevated ornithine  levels in the plasma, urine, cerebrospinal fluid and aqueous  humour. The visual prognosis is generally poor, with legal blind¬  ness occurring around the age of 50 from geographic atrophy.   • Symptoms. Myopia and nyctalopia in adolescence, with a  subsequent gradual worsening of vision.   o Mid-peripheral depigmented spots associated with diffuse  pigmentary mottling may be seen in asymptomatic cases,  o Sharply demarcated circular or oval areas of chorioretinal  atrophy develop; these may be associated with numerous  glistening crystals at the posterior pole (Fig. 15.40A).  o Coalescence of atrophic areas and gradual peripheral and  central spread (Fig. 15.40B).  o The fovea is spared until late (Fig. 15.40C).  o Extreme attenuation of retinal blood vessels,  o Vitreous degeneration and early-onset cataract is  common; CMO and ERM may also occur.   o FA shows sharp demarcation between areas of choroidal  atrophy and normal choriocapillaris.  o ERG is subnormal is early disease and later becomes  extinguished.   • Treatment. There are two clinically different subtypes of  gyrate atrophy based on the response to pyridoxine (vitamin  B 6 ), which may normalize plasma and urinary ornithine  levels. Patients who are responsive to vitamin B 6 generally  have a less severe and more slowly progressive clinical course  than those who are not. Reduction in ornithine levels with  an arginine-restricted diet is also beneficial.   In progressive bifocal chorioretinal atrophy (AD), the implicated  gene region overlaps with that responsible for North Carolina  macular dystrophy but the two conditions are believed to be due   Fig. 15.39 Choroideremia. (A) Female carrier; (B) advanced disease; (C) end-stage disease; (D) FA shows an intact fovea   (Courtesy of S Chen - fig. B; S Milewski - figs C and D)    to different mutations. Dual foci of chorioretinal atrophy develop  temporal and nasal to the disc, with inevitable macular involve¬  ment (Fig. 15.41). Nystagmus, myopia and retinal detachment may  occur.   Juvenile retinoschisis is characterized by bilateral maculopathy,  with associated peripheral retinoschisis in 50%. The basic defect  is mediated via the Muller cells, leading to splitting of the retinal  nerve fibre layer from the rest of the sensory retina, in contrast to  acquired (senile) retinoschisis in which splitting occurs at the    outer plexiform layer. Inheritance is XLR, with the implicated  gene in most cases designated RSi. The prognosis is often poor  due to progressive maculopathy; visual acuity deteriorates during  the first two decades, but may remain reasonably stable until the  fifth or sixth decades before further deterioration.   • Symptoms. Presentation in boys is usually between the ages  of 5 and 10 years with reading difficulties. Less frequently  squint or nystagmus occurs in infancy associated with  advanced peripheral retinoschisis, often with vitreous  haemorrhage. Carrier females are generally asymptomatic.   o The most common appearance is foveal schisis, appearing  as spoke-like striae radiating from the foveola, associated  with cystoid changes (Fig. 15.42A); over time the striae  become less evident, leaving a blunted foveal reflex.   Fig. 15.40 Gyrate atrophy. (A) Early disease; (B) advanced  disease; (C) end-stage disease with preservation of the  fovea    o Whitish drusen-like dots and pigment variation may be  seen (Fig. 15.42B); the macula is occasionally normal,  o Peripheral schisis predominantly involves the  inferotemporal quadrant. It does not extend but  secondary changes may occur; the inner layer, which    consists only of the internal limiting membrane and the  retinal nerve fibre layer, may develop oval defects (Figs  15.42C and D) and in extreme cases the defects coalesce,  leaving only retinal blood vessels floating in the vitreous  (Vitreous veils’) (Fig. 15.42E). Silvery peripheral dendritic  figures (Fig. 15.42F), vascular sheathing and pigmentary  changes are common, and retinal flecks and nasal  dragging of retinal vessels may be seen,  o Complications include vitreous and intra-schisis   haemorrhage, neovascularization, subretinal exudation  (Fig. 15.43 A), and rarely rhegmatogenous or tractional  retinal detachment and traumatic rupture of the foveal  schisis (Fig. 15.43B).   O OCT is useful for documenting maculopathy progression;  cystic spaces in the inner nuclear and outer plexiform  layers are commonly present (Fig. 15.44A), but the fovea  may simply appear disorganized,  o FAF shows variable macular abnormality, including  spoke-like patterns and central hypoautofluorescence  with surrounding hyperautofluorescence (Fig. 15.44B).  o ERG is normal in eyes with isolated maculopathy. Eyes  with peripheral schisis show a characteristic selective  decrease in amplitude of the b-wave as compared with  the a-wave on scotopic and photopic testing (Fig. 15.44C).  o EOG is normal in eyes with isolated maculopathy but  subnormal in eyes with advanced peripheral lesions,  o FA of maculopathy may show mild window defects but  no leakage, in contrast to CMO.   • Topical or oral carbonic anhydrase inhibitors (e.g.  dorzolamide three times daily) may reduce foveal thickness  and improve visual acuity in some patients.    Fig. 15.42 Juvenile retinoschisis. (A) ‘Bicycle wheel’-like maculopathy; (B) whitish macular dots and mild pigment change;  (C) and (D) large, typically oval, inner leaf defects; (E) ‘vitreous veils’; (F) peripheral dendritic lesions   (Courtesy of K Slowinski - fig. A; S Chen - fig. D; C Barry - fig. E; Moorfields Eye Hospital - fig. F)   (Courtesy of G-M Sarra - fig. A; K Slowinski - fig. B)   • Vitrectomy may be required for vitreous haemorrhage or  retinal detachment repair, but is technically challenging. As  retinoschisis cavities are non-progressive, surgery is not  performed purely to flatten these.   • Gene therapy is under investigation, with the aim of  restoring normal function of the protein abnormality  underlying retinoschisis.   Stickler syndrome (hereditary arthro-ophthalmopathy) is a genet¬  ically heterogeneous disorder of collagen connective tissue. Inher¬  itance is AD (STL1-STL3) or AR (STL4 and STL5) with complete  penetrance but variable expressivity. Stickler syndrome is the most  common inherited cause of retinal detachment in children. In  general, the prognosis has been poor but may be improving with  elevated standards of care.   • Stickler syndrome type I (STLi - membranous vitreous  type) is the most common form, and is the result of  mutations in the COL2A1 gene. The classic ocular and   Fig. 15.44 Investigation in X-linked retinoschisis. (A) OCT  showing cyst-like foveal changes; (B) fundus  autofluorescence - central hypofluorescence with  surrounding hyperfluorescence; (C) ERG showing selective  decrease in b-wave amplitude   systemic features are present as originally described by  Stickler, though there is also a solely or predominantly  ocular (non-syndromic) form of STLi.   • STL2 (beaded vitreous type) is caused by mutations in the  COL11A1 gene. Patients have congenital non-progressive high  myopia, sensorineural deafness and other features of Stickler  syndrome type 1.   • STL3 (non-ocular type) is due to mutations in the COL11A2  gene. Affected individuals have the typical systemic features,  but no ocular manifestations.   Systemic features include mid-facial hypoplasia (Fig. 15.45 A),  Pierre-Robin-type features (micrognathia, cleft palate - Fig.  15.45B, and glossoptosis - backward displacement of the tongue),  bifid uvula, mild spondyloepiphyseal dysplasia, joint hypermobil¬  ity and early-onset osteoarthritis. Deafness may be sensorineural  or caused by recurrent otitis media.   The three characteristic ocular features are high myopia, vitre-  oretinal degeneration with an associated extremely high rate of  retinal detachment, and cataract.   Fig. 15.45 Stickler syndrome. (A) Facial appearance; (B) cleft  and high-arched palate    membranes that extend a short way into the vitreous  cavity (Fig. 15.46A and see Figs 15.47A and B).  o In STL2 patients the vitreous has a fibrillary and beaded  appearance.   o Radial lattice-like degeneration associated with RPE  hyperplasia, vascular sheathing and sclerosis (Figs 15.46B  and C).   o Retinal detachment develops in approximately 50% in the  first decade of life, often as a result of multiple or giant  tears that may involve both eyes,  o Presenile cataract characterized by frequently non¬  progressive peripheral cortical wedge-shaped, fleck or  lamellar opacities is common,  o Ectopia lentis can occur, but is uncommon,  o Glaucoma (5-10%) is associated with congenital angle  anomaly.   • Prophylactic 360° retinal laser or cryotherapy may reduce the  incidence of retinal detachment, but as a minimum regular  screening with prophylactic treatment of retinal breaks is  essential. Long-term review of all patients is mandatory.   • Retinal detachment repair is challenging, with proliferative  vitreoretinopathy particularly common. Vitrectomy is  generally indicated. Re-detachment may occur later.   • Cataract in Stickler is often visually inconsequential,  particularly when early. If surgery is required, a careful  preoperative retinal evaluation with treatment of breaks  should be performed. Vitreous loss and postoperative retinal  detachment are relatively common.   • Glaucoma treatment may be required; if early-onset and  presumably related to angle anomaly, management is  generally as for congenital glaucoma (see Ch. 10).   Wagner syndrome (VCAN-related vitreoretinopathy) is a rare  condition having some features in common with Stickler syn¬  drome, but no association with systemic abnormalities; erosive  vitreoretinopathy is now known to be the same disorder. Inherit¬  ance is AD and mutations in the gene VCAN can be responsible.  Severity is variable, with up to 50% developing retinal detachment,  often before the age of 15.   o Patients tend to have low to moderate myopia,  o The key abnormal finding is an optically empty vitreous  cavity (Fig. 15.47A) lacking structural elements, and it is  thought this leads to reduced ‘scaffolding’ support for the  retina.   o The peripheral retinal vasculature is deficient,  o Greyish-white avascular strands and membranes extend  into the vitreous cavity and there may be a  circumferential ridge-like condensation of the gel at or  anterior to the retinal periphery (Fig. 15.47B).  o Peripheral retinal changes including progressive   Fig. 15.46 Stickler syndrome. (A) Vitreous liquefaction and  membranes; (B) radial lattice degeneration and pigmentary  changes - wide-field image; (C) wide-field autofluorescence  image of eye in (B)   o Cataract is common in younger adults, and glaucoma can  develop.   • Investigation. FA shows non-perfusion due to  choriocapillaris loss (Fig. 15.47D). The ERG may initially be  normal, but later shows a reduction of scotopic b-wave  amplitudes and diffuse cone-rod loss.   • Treatment. Retinal breaks and detachment are treated as  they occur, but extensive prophylaxis is avoided.   Familial exudative vitreoretinopathy (Criswick-Schepens syn¬  drome) is a slowly progressive condition characterized by failure  of vascularization of the temporal retinal periphery, similar to that  seen in retinopathy of prematurity. Inheritance is AD and rarely  XLR or AR, with high penetrance and variable expressivity; four  genes in a common pathway have been implicated. Presentation  is in childhood; the prognosis is frequently poor, especially with  early aggressive onset.   o Stage 1: peripheral avascularity. There is abrupt termination  of retinal vessels at the temporal equator. Vitreous  degeneration and peripheral vitreoretinal attachments are  associated with areas of‘white without pressure’. Vascular  straightening (Fig. 15.48A) maybe present,  o Stage 2: peripheral vascular tortuosity and telangiectasia  (Fig. 15.48B) progresses to preretinal fibrovascular  proliferation (Figs 15.48C and D), with or without  subretinal exudation (Fig. 15.48E).  o Stage 3: tractional and/or rhegmatogenous macular-  sparing retinal detachment, with or without exudation,  o Stages 4 and 5 are macula-involving (Fig. 15.48F) and  total retinal detachment, respectively,  o Vitreous haemorrhage, cataract and neovascular  glaucoma can occur.   • Investigation. Wide-field FA is invaluable (Fig. 15.49) in  confirming the diagnosis, ensuring accurate targeting and  completeness of ablation of avascular retina, and identifying  asymptomatic cases with subtle features.   o Laser ablation of avascular retina is recommended,  usually once neovascularization has occurred.   o Intravitreal anti-VEGF treatment can be useful as a  temporizing measure.   The human retina has three cone photoreceptor types: short-wave  sensitivity (S), middle-wave sensitivity (M) and long-wave    Fig. 15.47 Wagner syndrome. (A) Vitreous liquefaction; (B) peripheral chorioretinal atrophy and preretinal membranes;  (C) progressive chorioretinal atrophy; (D) FA shows gross loss of the choriocapillaris    sensitivity (L). Most inherited retinal dystrophies exhibit progres¬  sive attenuation of rods and all classes of cones. However, enhanced  S-cone syndrome is characterized by hyperfunction of S-cones and  severe impairment of M- and L-cones, with non-recordable rod  function. Goldmann-Favre syndrome represents a severe variant.  Inheritance is AR with variable expressivity; the gene implicated  is NR2E3. Presentation is with nyctalopia in childhood, and some¬  times hemeralopia (reduced vision in bright light). Pigmentary  changes along the vascular arcades or mid-periphery may be asso¬  ciated in more advanced cases with round pigment clumps (Fig.  15.50 A). Macular changes may include cystoid maculopathy  (without fluorescein leakage) and schisis (Fig. 15.50B). Vitreous  degeneration and peripheral retinoschisis can occur. The progno¬  sis for central and peripheral vision is poor in many patients,  particularly by late middle age, and there is no treatment other  than supportive measures.   This rare AD condition (gene KCNJ13 ) has some similarities to  Wagner syndrome; retinal detachment is less common, and the  prognosis is usually very good.   o Stage 1 shows extensive areas of white without pressure’  in patients typically under the age of 15 years,  o Stage 2 shows snowflake-like yellow-white crystalline  deposits in areas of white with pressure’ in patients  between 15 and 25.   o Stage 3 manifests with vascular sheathing and  pigmentation posterior to the area of snowflake  degeneration in patients between 25 and 50.  o Stage 4 is characterized by increased pigmentation, gross  vascular attenuation, areas of chorioretinal atrophy, and   Fig. 15.48 Familial exudative vitreoretinopathy. (A) Dragging and straightening of the macular vessels; (B) peripheral  telangiectasia; (C) fibrovascular ridge; (D) fibrovascular proliferation; (E) subretinal exudation; (F) ‘dragging’ of the disc and  macula, with underlying macular tractional detachment   (Courtesy of S Chen - fig. A; C Hoyng - fig. E)   Fig. 15.49 Wide-field FA shows vascular straightening and  abrupt termination in familial exudative vitreoretinopathy   Fig. 15.50 Enhanced S-cone and Goldmann-Favre syndrome.  (A) Severe pigment clumping; (B) macular schisis and  pigmentary changes along the arcade   (Courtesy of D Taylor and CS Hoyt , from Pediatric Ophthalmology and  Strabismus, Elsevier Saunders 2005 - fig. A; J Donald M Gass , from  Stereoscopic Atlas of Macular Diseases, Mosby 1997 - fig. B)    less prominent snowflakes in patients over the age of 6o  years. The macula remains normal,  o Other possible features include mild myopia, vitreous  fibrillary degeneration and liquefaction, a waxy optic  nerve head, corneal guttae, retinal detachment and  early-onset cataract.   A rare but interesting inherited (gene CAPN5) disorder, autosomal  dominant neovascular inflammatory vitreoretinopathy (ADNIV)  features panuveitis, often of onset in early adulthood. The initial  symptom is typically floaters due to vitritis, with the development  of peripheral vascular closure with peripheral and then disc neo¬  vascularization, fundus pigmentation, epiretinal and subretinal  fibrocellular membranes; complications include vitreous haemor¬  rhage, tractional retinal detachment, cystoid macular oedema,  cataract and neovascular glaucoma. The ERG shows selective loss  of b-wave amplitude. The prognosis can be poor. Peripheral  retinal photocoagulation and vitreous surgery may be required.   Autosomal dominant vitreoretinochoroidopathy (ADVIRC) can  be caused by BESTi mutations. Presentation is in adult life if  symptomatic, but frequently discovery is by chance. Vitreous cells  and fibrillary degeneration develop, with a non-progressive or  very slowly progressive encircling band of pigmentary disturbance  between the ora serrata and equator, with a discrete posterior   border. Within the band there can be arteriolar attenuation, neo¬  vascularization, punctate white opacities and later chorioretinal  atrophy. Complications are uncommon, but can include cystoid  macular oedema, vitreous haemorrhage and cataract; microcornea  and nanophthalmos have been described in some patients. The  full-field ERG is subnormal in older patients only. The prognosis  is good.   Kniest dysplasia is usually caused by a defect in the type II collagen  gene, COL2A1 , which is also involved in Stickler syndrome type 1.  Inheritance can be AD, but most cases represent a fresh mutation.  High myopia, vitreous degeneration, retinal detachment and  ectopia lentis can occur; systemic features may include short  stature, a round face and arthropathy.   Albinism is a genetically determined, heterogeneous group of dis¬  orders of melanin synthesis in which either the eyes alone (ocular  albinism) or the eyes, skin and hair (oculocutaneous albinism)  may be affected. The latter may be either tyrosinase-positive or  tyrosinase-negative. The different mutations are thought to act  through a common pathway involving reduced melanin synthesis  in the eye during development. Tyrosinase activity is assessed by  using the hair bulb incubation test, which is reliable only after 5  years of age. Patients with oculocutaneous, and probably ocular,  albinism have an increased risk of cutaneous basal cell and squa¬  mous cell carcinoma.   Tyrosinase-negative (complete) albinos are incapable of synthesiz¬  ing any melanin and have white hair and very pale skin (Fig. 15.52)  throughout life with a lack of melanin pigment in all ocular struc¬  tures. The condition is genetically heterogeneous, usually with AR  inheritance.   o VA is usually <6/60 due to foveal hypoplasia,  o Nystagmus is typically pendular and horizontal. It usually  increases in bright illumination and tends to lessen in  severity with age.   o The iris is diaphanous and translucent (Fig. 15.53A),  giving rise to a ‘pink-eyed’ appearance (Fig. 15.53B).  o The fundus lacks pigment and shows conspicuously large  choroidal vessels. There is also foveal hypoplasia with  absence of the foveal pit, and poorly formed perimacular  vascular arcades (Fig. 15.53C).  o The optic chiasm has fewer uncrossed nerve fibres than  normal - the majority of fibres from each eye cross to the  contralateral hemisphere. This can be demonstrated with  visual evoked potentials.    o Other features include high refractive errors of various  types, a positive angle kappa, squint and absent  stereopsis.   Tyrosinase-positive (incomplete) albinos synthesize variable  amounts of melanin. Patients’ hair may be white, yellow or red,  and darkens with age. Skin is pale at birth but usually darkens by  2 years of age (Fig. 15.54A). Inheritance is usually AR; mutation in  at least two distinct genes can be causative.   o Hermansky-Pudlak syndrome: lysosomal storage disease  with platelet dysfunction, and pulmonary fibrosis,  granulomatous colitis and renal failure in some cases.   o Waardenburg syndrome: an AD condition with a range  of systemic presentations including a white forelock,  poliosis, synophrys (‘monobrow’), deafness and  sometimes limb and neurological anomalies. Ocular  features include lateral displacement of the medial canthi,  hypochromic irides with segmental or total  heterochromia (Fig. 15.55), and choroidal depigmentation.    Fig. 15.53 Ocular signs in tyrosinase-negative  oculocutaneous albinism. (A) Marked iris translucency;  (B) ‘pink eye’ appearance; (C) severe fundus  hypopigmentation and foveal aplasia   Fig. 15.54 Tyrosinase-positive oculocutaneous albinism.  (A) Fair hair and normal skin colour; (B) mild fundus  hypopigmentation   Fig. 15.55 Waardenburg syndrome with iris heterochromia  (segmental in the right eye) and synophrys   In this variant, involvement is predominantly ocular, with normal  skin and hair, although occasionally hypopigmented skin macules  may be seen. Inheritance is usually XLR but occasionally AR.  Female carriers are asymptomatic, but may show partial iris trans-  lucency, macular stippling and mid-peripheral scattered areas of  depigmentation and granularity (Fig. 15.56). Affected males have  hypopigmented irides and fundi.    A cherry-red spot at the macula (Fig. 15.57) is a clinical sign seen  in the context of thickening and loss of transparency of the retina  at the posterior pole. The fovea is the thinnest part of the retina,  allowing persistent transmission of the underlying vascular  choroidal hue when the surrounding retina becomes relatively  opaque. Causes include:   • Metabolic storage diseases. A group of rare inherited  metabolic diseases, often enzyme deficiencies, leads to the  pathological accumulation of lipid-based material in various  tissues. With the passage of time the spot becomes less  evident due to retinal nerve fibre layer degeneration, and  consecutive optic atrophy is seen. They are almost  exclusively AR. Some individual storage disorders are:  o GMi gangliosidosis (generalized): neurological features  are severe, with death typically by the age of 2 years.   features myoclonus and seizures, but is compatible with a  normal life span; a more severe form causes severe  neurodegeneration and death in early childhood. Corneal  clouding and optic atrophy may be seen,  o GM2 gangliosidosis: this encompasses two conditions,  Tay-Sachs disease and Sandhoff disease. In both, there is  progressive neurological deterioration, with early  blindness and death.   o Niemann-Pick disease: of the three main types (A-C),  only the first two feature a cherry-red spot. Abnormal  ocular motility occurs in Type C (chronic neuropathic),  o Farber disease: Systemically, aphonia, dermatitis,   lymphadenopathy, psychomotor retardation, renal and  cardiopulmonary disease may develop. Ocular features  additional to cherry-red spot development include  pinguecula-like conjunctival lesions and nodular corneal  opacity.   13). Retinal clouding results from oedema; the appearance is  an acute sign only.   • Retinotoxicity due to specific agents including quinine,  dapsone, gentamicin, carbon monoxide and methanol.   • Commotio retinae (see Ch. 21); oedema due to blunt  trauma.   • Miscellaneous. The term can be used more loosely to  encompass a variety of conditions giving a dark or reddish  central macular appearance such as a macular hole.   Anatomy of the peripheral retina 682  Innocuous peripheral retinal  degenerations 682  Sites of vitreous adhesion 683  Definitions 683  Clinical examination 685  Ultrasonography 688   The ciliary body starts 1 mm from the limbus and extends poste¬  riorly for about 6 mm. The anterior 2 mm consist of the pars  plicata, the remaining 4 mm the flattened pars plana. In order not  to endanger either the lens or retina, the optimal location for a  pars plana surgical incision or intravitreal injection is 4 mm and  3.5 mm posterior to the limbus in phakic and pseudophakic eyes  respectively. An incision through the mid-pars plana will usually  be located anterior to the vitreous base (see below).   The ora serrata (Fig. 16.1) is the junction between the retina and  ciliary body. In retinal detachment (RD), fusion of the sensory  retina with the retinal pigment epithelium (RPE) and choroid  limits forward extension of sub retinal fluid (SRF) at the ora.  However, there is no equivalent adhesion between the choroid and  sclera, and choroidal detachments may progress anteriorly to  involve the ciliary body (ciliochoroidal detachment).   • Dentate processes are tapering extensions of retina onto the  pars plana; they are more marked nasally than temporally  and display marked variation in contour.   • Meridional folds (Fig. 16.2A) are small radial folds of  thickened retinal tissue in line with dentate processes, most    commonly in the superonasal quadrant. A fold may  occasionally exhibit a small retinal hole at its apex. A  meridional complex is a configuration in which a dentate  process, usually with an associated meridional fold, is  aligned with a ciliary process.   • Enclosed oral bays (Fig. 16.2B) are small islands of pars  plana surrounded by retina as a result of meeting of two  adjacent dentate processes. They should not be mistaken for  retinal holes.   The vitreous base (Fig. 16.3) is a 3-4 mm wide zone straddling the  ora serrata, throughout which the cortical vitreous is strongly  attached. Following posterior vitreous detachment (PVD), the  posterior hyaloid face remains attached at the vitreous base. Pre¬  existing retinal holes within the attached vitreous base do not lead  to RD. Blunt trauma may cause an avulsion of the vitreous base,  with tearing of the non-pigmented epithelium of the pars plana  along the base’s anterior border and of the retina along the base’s  posterior border.   Peripheral retinal degenerations and other lesions carrying the  potential to lead to RD are described separately.   • Microcystoid (peripheral cystoid) degeneration consists of  tiny vesicles with indistinct boundaries on a greyish-white  background, making the retina appear thickened and less  transparent (Figs 16.4A and B). The degeneration starts  adjacent to the ora serrata and extends circumferentially and   Fig. 16.2 Normal variants of the ora serrata. (A) Meridional  fold with a small retinal hole at its base; (B) enclosed oral  bay    posteriorly with a smooth undulating posterior border.  Microcystoid degeneration is present in essentially all adult  eyes, increasing in extent with age. It is not in itself causally  related to RD, though it may give rise to typical degenerative  retinoschisis.   • Paving stone degeneration is characterized by discrete  yellow-white patches of focal chorioretinal atrophy that may  have pigmented margins (Fig. 16.4B). It is typically found  between the equator and the ora, and is more common in  the inferior fundus. It is present to some extent in at least  25% of normal eyes.   • Reticular (honeycomb) degeneration is an age-related  change consisting of a fine network of perivascular  pigmentation that sometimes extends posterior to the  equator (Figs 16.4C and D).   • Peripheral drusen. Clustered or scattered small pale discrete  lesions (Fig. 16.4E) that may have hyperpigmented borders  (Fig. 16.4F); they are similar to drusen at the posterior pole  and usually occur in the eyes of older individuals.   • Pars plana cyst. Clear-walled cysts (Fig. 16.4G), usually  small, are derived from non-pigmented ciliary epithelium.  They are present in 5-10% of eyes, and are more common  temporally. They do not predispose to RD.   The peripheral cortical vitreous is loosely attached to the internal  limiting membrane (ILM) of the sensory retina. Sites of stronger  adhesion in the normal eye include:   Abnormal adhesions may lead to retinal tear formation following  PVD, or to vitreomacular interface disease; most are discussed in  detail later in this chapter.   • Retinal detachment (RD). RD refers to separation of the  neurosensory retina (NSR) from the RPE. This results in the  accumulation of SRF in the potential space between the NSR  and RPE.   • Rhegmatogenous (Greek rhegma - break) RD requires a  full-thickness defect in the sensory retina, which permits  fluid derived from synchytic (liquefied) vitreous to gain  access to the subretinal space. RRD, as opposed to the  presence merely of a cuff of SRF surrounding a retinal break,  is said to be present when fluid extends further than one  optic disc diameter from the edge of the break.   • Tractional RD. The NSR is pulled away from the RPE by  contracting vitreoretinal membranes in the absence of a  retinal break.   • Exudative (serous, secondary) RD. SRF is derived from the  vessels of the NSR and/or choroid.   • Combined tractional-rhegmatogenous RD results when a  retinal break is caused by traction from an adjacent area of  fibrovascular proliferation.   • Subclinical RD is generally used to refer to an asymptomatic  break surrounded by a relatively small amount of SRF, by   (A) Microcystoid seen on scleral indentation; (B) paving  stone with adjacent microcystoid; (C) and (D) honeycomb  (reticular); (E) and (F) peripheral drusen; (G) pars plana cyst   (Courtesy of U Rutnin, CL Schepens, from American Journal of Ophthalmology,  1967;64:1042 - fig. A; S Chen - figs B, C, E and G)    definition extending further than one disc diameter away  from the edge of the break but less than two disc diameters  posterior to the equator. It does not usually give rise to a  subjective visual field defect. The term is sometimes also  used to describe an asymptomatic RD of any extent.   The term binocular indirect ophthalmoscopy (BIO) is by conven¬  tion used to refer to the head-mounted technique, though strictly  it also applies to slit lamp indirect ophthalmoscopy. BIO allows  retinal visualization through a greater degree of media opacity  than slit lamp biomicroscopy, and readily facilitates scleral inden¬  tation. Light is transmitted from the headset to the fundus through  a condensing lens held at the focal point of the eye, providing an  inverted and laterally reversed image that is observed through a  stereoscopic viewing system (Fig. 16.5A).   • Lenses of various powers and diameters are available for  BIO (Fig. 16.5B); a lens of lower power confers increased  magnification but a smaller field of view. Yellow filters may  improve patient comfort.   commonly used for general examination of the fundus,  o 28 D (magnification with the head-mounted set of  X2.27, and a field of 53 0 ) has a shorter working distance   o 40 D (magnification X1.5, field 65°) is used mainly to  examine small children; a broad fundus scan can be  acquired rapidly; it can also be used at the slit lamp to  provide very high magnification.   O Panretinal 2.2 combines magnification similar to the 20 D  lens with a field of view similar to that of the 28 D, and  can be used with small pupils,  o Ultra-high magnification lenses for macular and  optic disc examination (e.g. Macula Plus® 5.5) are  available.   • Technique. The patient should be supine on a bed or   reclining chair rather than sitting upright. The pupils should  be dilated. Reducing the ambient illumination is often  helpful in improving contrast and allowing a lower incident  light intensity to be used. The eyepieces are set at the correct  interpupillary distance and the beam aligned so that it is  located in the centre of the viewing frame. The patient is  instructed to keep both eyes open at all times; if necessary,  the patient’s eyelids are gently separated with the fingers.   The lens is taken into one hand with the flat surface facing  the patient. The peripheral fundus should be examined first  in order to allow the patient to adapt to the light. The  patient is asked to move the eyes into optimal positions for  examination, e.g. looking away from the examiner to  facilitate examination of the retinal periphery. For the  examination of small children (e.g. retinopathy of  prematurity - see also Ch. 13) a speculum may be utilized to    keep the eyelids apart, with an implement such as a squint  hook employed to direct the position of the eye.   indentation (depression) is the enhancement of visualization  of the retina anterior to the equator; it also permits kinetic  evaluation (Fig. 16.6). Indentation should be attempted only  after the basic technique of BIO has been mastered; it  requires practised coordination between the relative position  of the indenter and the viewing apparatus, as well as care to  prevent patient discomfort. For example, to view the ora  serrata at 12 o’clock, the patient is asked to look down and  the scleral indenter (a cotton-tipped applicator is preferred   Fig. 16.6 Appearance of retinal breaks in detached retina.  (A) Without scleral indentation; (B) with indentation   Fig. 16.7 Technique of scleral indentation. (A) Insertion of  indenter; (B) indentation    by some practitioners) is applied to the outside of the upper  eyelid at the margin of the tarsal plate (Fig. 16.7A). With the  indenter in place, the patient is asked to look up; at the same  time the indenter is advanced into the anterior orbit parallel  with the globe, and the examiner’s eyes are aligned with the  condensing lens and indenter (Fig. 16.7B). Gentle pressure is  exerted so that a mound is created; after adequate viewing,  the indenter is gently moved to an adjacent part of the  fundus. The indenter should be kept tangential to the globe  at all times, as perpendicular indentation will cause pain and  even risk perforation if the sclera is very thin. For viewing  the 3 and 9 o’clock positions, indentation directly on the  sclera is sometimes necessary, facilitated by topical  anaesthesia. Indentation can also be performed at the slit  lamp using some fundus contact lenses.   A range of diagnostic contact and non-contact lenses are available  for use with the slit lamp. Contact lenses should not be used if a  penetrating injury is suspected or in the presence of corneal  trauma, hyphaema or corneal infection.   O 60 D. High-magnification lens optimized for viewing the  posterior pole. High working distance (13 mm).    Fig. 16.8 Diagnostic contact lenses. (A) Three-mirror lens;  (B) Goldmann 904® lens with indentation attachment    o 90 D. Wider-field lens with lower magnification and  shorter (7 mm) working distance. Can be used with  smaller pupils.   o Miscellaneous. Numerous other lenses are available,  offering qualities such as a very wide field of view and  extremely small pupil capability.   • Three-mirror contact lens (Fig. 16.8A). A central lens gives a  30° upright view of the posterior pole. An equatorial mirror  (the largest) enables visualization from 30° to the equator, a  peripheral mirror (intermediate) views the fundus between  the equator and the ora serrata, and a gonioscopy mirror  (smallest and dome-shaped) may be used for gonioscopy or    for visualization of the extreme retinal periphery and  sometimes the pars plana. A viscous coupling substance is  required to bridge a gap between the cornea and the  apposed lens. To visualize the entire fundus the lens is  rotated for 360° using first the equatorial mirror and then  the peripheral mirrors.   • Scleral indentation at the slit lamp can be accomplished  using a three-mirror lens with a special attachment (Eisner  funnel) or a purpose-made ora serrata contact lens that  combines a mirror angled similarly to a gonioscopy lens  with an incorporated attachment to facilitate scleral  depression (e.g. Goldmann 904® - Fig. 16.8B).   • Miscellaneous contact lenses are divided principally into  those conferring high magnification for an optimal posterior  pole view, and those offering a wide field of view, allowing  visualization extending to the ora serrata under optimal  conditions. Small pupil capability is available, and a flange is  offered on many lenses with the aim of improving stability  of retention and of lens position on the eye.   When available, wide-field photographic imaging can be an excel¬  lent aid in recording the features of a retinal detachment, but  documentation generally takes the form of a manually drawn illus¬  tration that optimally is colour-coded (Fig. 16.9). RD boundaries  are drawn by starting at the optic nerve and then extending to the  periphery; detached retina is shaded in blue and flat retina in red.  The course of retinal vessels (usually veins) is indicated with blue.  Retinal breaks are drawn in red with blue outlines; the flap of a  retinal tear is also drawn in blue. Thin retina may be represented  by red hatching outlined in blue and lattice degeneration by blue  hatching outlined in blue. Retinal pigment is indicated in black,  retinal exudates in yellow and vitreous opacities in green.   Ultrasonography (US) utilizes high frequency sound waves that  produce echoes as they strike the interface between acoustically  distinct structures. B-scan (two-dimensional) US is a key tool in  the diagnosis of RD in eyes with opaque media, particularly severe  vitreous haemorrhage (Fig. 16.10).   • The examiner typically sits behind the patient’s head and  holds the US probe with the dominant hand.   • Methylcellulose or an ophthalmic gel is placed on the tip of  the probe to act as a coupling agent.   • The B-scan probe incorporates a marker for orientation that  correlates with a point on the display screen, usually to the  left.   • Vertical scanning is performed with the marker on the probe  orientated superiorly (Fig. 16.11A).   • Horizontal scanning is performed with the marker  orientated towards the nose (Fig. 16.11B).   • The eye is then examined with the patient looking straight  ahead, up, down, left and right. For each position a vertical  and horizontal scan can be performed.   • The examiner then moves the probe in the opposite  direction to the movement of the eye. For example, when  examining the right eye the patient looks to the left and  probe is moved to the patient’s right, the nasal fundus  anterior to the equator is scanned and vice versa. Dynamic  scanning is performed by asking the patient to move the eye,  whilst the probe position is maintained.   • Gain adjusts the amplification of the echo signal, similar to  volume control of a radio. Higher gain increases the   (A) Vertical scanning with the marker pointing towards the  brow; (B) horizontal scanning with the marker pointing  towards the nose   sensitivity of the instrument in displaying weak echoes such  as vitreous opacities. Lower gain only allows display of  strong echoes such as the retina and sclera, though improves  resolution because it narrows the beam.    Patients with any predisposing lesion, or indeed any high risk  features for RD, should be educated about the nature of symptoms  of PVD and RD and the need to seek review urgently if these  occur.   • Prevalence. Lattice degeneration is present in about 8% of  the population. It probably develops early in life, with a peak  incidence during the second and third decades. It is found  more commonly in moderate myopes and is the most  important degeneration directly related to RD. Lattice is  present in about 40% of eyes with RD.   • Pathology. There is discontinuity of the internal limiting  membrane with variable atrophy of the underlying NSR. The  vitreous overlying an area of lattice is synchytic but the  vitreous attachments around the margins are exaggerated  (Fig. 16.12).   O Spindle-shaped areas of retinal thinning, commonly  located between the equator and the posterior border of  the vitreous base (Fig. 16.13A).  o Sclerosed vessels forming an arborizing network of white  lines is characteristic (Fig. 16.13B).  o Some lesions may be associated with ‘snowflakes’,  remnants of degenerate Muller cells,  o Associated hyperplasia of the RPE is common,  o Small holes are common (see Fig. 16.13A).   o Tears may develop consequent to a posterior vitreous  detachment (PVD), when lattice is sometimes visible on  the flap of the tear (Fig. 16.13C).  o Atrophic holes may rarely (2%) lead to RD; the risk is  higher in young myopes. In these patients the RD may  not be preceded by acute symptoms of PVD (see below)  and SRF usually spreads slowly so that diagnosis may be  delayed.   • Management. Asymptomatic areas of lattice are generally  not treated prophylactically, even if retinal breaks are seen,  unless particular risk factors are present, perhaps including  RD in the fellow eye; treatment of the fellow eye when  extensive lattice (more than 6 clock hours) is present, or  there is high myopia, may actually be associated with a  higher risk of detachment. However, the patient should be  advised of the symptoms of RD, optimally including the  provision of written information. Many practitioners advise  routine annual review of eyes with lattice, with or without  asymptomatic round holes, particularly in young myopes.  An associated asymptomatic U-tear should be managed as  discussed later in the chapter.   Snailtrack degeneration is characterized by sharply demarcated  bands of tightly packed ‘snowflakes’ that give the peripheral retina  a white frost-like appearance (Figs 16.14A and B). It is viewed by  some as a precursor to lattice degeneration. Marked vitreous   Fig. 16.13 Wide-field images of lattice degeneration. (A)  Multiple lesions with small holes; (B) sclerosed vessels  forming a characteristic white network; a vortex vein is  seen superonasally; (C) retinal detachment with lattice on  the flap of the tear   Fig. 16.14 (A) Snailtrack degeneration; (B) and (C) wide-field  images of lesions before and after limited laser retinopexy    traction is seldom present so that U-tears rarely occur, although  round holes are relatively common. Prophylactic treatment (Fig.  16.14C) is usually unnecessary, though review every 1-2 years may  be prudent as RD occurs in a minority.   A cystic retinal tuft (CRT), also known as a granular patch or  retinal rosette, is a congenital abnormality consisting of a small,  round or oval, discrete elevated whitish lesion, typically in the  equatorial or peripheral retina, more commonly temporally (Fig.  16.15A); there may be associated pigmentation at its base. It is  comprised principally of glial tissue; strong vitreoretinal adhesion  is commonly present and both small round holes (Fig. 16.15B) and  horseshoe tears can occur. It is likely to be an under-recognized  lesion, though this may change with the adoption of wide-field  imaging; CRT are present in up to 5% of the population (bilateral  in 20%) and may be the causative lesion in 5-10% of eyes with RD,  though the risk of RD in a given eye with CRT is probably well  under 1%.   • Prevalence. Degenerative retinoschisis (RS) is present in  about 5% of the population over the age of 20 years and is  particularly prevalent in hypermetropia.   • Pathology. RS is believed to develop from microcystoid  degeneration by a process of gradual coalescence of  degenerative cavities (Fig. 16.16A), resulting in separation or  splitting of the NSR into inner and outer layers (Figs 16.16B  and C), with severing of neurones and complete loss of  visual function in the affected area. In typical retinoschisis  the split occurs in the outer plexiform layer, and in the less  common reticular retinoschisis at the level of the nerve  fibre layer.   o Photopsia and floaters are absent because there is no  vitreoretinal traction.   o It is rare for the patient to notice a visual field defect,  even with spread posterior to the equator,  o Occasionally symptoms result from vitreous haemorrhage  or a progressive RD.   • Signs. RS is bilateral in up to 80%. Distinction between  the typical and reticular types is difficult clinically, though  the inner layer is thinner and tends to be more elevated  in the latter; differentiation is based principally on  behaviour, with complications much more common   inferotemporal periphery of both fundi, appearing as an  exaggeration of microcystoid degeneration with a smooth  immobile dome-shaped elevation of the retina (Fig.  16.16D).   o The elevation is convex, smooth, thin and relatively  immobile (Fig. 16.17), unlike the opaque and corrugated  appearance of a rhegmatogenous RD.   Fig. 16.15 Cystic retinal tuft. (A) Isolated uncomplicated lesion;  (B) tuft with small round hole   (Courtesy of S Lorenzon - fig. A; Courtesy of NE Byer, from The Peripheral  Retina in Profile, A Stereoscopic Atlas, Criterion Press, Torrance , CA 1982  - fig■ B)    o The thin inner leaf of the schisis cavity may be mistaken,  on cursory examination, for an atrophic long-standing  rhegmatogenous RD but demarcation lines and  secondary cysts in the inner leaf are absent,  o The lesion may progress circumferentially until it has  involved the entire periphery. The typical form usually  remains anterior to the equator; the reticular type is more  likely to spread posteriorly.   o The presence of a pigmented demarcation line is likely to  indicate the presence of associated RD.  o The surface of the inner layer may show ‘snowflakes’  (whitish remnants of Muller cell footplates - see Figs  16.17 and 16.18) as well as sclerosis of blood vessels, and  the schisis cavity may be bridged by grey-white tissue  strands.   o Breaks may be present in one or both layers. Inner layer  breaks are small and round (Fig. 16.18A), whilst the less  common outer layer breaks are usually larger, with rolled  edges (Figs 16.18A and B) and located behind the equator,  o Microaneurysms and small telangiectases are common,  particularly in the reticular type.    o If a visual field defect is detectable it is absolute, rather  than relative as in RD.   • Complications are uncommon, and are thought to be much  more likely in the reticular form.   o RD is rare; even in an eye with breaks in both layers the  incidence is only around 1%. The detachment is almost  always asymptomatic, infrequently progressive and rarely  requires surgery.   o Posterior extension of RS to involve the fovea is very rare  but can occur; progression is generally very slow,  o Vitreous haemorrhage is rare.   • Management. Though RD is rare, discussion of the  symptoms is prudent in all patients, especially those with  double layer breaks.   examination, especially if breaks are not present in both  layers, probably does not require routine review, though  a routine community optometric examination every 1-2  years may be prudent.   o A large RS should be observed periodically, particularly if  breaks are present in both layers or it extends posterior to   Fig. 16.16 Development of retinoschisis. (A) Histology showing intraretinal cavities bridged by Muller cells;   (B) OCT appearance showing separation principally in the outer plexiform layer; (C) OCT of retinal detachment for  comparison; (D) circumferential microcystoid degeneration with progression to retinoschisis supero- and  inferotemporally   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 - fig. A; S Chen - figs B and C)    the equator; the review interval is individualized.  Photography and visual field testing are useful, with  optical coherence tomography (OCT) imaging when  posterior extension is present. OCT is also useful  for distinguishing between RS and RD (see Figs 16.16B  and C).   o Retinopexy or surgical repair may be indicated for  relentless progression towards the fovea, when  complication by retinal detachment should be excluded.  Some authorities also advocate prophylactic retinopexy  of the posterior border of a large bullous RS with  substantial breaks to prevent progression to  symptomatic RD.    o Progressive symptomatic RD should be addressed  promptly. More than one procedure may be necessary;  scleral buckling may be adequate for smaller RD with  small outer layer breaks, but vitrectomy is generally  indicated for more complex RD.   This refers to a common (15%) phenomenon caused by an aber¬  rant zonular fibre extending posteriorly to be attached to the  retina near the ora serrata, and exerts traction on the retina at its  base. It is typically located nasally. The risk of retinal tear forma¬  tion is around 2%, and periodic long-term review is generally  recommended.   Fig. 16.17 (A) Retinoschisis; (B) composite image of the same  lesion showing merging microcystoid degeneration   • ‘White with pressure’ (WWP) refers to retinal areas in  which a translucent white-grey appearance can be induced  by scleral indentation (Fig. 16.19A). Each area has a fixed  configuration that does not change when indentation is  moved to an adjacent area. It may also be observed along the  posterior border of islands of lattice degeneration, snailtrack  degeneration and the outer layer of acquired retinoschisis. It  is frequently seen in normal eyes and may be associated with  abnormally strong attachment of the vitreous gel, though  may not indicate a higher risk of retinal break formation.   • ‘White without pressure’ (WWOP) has the same  appearance as WWP but is present without scleral  indentation (Fig. 16.19B). WWOP corresponds to an area of  fairly strong adhesion of condensed vitreous (Fig. 16.19C).   On cursory examination a normal area of retina surrounded  by white without pressure may be mistaken for a flat retinal  hole (Fig. 16.20A). However, retinal breaks, including giant    tears, occasionally develop along the posterior border of  white without pressure (Fig. 16.20B). For this reason, if white  without pressure is found in the fellow eye of a patient with  a spontaneous giant retinal tear, prophylactic therapy should  be considered. Regular review should be considered for  treated and untreated eyes, though evidence for the benefit  of this is limited.   Diffuse choroidal/chorioretinal atrophy in myopia is characterized  by diffuse or circumscribed (Fig. 16.21) choroidal depigmentation,  commonly associated with thinning of the overlying retina, and  occurs typically in the posterior pole and equatorial area of highly   (B) large outer layer break; retinal vessels in the inner layer  can be seen traversing the rolled edge undiverted   Fig. 16.19 (A) White with pressure; (B) white without pressure;  (C) strong attachment of condensed vitreous gel to an area  of ‘white without pressure’   (Courtesy of NE Byer, from The Peripheral Retina in Profile, A Stereoscopic  Atlas, Criterion Press, Torrance, CA 1982 - fig. A; S Chen - fig. B; CL  Schepens, ME Hartnett and T Hirose, from Schepens’ Retinal Detachment  and Allied Diseases, Butterworth-Heinemann 2000 - fig. C)    myopic eyes. Retinal holes developing in the atrophic retina may  occasionally lead to RD. Because of lack of contrast, small holes  may be very difficult to visualize.   Posterior vitreous detachment (PVD) refers to separation of the  cortical vitreous, along with the delineating posterior hyaloid  membrane (PHM), from the neurosensory retina posterior to the  vitreous base. PVD occurs due to vitreous gel liquefaction with age  (synchysis) to form fluid-filled cavities (Fig. 16.22A), and subse¬  quently condensation (syneresis), with access to the preretinal  space allowed by a dehiscence in the cortical gel and/or PHM. The  prevalence of PVD increases with age, and in individuals in their  80s is likely to be at least 60%. It is typically spontaneous, but can  be induced by events such as cataract surgery, trauma, uveitis and  panretinal photocoagulation. The time taken for a PVD to com¬  plete after initiation is believed to be variable, but probably occurs  in stages over the course of months in many patients. Perifoveal  hyaloid detachment is followed by foveal separation, then detach¬  ment from the posterior retina as far as the equator, attachment  initially being retained at the optic disc; subsequently complete  detachment of the cortical vitreous as far anteriorly as the vitreous  base takes place (Fig. 16.22B). With the exception of the vitreous  base, physiological attachments to the retina and other structures  are disengaged in the course of a normal PVD. Complications,  many of which require treatment, occur in up to 27%.   o Flashing lights (photopsia) in PVD is often described as a  lightning-like arc induced by eye or head movement, and  is more noticeable in dim illumination. It is almost  always seen in the temporal periphery; the mechanism is  uncertain, but may relate to traction on the optic disc  and possibly at sites of vitreoretinal adhesion, including  actual or potential retinal tears,  o Floaters (myodesopsia) are mobile vitreous opacities (Figs  16.22C and D) most evident against a bright pale  background. They are often described as spots, cobwebs  or flies (muscae volitantes), and are commonly present in  individuals without a PVD, especially myopes. A Weiss  ring (Figs 16.22E and F) is the detached former    attachment to the margin of the optic disc, and may be  seen by the patient as a circle or other large solitary lesion;  its presence does not necessarily indicate total PVD, nor  does its absence confirm the absence of PVD since it may  be destroyed during the process of separation. Floaters  can also be due to vitreous blood (see below),  o Blurred vision. A diffuse haze may be due to dispersed  haemorrhage within the vitreous gel, with a variable  accompanying reduction in VA; bleeding can arise from a  torn retinal blood vessel or from the site of a retinal  break. Blurring can also be caused by a visually significant  PHM or floaters in the visual axis, which may also cause  impairment (usually slight) of acuity.   o The detached PHM can often be seen clinically on slit  lamp examination as a crumpled translucent membrane  in the mid-vitreous cavity behind which the cavity is  optically clear (Fig. 16.23 A).   o Haemorrhage may be indicated by the presence of red  blood cells in the anterior vitreous or as (usually small)  focal intragel collections, or preretinally, when it  sometimes forms a crescent shape bordering the limit of  PHM detachment. Its presence should prompt a careful  search for a retinal break (40-90%), particularly with  larger amounts - in such cases breaks tend to be  posterior.   o Pigment granules in the anterior vitreous on slit lamp  examination (the Shafer sign or ‘tobacco dust’ - see Fig.  16.28) are larger, darker and less reflective than red blood  cells. Their presence raises the possibility of a retinal break  (up to 95% sensitivity), with loss of continuity allowing  communication between the RPE and vitreous cavity,  o Vitreous cells, if numerous, may signify the presence of a  break.   • Investigation. B-scan ultrasound (Fig. 16.23B) can  demonstrate the extent of PVD; OCT can show posterior  pole separation (Fig. 16.23C).   Patients with substantial acute symptoms of a PVD should be  examined as soon as practicable, usually within 24-48 hours, with  greater urgency in the presence of risk factors including myopia,  a past or family history of RD, high-risk syndromes such as Stick¬  ler, pseudophakia and symptoms such as a visual field defect,  reduced vision or very prominent floaters. Enquiry should be  made about the presence of any condition predisposing to  non-PVD vitreous haemorrhage, usually diabetes mellitus. If there  is only a single small floater and no photopsia, evidence suggests  the risk of retinal break in the symptomatic eye is insignificantly  higher than that of the asymptomatic fellow eye, so that urgent  assessment may not necessarily be required.   • Examination. The anterior vitreous should be assessed for  the presence of blood and pigment. Careful retinal  examination including visualization of the ora serrata for    Fig. 16.22 Vitreous degenerative changes. (A) Synchysis and syneresis; (B) complete posterior vitreous detachment; (C)  biomicroscopy showing vitreous condensation in a pseudophakic eye; (D) vitreous degenerative condensation on wide-field  imaging; (E) Weiss ring on slit lamp biomicroscopy, with the optic disc in the background; (F) Weiss ring on wide-field  imaging    Fig. 16.23 Posterior vitreous detachment. (A) Biomicroscopy showing detached and collapsed gel; (B) ultrasound B-scan;   (Courtesy of CL Schepens, CL Trempe and M Takahashi, from Atlas of Vitreous Biomicroscopy, Butterworth-Heinemann 1999 - fig. A; S Chen - figs B and C)    360° should be performed, and should generally include  binocular indirect ophthalmoscopy or contact lens scleral  indentation. An asymptomatic fellow eye should always be  examined; if 10 or more vitreous cells are present in a 1 mm  slit lamp field the incidence of a retinal break in a fellow  asymptomatic eye has been reported as over 30%.   • Subsequent management. Recommendations for review  vary and the following is a general guide,  o If there are no suspicious findings (e.g. vitreous blood)  on examination and no pre-existing risk factors as  discussed above then routine review may not be  necessary; the presence of features associated with higher  risk should lead to review after an interval of 1-6 weeks  depending on individual characteristics. Some authorities  recommend further review in 6-12 months,  o Patients who present with multiple prominent floaters or  hazy vision should be reviewed carefully as this has been  found to be associated with a higher risk of retinal break.    o Discharged patients should be given clear instructions  emphasizing the need to re-attend urgently in the event  of significant new symptoms; optimally, written  information reiterating the advice should be provided.  Assurance can be given that in most cases the floaters will  resolve and become much less noticeable with time,  though exceptionally vitrectomy is necessary,  o If an area of the fundus cannot be viewed clearly due to  obscuration by blood then weekly review is prudent,  o Presentation with diffuse fundus-obscuring vitreous  haemorrhage (in the absence of a condition predisposing  to non-PVD vitreous haemorrhage) is associated with a  very high risk of retinal break (90%) and retinal  detachment (40%). A relative afferent pupillary defect  should be excluded, and B-scan ultrasonography  performed regularly until resolution in order to exclude  an underlying detachment or identifiable break. A very  low threshold for vitrectomy should be adopted,   particularly in the presence of other risk factors, notably  prior RD in the fellow eye.   Retinal breaks develop in most cases as a result of traction at sites  of vitreoretinal adhesion, and occur in up to about 1 in 5 eyes with  symptomatic PVD. In the presence of a break, retrohyaloid fluid  has access to the subretinal space. Asymptomatic retinal breaks of  some sort are present in about 8% of the general population.   • Timing. Breaks are usually present at or soon after the onset  of symptoms of PVD, although in a significant minority (up  to 5%) tear formation may be delayed by several weeks.   • Location. Tears associated with PVD are usually located in  the upper fundus and are more commonly temporal than  nasal. Macular breaks related to PVD are rare, but when  they occur are usually round and in a myopic eye; they are  aetiologically distinct from age-related macular holes.   • Morphology. Retinal breaks may be flat or associated with a  surrounding cuff of SRF. If fluid extends more than one disc  diameter from the edge of a break, a retinal detachment is  said to be present.   o U-tears (horseshoe) consist of a flap, its apex pulled  anteriorly by the vitreous, the base remaining attached to  the retina (Fig. 16.24A).   o Operculated tears in which the flap is completely torn  away from the retina by detached vitreous gel to leave a  round or oval break (Fig. 16.24B); the separated retinal  patch is known as an operculum and can usually be seen  suspended in the vitreous cavity in the region of the  break, which can be difficult to delineate - this may be  aided by the presence of preretinal blood at the site,  o Retinal holes (Fig. 16.24C) are round or oval, usually  smaller than tears and carry a lower risk of RD, which  when it does occur is most commonly a slowly  progressive shallow RD in a young female myope. A PVD  is not necessarily present, but if vitreous separation has  occurred an operculum may be visible in the nearby  vitreous cavity. Round holes may occur in lattice  degeneration. Round holes leading to RD may be distinct  in most cases from the round atrophic retinal holes that  are a variant of paving stone degeneration and probably  carry a lower risk, though clinically distinction is  commonly not possible.   o Dialyses are circumferential tears along the ora serrata;  vitreous gel remains attached to the posterior margin.  They can cause RD, often slowly progressive, in the  absence of a PVD, and can result from blunt ocular  trauma. They typically appear as large very peripheral  breaks with a regular rolled edge (Fig. 16.24D).    o Giant retinal tears (Fig. 16.24E and F) are a variant of  U-tear, by definition involving 90° or more of the retinal  circumference. In contrast to dialysis, vitreous gel  remains attached to the anterior margin of the break.  They are most frequently located in the immediate  post-oral retina or, less commonly, at the equator.   The management of many categories of break remains imperfectly  defined, and approaches differ between retinal subspecialists,  according to locally available resources and taking into account  general patient considerations such as the likelihood of attendance  for review. There has broadly been a trend in recent years towards  less aggressive prophylactic treatment of asymptomatic and oper¬  culated breaks, with substitution by observation and patient edu¬  cation. Patients should always be instructed about the symptoms  of vitreous and retinal detachment, optimally supplemented by  written information, and should seek review urgently in the event  of new features. The risk of prophylaxis is usually very small but  include new break formation; very severe complications have  exceptionally been reported.   o Miscellaneous factors include a history of RD in the  fellow eye, prior cataract surgery (particularly if vitreous  loss occurred), myopia, a family history of RD and  systemic conditions such as Marfan, Stickler and  Ehlers-Danlos syndromes. Evidence suggests that  prophylactic treatment should be considered for  asymptomatic breaks, including round operculated and  atrophic holes prior to cataract surgery, laser  capsulotomy and possibly trabeculectomy and intravitreal  injection, particularly when other risk factors are present,  o Symptomatic breaks associated with an acute PVD are  higher risk than asymptomatic breaks detected on routine  examination.   o Size. Larger breaks carry a higher risk of progression,  o Persistent vitreoretinal traction. An operculated tear, in  which the focus of vitreous traction has detached from  the break, is safer than a break, typically a U-tear, in  which traction persists; round holes are rarely associated  with ongoing vitreoretinal traction. Apparent  demonstration of a complete PVD clinically or on  ultrasonography, with no residual attachment in the  region of the break, is a favourable feature, though  cannot be relied upon.   o Shape. U-tears are higher risk than round holes,  o Location. Superior breaks are at higher risk of   progression to RD, probably due to the protective effect  of gravity upon inferior breaks. With superotemporal  tears, the macula is threatened early in the event of RD.  Equatorial breaks are more likely to progress than oral  breaks, as the latter are usually located within the vitreous  base.   o Pigmentation around a retinal break indicates chronicity  and a degree of stability,  o Aphakia, now rare, confers a higher risk.    Fig. 16.24 Retinal tears. (A) Large U-tear in an area of lattice - laser retinopexy has been performed; (B) operculated tear;   (C) round holes; the white arrows show probable atrophic holes, the black arrow shows a probable operculated hole with  localized subretinal fluid; (D) retinal dialysis; (E) giant retinal tear; (F) vitreous attached to the anterior edge of a giant tear   (Courtesy of S Chen - figs A and B; N Turner - fig. C; C Barry - figs D and E; CL Schepens, ME Hartnett and T Hirose, from Schepens’ Retinal Detachment and  Allied Diseases, Butterworth-Heinemann 2000 - fig. F)   • Acutely symptomatic U-tears. Up to 90% of these lead to  retinal detachment; treatment (see below) reduces the risk to  5% so should always be performed urgently.   • Operculated tears, particularly if asymptomatic, are believed  to generally have a very low risk of progression to RD, and  can safely be observed in most cases. A recommended review  schedule (symptomatic or asymptomatic) is an initial  interval of 2-4 weeks, then 1-3 months, then 6-12 months,  then annually. The presence of an intact bridging vessel  overlying the break may indicate ongoing vitreoretinal  traction - which may also cause vitreous haemorrhage - and  treatment should be considered. Higher-risk factors may  prompt treatment in an individual case.   • Asymptomatic U-tears. The risk of progression to RD is low  at 5%, which is a similar rate to that in treated symptomatic  U-tears, and observation as for operculated tears is generally  safe in the absence of factors indicating higher risk.   • Traumatic retinal breaks, including acute dialyses, should  always be treated.   • Asymptomatic dialyses are sometimes observed, but in most  cases are treated surgically if an associated RD is present.   • Asymptomatic subclinical RD. Progression is not invariable  in RD discovered incidentally, with perhaps 10% becoming  symptomatic over 2-3 years, and a decision regarding  intervention should be made on a case-by-case basis; for  example, many practitioners would prefer to treat rather  than observe a large superotemporal RD that extends  posterior to the equator, but may observe a small inferior  longstanding-appearing RD. With any option, fully informed  patient consent is vital. If observation is elected, appropriate  review and careful patient advice are critical. Surgery is  generally indicated if progression occurs.   • Asymptomatic flat round holes do not require prophylactic  treatment, but some guidelines recommend review every 1-2  years.   • Long-term review after treatment of retinal breaks may be  important, as a significant minority of index and fellow eyes  will develop further breaks.   Retinal breaks without RD can be treated with laser (via a slit lamp  or BIO) or cryotherapy. In most cases laser is the optimal tech¬  nique as it is more precise, causing less collateral retinal damage,  with a likely lower risk of epiretinal membrane formation. Ade¬  quate treatment of the base of a very peripheral lesion may only  be possible with BIO or cryotherapy due to the requirement for  indentation to visualize the area, unless the practitioner is skilled  at slit lamp indentation. Cryotherapy may be preferred for multi¬  ple contiguous tears or extensive lesions, and in eyes with hazy  media or small pupils.   • Laser retinopexy. Using slit lamp delivery under topical  anaesthesia (occasionally regional or even general  anaesthesia is required), typical settings are a duration of  0.1 second, a spot size of 200-300 pan with a three-mirror  contact lens or 100-200 pan with a wide-field lens, and a    starting power of 200 mW; the power should be adjusted as  appropriate to obtain moderate blanching. With head-  mounted BIO delivery, the spot size is estimated and  adjusted by adjusting the condensing lens (usually 20 D)  position. The lesion is surrounded with two to three rows of  confluent burns (Fig. 16.25). With both forms of laser, care  should be taken to identify appropriate landmarks frequently  to avoid inadvertent macular damage.   Fig. 16.25 Laser retinopexy. (A) U-tear in lattice prior to,  (B) immediately following and (C) 2 months after laser    Fig. 16.26 Pigmentation and chorioretinal atrophy following  prophylactic cryotherapy to several retinal breaks    • Cryoretinopexy. Subconjunctival or regional anaesthesia is  commonly required. For lesions behind the equator, a small  conjunctival incision may be necessary for access. A lid  speculum is used. The cryotherapy probe tip must be  exposed beyond its rubber sleeve. The instrument should  initially be purged (e.g. 10 seconds at -25 °C, repeating after  a minute). The treatment temperature is set (typically   -85 °C); it is useful to check the effectiveness of the  instrument by activating it in sterile water for 10 seconds,  when a 5 mm ice ball should form. Under BIO visualization,  the lesion is indented and the foot pedal depressed until  visible whitening of the retina is seen. It is critical not to  remove the tip from the treated area until thawing is allowed  (2-3 seconds). Care should be taken to maintain orientation  of the probe whilst the tip is not visible, and not to mistake  indentation by the shaft of the probe for that of the tip. The  lesion is surrounded by a single row of applications, in most  cases achieved by one or two applications to a tear. The eye  is usually padded afterwards; analgesia is commonly  necessary.   • After treatment the patient should avoid strenuous physical  exertion for about a week until an adequate adhesion has  formed (Fig. 16.26); review should usually take place after  1-2 weeks.   Rhegmatogenous RD affects about 1 in 10 000 of the population  each year, with both eyes eventually affected in about 10%. In most    cases it is characterized by the presence of a retinal break in concert  with vitreoretinal traction that allows accumulation of liquefied  vitreous under the neurosensory retina, separating it from the  RPE. Even though a retinal break is present, a RD will almost never  occur if the vitreous is not at least partially liquefied and traction  is absent. Over 40% of RDs occur in myopic eyes; the higher the  refractive error the greater the risk of RD. Vitreous degeneration  and PVD, and predisposing lesions such as lattice and snailtrack  degeneration, are more common in myopia. Highly myopic eyes  are also at risk from RD due to small round holes in chorioretinal  atrophy and from macular holes. Vitreous loss during cataract  surgery, and laser capsulotomy, also carry a higher risk of RD in  highly myopic eyes.   • Distribution of breaks in eyes with RD is approximately as  follows: 60% superotemporal quadrant, 15% superonasal,   15% inferotemporal and 10% inferonasal. The upper  temporal region should therefore be examined in detail if a  break cannot be detected initially. It should also be  remembered that about 50% of eyes with RD have more  than one break, often within 90° of each other.   • Configuration of SRF. SRF spread is governed by gravity, by  anatomical limits (ora serrata and optic nerve) and by the  location of the primary retinal break. If the primary break is  located superiorly, the SRF first spreads inferiorly on the  same side of the fundus as the break and then superiorly on  the opposite side, so that the likely location of the primary  retinal break can be predicted (modified from Lincoff s  rules):   o A shallow inferior RD in which the SRF is slightly higher  on the temporal side points to a primary break located  inferiorly on that side (Fig. 16.27A).  o A primary break located at 6 o’clock will cause an inferior  RD with equal fluid levels (Fig. 16.27B).  o In a bullous inferior RD the primary break usually lies  above the horizontal meridian (Fig. 16.27C).  o If the primary break is located in the upper nasal   quadrant the SRF will revolve around the optic disc and  then rise on the temporal side until it is level with the  primary break (Fig. 16.27D).   o A subtotal RD with a superior wedge of attached retina  points to a primary break located in the periphery nearest  its highest border (Fig. 16.27E).  o When the SRF crosses the vertical midline above, the  primary break is near to 12 o’clock, the lower edge of the  RD corresponding to the side of the break (Fig. 16.27F).   The classic premonitory symptoms reported in about 60% of  patients with spontaneous rhegmatogenous RD are flashing lights  and floaters associated with acute PVD. After a variable period of  time a curtain-like relative peripheral visual field defect may ensue,  and can progress to involve central vision; in some patients this  may not be present on waking in the morning, due to spontaneous   Fig. 16.27 Distribution of subretinal fluid in relation to the location of the primary retinal break (see text)    absorption of SRF while inactive overnight, only to reappear later  in the day. A lower field defect is usually appreciated more quickly  by the patient than an upper defect. The quadrant of the visual  field in which the field defect first appears is useful in predicting  the location of the primary retinal break, which will be in the  opposite quadrant; the location of photopsia is of no value in  predicting the site of the primary break; flashes are virtually always  temporal. Loss of central vision may be due to involvement of the  fovea by SRF or, infrequently, obstruction of the visual axis by a  large bullous RD.   • Relative afferent pupillary defect (Marcus Gunn pupil) is  present in an eye with an extensive RD.   • Intraocular pressure (IOP) is often lower by about 5 mmHg  compared with the normal eye. If the intraocular pressure is  extremely low, an associated choroidal detachment may be  present. It may be raised, characteristically in Schwartz-  Matsuo syndrome in which RRD is associated with an  apparent mild anterior uveitis, often due to a dialysis due to  prior blunt trauma in a young man; the aqueous cells are  believed in most cases actually to be displaced photoreceptor  outer segments that compromise trabecular outflow. Both  the aqueous ‘cells’ and the elevated IOP typically resolve  following repair of the RD.   • Iritis is very common but usually mild and should be  differentiated from Schwartz-Matsuo syndrome (above).    Occasionally it may be severe enough to cause posterior  synechiae; the underlying RD may be overlooked.   • Retinal breaks (see Fig. 16.24) appear as discontinuities in  the retinal surface. They are usually red because of the   colour contrast between the sensory retina and underlying  choroid. However, in eyes with hypopigmented choroid (e.g.  high myopia), the colour contrast is decreased and small  breaks may be overlooked.   • Retinal signs depend on the duration of RD and the   • The RD has a convex configuration and a slightly opaque  and corrugated appearance as a result of retinal oedema  (Figs 16.29A-D). There is loss of the underlying choroidal  pattern and retinal blood vessels appear darker than in flat  retina.   Fig. 16.29 Fresh retinal detachment. (A) U-tear with  superotemporal detachment, threatening the central macula;  note that substantially elevated retina appears dark on  the wide-field image; (B) autofluorescence demonstrating  extent of fluid spread; (C) superior bullous detachment;   (E) macular hole surrounded by shallow subretinal fluid  confined to the posterior pole   (Courtesy of S Chen - figs A, B and D; M Khairallah - fig. E)    • SRF extends up to the ora serrata, except in the rare cases  caused by a macular hole in which fluid is initially confined  to the posterior pole (Fig. 16.29E).   • Macular pseudohole. Because of the thinness of the foveal  retina, the impression of a macular hole may be given if the  posterior pole is detached. This should not be mistaken for a  true macular hole, which may give rise to RD in highly  myopic eyes or following blunt trauma.   • B-scan ultrasonography shows good mobility of the retina  and vitreous (see Fig. 16.10).   • Retinal thinning secondary to atrophy is a characteristic  finding, and should not lead to a misdiagnosis of  retinoschisis.   • Intraretinal cysts (Fig. 16.30A-C) may develop if the RD has  been present for about 1 year; these tend to disappear after  retinal reattachment.   Fig. 16.30 Long-standing retinal detachment. (A) Retinal cysts;  (B) multiple cysts in chronic total detachment (red-free  wide-field image); (C) B-scan ultrasonogram demonstrating  cyst; (D) demarcation line; (E) demarcation line surrounding  localized fluid associated with a small round asymptomatic  hole (wide-field image)   (Courtesy of C Barry - fig. B; RF Spaide, from Diseases of the Retina and  Vitreous, WB Saunders 1999 - fig. C; S Chen - fig. D; S Lorenzon - fig. E)   and detached retina (Fig. 16.30D and E) are common, taking  about 3 months to develop. Pigmentation tends to decrease  over time. Although representing sites of increased adhesion,  they do not invariably limit the spread of SRF.   Proliferative vitreoretinopathy (PVR) is caused by epiretinal and  subretinal membrane formation, contraction of which leads    to tangential retinal traction and fixed retinal fold formation  (Fig. 16.31). Usually, PVR occurs following surgery for rhegmato-  genous RD or penetrating injury, though it may also occur in eyes  with rhegmatogenous RD that have not had previous retinal  surgery. The main features are retinal folds and rigidity so that  retinal mobility induced by eye movements or scleral indentation  is decreased. Progression from one stage to the next is not  inevitable.   • Grade A (minimal) PVR is characterized by diffuse vitreous  haze and tobacco dust. There may also be pigmented clumps   Fig. 16.31 Development of proliferative vitreoretinopathy (PVR). (A) Extensive vitreous syneresis; (B) total retinal detachment  without PVR; shrunken vitreous is condensed and attached to the equator of the retina; (C) early PVR with anteriorly  retracted vitreous gel and equatorial circumferential retinal folds; (D) advanced PVR with a funnel-like retinal detachment  bridged by dense vitreous membranes   (Courtesy of CL Schepens, ME Hartnett and T Hirose, from Schepens’ Retinal Detachment and Allied Diseases, Butterworth-Heinemann 2000)    on the inferior surface of the retina. Although these findings  occur in many eyes with RD, they are particularly severe in  eyes with early PVR.   • Grade B (moderate) PVR is characterized by wrinkling of  the inner retinal surface (Fig. 16.32A), decreased mobility of  vitreous gel, rolled edges of retinal breaks, tortuosity of  blood vessels and retinal stiffness (Fig. 16.32B). The epiretinal  membranes responsible for these findings typically cannot be  identified clinically.   • Grade C (marked) PVR is characterized by rigid full-  thickness retinal folds (often star-shaped) with heavy  vitreous condensation and strands (Fig. 16.32C and D). It  can be either anterior (A) or posterior (P), the approximate  dividing line being the equator of the globe. The severity of  proliferation in each area is expressed by the number of  clock hours of retina involved although proliferations need  not be contiguous.   • Advanced disease shows gross reduction of retinal mobility  with retinal shortening and a characteristic funnel-like  triangular conformation (see Fig. 16.31D).   The tractional and exudative forms of RD are described later in  the chapter.   Causes of choroidal detachment (also known as ciliochoroidal  or choroidal effusion) include hypotony, particularly following  glaucoma drainage surgery (see Ch. 10), sulfa drugs such as aceta-  zolamide and topiramate, uveitis, posterior scleritis, choroidal  tumours and a cyclodialysis cleft following trauma (including  surgical); occasionally it occurs secondary to retinal detachment.  Idiopathic cases are generally labelled as uveal effusion syndrome  (see below).   • Symptoms. Photopsia and floaters are absent because  there is no vitreoretinal traction. A visual field defect   Fig. 16.32 Proliferative vitreoretinopathy (PVR). (A) Early retinal wrinkling in minimal grade B; (B) marked grade B with rolled  retinal break edges; (C) grade C with prominent star fold; (D) grade C with characteristic funnel-shaped detachment    Fig. 16.33 Choroidal effusion. (A) Effusion secondary to  hypotony associated with a cyclodialysis cleft; (B) B-scan  showing limitation of posterior fluid spread by the vortex  veins   (Courtesy of S Chen - fig. A; R Bates - fig. B)   The uveal effusion syndrome is a rare idiopathic, often bilateral,  condition that most frequently affects middle-aged hypermetropic  men but can occur in association with nanophthalmos. The cause  is thought to be impairment of normal fluid drainage from the  choroid via the sclera (which is sometimes of abnormal thickness  and composition) or vortex veins.   O Inflammation is absent or mild,  o Ciliochoroidal detachment followed by exudative RD.   • Differential diagnosis includes uveal effusion secondary to  other causes (see above), choroidal haemorrhage and ring  melanoma of the anterior choroid.   • Treatment is usually with full-thickness sclerectomies; pars  plana vitrectomy alone may also be successful, but  sclerectomies are usually first-line in nanophthalmos.   In general, an acutely symptomatic RD should be operatively  repaired urgently, particularly if the macula is as yet uninvolved  (Fig. 16.34). Other factors that may increase the urgency of inter¬  vention include the presence of a superior or large break, from  which SRF is likely to spread more rapidly, and advanced syneresis  as in myopia. Patients with dense fresh vitreous haemorrhage in  whom visualization of the fundus is impossible should also be  operated on as soon as possible if B-scan ultrasonography shows   o Low intraocular pressure is common as a result of the  cause and of concomitant detachment of the ciliary body,  o The anterior chamber may be shallow in eyes with  extensive choroidal detachments; non-pupillary block  angle closure can occur.   o The elevations are brown, convex, smooth and relatively  immobile (Fig. 16.33A). Four lobes are typically present;  temporal and nasal bullae tend to be most prominent,  o Large ‘kissing’ choroidal detachments may obscure the  view of the fundus.   because they are limited by the vortex veins entering their  scleral canals (Fig. 16.33B); however, in contrast to retinal  detachments they extend anteriorly beyond the ora  serrata.   • Treatment is directed at the cause; drainage via partial¬  thickness sclerectomies is occasionally required.   Fig. 16.34 Superotemporal retinal detachment with intact but  imminently threatened macula, requiring urgent repair    an underlying RD. When an RD likely to require an urgent opera¬  tion is diagnosed or suspected, it is important that the patient does  not eat or drink in the hours before assessment so that surgery is  not delayed. Minimizing activity may be helpful, and some  authorities advocate bed rest with the head turned so that the  retinal break is in the most dependent position, which may lessen  the amount of SRF and facilitate surgery.   Pneumatic retinopexy (Fig. 16.35) is an outpatient procedure in  which an intravitreal gas bubble together with cryotherapy or laser  are used to seal a retinal break and reattach the retina without  scleral buckling. The most frequently used gases are sulfur hex¬  afluoride (SF 6 ) and the longer-acting perfluoropropane (C 3 F 8 ). It  has the advantage of being a relatively quick, minimally invasive,  ‘office-based’ procedure. However, success rates are usually worse  than those achievable with conventional scleral buckling. The pro¬  cedure is usually reserved for treatment of uncomplicated RD with  a small retinal break or a cluster of breaks extending over an area  of less than two clock hours in the upper two-thirds of the periph¬  eral retina.   Scleral buckling, sometimes referred to as conventional or external  RD surgery as opposed to the internal approach of pars plana  vitrectomy (see below), is a surgical procedure in which material   sutured onto the sclera (explant - Fig. 16.36A) creates an inward  indentation (buckle - Figs 16.36B and C). Its purposes are to close  retinal breaks by apposing the RPE to the sensory retina, and to  reduce dynamic vitreoretinal traction at sites of local vitreoretinal  adhesion.   • Explants are made from soft or hard silicone. The entire  break should ideally be surrounded by about 2 mm of  buckle. It is also important for the buckle to involve the area  of the vitreous base anterior to the tear in order to prevent  the possibility of subsequent reopening of the tear and  anterior leakage of SRF. The dimensions of the retinal break  can be assessed by comparing it with the diameter of the  optic disc.   • Buckle configuration can be radial, segmental,  circumferential or encircling, depending on the size,  configuration and number of breaks.   • Technique. The conjunctiva is incised (peritomy) to  facilitate access, following which retinal breaks are localized  and cryotherapy applied. An explant of appropriate  dimensions and orientation is then sutured to the sclera  and the position of the buckle checked in relation to the  break.   Drainage of SRF via the sclera (e.g. the D-ACE: Drainage-Air-  Cryotherapy-Explant) surgical technique (Fig. 16.37A) is advocated  by many practitioners, citing more rapid retinal reattachment   Fig. 16.35, Continued (C) gas has sealed the retinal break and the retina is flat; (D) gas has absorbed; (E) gas bubble in  vitreous cavity; (F) ‘fish eggs’ due to gas bubble break-up    in the presence of deep or long-standing viscous SRF; other  authorities prefer to avoid external drainage due to its potential  complications such as retinal perforation or incarceration in the  drainage site (Fig. 16.37B) and choroidal haemorrhage, and would  perform a pars plana vitrectomy in such cases.   • Diplopia due to the mechanical effect of the buckle is very  common. Early spontaneous resolution is typical, though  intervention is sometimes necessary.    • Cystoid macular oedema occurs in up to 25%, but usually  responds to treatment. Other macular complications include  epiretinal membrane (around 15%), persistent subfoveal  fluid and foveal structural disruption, usually in macular-off  detachments.   • Anterior segment ischaemia due to vascular compromise. This  is a particular risk with an encircling band, and with predisposing  systemic conditions such as sickle haemoglobinopathies.   • Buckle extrusion, intrusion or infection (Figs 16.38A and  B). Removal is usually required, with aggressive antibacterial  therapy as indicated.   (B) buckle induced by radial explant; (C) buckle induced  by circumferential explant   (Courtesy of S Chen - figs A and B; H Notaras - fig. C)   • Elevated IOP. Early IOP spikes usually resolve rapidly, but  occasionally persist. Angle closure can occur.   • Choroidal detachment usually resolves spontaneously,  presumably as scleral oedema settles and allows improved  vortex vein function.   o Missed breaks. A thorough search should always be made  for the presence of multiple breaks, particularly if the    configuration of the RD does not correspond to the  position of the primary break.   o Buckle failure may occur due to inadequate size, incorrect  positioning (Fig. 16.38C), or inadequate height; the  explant may have to be replaced or repositioned to  address the first two, but drainage of SRF or intravitreal  gas injection may suffice for the latter, though pars plana  vitrectomy (PPV) may be preferred as a more definitive  measure. ‘Fish-mouthing’ (Fig. 16.38D) describes the  phenomenon of a tear, typically a large superior  equatorial U-tear in a bullous RD, to open widely  following scleral buckling, requiring further operative  treatment.   Fig. 16.37 Drainage of subretinal fluid during scleral  buckling. (A) A circumferential explant is visible but has not  yet been tightened into place. A cotton-tipped applicator is  being used to apply pressure to encourage fluid drainage  from the sclerotomy (incision to the left of the applicator);  (B) retinal incarceration into the drainage site   O Proliferative vitreoretinopathy is the most common cause  of late failure. The tractional forces associated with PVR  can occasionally open old breaks and create new ones.  Presentation is typically several weeks postoperatively  with re-detachment.   o Reopening of a retinal break in the absence of PVR can  occur as a result of inadequate cryotherapy or scleral  buckling, or sometimes when buckle height decreases  either with time or following late surgical removal.    The main causes of tractional RD are proliferative retinopathy  such as diabetic and retinopathy of prematurity, and penetrating  posterior segment trauma (see Ch. 21).   Fig. 16.38 Complications of scleral buckling. (A) Buckle extrusion; (B) buckle intrusion subretinally; (C) failure due to  incorrectly positioned buckle; (D) ‘fish-mouthing’ of a U-tear communicating with a radial retinal fold   Tractional RD is caused by progressive contraction of fibrovascu-  lar membranes over large areas of vitreoretinal adhesion. In con¬  trast to acute PVD in eyes with rhegmatogenous RD, PVD in  diabetic eyes is gradual and frequently incomplete. It is thought to  be caused by leakage of plasma constituents into the vitreous gel  from a fibrovascular network adherent to the posterior vitreous  surface. Owing to the strong adhesions of the cortical vitreous to  areas of fibrovascular proliferation, PVD is usually incomplete. In  the rare event of a subsequent complete PVD, the new blood  vessels are avulsed and RD does not develop. Vitreoretinal traction  can be (i) tangential, caused by the contraction of epiretinal  fibrovascular membranes with puckering of the retina and distor¬  tion of blood vessels, (ii) anteroposterior, due to the contraction  of fibrovascular membranes extending from the posterior retina,  usually in association with the major arcades, to the vitreous base  anteriorly, and/or (iii) bridging (trampoline), the result of con¬  traction of fibrovascular membranes stretching from one part of  the retina to another or between vascular arcades, tending to pull  the two involved points together (Fig. 16.39).   because vitreoretinal traction develops insidiously and is not  associated with acute PVD. A visual field defect usually  progresses slowly and may be stable for months or even  years.   (Courtesy of CL Schepens, ME Hartnett and T Hirose, from Schepens’ Retinal  Detachment and Allied Diseases, Butterworth-Heinemann 2000)   o Retinal mobility is severely reduced and shifting fluid is  absent.   o The SRF is shallower than in a rhegmatogenous RD and  seldom extends to the ora serrata.  o The highest elevation of the retina occurs at sites of  vitreoretinal traction.   o If a tractional RD develops a break it assumes the  characteristics of a rhegmatogenous RD and  progresses rapidly (combined tractional-  rhegmatogenous RD).   • B-scan ultrasonography shows incomplete posterior  vitreous detachment and a relatively immobile retina  (Fig. 16.40D).   Exudative RD is characterized by the accumulation of SRF in the  absence of retinal breaks or traction. It may occur in a variety of  vascular, inflammatory and neoplastic diseases involving the  retina, RPE and choroid in which fluid leaks outside the vessels  and accumulates under the retina. As long as the RPE is able to  compensate by pumping the leaking fluid into the choroidal cir¬  culation, RD does not occur. However, when the mechanism is  overwhelmed or functions subnormally, fluid accumulates in the  subretinal space. Causes include:   • Choroidal tumours such as melanomas, haemangiomas and  metastases; it is therefore very important to consider that  exudative RD is caused by an intraocular tumour until  proved otherwise.   • Choroidal neovascularization which may leak and give rise  to extensive subretinal accumulation of fluid at the posterior  pole.   • Hypertensive choroidopathy, as may occur in toxaemia of  pregnancy, is a very rare cause.   • Symptoms. Depending on the cause, both eyes may be  involved simultaneously.   o Floaters may be present if there is associated vitritis.  o A visual field defect may develop suddenly and progress  rapidly.   Fig. 16.40 Tractional retinal detachment. (A) Secondary to proliferative diabetic retinopathy; (B) composite photograph of  severe tractional detachment; (C) OCT showing concave configuration; (D) B-scan   (Courtesy of S Chen - figs A-C; RF Spaide, from Diseases of the Retina and Vitreous, WB Saunders , 1999 - fig. D)   o The detached retina is very mobile and exhibits the  phenomenon of ‘shifting fluid’ in which SRF detaches  the area of retina under which it accumulates (Fig. 16.41).  For example, in the upright position the SRF collects  under the inferior retina, but on assuming the supine  position for several minutes, the inferior retina flattens  and SRF shifts posteriorly, detaching the superior  retina.   o The cause of the RD, such as a choroidal tumour (Fig.  16.42), may be apparent when the fundus is examined or  on B-scan ultrasonography, or the patient may have an  associated systemic disease responsible for the RD (e.g.  Harada disease, toxaemia of pregnancy).   Treatment depends on the cause. Some cases resolve spontane¬  ously, whilst others are treated with systemic corticosteroids  (Harada disease and posterior scleritis). In some eyes with bullous  central serous chorioretinopathy, the leak in the RPE can be sealed  by laser photocoagulation.   The diameter of the shaft of vitrectomy instrumentation has con¬  ventionally been 0.9 mm (20-gauge), but smaller 23-gauge,  25-gauge and even 27-gauge sutureless systems (transconjunctival  microincision vitrectomy - MI VS) are increasingly becoming the  standard of care, offering shorter operating time, less trauma and   Fig. 16.41 Exudative retinal detachment with shifting fluid. (A)  Inferior collection of subretinal fluid with the patient sitting;  (B) the subretinal fluid shifts upwards when the patient  assumes the supine position   (Courtesy of CL Schepens, E Hartnett and T Hirose, from Schepens’ Retinal  Detachment and Allied Diseases, Butterworth-Heinemann 2000)    scarring and faster rehabilitation. Early concerns about an  increased risk of postoperative endophthalmitis do not seem to  have been borne out, and operative success rates are comparable  to larger-gauge instrumentation.   • Vitreous cutter (Fig. 16.44) has an inner guillotine blade that  oscillates at very high speed (from 1500 up to 5000-7500  cuts/minute - cpm - in the latest ‘ultra-high speed’ cutters),  cutting the vitreous gel into tiny pieces and simultaneously    removing it by suction into a collecting cassette. Faster  cutting speeds translate into a lower level of traction exerted  on the vitreoretinal interface during surgery. Safer more  efficient fluidic control has been introduced in tandem.   • Intraocular illumination is supplied by a fibreoptic probe  (light pipe - Fig. 16.44). Initially, reduced illumination was  problematic with the narrower calibre MIVS systems due to  the limitations of halogen bulbs, and brighter sources  consisting of xenon and potentially less phototoxic mercury  vapour sources have been introduced that match or exceed    the levels of 20-gauge systems. These minimize retinal  phototoxicity by filtering out higher-energy ultraviolet and  blue light; some systems offer adjustable lighting  characteristics to increase the contrast of particular  structures. Wide-angle lighting and self-retaining  ‘chandelier’ sources are available - the latter offer the  advantages of freeing both of the surgeon’s hands to carry  out true bimanual surgery, which can be particularly useful  in challenging cases, and of increasing the working distance  of the light probe from the retina to decrease phototoxicity;  glare is sometimes problematic, however. Extremely  small-gauge dual chandelier probes are available to eliminate  shadowing from the working field.   • An infusion cannula is required in order to maintain the  vitreous cavity pressure and volume. These are generally  self-retaining in smaller gauge systems.   • Wide-angle viewing systems consist of an indirect lens  beneath the operating microscope and an incorporated series  of prisms to reinvert the image (Fig. 16.45). The field of view  extends almost to the ora serrata; higher magnification  smaller field lenses are available for macular surgery.   • Accessory instruments include scissors, forceps, flute needle  and endodiathermy and endolaser delivery systems. With the  introduction of smaller-calibre cutters that are able to  manipulate fibrovascular membranes more precisely and  safely, the requirement for additional instrumentation may  decrease.   • Expanding gases. Although air can be used, an expanding  gas is usually preferred in order to achieve prolonged  tamponade. Postoperative positioning of the patient is used  to maximize the effective vector and maintain surface  tension around the break.   o Sulfur hexafluoride (SF 6 ) doubles its volume if used at a  100% concentration and lasts 10-14 days,  o Perfluorethane (C 2 F 6 ) triples its volume at 100% and lasts  30-35 days.   o Perfluoropropane (C 3 F 8 ) quadruples its volume at 100%  and lasts 55-65 days.   • Because the eye is usually left almost entirely gas-filled at the  end of the procedure, most are used at only an isovolumetric  (non-expansile) concentration (e.g. 20-30% for SF 6 and  12-16% for C 3 F 8 ). Eow pressure environments, typically air  travel, and nitrous oxide anaesthesia must be avoided until  gas absorption is complete as these will increase the  intraocular gas pressure.   • Silicone oils have low specific gravity - they are lighter than  water and thus buoyant. They are commonly used for both  intraoperative retinal manipulation and prolonged  postoperative intraocular tamponade, and are particularly  helpful in the management of proliferative vitreoretinopathy.  1000 cs silicone is easier to inject and to remove whilst  5000 cs is more viscous but may be less prone to  emulsification.   • Heavy liquids (perfluorocarbons) have high specific gravity  and thus settle inferiorly in the vitreous cavity. Although  primarily developed solely for intraoperative use (Fig. 16.46),  newer compounds are available for postoperative tamponade  of the inferior retina. However, cases of retinal toxicity and  severe inflammation have been reported.   Although many simple rhegmatogenous RD can be treated suc¬  cessfully by scleral buckling techniques, pars plana vitrectomy   Fig. 16.47 Some indications for pars plana vitrectomy. (A) Giant  vitreoretinopathy; (D) tractional retinal detachment   (Courtesy of P Gili - fig. A; C Barry - fig. B; S Chen - fig. D)    detachments. As techniques have improved and surgeons’ famili¬  arity and confidence has grown, the threshold for vitrectomy  surgery has fallen. Many surgeons now feel that morbidity and  success rates are better with vitrectomy for all pseudophakic and  aphakic RD, and for those that would otherwise require external  drainage of SRF; some advocate primary vitrectomy for virtually  all cases. The guidelines below are therefore not absolute.   • When retinal breaks cannot be visualized as a result of  haemorrhage, vitreous debris, posterior capsular opacity,   IOL edge effects. Vitrectomy is crucial to provide an  adequate retinal view. Scleral buckling carries a high risk of  failure if any breaks are missed.   • In which retinal breaks are unlikely to be closed by scleral  buckling such as giant tears, large posterior breaks and in  the presence of PVR (Figs 16.47A-C).   o Tractional RD threatening or involving the macula (Fig.  16.47D). Vitrectomy is always combined with internal  panretinal photocoagulation to prevent postoperative  neovascularization that may cause vitreous haemorrhage  or rubeosis iridis. Extramacular tractional RD may be  observed without surgery because, in many cases, it  remains stationary for a long time provided proliferative  retinopathy has been controlled.   o Combined tractional-rhegmatogenous RD should be  treated urgently, even if the macula is not involved,  because SRF is likely to spread quickly.   o Prevention of tractional RD. Unlike diabetic retinopathy  where epiretinal membrane proliferation occurs mostly  on the posterior retina, fibrocellular proliferation after  penetrating trauma tends to develop on the pre-  equatorial retina and/or the ciliary body. Treatment is  usually aimed at visual rehabilitation and minimizing the  tractional process.   o Late tractional RD, which may be associated with an  intraocular foreign body or retinal incarceration,  occasionally develops months after otherwise successful  surgery.    Localized fixed retinal folds may be freed by the removal of the  central plaque of epiretinal membrane. This can usually be  achieved by engaging the tip of vertically cutting scissors or a pic-  type instrument in the edge of a valley between two adjacent folds  (Fig. 16.50). The membrane is then either surgically dissected or  simply peeled from the surface of the retina. Smaller gauge cutters  may be used in some cases to engage membranes directly, and  forceps can facilitate this. A relieving retinotomy is considered if  the mobility of the retina is believed to be insufficient for sustained  reattachment.    • An infusion cannula is inserted (3.5 mm behind the limbus  in pseudophakic or aphakic eyes and 4 mm in phakic eyes)  at the level of the inferior border of the lateral rectus muscle;  limbal peritomy (conjunctival dissection) is required for  conventional larger gauge systems, but unnecessary in small  gauge systems.   • Further sclerotomies are made at the 10 and 2 o’clock  positions, through which the vitreous cutter and fibreoptic  probe are introduced (Fig. 16.48). These sclerotomies are  self-sealing with modern small gauge systems, though  wound leak occasionally occurs (Fig. 16.49).   • The central vitreous gel and posterior hyaloid face are  excised.   • The above basic steps apply to all vitrectomies; subsequent  steps depend on the specific indication.   The aims of surgery in PVR are to release both transvitreal traction  by vitrectomy and tangential (surface) traction by membrane dis¬  section in order to restore retinal mobility and allow closure of  retinal breaks.   The goal of vitrectomy in tractional RDs is to release anteropos¬  terior and/or circumferential vitreoretinal traction. Because the  membranes are vascularized, and the retina often friable, they   Fig. 16.50 Dissection of retinal folds in proliferative  vitreoretinopathy Fig. 16.51 (A) Delamination with horizontally cutting scissors;    cannot be simply peeled from the surface of the retina as this  would result in haemorrhage and tearing of the retina. The two  methods of removing fibrovascular membranes in diabetic trac-  tional RDs are the following:   • Delamination involves the horizontal cutting of individual  vascular pegs connecting a membrane to the surface of the  retina (Fig. 16.51A). This allows the complete removal of  fibrovascular tissue from the retinal surface (Fig. 16.51B).   • Segmentation involves the vertical cutting of epiretinal  membranes into small segments (Fig. 16.52). It is used to  release circumferential vitreoretinal traction when  delamination is difficult or impossible.   • Overexpansion of intraocular gas, usually when the  concentration or volume of expansile gas is inadvertently too  great. Medical measures alone may be sufficient in some  cases as the gas is allowed to absorb, but in very substantial  elevation a gas tap via the pars plana with a 30-gauge needle  on a 1 ml syringe may be necessary.   o Early glaucoma may be caused by direct pupillary block  by silicone oil (Fig. 16.53A). This occurs particularly in  the aphakic eye with an intact iris diaphragm. In aphakic  eyes this can be prevented by performing an inferior  (Ando) iridectomy at the time of surgery to allow free  passage of aqueous to the anterior chamber. Intraocular  gas can also cause pupillary block.    o Late glaucoma is caused by emulsified silicone in the  anterior chamber (Fig. 16.53B) causing trabecular  obstruction and scarring. The risk may be reduced by  early oil removal, though glaucoma can still occur. A  glaucoma drainage device or enhanced trabeculectomy  may be required.   Fig. 16.53 Some complications of silicone oil injection. (A) Pupillary block glaucoma caused by oil in the anterior chamber;   (B) late glaucoma due to emulsified oil in the anterior chamber; an inverted pseudo-hypopyon (hyperoleon) is seen;    • Other mechanisms include ghost cell, inflammatory and  steroid-induced glaucoma. Angle closure can also result from  ciliochoroidal effusion with anterior rotation of the lens-iris  diaphragm; this may respond to cycloplegia and steroids.   • Gas-induced. A large or long-lasting intravitreal gas bubble  typically gives rise to feathering of the posterior subcapsular  lens, though this is usually transient.    • Silicone-induced. Almost all phakic eyes with silicone oil  eventually develop cataract (Fig. 16.53C).   • Delayed. Following vitrectomy, substantial nuclear sclerosis  commonly develops within a year, especially if the patient is  over 50 years of age.   The vitreous is a transparent extracellular gel consisting of colla¬  gen, soluble proteins, hyaluronic acid and water. Its total volume  is approximately 4.0 ml. The few cells normally present in the gel  are located predominantly in the cortex and include hyalocytes,  astrocytes and glial cells. The vitreous provides structural support  to the globe while allowing a clear and optically uniform path to  the retina. Once liquefied or surgically removed it does not  re-form. Vitreous opacities can be caused by a variety of patho¬  logical processes primarily involving other ocular sites; apart from  vitreous haemorrhage, the conditions discussed below are those in  which the vitreous gel is the primary site of pathology.   Muscae volitantes (Latin for ‘hovering flies’), commonly referred  to as ‘floaters’, is an almost ubiquitous entoptic phenomenon of  fly-, cobweb- or thread-like lesions best seen against a pale back¬  ground. It is thought to predominantly represent tiny embryologi-  cal remnants in the vitreous gel. A sudden exacerbation can occur  due to vitreous haemorrhage or, more commonly, a change in the  conformation of the gel, such as a posterior vitreous detachment  (see Fig. 16.22).   Vitreous haemorrhage is a common condition with many causes  (Table 17.1). Symptoms vary according to severity. Mild haemor¬  rhage (Fig. 17.1A) causes sudden onset floaters and diffuse blurring  of vision, but may not affect visual acuity, whilst a dense bleed  (Fig. 17.1B) may result in very severe visual loss. B-scan ultrasono¬  graphy in unclotted vitreous haemorrhage generally shows a  uniform appearance, and once cellular aggregates develop, small  particulate echoes become visible (Fig. 17.1C); ultrasonography is  critical in the evaluation of eyes with dense vitreous haemorrhage  to exclude an underlying retinal tear or detachment (Fig. 17.1D).  Treatment is dictated by severity and cause, but an increasingly  low threshold is being adopted for early vitrectomy (see Ch. 16) in  cases of dense haemorrhage.   • Acute posterior vitreous detachment associated  either with a retinal tear or avulsion of a peripheral  vessel   Terson syndrome refers to the combination of intraocular and  subarachnoid haemorrhage secondary to aneurysmal rupture,  most commonly arising from the anterior communicating artery.  However, intraocular haemorrhage may also occur with subdural  haematoma and acute elevation of intracranial pressure from  other causes. The haemorrhage is frequently bilateral and is typi¬  cally intraretinal and/or preretinal (Fig. 17.2), although occasion¬  ally subhyaloid blood may break into the vitreous. It is probable  that intraocular bleeding is due to retinal venous stasis secondary  to increase in cavernous sinus pressure. Vitreous haemorrhage  usually resolves spontaneously within a few months and the long¬  term visual prognosis is good in the majority. Early vitrectomy  may be considered in some cases.   Asteroid hyalosis is a common degenerative process in which  calcium pyrophosphate particles collect within the vitreous gel. It  is seen clinically as numerous tiny round yellow-white opacities  of varying size and density (Figs 17.3A and B). These move  with the vitreous during eye movements but do not sediment  inferiorly when the eye is immobile. Only one eye is affected  in 75% of patients; it rarely causes visual problems and the  majority of patients are asymptomatic. An association with diabe¬  tes has been suggested, but is unproven. The prevalence of  asteroid hyalosis increases with age and affects 3% of those aged  75-86 years. It is more common in men than in women. OCT  (Figs 17.3C and D) and ultrasonography (Fig. 17.3E) show high  reflectivity foci.   Synchysis (synchisis) scintillans occurs as a consequence of chronic  vitreous haemorrhage, often in a blind eye. The condition is  usually discovered when frank haemorrhage is no longer present.  The crystals are composed of cholesterol and are derived from  plasma cells or degraded products of erythrocytes, and lie either  freely or engulfed within foreign body giant cells. Numerous flat  golden-brown refractile particles are seen; these tend to sediment  inferiorly when the eye is immobile. Occasionally the anterior  chamber may also be involved (Fig. 17.4).   Amyloidosis is a localized or systemic condition in which there is  extracellular deposition of fibrillary protein. Vitreous involvement  typically occurs in familial amyloidosis, also characterized by  polyneuropathy, prominent corneal nerves and pupillary light-  near dissociation. Vitreous opacities may be unilateral or bilateral  and are initially perivascular. Later they involve the anterior gel  and take on a characteristic sheet-like (‘glass wool’) appearance  (Fig. 17.5A). The opacities may become attached to the posterior  lens by thick footplates (Fig. 17.5B). Dense opacification resulting  in significant visual impairment may require vitrectomy.    Fig. 17.1 (A) Mild vitreous haemorrhage seen against the red reflex; (B) severe diffuse vitreous haemorrhage; (C) B-scan  image showing vitreous haemorrhage and flat retina; (D) B-scan image showing vitreous haemorrhage and funnel-shaped  retinal detachment   Fig. 17.2 Terson syndrome. (A) Acute intra- and preretinal haemorrhages in a 48-year-old man with subarachnoid  haemorrhage; (B) composite image   (Courtesy of A Agarwal, from Gass’ Atlas of Macular Diseases, Elsevier 2012)   Fig. 17.3 Asteroid hyalosis. (A) Clinical appearance of moderate severity; (B) wide-field image; (C) appearance on OCT; (D)  three-dimensional OCT reconstruction;   Fig. 17.4 Synchysis scintillans in the anterior chamber of a  degenerate eye   Vitreous cysts can be congenital or acquired, acquired cysts being  caused by a range of pathology such as trauma and inflammation.  Congenital cysts are pigmented or non-pigmented, the former  usually arising from the ciliary body pigment epithelium, the latter  from remnants of the primary hyaloid vascular system. They are  generally fixed - non-pigmented cysts are typically attached to the  optic disc - but can be found floating freely in the posterior (occa¬  sionally anterior) segment (Fig. 17.6). Treatment is seldom    required, but laser cystotomy or vitrectomy can be performed for  troublesome symptoms.   In addition to non-pigmented vitreous cysts, remnants of the  hyaloid vessels can form a Bergmeister papilla, seen as a tuft at the  optic disc (Fig. 17.7), a Mittendorf dot on the posterior lens surface,  and the more marked manifestations for which the term persistent  fetal vasculature is generally reserved, previously termed persistent  hyperplastic primary vitreous (see Ch. 12).   Definitions 728  Anatomy of the extraocular  muscles 728  Ocular movements 731  Sensory considerations 733   History 738  Visual acuity 739  Tests for stereopsis 740  Tests for binocular fusion in infants  without manifest squint 741  Tests for sensory anomalies 742  Measurement of deviation 746  Motility tests 749  Hess chart 751   Early-onset esotropia 757  Accommodative esotropia 760  Microtropia 761  Other esotropias 762   Constant (early-onset) exotropia 762  Intermittent exotropia 762  Sensory exotropia 763  Consecutive exotropia 763   Duane retraction syndrome 764  Mobius syndrome 765  Congenital fibrosis of the extraocular  muscles 766   Weakening procedures 769  Strengthening procedures 770  Transposition 771  Adjustable sutures 771   • The visual axis passes from the fovea, through the nodal  point of the eye, to the point of fixation. In normal  binocular single vision (BSV) the visual axes of the two eyes  intersect at the point of fixation, the images being aligned by  the fusion reflex and combined by binocular responsive cells  in the visual cortex to give BSV.   • Orthophoria implies perfect ocular alignment in the absence  of any stimulus for fusion; this is uncommon.   • Heterophoria (‘phoria’) implies a tendency of the eyes to  deviate when fusion is blocked (latent squint).   O Slight phoria is present in most normal individuals and is  overcome by the fusion reflex. The phoria can be either a  small inward imbalance (esophoria) or an outward  imbalance (exophoria).   o When fusion is insufficient to control the imbalance, the  phoria is described as decompensating and is often  associated with symptoms of binocular discomfort  (asthenopia) or double vision (diplopia).   • Heterotropia (‘tropia’) implies a manifest deviation in  which the visual axes do not intersect at the point of  fixation.   o The images from the two eyes are misaligned so that  either double vision is present or, more commonly in  children, the image from the deviating eye is suppressed  at cortical level.   o A childhood squint may occur because of failure of the  normal development of binocular fusion mechanisms or  as a result of oculomotor imbalance secondary to a  difference in refraction between the two eyes  (anisometropia).   o Failure of fusion, for example secondary to poor vision in  one eye, may cause heterotropia in adulthood, or a squint  may develop because of weakness or mechanical  restriction of the extraocular muscles, or damage to their  nerve supply.   o Horizontal deviation of the eyes (latent or manifest) is  the most common form of strabismus,  o Upward displacement of one eye relative to the other is  termed a hypertropia and a latent upward imbalance a  hyperphoria.   o Downward displacement is termed a hypotropia and a  latent imbalance a hypophoria.   • The anatomical axis is a line passing from the posterior pole  through the centre of the cornea. Because the fovea is  usually slightly temporal to the anatomical centre of the  posterior pole of the eye, the visual axis does not usually  correspond to the anatomical axis of the eye.   • Angle kappa is the angle, usually about 5 0 , subtended by the  visual and anatomical axes (Fig. 18.1).   o The angle is positive (normal) when the fovea is temporal  to the centre of the posterior pole resulting in a nasal    displacement of the corneal reflex, and negative when the  converse applies.   o A large angle kappa may give the appearance of a squint  when none is present (pseudosquint) and is seen most  commonly as a pseudoexotropia following displacement  of the macula in retinopathy of prematurity, where the  angle may significantly exceed +5 0 (see Fig. 18.46).   The lateral and medial orbital walls are at an angle of 45 0 with each  other. The orbital axis therefore forms an angle of 22.5 0 with both  lateral and medial walls, though for the sake of simplicity this angle  is usually regarded as being 23 0 (Fig. 18.2A). When the eye is  looking straight ahead at a fixed point on the horizon with the  head erect (primary position of gaze), the visual axis forms an  angle of 23 0 with the orbital axis (Fig. 18.2B); the actions of the  extraocular muscles depend on the position of the globe at the  time of muscle contraction (Figs 18.2C and D).   • The primary action of a muscle is its major effect when the  eye is in the primary position.   • Subsidiary actions are the additional effects; these depend  on the position of the eye.   • The Listing plane is an imaginary coronal plane passing  through the centre of rotation of the globe. The globe rotates  on the axes of Fick, which intersect in the Listing plane  (Fig. 18.3).   o The globe rotates left and right on the vertical Z axis,  o The globe moves up and down on the horizontal X axis,  o Torsional movements (wheel rotations) occur on the Y  (sagittal) axis which traverses the globe from front to  back (similar to the anatomical axis of the eye),  o Intorsion occurs when the superior limbus rotates  nasally, and extorsion on temporal rotation.   When the eye is in the primary position, the horizontal recti are  purely horizontal movers on the vertical Z axis and have only  primary actions.   • Medial rectus originates at the annulus of Zinn at the orbital  apex and inserts 5.5 mm behind the nasal limbus. Its sole  action in the primary position is adduction.   • Lateral rectus originates at the annulus of Zinn and inserts  6.9 mm behind the temporal limbus. Its sole action in the  primary position is abduction.   The vertical recti run in line with the orbital axis and are inserted  in front of the equator. They therefore form an angle of 23 0 with  the visual axis (see Fig. 18.2C).   • Superior rectus originates from the upper part of the  annulus of Zinn and inserts 7.7 mm behind the superior  limbus.   o The primary action is elevation (Fig. 18.4A); secondary  actions are adduction and intorsion,  o When the globe is abducted 23 0 , the visual and orbital  axes coincide. In this position it has no subsidiary actions  and can act only as an elevator (Fig. 18.4B). This is  therefore the optimal position of the globe for testing the  function of the superior rectus muscle.    o If the globe were adducted 67°, the angle between the  visual and orbital axes would be 90°. In this position the  superior rectus could only act as an intortor (Fig. 18.4C).   • Inferior rectus originates at the lower part of the annulus of  Zinn and inserts 6.5 mm behind the inferior limbus.   o The primary action is depression; secondary actions are  adduction and extorsion.   o When the globe is abducted 23 0 , the inferior rectus acts  purely as a depressor. As for superior rectus, this is the  optimal position of the globe for testing the function of  the inferior rectus muscle.   o If the globe were adducted 67°, the inferior rectus could  act only as an extortor.   The spiral of Tillaux (Fig. 18.5) is an imaginary line joining the  insertions of the four recti and is an important anatomical land¬  mark when performing surgery. The insertions are located progres¬  sively further away from the limbus in a spiral pattern; the medial  rectus insertion is closest (5.5 mm) followed by the inferior rectus  (6.5 mm), lateral rectus (6.9 mm) and superior rectus (7.7 mm).   The obliques are inserted behind the equator and form an angle  of 51 0 with the visual axis (see Fig. 18.2D).   • Superior oblique originates superomedial to the optic  foramen. It passes forwards through the trochlea at the angle  between the superior and medial walls and is then reflected  backwards and laterally to insert in the posterior upper  temporal quadrant of the globe (Fig. 18.6).   O The primary action is intorsion (Fig. 18.7A); secondary  actions are depression and abduction.   Fig. 18.5 Spiral of Tillaux. IR = inferior rectus; LR = lateral  rectus; MR = medial rectus; SR = superior rectus   Fig. 18.6 Insertion of the superior oblique (SO) tendon; SR =  superior rectus    o The anterior fibres of the superior oblique tendon are  primarily responsible for intorsion and the posterior  fibres for depression, allowing separate surgical  manipulation of these two actions (see below),  o When the globe is adducted 51 0 , the visual axis coincides  with the line of pull of the muscle. In this position it can  act only as a depressor (Fig. 18.7B). This is, therefore, the  best position of the globe for testing the action of the  superior oblique muscle. Thus, although the superior  oblique has an abducting action in primary position, the  main effect of superior oblique weakness is seen as failure  of depression in adduction.   o When the eye is abducted 39 0 , the visual axis and the  superior oblique make an angle of 90° with each other. In  this position the superior oblique can cause only  intorsion (Fig. 18.7C).   • Inferior oblique originates from a small depression just  behind the orbital rim lateral to the lacrimal sac. It passes  backwards and laterally to insert in the posterior lower  temporal quadrant of the globe close to the macula.   o The primary action is extorsion; secondary actions are  elevation and abduction.   o When the globe is adducted 51 0 , the inferior oblique acts  as an elevator only.   o When the eye is abducted 39 0 , its main action is  extorsion.   • The four rectus muscles pass through condensations of  connective tissue and smooth muscle just posterior to the  equator. These condensations act as pulleys and minimize  upward and downward movements of the bellies of the  medial and lateral rectus muscles during upgaze and  downgaze, and horizontal movements of the superior and  inferior rectus bellies in left and right gaze.   • Pulleys are the effective origins of the rectus muscles and  play an important role in the coordination of eye  movements by reducing the effect of horizontal movements  on vertical muscle actions and vice versa.   • Displacement of the pulleys is a cause of abnormalities  of eye movements such as C V’ and ‘A’ patterns (see  below).   • Lateral rectus. Sixth cranial nerve (abducent nerve -  abducting muscle).   • Superior oblique. Fourth cranial nerve (trochlear nerve -  muscle associated with the trochlea).    • Other muscles together with the levator muscle of the upper  lid and the ciliary and sphincter pupillae muscles are  supplied by the third (oculomotor) nerve.   Ductions are monocular movements around the axes of Fick.  They consist of adduction, abduction, elevation, depression,  intorsion and extorsion. They are tested by occluding the fellow  eye and asking the patient to follow a target in each direction  of gaze.   Versions (Fig. 18.8, top) are binocular, simultaneous, conjugate  movements (conjugate - in the same direction, so that the angle  between the eyes remains constant).   • Dextroversion and laevoversion (gaze right and gaze left),  elevation (upgaze) and depression (downgaze). These four  movements bring the globe into the secondary positions of  gaze by rotation around either the vertical (Z) or the  horizontal (X) axes of Fick.   • Dextroelevation and dextrodepression (gaze up and right;  gaze down and right) and laevoelevation and  laevodepression (gaze up and left; gaze down and left).   These four oblique movements bring the eyes into the  tertiary positions of gaze by rotation around oblique axes  lying in the Listing plane, equivalent to simultaneous  movement about both the horizontal and vertical axes.   • Torsional movements to maintain upright images occur on  tilting of the head; these are known as the righting reflexes.    On head tilt to the right the superior limbi of the two eyes  rotate to the left, causing intorsion of the right globe and  extorsion of the left (laevocycloversion).   Vergences (Fig. 18.8, bottom) are binocular, simultaneous, dis-  jugate movements (disjugate - in opposite directions, so that  the angle between the eyes changes; also termed disjunctive).  Convergence is simultaneous adduction (inward turning); diver¬  gence is outwards movement from a convergent position. Conver¬  gence may be voluntary or reflex; reflex convergence has four  components:   • Tonic convergence, which implies inherent innervational  tone to the medial recti.   • Proximal convergence is induced by psychological awareness  of a near object.   • Fusional convergence is an optomotor reflex that maintains  binocular single vision (BSV) by ensuring that similar  images are projected onto corresponding retinal areas of  each eye. It is initiated by bitemporal retinal image disparity.   • Accommodative convergence is induced by the act of  accommodation as part of the synkinetic-near reflex.   o Each dioptre of accommodation is accompanied by a  constant increment in accommodative convergence,  giving the ‘accommodative convergence to  accommodation’ (AC/A) ratio,  o This is the amount of convergence in prism dioptres (A)  per dioptre (D) change in accommodation.    o The normal value is 3-5 A. This means that 1 D of  accommodation is associated with 3-5 A of  accommodative convergence. Abnormalities of the AC/A  ratio play an important role in the aetiology of  strabismus.   o Changes in accommodation, convergence and pupil size  which occur in concert with a change in the distance of  viewing are known as the ‘near triad’.   • Six cardinal positions of gaze are identified in which one  muscle in each eye is principally responsible for moving the  eye into that position as follows:   o Laevoversion (left lateral rectus and right medial rectus),  o Dextroelevation (right superior rectus and left inferior  oblique).   • Nine diagnostic positions of gaze are those in which  deviations are measured. They consist of the six cardinal  positions, the primary position, elevation and depression  (Fig. 18.9).   Fig. 18.9 Diagnostic positions of gaze. 10 = inferior oblique; IR = inferior rectus; LR = lateral rectus; MR = medial rectus;  SO = superior oblique; SR = superior rectus   • Agonist-antagonist pairs are muscles of the same eye that  move the eye in opposite directions. The agonist is the  primary muscle moving the eye in a given direction. The  antagonist acts in the opposite direction to the agonist. For  example, the right lateral rectus is the antagonist to the right  medial rectus.   • Synergists are muscles of the same eye that move the eye  in the same direction. For example, the right superior  rectus and right inferior oblique act synergistically in  elevation.   • Yoke muscles (contralateral synergists) are pairs of muscles,  one in each eye, that produce conjugate ocular movements.  For example, the yoke muscle of the left superior oblique is  the right inferior rectus.   • The Sherrington law of reciprocal innervation (Fig. 18.10)  states that increased innervation to an extraocular muscle  (e.g. right medial rectus) is accompanied by a reciprocal  decrease in innervation to its antagonist (e.g. right lateral  rectus). This means that when the medial rectus contracts  the lateral rectus automatically relaxes and vice versa. The  Sherrington law applies to both versions and vergences.   • The Hering law of equal innervation states that during any  conjugate eye movement, equal and simultaneous  innervation flows to the yoke muscles (Fig. 18.11).   O In the case of a paretic squint, the amount of innervation  to both eyes is symmetrical, and always determined by  the fixating eye, so that the angle of deviation will vary  according to which eye is used for fixation,  o For example if, in the case of a left lateral rectus palsy,  the right normal eye is used for fixation, there will be an  inward deviation of the left eye due to the unopposed  action of the antagonist of the paretic left lateral rectus  (left medial rectus). The amount of misalignment of the    two eyes in this situation is called the primary deviation  (Fig. 18.12, left).   o If the paretic left eye is now used for fixation, additional  innervation will flow to the left lateral rectus, in order to  establish this. However, according to the Hering law, an  equal amount of innervation will also flow to the right  medial rectus (yoke muscle). This will result in an  overaction of the right medial rectus and an excessive  amount of adduction of the right eye.  o The amount of misalignment between the two eyes in  this situation is called the secondary deviation (see Fig.  18.12, right). In a paretic squint, the secondary deviation  exceeds the primary deviation.   • Muscle sequelae are the effects of the interactions described  by these laws. They are of prime importance in diagnosing  ocular motility disorders and in particular in distinguishing  a recently acquired from a longstanding palsy (see ‘Clinical  evaluation’). The full pattern of changes takes a variable  period to develop:   O Primary underaction (e.g. left superior oblique),  o Secondary overaction of the contralateral synergist or  yoke muscle (right inferior rectus; Hering law),  o Secondary overaction and later contracture of the  unopposed ipsilateral antagonist (left inferior oblique;  Sherrington law).   o Secondary inhibition of the contralateral antagonist (right  superior rectus; Hering and Sherrington laws).   simultaneous use of both eyes with bifoveal fixation, so that  each eye contributes to a common single perception of the  object of regard. This represents the highest form of   o Binocularly driven neurones in the visual cortex,  o Normal retinal (retinocortical) correspondence (NRC)  resulting in ‘cyclopean’ viewing,  o Accurate neuromuscular development and coordination,  so that the visual axes are directed at, and maintain  fixation on, the object of regard,  o Approximately equal image clarity and size for both eyes,  o BSV is based on NRC, which requires first an  understanding of uniocular visual direction and  projection.   • Visual direction is the projection of a given retinal element  in a specific direction in subjective space.   o The principal visual direction is the direction in external  space interpreted as the line of sight. This is normally the  visual direction of the fovea and is associated with a sense  of direct viewing.   o Secondary visual directions are the projecting directions  of extrafoveal points with respect to the principal  direction of the fovea, associated with indirect (eccentric)  viewing.   • Projection is the subjective interpretation of the position of  an object in space on the basis of stimulated retinal  elements.   o If a red object stimulates the right fovea (F), and a black  object which lies in the nasal field stimulates a temporal  retinal element (T), the red object will be interpreted by  the brain as having originated from the straight-ahead  position and the black object will be interpreted as having  originated in the nasal field (Fig. 18.13A). Similarly, nasal  retinal elements project into the temporal field, upper  retinal elements into the lower field and vice versa.   Fig. 18.13 Principles of projection. F = fovea; N = nasal  retinal element; T = temporal retinal element    o With both eyes open, the red fixation object is now  stimulating both foveae, which are corresponding retinal  points. The black object is now not only stimulating the  temporal retinal elements in the right eye but also the  nasal elements of the left eye. The right eye therefore  projects the object into its nasal field and the left eye  projects the object into its temporal field,  o Because both of these retinal elements are corresponding  points, they will both project the object into the same  position in space (the left side) and there will be no  double vision.   o The image of an object in the peripheral visual field falls  on an extrafoveal element. To establish fixation on this  object a saccadic version of accurate amplitude is  required.   o Retinomotor value, zero at the fovea, increases  progressively towards the retinal periphery.   • Corresponding points are areas on each retina that share  the same subjective visual direction (for example, the foveae  share the primary visual direction).   o Points on the nasal retina of one eye have corresponding  points on the temporal retina of the other eye and vice  versa. For example, an object producing images on the  right nasal retina and the left temporal retina will be  projected into the right side of visual space. This is the  basis of normal retinal correspondence,  o This retinotopic organization is reflected back along the  visual pathways, each eye maintaining separate images  until the visual pathways converge onto binocularly  responsive neurones in the primary visual cortex.   • The horopter is an imaginary plane in external space,  relative to both the observer’s eyes for a given fixation target,  all points on which stimulate corresponding retinal elements  and are therefore seen singly and in the same plane (Fig.  18.13B). This plane passes through the intersection of the  visual axes and therefore includes the point of fixation in  BSV.   • The Panum fusional space (or volume) is a zone in front of  and behind the horopter in which objects stimulate slightly  non-corresponding retinal points (retinal disparity).   o Objects within the limits of the fusional space are seen  singly and the disparity information is used to produce a  perception of binocular depth (stereopsis). Objects in  front of and behind Panum space appear double,  o This is the basis of physiological diplopia. The Panum  space is shallow at fixation (6 seconds of arc) and deeper  towards the periphery (30-40 seconds of arc at 15 0 from  the fovea).   o The retinal areas stimulated by images falling within  the Panum fusional space are termed Panum fusional  areas.    o Therefore objects on the horopter are seen singly and in  one plane. Objects in Panum fusional areas are seen  singly and stereoscopically. Objects outside Panum  fusional areas appear double,  o Physiological diplopia is usually accompanied by  physiological suppression.   • BSV is characterized by the ability to fuse the images from  the two eyes and to perceive binocular depth:   o Sensory fusion involves the integration by the visual areas  of the cerebral cortex of two similar images, one from  each eye, into one image. It may be central, which  integrates the image falling on the foveae, or peripheral,  which integrates parts of the image falling outside the  foveae. It is possible to maintain fusion with a central  visual deficit in one eye, but peripheral fusion is essential  to BSV and may be affected in patients with advanced  field changes in glaucoma and pituitary lesions,  o Motor fusion involves the maintenance of motor  alignment of the eyes to sustain bifoveal fixation. It is  driven by retinal image disparity, which stimulates  fusional vergences.   • Fusional vergence involves disjugate eye movements to  overcome retinal image disparity. Fusional convergence  helps to control an exophoria whereas fusional divergence  helps to control an esophoria. The fusional vergence  mechanism may be decreased by fatigue or illness,  converting a phoria to a tropia. The amplitude of fusional  vergence mechanisms can be improved by orthoptic  exercises, particularly in the case of near fusional  convergence for the relief of convergence insufficiency.  Amplitudes can be measured with prisms or a synoptophore.  Normal values are:   o Convergence: about 15-20 A for distance and 25 A for near,  o Divergence: about 6-10 A for distance and 12-14 A for  near.   • Stereopsis is the perception of depth. It arises when objects  behind and in front of the point of fixation (but within  Panum fusional space) stimulate horizontally disparate  retinal elements simultaneously. The fusion of these  disparate images results in a single visual impression  perceived in depth. A solid object is seen stereoscopically (in  3D) because each eye sees a slightly different aspect of the  object.   • Sensory perceptions. At the onset of a squint two sensory  perceptions arise based on the normal projection of the  retinal areas stimulated; confusion and pathological diplopia  may result. These require simultaneous visual perception,  that is, the ability to perceive images from both eyes  simultaneously. Young children readily suppress diplopia  but it is persistent and usually troublesome with strabismus  in older children and adults, when it arises after the sensitive  period for binocularity (see below).   o Confusion is the simultaneous appreciation of two  superimposed but dissimilar images caused by    stimulation of corresponding retinal points (usually the  foveae) by images of different objects (Fig. 18.14).  o Pathological diplopia is the simultaneous appreciation of  two images of the same object in different positions and  results from images of the same object falling on  non-corresponding retinal points. In esotropia the  diplopia is homonymous (uncrossed - Fig. 18.15A),  in exotropia the diplopia is heteronymous (crossed -  Fig. 18.15B).   The ocular sensory system in children has the ability to adapt to  anomalous states (confusion and diplopia) by two mechanisms:  suppression and abnormal retinal correspondence (ARC). These  occur because of the plasticity of the developing visual system in  children under the age of 6-8 years. Occasional adults who develop  sudden-onset strabismus are able to ignore the second image after  a time and therefore do not complain of diplopia.   • Suppression involves active inhibition by the visual cortex  of the image from one eye when both eyes are open. Stimuli  for suppression include diplopia, confusion and a blurred  image from one eye resulting from astigmatism/  anisometropia. Clinically, suppression may be:  o Central or peripheral. In central suppression the image  from the fovea of the deviating eye is inhibited to avoid  confusion. Diplopia, on the other hand, is eradicated by  the process of peripheral suppression, in which the image  from the peripheral retina of the deviating eye is  inhibited.    o Monocular or alternating. Suppression is monocular when  the image from the dominant eye always predominates  over the image from the deviating (or more ametropic)  eye, so that the image from the latter is constantly  suppressed. This type of suppression leads to amblyopia.  When suppression alternates (switches from one eye to  the other), amblyopia is less likely to develop,  o Facultative or obligatory. Facultative suppression occurs  only when the eyes are misaligned. Obligatory  suppression is present at all times, irrespective of whether  the eyes are deviated or straight. Examples of facultative  suppression include intermittent exotropia and Duane  syndrome.    Fig. 18.15 Diplopia. (A) Homonymous (uncrossed) diplopia in  right esotropia with normal retinal correspondence; (B)  heteronymous (crossed) diplopia in right exotropia with  normal retinal correspondence   condition in which non-corresponding retinal elements  acquire a common subjective visual direction, i.e. fusion  occurs in the presence of a small angle manifest squint; the  fovea of the fixating eye is paired with a non-foveal element  of the deviated eye. Binocular responses in ARC are never as  good as in normal bifoveal BSV. It represents a positive  sensory adaptation to strabismus (as opposed to negative  adaptation by suppression), which allows some anomalous  binocular vision in the presence of a heterotropia. It is most  frequently encountered in small angle esotropia  (microtropia), but is less common in accommodative  esotropia because of the variability of the angle of deviation  and in large angle deviations because the separation of the  images is too great.   o The fovea of the squinting eye is suppressed to avoid  confusion.   o Diplopia will occur, since corresponding retinal elements  receive different images.   o To avoid diplopia, the patient will develop either  peripheral suppression of the squinting eye or ARC.  o If constant unilateral suppression occurs this will  subsequently lead to strabismic amblyopia.   Motor adaptation involves the adoption of a compensatory head  posture (CHP) and occurs primarily in children with congenitally  abnormal eye movements who use the CHP to maintain BSV. In  these children loss of a CHP may indicate loss of binocular func¬  tion and the need for surgical intervention. These patients may  present in adult life with symptoms of decompensation, often  unaware of their CHP. Acquired paretic strabismus in adults may  be consciously controlled by a CHP provided the deviation is  neither too large nor too variable with gaze (incomitance). The  CHP eliminates diplopia and helps to centralize the binocular  visual field. The patient will turn the head into the direction of the  field of action of the weak muscle, so that the eyes are then auto¬  matically turned the opposite direction and as far as possible away  from its field of action (i.e. the head will turn where the eye  cannot).   • A face turn will be adopted to control a purely horizontal  deviation. For example, if the left lateral rectus is paralysed,  diplopia will occur in left gaze; the face will be turned to the  left which deviates the eyes to the right away from the field  of action of the weak muscle and area of diplopia. A face  turn may also be adopted in a paresis of a vertically acting  muscle to avoid the side where the vertical deviation is  greatest (e.g. in a right superior oblique weakness the face is  turned to the left).   • A head tilt is adopted to compensate for torsional and/or  vertical diplopia. In a right superior oblique weakness, the  right eye is relatively elevated and the head is tilted to the  left (Fig. 18.16), towards the hypotropic eye; this reduces the   Fig. 18.16 Compensatory head posture in a right fourth  nerve palsy    vertical separation of the diplopic images and permits fusion  to be regained. If there is a significant torsional component  preventing fusion, tilting the head in the same left direction  will reduce this by invoking the righting reflexes (placing the  extorted right eye in a position that requires extorsion).   • Chin elevation or depression may be used to compensate  for weakness of an elevator or depressor muscle or to  minimize the horizontal deviation when an C A’ or C V’ pattern  is present.   Amblyopia is the unilateral, or rarely bilateral, decrease in best  corrected visual acuity (VA) caused by form vision deprivation  and/or abnormal binocular interaction, for which there is no iden¬  tifiable pathology of the eye or visual pathway.   • Strabismic amblyopia results from abnormal binocular  interaction where there is continued monocular suppression  of the deviating eye.   • Anisometropic amblyopia is caused by a difference in  refractive error between the eyes and may result from a  difference of as little as 1 dioptre. The more ametropic  eye receives a blurred image, in a mild form of visual   deprivation. It is frequently associated with microstrabismus  and may coexist with strabismic amblyopia.   • Stimulus deprivation amblyopia results from vision  deprivation. It may be unilateral or bilateral and is typically  caused by opacities in the media (e.g. cataract) or ptosis that  covers the pupil.   • Bilateral ametropic amblyopia results from high  symmetrical refractive errors, usually hypermetropia.   • Meridional amblyopia results from image blur in one  meridian. It can be unilateral or bilateral and is caused by  uncorrected astigmatism (usually >1 D) persisting beyond  the period of emmetropization in early childhood.   In the absence of an organic lesion, a difference in best corrected  VA of two Snellen lines or more (or >1 log unit) is indicative of  amblyopia. Visual acuity in amblyopia is usually better when  reading single letters than letters in a row. This ‘crowding’ phe¬  nomenon occurs to a certain extent in normal individuals but is  more marked in amblyopes and must be taken into account when  testing preverbal children.   It is essential to examine the fundi to diagnose any visible organic  disease prior to commencing treatment for amblyopia. Organic  disease and amblyopia may coexist and a trial of patching may still  be indicated in the presence of organic disease. If acuity does not  respond to treatment, investigations such as electrophysiology or  imaging should be reconsidered. The sensitive period during  which acuity of an amblyopic eye can be improved is usually up  to 7-8 years in strabismic amblyopia and may be longer (into the  teens) for anisometropic amblyopia where good binocular func¬  tion is present.   • Occlusion of the normal eye, to encourage use of the  amblyopic eye, is the most effective treatment. The regimen,  full-time or part-time, depends on the age of the patient and  the density of amblyopia.   o The younger the patient, the more rapid the likely  improvement but the greater the risk of inducing  amblyopia in the normal eye. It is therefore very  important to monitor VA regularly in both eyes during  treatment.   o The better the VA at the start of occlusion, the shorter  the duration required, although there is wide variation  between patients.   O If there has been no improvement after 6 months of  effective occlusion, further treatment is unlikely to be  fruitful.   o Poor compliance is the single greatest barrier to  improvement and must be monitored. Amblyopia  treatment benefits from time spent at the outset on  communication of the rationale and the difficulties  involved.   • Penalization, in which vision in the normal eye is blurred  with atropine, is an alternative method. It may work best    in the treatment of moderate amblyopia (6/24 or better).  Patch occlusion is likely to produce a quicker response than  atropine, which has conventionally been reserved for use  when compliance with patch occlusion is poor. Weekend  instillation may be adequate.   o The earlier the onset, the more likely the need for surgical  correction.   o The later the onset, the greater the likelihood of an  accommodative component (mostly arising between 18  and 36 months).   O The longer the duration of squint in early childhood the  greater the risk of amblyopia, unless fixation is freely  alternating. Inspection of previous photographs may be  useful for the documentation of strabismus or CHP.   • Symptoms may indicate decompensation of a pre-existent  heterophoria or more significantly a recently acquired  (usually paretic) condition. In the former, the patient usually  complains of discomfort, blurring and possibly diplopia of  indeterminate onset and duration compared to the acquired  condition with the sudden onset of diplopia.   o The type of diplopia (horizontal, cyclovertical) should be  established, together with the direction of gaze in which  it predominates and whether any BSV is retained,  o In adults it is very important to determine exactly what  problems the squint is causing as a basis for decisions  about treatment.   o It is not unusual for patients to present with spurious  symptoms that mask embarrassment over a cosmetically  noticeable squint.   • Variability is significant because intermittent strabismus  indicates some degree of binocularity. An equally alternating  deviation suggests symmetrical visual acuity in both eyes.   • General health or developmental problems may be  significant (e.g. children with cerebral palsy have an  increased incidence of strabismus). In older patients poor  health and stress may cause decompensation, and in  acquired paresis patients may report associations or causal  factors (trauma, neurological disease, diabetes etc.).   • Birth history, including period of gestation, birth weight  and any problems in utero , with delivery or in the neonatal  period.   • Family history is important because strabismus is frequently  familial, although no definitive inheritance pattern is  recognized. It is also important to know what therapy was  necessary in other family members.   • Previous ocular history including refractive prescription  and compliance with spectacles or occlusion, previous  surgery or prisms is important to future treatment options  and prognosis.   The evaluation can be separated into the qualitative assessment of  visual behaviour and the quantitative assessment of visual acuity  using preferential looking tests. Assessment of visual behaviour is  achieved as follows:   • Fixation and following may be assessed using bright  attention-grabbing targets (a face is often best). This method  indicates whether the infant is visually alert and is of  particular value in a child suspected of being blind.   • Comparison between the behaviour of the two eyes may  reveal a unilateral preference. Occlusion of one eye, if  strongly objected to by the child, indicates poorer acuity in  the other eye. However, it is possible to have good visual  attention with each eye but unequal visual acuity and all risk  factors for amblyopia must be considered in the  interpretation of results.   • Fixation behaviour can be used to establish unilateral  preference if a manifest squint is present.   o Fixation is promoted in the squinting eye by occluding  the dominant eye while the child fixates a target of  interest (preferably incorporating a light),  o Fixation is then graded as central or non-central and  steady or unsteady (the corneal reflection can be  observed).   o The other eye is then uncovered and the ability to  maintain fixation is observed.   o If fixation immediately returns to the uncovered eye, then  visual acuity is probably impaired,  o If fixation is maintained through a blink, then visual  acuity is probably good.   o If the patient alternates fixation, then the two eyes  probably have equal vision.   • The 10 A test is similar and can be used regardless of  whether a manifest squint is present. It involves the  promotion of diplopia using a 10 A vertical prism.   • Rotation test is a gross qualitative test of the ability of an  infant to fixate with both eyes open. The test is performed as  follows:   o The examiner holds the child facing him or her and  rotates briskly through 360°.   o If vision is normal, the eyes will deviate in the direction  of rotation under the influence of the vestibulo-ocular  response. The eyes flick back to the primary position to  produce a rotational nystagmus,  o When rotation stops, nystagmus is briefly observed in the  opposite direction for 1-2 seconds and should then cease  due to suppression of post-rotary nystagmus by fixation,  o If vision is severely impaired, the post-rotation nystagmus  does not stop as quickly when rotation ceases because the  vestibulo-ocular response is not blocked by visual  feedback.    • Preferential looking tests can be used from early infancy  and are based on the fact that infants prefer to look at a  pattern rather than a homogeneous stimulus. The infant is  exposed to a stimulus and the examiner observes the eyes for  fixation movements, without themselves knowing the  stimulus position.   o Tests in common use include the Teller and Keeler acuity  cards, which consist of black stripes (gratings) of varying  widths, and Cardiff acuity cards (Fig. 18.17), which consist  of familiar pictures with variable outline width.   O Low frequency (coarse) gratings or pictures with a  wider outline are seen more easily than high frequency  gratings or thin outline pictures, and an assessment of  resolution (not recognition) visual acuity is made  accordingly.   o Since grating acuity often exceeds Snellen acuity in  amblyopia, Teller cards may overestimate visual acuity.  These methods may not be reliable if a proper forced-  choice staircase protocol is not followed during testing,  and neither method has high sensitivity to the presence of  amblyopia. The results must be considered in  combination with risk factors for amblyopia.   • Pattern visual evoked potentials (VEP) give a  representation of spatial acuity but are more commonly used  in the diagnosis of optic neuropathy.   The tests described below should be performed at 3-4 metres from  the target, as it is easier to obtain compliance than at 6 metres,  with little or no clinical detriment. It is important to note that  amblyopia can only be accurately diagnosed using a crowded test  requiring target recognition and that logMAR tests (logarithm of  the minimal angle of resolution - see Ch. 14) provide the best  measure against which improvement with amblyopia therapy can  be assessed. These are readily available in formats suited to normal  children from 2 years onwards.   • At age 2 years most children will have sufficient language  skills to undertake a picture naming test such as the crowded  Kay pictures (Fig. 18.18A).   • At age 3 years most children will be able to undertake the  matching of letter optotypes as in the Keeler logMAR (Fig.  18.18B) or Sonksen crowded tests. If a crowded letter test  proves too difficult it is preferable to perform the crowded  Kay pictures than to use single optotype letters.   • Older children may continue with the crowded letter tests,  naming or matching them; LogMAR tests are in common  usage and are preferable to Snellen for all children at risk of  amblyopia.   Stereopsis is measured in seconds of arc (i° = 60 minutes of arc;  1 minute = 60 seconds); the lower the value the better the stereo¬  acuity. It is useful to remember that normal spatial resolution  (visual acuity) is 1 minute and normal stereoacuity is 60 seconds  (also 1 minute, but conventionally expressed in seconds). Various  tests, using differing principles, are employed to assess the stereo¬  acuity. Random dot tests (e.g. TNO, Frisby) provide the most  definitive evidence of high grade BSV. Where this is weak and/or  based on ARC (see above), contour-based tests (e.g. Titmus) may  provide more reliable information.   The Titmus test consists of a three-dimensional polarized vecto-  graph comprising two plates in the form of a booklet viewed  through polarized spectacles. On the right is a large fly, and on the  left is a series of circles and animals (Fig. 18.19). The test should  be performed at a distance of 40 cm.   • The fly is a test of gross stereopsis (3000 seconds), and is  especially useful for young children. It should appear to  stand out from the page and the child is encouraged to  pick up the tip of one of its wings between finger and  thumb.   • The animals component consists of three rows of stylized  animals (400-100 seconds), one of which will appear  forward of the plane of reference.   • The circles comprise a graded series measuring 800-40  seconds; one of a set of four circles should appear to stand  out from the plate surface.   The TNO random dot test consists of seven plates of randomly  distributed paired red and green dots viewed with red-green spec¬  tacles, and measures from 480 down to 15 seconds of arc at 40 cm.  Within each plate the dots of one colour forming the target shape  (squares, crosses etc. - Fig. 18.20) are displaced horizontally in  relation to paired dots of the other colour so that they have a   The Frisby stereotest consists of three transparent plastic plates of  varying thickness. On the surface of each plate are printed four  squares of small randomly distributed shapes (Fig. 18.21). One  of the squares contains a ‘hidden’ circle, in which the random  shapes are printed on the reverse of the plate. The test does not  require special spectacles because disparity (600-15 seconds) is  created by the thickness of the plate; the working distance must  be measured.   The Lang stereotest does not require special spectacles; the targets  are seen alternately by each eye through the built-in cylindrical  lens elements. Displacement of the dots creates disparity (1200-  200 seconds) and the patient is asked to name or point to a simple  shape, such as a star, on the card (Fig. 18.22).   This is a simple method for detecting fusion in children. The test  is performed by placing a 20 A base-out prism in front of one eye  (the right eye in Fig. 18.23). This displaces the retinal image tem¬  porally with resultant diplopia.   • There will be a shift of the right eye to the left to resume  fixation (right adduction) with a corresponding shift of the    left eye to the left (left abduction) in accordance with the  Hering law (Fig. 18.23B).   • The left eye will then make a corrective re-fixational saccade  to the right (left re-adduction) (Fig. 18.23C).   • On removal of the prism both eyes move to the right (Fig.  18.23D).   • The left eye then makes an outward fusional movement (Fig.  18.23E).   • Most children with good BSV should be able to overcome a  20 A prism from the age of 6 months; if not, weaker prisms  (16 A or 12 A) may be tried, but the response is then more  difficult to identify.   Simple convergence to an interesting target can be demonstrated  from 3 to 4 months. Both eyes should follow the approaching  target symmetrically c to the nose’. Over-convergence in the infant  may indicate an incipient esotropia; divergence may be due either  to a tendency to a divergent deviation or simply lack of interest.   This is a dissociation test that can be used with both distance  and near fixation and differentiates between BSV, ARC and sup¬  pression. Results can only be interpreted if the presence or absence  of a manifest squint is known at time of testing.   o The patient wears a green lens in front of the right eye,  which filters out all colours except green, and a red lens  in front of the left eye which will filter out all colours  except red (Fig. 18.24A).   o The patient then views a box with four lights: one red,  two green and one white.   o If BSV is present all four lights are seen,  o If all four lights are seen in the presence of a manifest  deviation, harmonious ARC (see ‘Synoptophore’ below)  is present.   o If two red lights are seen, right suppression is present,  o If three green lights are seen, left suppression is present,  o If two red and three green lights are seen, diplopia is  present.   o If the green and red lights alternate, alternating  suppression is present.   This is a test for detecting BSV, ARC or suppression. Each lens has  fine striations that convert a point source of light into a line, as  with the Maddox rod (see below).   • Procedure. The two lenses are placed at 45 0 and 135 0 in front  of each eye and the patient fixates on a focal light source  (Fig. 18.25A). Each eye perceives an oblique line of light,    perpendicular to that perceived by the fellow eye (Fig.  18.25B). Dissimilar images are thus presented to each eye  under binocular viewing conditions.   • Results (Fig. 18.25C) cannot be interpreted unless it is  known whether strabismus is present,  o If the two streaks intersect at their centres in the form of  an oblique cross (an C X’), the patient has BSV if the eyes  are straight, or harmonious ARC in the presence of  manifest strabismus.   o If the two lines are seen but they do not form a cross,  diplopia is present.   o If only one streak is seen, there is no simultaneous  perception and suppression is present,  o In theory, if a small gap is seen in one of the streaks, a  central suppression scotoma (as found in microtropia) is  present. In practice this is often difficult to demonstrate  and the patient describes a cross. The scotoma can be  confirmed with the 4 A prism test (see below).   Fig. 18.24 Worth four-dot test. (A) Red-green glasses;  (B) possible results    Fig. 18.25 Bagolini test. (A) Striated glasses; (B) appearance  of a point of light through Bagolini lenses; (C) possible  results    in microtropia and employs the principle described in the 20 A  test (the Hering law and convergence) to overcome diplopia.   o The prism is placed base-out (microtropia is commonly  esotropic not exotropic) in front of the right eye with  deviation of the image away from the fovea temporally,  followed by corrective movement of both eyes to the left  (Fig. 18.26A).   o The left eye then converges to fuse the images  (Fig. 18.26B).   o The patient fixates a distance target with both eyes open  and a 4 A prism is placed base-out in front of the eye  with suspected CSS (the left in Fig. 18.27).  o The image is moved temporally in the left eye but falls  within the CSS and no movement of either eye is  observed (Fig. 18.27A).   o The prism is then moved to the right eye which adducts  to maintain fixation; the left eye similarly moves to the  left consistent with the Hering law of equal innervation,  but the second image falls within the CSS of the left eye  and so no subsequent re-fixation movement is seen  (Fig. 18.27B).   The synoptophore compensates for the angle of squint and allows  stimuli to be presented to both eyes simultaneously (Fig. 18.28A).  It can thus be used to investigate the potential for binocular func¬  tion in the presence of a manifest squint and is of particular value  in assessing young children (from age 3 years), who generally find  the test process enjoyable. It can also detect suppression and ARC.   • The instrument consists of two cylindrical tubes with a  mirrored right-angled bend and a +6.50 D lens in each  eyepiece (Fig. 18.28B, top). This optically sets the testing  distance as equivalent to about 6 metres.   • Pictures are inserted in a slide carrier situated at the outer  end of each tube. The two tubes are supported on columns  that enable the pictures to be moved in relation to each  other, and any adjustments are indicated on a scale.   • The synoptophore can measure horizontal, vertical and  torsional misalignments simultaneously and is valuable in  determining surgical approach by assessing the different  contributions in the cardinal positions of gaze.   Binocular vision can be graded on the synoptophore as below  (Fig. 18.28B, bottom).   • First grade (simultaneous perception - SP) is tested by  introducing two dissimilar but not mutually antagonistic  pictures, such as a bird and a cage.   o The subject is then asked to put the bird into the cage by  moving the arm of the synoptophore.  o If the two pictures cannot be seen simultaneously, then  suppression is present.   Fig. 18.26 4 A prism test in bifoveal fixation. (A) Shift of both eyes away from the prism base; (B) fusional re-fixation  movement of the left eye    O Some retinal ‘rivalry’ will occur although one picture is  smaller than the other, so that while the small one is seen  foveally, the larger one is seen parafoveally (and is thus  placed in front of the deviating eye),  o Larger macular and paramacular slides are used if foveal  slides cannot be superimposed.   • Second grade (fusion). If simultaneous perception slides  can be superimposed then the test proceeds to the second  grade which is the ability of the two eyes to produce a  composite picture (sensory fusion) from two similar    pictures, each of which is incomplete in one small different  detail.   o The classic example is two rabbits, one lacking a tail and  the other lacking a bunch of flowers. If fusion is present,  one rabbit complete with tail and flowers will be seen,  o The range of fusion (motor fusion) is then tested by  moving the arms of the synoptophore so that the eyes  have to converge and diverge in order to maintain fusion,  o The presence of simple fusion without any range is of  little value in everyday life.   Fig. 18.27 4 A prism test in left microtropia with a central suppression scotoma. (A) No movement of either eye; (B) both  eyes move to the left but there is absence of re-fixation    • Third grade (stereopsis) is the ability to obtain an  impression of depth by the superimposition of two pictures  of the same object which have been taken from slightly  different angles. The classic example is a bucket, which  should be appreciated in three dimensions.   • The subjective angle of deviation is that at which the SP  slides are superimposed. The examiner determines the    objective angle of the deviation by presenting each fovea  alternately with a target by extinguishing one or other light  and moving the slide in front of the deviating eye until no  movement of the eyes is seen.   • If the subjective and objective angles coincide then retinal  correspondence is normal.   • If the objective and subjective angles are different, ARC is  present. The difference in degrees between the subjective and  objective angles is the angle of anomaly. ARC is said to be  harmonious when the objective angle equals the angle of  anomaly and inharmonious when it exceeds the angle of   anomaly. It is only in harmonious ARC that binocular  responses can be demonstrated; the inharmonious form may  represent a lesser adaptation or an artefact of testing.   The Hirschberg test gives a rough objective estimate of the angle  of a manifest strabismus and is especially useful in young or unco¬  operative patients or when fixation in the deviating eye is poor. It  is also useful in excluding pseudostrabismus. A pen torch is shone  into the eyes from arm’s length and the patient asked to fixate the  light. The corneal reflection of the light will be (more or less)  centred in the pupil of the fixating eye, but will be decentred in a  squinting eye, in the direction opposite to that of the deviation  (Fig. 18.29). The distance of the corneal light reflection from the  centre of the pupil is noted; each millimetre of deviation is approx¬  imately equal to 7 0 (i° ~ 2 prism dioptres). For example, if the  reflex is situated at the temporal border of the pupil (assuming a  pupillary diameter of 4 mm), the angle is about 15 0 ; if it is at the  limbus, the angle is about 45 0 .   Corneal reflex assessment can be combined with prisms to give  a more accurate approximation of the angle in a manifest  deviation.   • The Krimsky test involves placement of prisms in front of  the fixating eye until the corneal light reflections are  symmetrical (Fig. 18.30). This test reduces the problem of  parallax and is more commonly used than the prism  reflection test.    • The prism reflection test involves the placement of prisms  in front of the deviating eye until the corneal light reflections  are symmetrical.   • Cover test to detect a heterotropia. It is helpful to begin the  near test using a light to observe the corneal reflections and  to assess fixation in the deviating eye. It should then be  repeated for near using an accommodative target and for  distance as follows:   o The patient fixates on a straight-ahead target,  o If a right deviation is suspected, the examiner covers the  fixing left eye and notes any movement of the right eye to  take up fixation.   o No movement indicates orthotropia (Fig. 18.31A) or left  heterotropia (Fig. 18.31B).   o Adduction of the right eye to take up fixation indicates  right exotropia and abduction, right esotropia (Fig.  18.31C).   o Downward movement indicates right hypertropia and  upward movement right hypotropia.  o The test is repeated on the opposite eye.   • The uncover test detects heterophoria. It should be  performed both for near (using an accommodative target)  and for distance as follows:   o The patient fixates a straight-ahead distant target,  o The examiner covers the right eye and, after 2-3 seconds,  removes the cover.   o No movement indicates orthophoria (Fig. 18.32A); a keen  observer will frequently detect a very slight latent  deviation in most normal individuals, as few individuals  are truly orthophoric, particularly on near fixation.    Fig. 18.29 Hirschberg test. (A) The right corneal reflex is near  the temporal border of the pupil indicating an angle of  about 15°; (B) the left corneal reflex is near the limbus  indicating an angle of close to 45° - convergent squint;   o If the right eye had deviated while under cover, a   o Adduction (nasal recovery) of the right eye indicates  exophoria (Fig. 18.32B) and abduction esophoria  (Fig. 18.32C).   o After the cover is removed, the examiner notes the speed  and smoothness of recovery as evidence of the strength of  motor fusion.   o The test is repeated for the opposite eye.  o Most examiners perform the cover test and the uncover  test sequentially, hence the term cover-uncover test.   The alternate cover test induces dissociation to reveal the total  deviation when fusion is disrupted. It should be performed only  after the cover-uncover test.   • The occluder is quickly shifted to the opposite eye for 2  seconds, then back and forth several times. After the cover  is removed, the examiner notes the speed and smoothness  of recovery as the eyes return to their pre-dissociated  state.   • A patient with a well-compensated heterophoria will have  straight eyes before and after the test has been performed  whereas a patient with poor control may decompensate to a  manifest deviation.   The prism cover test measures the angle of deviation on near or  distance fixation and in any gaze position. It combines the alter¬  nate cover test with prisms and is performed as follows:   • The alternate cover test is first performed to establish the  direction and approximate extent of deviation.   • Prisms of increasing strength are placed in front of one eye  with the base opposite the direction of the deviation (i.e. the  apex of the prism is pointed in the direction of the  deviation). For example, in a convergent strabismus the  prism is held base-out, and in a right hypertropia, base  down before the right eye.   • The alternate cover test is performed continuously as  stronger prisms are introduced, typically using a prism bar  consisting of a column of prisms of progressive strength  (Fig. 18.33). The amplitude of the re-fixation movement  should gradually decrease as the strength of prism  approaches the extent of deviation.   • The end-point is approached when no movement is seen. To  ensure the maximum angle is found, the prism strength can  be increased further until a movement is observed in the  opposite direction (the point of reversal) and then reduced  again to find the neutral value; the angle of deviation is then  taken from the strength of the prism.   The Maddox wing dissociates the eyes for near fixation (1/3 m)  and measures heterophoria. The instrument is constructed in such  a way that the right eye sees only a white vertical arrow and a red  horizontal arrow, whereas the left eye sees only horizontal and  vertical rows of numbers (Fig. 18.34).   • Horizontal deviation is measured by asking the patient to  which number the white arrow points.   • Vertical deviation is measured by asking the patient which  number intersects with the red arrow.   • The amount of cyclophoria is determined by asking the  patient to move the red arrow so that it is parallel with the  horizontal row of numbers.   The Maddox rod consists of a series of fused cylindrical red glass  rods that convert the appearance of a white spot of light into a red  streak. The optical properties of the rods cause the streak of light  to be at an angle of 90° with the long axis of the rods; when the  glass rods are held horizontally, the streak will be vertical and vice  versa.   • The rod is placed in front of the right eye (Fig. 18.35A). This  dissociates the two eyes: the red streak seen by the right eye  cannot be fused with the unaltered white spot of light seen  by the left eye (Fig. 18.35B).   • The amount of dissociation (Fig. 18.35C) is measured by the  superimposition of the two images using prisms. The base of  the prism is placed in the position opposite to the direction  of the deviation.   • Both vertical and horizontal deviations can be measured in  this way but the test cannot differentiate a phoria from a  tropia.   • Versions towards the eight eccentric positions of gaze are  tested by asking the patient to follow a target, usually a pen  or pen torch (the latter offers the advantage of corneal light  reflections to aid assessment). A cover test is performed in  each position of gaze to confirm whether a phoria has  become a tropia or the angle of deviation has increased and  the patient is questioned regarding diplopia. Versions may  also be elicited involuntarily in response to a noise or by the  doll’s head manoeuvre in uncooperative patients.   • Ductions are assessed if reduced ocular motility is noted in  either or both eyes. A pen torch should be used with careful  attention to the position of the corneal reflexes. The fellow    Fig. 18.35 (A) Maddox rod test; (B) appearance of a point of light through the Maddox rod; (C) possible results    eye is occluded and the patient asked to follow the torch  into various positions of gaze. A simple numeric system may  be employed using o to denote full movement, and -1 to -4  to denote increasing degrees of underaction (Fig. 18.36).   The near point of convergence (NPC) is the nearest point on  which the eyes can maintain binocular fixation. It can be measured  with the RAF rule, which rests on the patient’s cheeks (Fig. 18.37A).  A target (Fig. 18.37B) is slowly moved along the rule towards the  patient’s eyes until one eye loses fixation and drifts laterally (objec¬  tive NPC). The subjective NPC is the point at which the patient  reports diplopia. Normally, the NPC should be nearer than 10 cm  without undue effort.   The near point of accommodation (NPA) is the nearest point on  which the eyes can maintain clear focus. It can also be measured  with the RAF rule. The patient fixates a line of print, which is then  slowly moved towards the patient until it becomes blurred. The  distance at which this is first reported is read off the rule and  denotes the NPA. The NPA recedes with age; when sufficiently far  away to render reading difficult without optical correction, pres¬  byopia is present. At the age of 20 years the NPA is 8 cm and by  the age of 50 years it has receded to approximately 46 cm. The    amplitude of accommodation can also be assessed using concave  lenses in 0.5 DS steps whilst fixating the 6/6 Snellen line and  reporting when the vision blurs.   Fusional amplitudes measure the efficacy of vergence movements.  They may be tested with prisms bars or the synoptophore. An  increasingly strong prism is placed in front of one eye, which will  then abduct or adduct (depending on whether the prism is base-in  or base-out), in order to maintain bifoveal fixation. When a prism  greater than the fusional amplitude is reached, diplopia is reported  or one eye drifts in the opposite direction, indicating the limit of  vergence ability.   This simple test is mandatory prior to strabismus surgery in all  non-binocular patients over 7-8 years of age to assess the risk of  diplopia after surgery.   • Corrective prisms are placed in front of one eye (usually the  deviating eye) and the patient asked to fixate a straight¬  ahead target with both eyes open. The prisms are slowly  increased until the angle has been significantly overcorrected  and the patient reports if diplopia occurs.    • If suppression persists throughout there is little risk of  diplopia following surgery; however, in a consecutive  exotropia of 35 A, diplopia may be reported from 30 A and  persist as the prism correction mimics an esotropia.   • Diplopia may be intermittent or constant but in either case  constitutes an indication to perform a diagnostic botulinum  toxin test (see below).   • Diplopia is not restricted to patients with good visual acuity  in the deviating eye.   A Hess chart is plotted to aid in the diagnosis and monitoring of  a patient with incomitant strabismus, such as an extraocular  muscle palsy (e.g. third, fourth or sixth nerve paresis) or a  mechanical or myopathic limitation (e.g. thyroid ophthalmopa¬  thy, blow-out fracture or myasthenia gravis). The chart is com¬  monly prepared using either the Lees or Hess screen, which  facilitate plotting of the dissociated ocular position as a measure  of extraocular muscle action. Information provided by the Hess  chart should be regarded in the context of other investigations  such as the field of binocular single vision. The prism cover test is  also very useful in the assessment of incomitant squint.   The Hess screen contains a tangent pattern displayed on a dark  grey background. Red lights that can be individually illuminated  by a control panel indicate the cardinal positions of gaze within a  central field (15 0 from primary position) and a peripheral field  (30°); each square represents 5 0 of ocular rotation. The eyes are  dissociated by the use of reversible goggles incorporating a red and  a green lens, the red lens in front of the fixating eye and the green  lens the non-fixating eye. Red points of lights are illuminated at  selected positions on the screen. The patient holds a green pointer,  and is asked to superimpose a green light over each red light in  turn. In orthophoria the two lights should be more or less super¬  imposed in all positions of gaze. The goggles are then reversed and  the procedure repeated. Software is available that facilitates the  plotting of a Hess chart using a standard desktop computer screen.   This apparatus (Fig. 18.38) consists of two opalescent glass screens  at right-angles to each other, bisected by a two-sided plane mirror  that dissociates the eyes; each of the eyes can see only one of the  two screens. Each screen has a tangent pattern (two-dimensional  projection of a spherical surface) that is revealed only when the  screen is illuminated. The patient is positioned facing the non-  illuminated screen with his or her chin stabilized on a rest. Using  a pointer, the examiner indicates a target point on the illuminated  tangent pattern and the patient positions a pointer on the non-  illuminated screen, at a position perceived to be superimposed on  the dot indicated by the examiner. The non-illuminated screen is  briefly illuminated by the examiner using a footswitch to facilitate  recording of the dot indicated by the patient. When the procedure  has been completed for one eye, the patient is rotated through 90°   Figure 18.39 shows a typical Hess chart appearance in right lateral  rectus paresis of recent onset.   • The smaller chart indicates the eye with the paretic muscle  (right eye).   • The larger chart indicates the eye with the overacting yoke  muscle (left eye).   • The smaller chart will show its greatest restriction in the main  direction of action of the paretic muscle (right lateral rectus).   • The larger chart will show its greatest expansion in the main  direction of action of the yoke muscle (left medial rectus).   • The degree of disparity between the plotted point and the  template in any position of gaze gives an estimate of the  angle of deviation (each square = 5 0 ).   Progressive changes in the Hess chart with time are character¬  istic, and useful both as a prognostic indicator and to guide  management.   • In right superior rectus palsy, the Hess chart will show  underaction of the affected muscle with an overaction of its  yoke muscle, the left inferior oblique (Fig. 18.40A). Because  of the great incomitance of the two charts, the diagnosis is   Fig. 18.39 Hess chart of a recent right lateral rectus palsy.  10 = inferior oblique; IR = inferior rectus; LR = lateral  rectus; MR = medial rectus; SO = superior oblique;   Fig. 18.40 Hess chart showing changes with time of a right  superior rectus palsy. 10 = inferior oblique; IR = inferior  rectus; SO = superior oblique; SR = superior rectus    straightforward. If the paretic muscle recovers its function,  both charts will revert to normal.   • Secondary contracture of the ipsilateral antagonist (right  inferior rectus) will manifest as an over action which will lead  to a secondary (inhibitional) palsy of the antagonist of the  yoke muscle (left superior oblique), which will show up on  the chart as an underaction (Fig. 18.40B). This could lead to  the incorrect impression that the left superior oblique is the  primarily paretic muscle.   • With further passage of time, the two charts become  progressively more concomitant, such that it may be  impossible to determine the initiating muscle weakness (Fig.  18.40C).   o The area enclosed on the left chart is much smaller than  that on the right.    o Left exotropia - note that the fixation spots in the inner  charts of both eyes are deviated laterally. The deviation is  greater on the right chart (when the left eye is fixating),  indicating that secondary deviation exceeds the primary,  typical of a paretic squint.   o Left chart shows underaction of all muscles except the  lateral rectus.   o The primary angle of deviation (fixing right eye - FR) in  the primary position is -20° and R/L io°.  o The secondary angle (fixing left eye - FL) is -28° and R/L  12 °.   O In inferior rectus palsy, the function of the superior  oblique muscle can only be assessed by observing  intorsion on attempted depression. This is best  performed by observing a conjunctival landmark using  the slit lamp.   O Right chart shows underaction of the superior oblique  and overaction of the inferior oblique,  o Left chart shows overaction of the inferior rectus and  underaction (inhibitional palsy) of the superior rectus.   O The primary deviation (FL) is R/L 8°; the secondary  deviation FR is R/L 17 0 .   o Primary and secondary deviation R/L 4 0 .  o Right hypertropia - note that the fixation spot of the  right inner chart is deviated upwards and the left is  deviated downwards.   O Right chart shows underaction of the superior oblique  and overaction of the inferior oblique,  o Left chart shows overaction of the inferior rectus and  underaction (inhibitional palsy) of the superior rectus.   o Right chart is smaller than the left,  o Right esotropia - note that the fixation spot of the right  inner chart is deviated nasally,  o Right chart shows marked underaction of the lateral  rectus and slight overaction of the medial rectus,  o Left chart shows marked overaction of the medial  rectus.   o The primary angle FL is +15 0 and the secondary angle FR  + 20 °.   o Inhibitional palsy of the left lateral rectus has not yet  developed.    cause of the deviation. More commonly, strabismus is secondary  to refractive error; hypermetropia (hyperopia), astigmatism, ani¬  sometropia and myopia may all be associated.   The most common refractive error to cause strabismus is hyper¬  metropia. Accurate measurements of hypermetropia necessitate  effective paralysis of the ciliary muscle (cycloplegia), in order to  neutralize the masking effect of accommodation. In a young child  the risk of penalization amblyopia should be avoided by always  inducing cycloplegia in both eyes at one sitting, particularly if  atropine is used.   • Cyclopentolate (0.5% under 6 months and 1%  subsequently). One drop, repeated after 5 minutes, usually  results in maximal cycloplegia within 30 minutes, with  recovery of accommodation within 2-3 hours and resolution  of mydriasis within 24 hours. The adequacy of cycloplegia  can be determined by comparing retinoscopy readings with  the patient fixating for distance and then for near. Topical  anaesthesia with a well-tolerated agent such as  proxymetacaine prior to instillation of cyclopentolate is  useful in preventing ocular irritation and reflex tearing, thus  affording better retention of the cyclopentolate in the  conjunctival sac and effective cycloplegia.   • Atropine (0.5% under the age of 12 months and 1%  subsequently) has a somewhat stronger cycloplegic effect  than cyclopentolate. In most cases this is clinically  insignificant, but may be helpful in instances such as high  hypermetropia or heavily pigmented irides. As the onset of  cycloplegia is slower, a carer may be supplied with topical  atropine for instillation at home twice daily over 1-3 days  prior to attendance (but not on the day of examination) as  either eye drops or ointment; drops are easier to instil, but  there may be less risk of overdose with ointment. The  atropine should be discontinued if there are signs of  systemic toxicity, such as flushing, fever or restlessness, and  immediate medical attention sought. The visual effects may  last for up to 2 weeks.   Because refraction changes with age, it is important to check this  in patients with strabismus at least every year and more frequently  in younger children and if acuity is reduced. At birth most babies  are hypermetropic. After the age of 2 years there may be an increase  in hypermetropia and a decrease in astigmatism. Hypermetropia  may continue to increase until the age of about 6 years, levelling  off between the ages of 6 and 8 and subsequently decreasing.   Most children are mildly hypermetropic (1-3 D). There is some  evidence that fully correcting hypermetropia in a normal child  may reduce physiological emmetropization.   • Hypermetropia. In general up to 4 D of hypermetropia  should not be corrected in a child without a squint unless  they are experiencing problems with near vision. With    hypermetropia greater than this a two-thirds correction is  usually given. However, in the presence of esotropia, the full  cycloplegic correction should be prescribed, even under the  age of 2 years.   • Astigmatism. A cylinder of 1.50 D or more should probably  be prescribed, especially in anisometropia after the age of 18  months.   • Myopia. The necessity for correction depends on the age of  the child. Under the age of 2 years, -5.00 D or more of  myopia should be corrected; between the ages of 2 and 4 the  amount is -3.00 D. Older children should have correction of  even low myopia to allow clear distance vision.  Undercorrection and bifocals may retard progression and  are under investigation.   • Anisometropia. After the age of 3 the full difference in  refraction between the eyes should be prescribed if it is  more than 1 D, with full hypermetropic correction in squint.    Pseudostrabismus is the clinical impression of ocular deviation  when no squint is present.   • Abnormal interpupillary distance, if short may simulate an  esotropia and if wide an exotropia (Fig. 18.45B).   Fig. 18.45 Pseudostrabismus. (A) Prominent epicanthic folds  simulating esotropia; (B) wide interpupillary distance  simulating exotropia    • Angle kappa is the angle between the visual and anatomical  (pupillary) axes.   o Normally, the fovea is situated temporal to the  anatomical centre of the posterior pole. The eyes are  therefore slightly abducted to achieve bifoveal fixation  and a light shone onto the cornea will therefore cause a  reflex just nasal to the centre of the cornea in both eyes  (Fig. 18.46A). This is termed a positive angle kappa.   Fig. 18.46 Angle kappa. (A) Normal; (B) positive, simulating an  exotropia; (C) negative, simulating an esotropia    o A large positive angle kappa (e.g. temporally displaced  macula) may give a pseudoexotropia (Fig. 18.46B).  o A negative angle kappa occurs when the fovea is situated  nasal to the posterior pole (e.g. high myopia). In this  situation, the corneal reflex is situated temporally to the  centre of the cornea and it may simulate an esotropia  (Fig. 18.46C).    Heterophoria may present clinically with associated visual symp¬  toms when the fusional amplitudes are insufficient to maintain  alignment, particularly at times of stress or poor health.   • Signs. Both esophoria and exophoria can be classified by the  distance at which the angle is greater: respectively,  convergence excess or weakness, divergence weakness or  excess and mixed.   o Orthoptic treatment is of most value in convergence  weakness exophoria.   o Symptom relief may otherwise be obtained using  temporary stick-on Fresnel prisms and may be  subsequently incorporated into spectacles (maximum  usually 10-12 A, split between the two eyes),  o Surgery may occasionally be required for larger  deviations.   Convergence insufficiency (Cl) typically affects individuals with  high near visual demand, such as students.   • Signs. Reduced near point of convergence independent of  any heterophoria.   • Treatment involves orthoptic exercises aimed at normalizing  the near point and maximizing fusional amplitudes. With  good compliance, symptoms should be eliminated within a  few weeks but if persistent can be treated with base-in  prisms.   • Accommodative insufficiency (AI) is occasionally also  present. It may be idiopathic (primary) or post-viral and  typically affects school-age children. The minimum reading  correction to give clear vision is prescribed but is often  difficult to discard.   Divergence paresis or paralysis is a rare condition typically associ¬  ated with underlying neurological disease, such as intracranial  space-occupying lesions, cerebrovascular accidents and head  trauma. Presentation may be at any age and may be difficult to  differentiate from sixth nerve palsy, but is primarily a concomitant    Fig. 18.47 (A) Spasm of the near reflex precipitated on  testing ocular movements; (B) right esotropia and miosis    esodeviation with reduced or absent divergence fusional ampli¬  tudes. It is difficult to treat; prisms are the best option.   • Paresis of the near reflex presents as dual convergence and  accommodation insufficiency. Mydriasis may be seen on  attempted near fixation. Treatment involves reading glasses,  base-in prisms and possibly botulinum toxin (orthoptic  exercises have no effect). It is difficult to eradicate.   • Complete paralysis in which no convergence or  accommodation can be initiated may be of functional origin,  due to midbrain disease or after head trauma; recovery is  possible.   Spasm of the near reflex is a functional condition affecting patients  of all ages (mainly females). Diplopia, blurred vision and head¬  aches are the presenting symptoms.   o Esotropia, pseudomyopia and miosis,  o Spasm may be triggered when testing ocular movements  (Fig. 18.47A).   o Observation of miosis is the key to the diagnosis  (Fig. 18.47B).   o Refraction with and without cycloplegia confirms the  pseudomyopia, which must not be corrected optically.   • Treatment involves reassurance and advising the patient to  discontinue any activity that triggers the response. If  persistent, atropine and a full reading correction are  prescribed but it is difficult later to abandon treatment  without recurrence. Patients usually manage to live a fairly  normal life despite the symptoms.    Esotropia (manifest convergent squint) may be concomitant or  incomitant. In a concomitant esotropia the variability of the angle  of deviation is within 5 A in different horizontal gaze positions. In  an incomitant deviation the angle differs in various positions of  gaze as a result of abnormal innervation or restriction. This section  deals only with concomitant esotropia. A classification is shown  in Table 18.1; however, all squints are different and not all fit neatly  into a classification. For example, a microtropia may occur with a  number of the other categories. It is more important to under¬  stand the part played by binocular function, refractive error and  accommodation in the pathophysiology of each individual squint  and to tailor treatment accordingly.   Up to the age of 4 months, infrequent episodes of convergence are  normal but thereafter ocular misalignment is abnormal. Early-  onset (congenital, essential infantile) esotropia is an idiopathic  esotropia developing within the first 6 months of life in an other¬  wise normal infant with no significant refractive error and no  limitation of ocular movements.   • The angle is usually fairly large (>30 A) and stable.   • Fixation in most infants is alternating in the primary  position (Fig. 18.48).   • There is cross-fixating in side gaze, so that the child uses the  left eye in right gaze (Fig. 18.49A) and the right eye on left  gaze (Fig. 18.49B). Such cross-fixation may give a false  impression of bilateral abduction deficits, as in bilateral sixth  nerve palsy.   Fig. 18.48 Alternating fixation in early-onset esotropia. (A)  Fixating with right eye; (B) fixating with left eye    • Abduction can usually be demonstrated, either by the doll’s  head manoeuvre or by rotating the child.   • Should these fail, uniocular patching for a few hours will  often unmask the ability of the other eye to abduct.   • Latent nystagmus (LN) is seen only when one eye is covered  and the fast phase beats towards the side of the fixing eye.  This means that the direction of the fast phase reverses  according to which eye is covered.   • Manifest latent nystagmus (MLN) is the same except that  nystagmus is present with both eyes open, but the amplitude  increases when one is covered.   • The refractive error is usually normal for the age of the child  (about +1 to +2 D).   • Inferior oblique overaction may be present initially or  develop later (see Fig. 18.51).   • Dissociated vertical deviation (DVD) develops in 80% by the  age of 3 years (see Fig. 18.52).   • Differential diagnosis includes bilateral congenital sixth  nerve palsy, secondary (sensory) esotropia due to organic  eye disease, nystagmus blockage syndrome in which    convergence dampens a horizontal nystagmus, and  mechanical limitations of eye movement such as Duane and  Mobius syndromes and strabismus fixus.   Early ocular alignment gives the best chance of the development  of some degree of binocular function. Ideally, the eyes should be  surgically aligned by the age of 12 months, and at the very latest  by the age of 2 years, but only after amblyopia and any significant  refractive error have been corrected.   • The initial procedure can be either recession of both medial  recti or unilateral medial rectus recession with lateral rectus  resection. Very large angles may require recessions of   6.5 mm or more. Associated significant inferior oblique  overaction should also be addressed.   • An acceptable goal is alignment of the eyes to within 10 A,  associated with peripheral fusion and central suppression  (Fig. 18.50). This small-angle residual strabismus is often  stable, even though bifoveal fusion is not achieved.   Fig. 18.49 Cross fixation in early-onset esotropia. (A) Left  fixation on right gaze; (B) right fixation on left gaze   • Undercorrection may require further recession of the  medial recti, resection of one or both lateral recti or  surgery to the other eye, depending on the initial  procedure.   • Inferior oblique overaction may develop subsequently, most  commonly at age 2 years (Fig. 18.51). The parents should  therefore be warned that further surgery may be necessary  despite an initially good result. Initially unilateral, it  frequently becomes bilateral within 6 months. Inferior  oblique weakening procedures include disinsertion, recession  and myectomy.   • DVD (Fig. 18.52) is characterized by up-drift with  excyclorotation (extorsion) of the eye when under cover, or  spontaneously during periods of visual inattention. When  the cover is removed the affected eye will move down  without a corresponding down-drift of the other eye. It is  usually bilateral. Surgical treatment may be indicated for  cosmesis; options include superior rectus recession with or  without posterior fixation sutures and inferior oblique  anterior transposition.   • Amblyopia subsequently develops in about 50% of cases as  unilateral fixation preference commonly develops  postoperatively.   • An accommodative element should be suspected if the eyes  are initially straight or almost straight after surgery and then  start to reconverge. Regular refraction is therefore  important.   Fig. 18.51 Bilateral inferior oblique overaction. (A) Straight  eyes in the primary position; (B) left inferior oblique  overaction on right gaze; (C) right inferior oblique overaction  on left gaze   Fig. 18.52 Dissociated vertical deviation. (A) Straight eyes in  the primary position; (B) up-drift of left eye under cover;   Near vision involves both accommodation and convergence.  Accommodation is the process by which the eye focuses on a near  target, by altering the curvature of the crystalline lens. Simultane¬  ously, the eyes converge, in order to fixate bifoveally on the target.  Both accommodation and convergence are quantitatively related  to the proximity of the target, and have a fairly constant relation¬  ship to each other (AC/A ratio) as described previously. Abnor¬  malities of the AC/A ratio are an important cause of certain types  of esotropia.   In this type of accommodative esotropia, the AC/A ratio is normal  and esotropia is a physiological response to excessive hyper-  metropia, usually between +2.00 and +7.00 D. The considerable  degree of accommodation required to focus clearly on even a  distant target is accompanied by a proportionate amount of  convergence, which is beyond the patient’s fusional divergence  amplitude. It cannot therefore be controlled, and a manifest  convergent squint results. The magnitude of the deviation varies  little (usually <10 A) between distance and near. The deviation  typically presents at the age of 18 months to 3 years (range 6  months to 7 years).   hypermetropia with esotropia when the refractive error is  uncorrected (Fig. 18.53A). The deviation is eliminated and   Fig. 18.53 Fully accommodative esotropia. (A) Right esotropia  without glasses; (B) straight eyes for near and distance  with glasses   Fig. 18.54 Partially accommodative esotropia. (A) Right  esotropia without glasses; (B) angle is reduced but not  eliminated with glasses    BSV is present at all distances following optical correction of  hypermetropia (Fig. 18.53B).   • Partially accommodative esotropia is reduced, but not  eliminated by full correction of hypermetropia (Fig. 18.54).  Amblyopia is frequent as well as bilateral congenital superior  oblique weakness. Most cases show suppression of the  squinting eye although ARC may occur, but of lower grade  than in microtropia.   In this type of accommodative esotropia the AC/A ratio is high so  that a unit increase of accommodation is accompanied by a dis¬  proportionately large increase in convergence. This occurs inde¬  pendently of refractive error, although hypermetropia frequently  coexists. Subtypes are set out below.   o High AC/A ratio due to increased accommodative  convergence (accommodation is normal, convergence is  increased).   o Normal near point of accommodation,  o Straight eyes with BSV for distance (Fig. 18.55A).  o Esotropia for near, usually with suppression (Fig. 18.55B).  o Straight eyes through bifocals (Fig. 18.55C).   o High AC/A ratio due to decreased accommodation  (accommodation is weak, necessitating increased effort,  which produces over-convergence),  o Remote near point of accommodation,  o Straight eyes with BSV for distance,  o Esotropia for near, usually with suppression.    Fig. 18.55 Convergence excess esotropia. (A) Eyes straight  for distance; (B) right esotropia for near; (C) eyes straight  when looking through bifocals   o In children under the age of 6 years, the full cycloplegic  refraction revealed on retinoscopy should be prescribed,  with a deduction only for the working distance. In the  fully accommodative refractive esotrope this will control  the deviation for both near and distance.   o After the age of 8 years, refraction should be performed  without cycloplegia and the maximal amount of ‘plus’  that can be tolerated (manifest hypermetropia)  prescribed.   o For convergence excess esotropia bifocals may be  prescribed to relieve accommodation (and thereby  accommodative convergence), thus allowing the child to  maintain bi-foveal fixation and ocular alignment at near  (see Fig. 18.55C). The minimum ‘add’ required to achieve  this is prescribed.   o The most satisfactory form of bifocals is the executive  type in which the intersection crosses the lower border of  the pupil. The strength of the lower segment should be  gradually reduced and eliminated by the early teenage  years.   o Bifocals are also used in hypoaccommodative esotropia  where the AC/A ratio is not overly excessive and there is  a reasonable chance of discarding bifocal correction with  time.    o At higher levels surgery is the better long-term option.  The ultimate prognosis for complete withdrawal of  spectacles is related to the magnitude of the AC/A ratio  and to the degree of hypermetropia and associated  astigmatism. Spectacles may be needed only for close  work.   • Surgery is aimed at restoring or improving BSV, or at  improving the appearance of the squint and so the child’s  social functioning. It should be considered only if spectacles  do not fully correct the deviation and after every attempt has  been made to treat amblyopia.   o Bilateral medial rectus recessions are performed in  patients in whom the deviation for near is greater than  that for distance.   o If there is no significant difference between distance and  near measurements, and equal vision in both eyes, some  perform unilateral medial rectus recession combined with  lateral rectus resection, whereas others prefer bilateral  medial rectus recessions.   o In patients with residual amblyopia, surgery is usually  performed on the amblyopic eye.  o In partially accommodative esotropia, surgery to improve  appearance is best delayed until requested by the child;  this avoids early consecutive exotropia. It should aim to  correct only the residual squint present with glasses,  o The usual first procedure for convergence excess   esotropia is recession of both medial rectus muscles. This  relies on fusion to prevent a distance exotropia; a few  patients become divergent after surgery and need a  further procedure.   operation) can also be used either as a first procedure, or  in the case of undercorrection, following bimedial  recessions.   Microtropia is a small angle (<10 A) squint. Binocular cooperation  in microtropia is more substantial than in most manifest devia¬  tions, and it may be considered more a description of binocular  status than a specific diagnosis. It may be primary or secondary,  the latter representing the sequela to strabismus surgery or other  treatment (e.g. optical, such as fully accommodative esotropia  controlled with glasses to a microtropia rather than true bifoveal  BSV) for a larger deviation, and occasionally to other pathology.   • Symptoms are rare unless there is an associated  decompensating heterophoria.   • The small manifest angle of deviation may not be readily  detectable on cover testing.   • There is a prominent association with anisometropia,  commonly hypermetropia or hypermetropic astigmatism,  with amblyopia (typically mild) of the more ametropic eye.   • There is normal motor fusion as demonstrated by fusional  amplitudes.   • Anomalous retinal correspondence (ARC) is present, with  associated abnormal binocular single vision (BSV); there is    monocular fixation eccentric to the fovea in the deviating  eye and a central suppression scotoma, and stereopsis is  usually present but reduced.   o In microtropia with identity the point used for fixation  by the deviating eye (monocular eccentric fixation)  corresponds with the fovea of the straight eye under  binocular viewing conditions (the angle of anomaly in  ARC). Therefore on cover test there is no movement of  the squinting eye when it takes up monocular fixation,  o In microtropia without identity the monocular fixation  point of the squinting eye does not correspond with the  fovea of the straight eye in binocular viewing. There is  therefore a small movement of the deviating eye when it  takes up monocular fixation on cover testing.   • The 4 A prism test, discussed earlier in the chapter, is useful  in assessment.   Treatment involves correction of refractive error and occlusion for  amblyopia as indicated; there is evidence that aggressive treatment  sometimes leads to normalization. Most patients remain stable  and symptom-free.   o Orthophoria or small esophoria with BSV for distance,  o Esotropia for near but normal or low AC/A ratio,  o Normal near point of accommodation.   • Presentation is in healthy young adults, who are often  myopic.   • Treatment is with prisms until spontaneous resolution or  surgery in persistent cases.   O Normal ocular motility without significant refractive error,  o Underlying sixth nerve palsy must be excluded.    • Treatment is aimed at re-establishing BSV to prevent  suppression, using prisms, botulinum toxin or surgery.   Secondary esotropia is caused by a unilateral reduction in visual  acuity that interferes with or abolishes fusion; causes can include  cataract, optic atrophy or hypoplasia, macular scarring or retino¬  blastoma. Fundus examination under mydriasis is therefore essen¬  tial in all children with strabismus.   Consecutive esotropia follows surgical overcorrection of an exo¬  deviation. If it occurs following surgery for an intermittent exo¬  tropia in a child it should not be allowed to persist for more than  6 weeks without further intervention.   Cyclic esotropia is a very rare condition characterized by alternat¬  ing manifest esotropia with suppression and BSV, each typically  lasting 24 hours. The condition may persist for months or years  and the patient may eventually develop a constant esotropia  requiring surgery.   Patients with high myopia may have instability of the muscle  pulleys that stabilize the superior rectus and lateral rectus muscles.  This results in nasal displacement of the superior rectus and infe¬  rior displacement of the lateral rectus. The possibility of this con¬  dition should be considered in high myopes with acquired  esotropia; MR is key to the diagnosis. Treatment involves plication  of the superior and lateral recti with a non-absorbable suture.   o Normal refraction,  o Farge and constant angle,  o DVD may be present.   • Neurological anomalies are frequently present, in contrast  with infantile esotropia.   • Treatment is mainly surgical and consists of lateral rectus  recession and medial rectus resection.   • Differential diagnosis is secondary exotropia, which may  conceal serious ocular pathology.   • Presentation is often at around 2 years with exophoria  which breaks down to exotropia under conditions of visual    Fig. 18.56 Intermittent exotropia. (A) Eyes straight most of  the time; (B) left exotropia under conditions of visual  inattention or fatigue    inattention, bright light (resulting in reflex closure of the  affected eye), fatigue or ill health.   • Signs. The eyes are straight with BSV at times (Fig. 18.56A)  and manifest with suppression at other times (Fig. 18.56B).  Control of the squint varies with the distance of fixation and  other factors such as concentration.   • Distance exotropia, in which the angle of deviation is greater  for distance than near and increases further beyond 6  metres. Simulated and true forms are recognized.   o Simulated (formerly pseudo-divergence excess) is  associated with a high AC/A ratio or with ‘tenacious  proximal fusion’ (TPF - tonic fusional convergence that  relaxes after occlusion). The distance angle initially seems  to be larger than the near angle, but the deviation for  near and distance is similar when the near angle is  remeasured with the patient looking through +3.00 D  lenses (high AC/A controlling exodeviation) or after  30-60 minutes of uniocular occlusion to relax TPF, the  latter with a normal AC/A ratio),  o True. The angle for near remains significantly less than  that for distance with the above tests.   • Non-specific exotropia, in which control of the squint and  the angle of deviation are the same for distance and near  fixation.   • Near exotropia, in which the deviation is greater for near  fixation. It tends to occur in older children and adults and  may be associated with acquired myopia or presbyopia.   • Spectacle correction in myopic patients may, in some cases,  control the deviation by stimulating accommodation, and  with it, convergence. In some cases over-minus prescription  may be useful.   • Part-time occlusion of the non-deviating eye may improve  control in some patients, and orthoptic exercises may be  helpful for near exotropia.   • Surgery. Patients with effective and stable control of their  intermittent exotropia are often just observed. Surgery is  indicated if control is poor or is progressively deteriorating.  Unilateral lateral rectus recession and medial rectus  resection are generally preferred except in true distance  exotropia when bilateral lateral rectus recessions are more  usual. The exodeviation is rarely completely eliminated by  surgery.   Secondary (sensory) exotropia is the result of monocular or  binocular visual impairment by acquired lesions, such as cataract  (Fig. 18.57) or other media opacity. Treatment consists of correc¬  tion of the visual deficit, if possible, followed by surgery if appro¬  priate. A minority of patients develop intractable diplopia due to  loss of fusion, even when good visual acuity is restored to both  eyes and the eyes are realigned.   Consecutive exotropia develops spontaneously in an amblyopic  eye, or more frequently following surgical correction of an esode-  viation. In early postoperative divergence, muscle slippage must  be considered. Most cases present in adult life with concerns  about cosmesis and social function, and can be greatly helped by  surgery. Careful evaluation of the risk of postoperative diplopia is  required, although serious problems are uncommon. About 75%  of patients are still well aligned 10 years after surgery, although  re-divergence may occur.    Congenital cranial dysinnervation disorders (CCDD) or congeni¬  tal innervation dysgenesis syndromes constitute a group of disor¬  ders originally believed to be the result of congenital muscular  fibrosis, but now known to be the result of brainstem or cranial  nerve developmental disturbance, in most cases having an iden¬  tifiable genetic basis. Systemic associations are recognized for  several.   In Duane retraction syndrome (DRS) there is failure of innerv¬  ation of the lateral rectus by a hypoplastic sixth nerve nucleus, with  anomalous innervation of the lateral rectus by fibres from the  third nerve. The condition is often bilateral. Up to half of patients  have associated systemic defects such as deafness, external ear  abnormalities, speech disorder and skeletal abnormalities. Associ¬  ated mutations in several genes have been found. Approximately  10% of cases are familial.   • Retraction of the globe on adduction as a result of   co-contraction of the medial and lateral recti with resultant  narrowing of the palpebral fissure.   • An up-shoot or down-shoot in adduction may be present;  in some cases this is produced by a tight lateral rectus  muscle slipping over or under the globe to produce an  anomalous vertical movement.   • Deficiency of convergence in which the affected eye remains  fixed in the primary position while the unaffected eye is  converging.   • Type I, the most common, is characterized by  (Fig. 18.58):   o Limited or absent abduction,  o Normal or mildly limited adduction.   • Type II, the least common, is characterized by:  o Limited adduction.   O In the primary position, straight or slight esotropia,  o In some cases phenotypic variants have been allied to  differing genotypes.   Fig. 18.58 Duane syndrome - Huber type I in a 68-year-old  woman. (A) Straight eyes in the primary position; (B)  extremely limited left abduction; (C) narrowing of the left  palpebral fissure on adduction   The majority of patients with Duane syndrome do not need any   • Most young children maintain BSV by using a CHP to  compensate for their lateral rectus weakness and surgery  is needed only if there is evidence of loss of binocular  function; this may be indicated by failure to continue to  use a CHP.   • In adults or children over the age of about 8 years surgery  can reduce a head posture that is cosmetically unacceptable  or causing neck discomfort. Surgery may also be necessary  for cosmetically unacceptable up-shoots, down-shoots or  severe globe retraction.   • Amblyopia, when present, is usually the result of  anisometropia rather than strabismus. Unilateral or  bilateral muscle recession or transposition of the vertical  recti are the procedures of choice. The lateral rectus of the  involved side should not be resected, as this increases  retraction.    Fig. 18.59 Duane syndrome type III in an infant. (A) Straight  eyes in the primary position; (B) limitation of left abduction  with widening of the left palpebral fissure; (C) grossly limited  left adduction with narrowing of the palpebral fissure   Mobius syndrome is a rare, usually sporadic, condition, the basic  components of which are congenital non-progressive bilateral  sixth and seventh cranial nerve palsies that are believed to relate  to a developmental abnormality of the brainstem.   o Bilateral facial palsy, which is usually asymmetrical and  often incomplete, giving rise to an expressionless facial  appearance (Fig. 18.60A) and problems with eyelid  closure (Fig. 18.60B).   o The fifth, eighth, tenth and twelfth (Fig. 18.60C) cranial  nerves may also be affected.   Fig. 18.60 Mobius syndrome. (A) Bilateral facial nerve palsy  with a typical smooth expressionless facial appearance;   Congenital fibrosis of the extraocular muscles (CFEOM) is a  rare non-progressive, usually autosomal dominant, disorder char¬  acterized by bilateral ptosis and restrictive external ophthalmople¬  gia. Numerous forms have been identified, of which CFEOMi  is the most common, and there is considerable genetic hetero¬  geneity; CFEOMi is caused by mutations in the KIF21A gene,  which produces a protein used for intracellular transport that  plays a key role in some aspects of cranial nerve development,  and pathologically there is a hypoplastic superior division of the  oculomotor nerve. Typically, vertical movements are severely  restricted with inability to elevate the eyes above the horizontal  plane.   In the primary position each eye is fixed below the horizontal  by about io°, with a corresponding compensatory chin elevation.  The degree of residual horizontal movement varies markedly.  Ptosis is common (Fig. 18.61).   Strabismus fixus is a rare condition in which both eyes are  fixed by fibrous tightening of the medial recti (convergent strabis¬  mus fixus - Fig. 18.62A), or the lateral recti (divergent strabismus  fixus - Fig. 18.62B). Congenital and acquired forms have been  described.   Marcus Gunn jaw-winking syndrome (see Ch. 1) is now believed  to be a CCDD, as are horizontal gaze palsy and progressive scol¬  iosis, many cases of congenital ptosis, congenital fourth cranial  nerve palsy and congenital facial nerve palsy.   Fig. 18.61 Congenital fibrosis of the extraocular muscles  - bilateral ptosis and divergent strabismus    Monocular elevation deficiency (MED), formerly double elevator  palsy, is a rare sporadic condition that in at least some cases may  be categorized as a CCDD. It is thought to manifest primarily with  a tight or contracted inferior rectus muscle or a hypoplastic or  ineffective superior rectus muscle. There is a profound inability to  elevate one eye across the horizontal plane, from abduction to  adduction (Fig. 18.63), with orthophoria in the primary position  in about one-third of cases. Chin elevation may be present. A  base-up prism can be helpful.    Brown syndrome is a condition involving mechanical restriction,  typically of the superior oblique tendon. It is usually congenital  but occasionally acquired. Recent evidence strongly suggests that  at least some congenital cases should be categorized as a CCDD.   o Inflammation of the tendon, which may be caused by  rheumatoid arthritis, pansinusitis or scleritis.    Fig. 18.63 Right monocular elevation deficiency. (A) Defective  elevation in abduction; (B) in upgaze; (C) and in adduction   o Limited elevation in adduction (Fig. 18.64B).  o Limited elevation on upgaze is common (Fig. 18.64C).  o Normal elevation in abduction (Fig. 18.64D).  o Absence of superior oblique overaction (Fig. 18.64E).  o Positive forced duction test on elevating the globe in  adduction.   O Hypotropia in primary position,  o CHP with chin elevation and ipsilateral head tilt (Fig.  18.64F).   • Congenital cases do not usually require treatment as long as  binocular function is maintained with an acceptable head  posture. Spontaneous improvement is often seen towards    the end of the first decade. Indications for treatment include  significant primary position hypotropia, deteriorating  control and/or an unacceptable head posture. The  recommended procedure for congenital cases is lengthening  of the superior oblique tendon.   specifically. Depending on the cause, acquired cases may  benefit from steroids, either orally or by injection near the  trochlea.    C V’ or C A’ patterns occur when the relative contributions of the  superior rectus and inferior oblique to elevation, or of the inferior  rectus and superior oblique to depression, are abnormal, resulting  in derangement of the balance of their horizontal vectors in up-  and downgaze. They can also be caused by anomalies in the posi¬  tion of the rectus muscle pulleys. Assessment is by measuring  horizontal deviations in the primary position, upgaze and down-  gaze. They can occur in both concomitant and incomitant  deviations.   A C V’ pattern is said to be significant when the difference between  upgaze and downgaze is >15 A.   • Superior oblique underaction with subsequent inferior  oblique overaction, seen in infantile esotropia as well as  other childhood esotropias. The eyes are often straight in  upgaze with a marked esodeviation in downgaze.   Treatment is by inferior oblique weakening or superior oblique  strengthening when oblique dysfunction is present. Without  oblique muscle dysfunction treatment is as follows:   • ‘V’ pattern esotropia (Fig. 18.65A) can be treated by bilateral  medial rectus recessions and downward transposition of the  tendons.   • ‘V’ pattern exotropia (Fig. 18.65B) can be treated by bilateral  lateral rectus recessions and upward transposition of the  tendons.   An ‘A’ pattern is considered significant if the difference between  upgaze and downgaze is >10 A. A particular complaint may be  difficulty with reading if the patient is binocular.   Fig. 18.64 Left Brown syndrome. (A) Straight in the primary position; (B) limited left elevation in adduction; (C) limited left  elevation on upgaze; (D) normal left elevation in abduction; (E) absence of left superior oblique overaction; (F) chin  elevation and left head tilt   • Primary superior oblique overaction is usually associated  with exodeviation in the primary position of gaze.   • ‘A’ pattern esotropia (Fig. 18.66A) is treated by bilateral  medial rectus recessions and upward transposition of the  tendons.   • ‘A’ pattern exotropia (Fig. 18.66B) is treated by bilateral  lateral rectus recessions and downward transposition of the  tendons.    The most common aims of surgery on the extraocular muscles are  to correct misalignment to improve appearance, and if possible to  restore BSV. Surgery can also be used to reduce an abnormal head  posture and to expand or centralize a field of BSV. However, the    first step in the management of childhood strabismus involves  correction of any significant refractive error and/or treatment of  amblyopia. Once maximal visual potential is reached in both eyes,  any residual deviation can be treated surgically. The three main  types of procedure are:   • Weakening to decrease the effective strength of action of a  muscle.   • Vector adjustment procedures that have the primary aim of  altering the direction of muscle action.   Recession slackens a muscle by moving it away from its insertion.   It can be performed on any muscle except the superior oblique.   o The muscle is exposed and two absorbable sutures are  tied through the outer quarters of the tendon,  o The tendon is disinserted from the sclera, and the  amount of recession is measured and marked on the  sclera with callipers.    o The detached end of the muscle is sutured to the sclera  at the measured distance behind its original insertion  (Fig. 18.67).   o The muscle belly is exposed through an inferotemporal  fornix incision.   o A squint hook is passed behind the posterior border of  the muscle which must be clearly visualized. Care is taken  to pick up the muscle without disrupting the Tenon  capsule and fat posterior to it.  o An absorbable suture is passed through the anterior  border of the muscle at its insertion and tied,  o The muscle is disinserted and the cut end sutured to the  sclera 3 mm posterior and temporal to the temporal edge  of the inferior rectus insertion (Fig. 18.68).   Disinsertion (or myectomy) involves detaching a muscle from its  insertion without reattachment. It is most commonly used to  weaken an overacting inferior oblique muscle, when the technique  is the same as for a recession except that the muscle is not sutured.  Very occasionally, disinsertion is performed on a severely con¬  tracted rectus muscle.   The principle of this (Faden) procedure is to suture the muscle  belly to the sclera posteriorly so as to decrease the pull of the  muscle in its field of action without affecting the eye in the primary  position. The Faden procedure may be used on the medial rectus  to reduce convergence in a convergence excess esotropia and on  the superior rectus to treat DVD. When treating DVD, the supe¬  rior rectus muscle may also be recessed. The belly of the muscle is   then anchored to the sclera with a non-absorbable suture about  12 mm behind its insertion.   • Resection shortens a muscle to enhance its effective pull. It  is suitable only for a rectus muscle and involves the  following steps:   o The muscle is exposed and two absorbable sutures inserted  at a measured distance behind its insertion,  o The muscle anterior to the sutures is excised and the cut  end reattached to the original insertion (Fig. 18.69).   • Tucking of a muscle or its tendon is usually confined to  enhancement of the action of the superior oblique muscle in  congenital fourth nerve palsy.   • Advancement of the muscle nearer to the limbus can be  used to enhance the action of a previously recessed rectus  muscle.   Transposition refers to the relocation of one or more extraocular  muscles to substitute for the action of an absent or severely  deficient muscle. The most common indication is severe lateral  rectus weakness due to acquired sixth cranial nerve palsy (Fig.  18.70); other applications include CCDD (e.g. Duane syndrome),  alphabet patterns and monocular elevation deficit. A variety  of techniques involving recti and oblique muscles have been  described.   The results of strabismus surgery can be improved by the use of  adjustable suture techniques on the rectus muscles. These are par¬  ticularly indicated when a precise outcome is essential and when  the results with more conventional procedures are likely to be  unpredictable; for example, acquired vertical deviations associated  with thyroid myopathy or following a blow-out fracture of the   Fig. 18.70 Transposition of the superior and inferior rectus  muscles in lateral rectus palsy    floor of the orbit. Other indications include sixth nerve palsy,  adult exotropia and re-operations in which scarring of surround¬  ing tissues may make the final outcome unpredictable. The main  contraindication is inability to tolerate postoperative suture  adjustment (e.g. young children).   • The muscle is exposed, sutures inserted and the tendon  disinserted from the sclera as for a rectus muscle recession.   • The two ends of the suture are passed, side by side, through  the stump of the insertion.   • A second suture is knotted and tied tightly around the  muscle suture anterior to its emergence from the stump  (Fig. 18.71A).   • One end of the suture is cut short and the two ends tied  together to form a loop (Fig. 18.71B).   This is performed under topical anaesthesia, usually a few hours  after surgery when the patient is fully awake.   • If ocular alignment is satisfactory the muscle suture is tied  off and its long ends cut short.   • If more recession is required, the bow is pulled anteriorly  along the muscle suture, thereby providing additional slack  to the recessed muscle and enabling it to move posteriorly  (Fig. 18.71C).   • If less recession is required, the muscle suture is pulled  anteriorly and the knot tightened against the muscle stump  (Fig. 18.71D).   • Once alignment is satisfactory, the main knot is secured, the  sliding loop removed and the conjunctiva closed.    Temporary paralysis of an extraocular muscle can be induced by  an injection of botulinum toxin under topical anaesthesia and  EMG control. The effect takes several days to develop, is usually  maximal at 1-2 weeks following injection and has generally worn  off by 3 months. Side effects are uncommon, although about 5%  of patients may develop some degree of temporary ptosis. The  following are the main indications:   example, in an adult with a consecutive left divergent squint  and left suppression, straightening the eyes may make  suppression less effective resulting in diplopia. If  postoperative diplopia testing by correcting the angle with  prisms is negative then the risk of double vision after surgery  is very low. If testing is positive then the left lateral rectus  muscle can be injected with toxin so that the eyes will either  straighten or converge and the risk of diplopia can be  assessed over several days while the eyes are straight. If  diplopia does occur, the patient is able to judge whether it is  troublesome.   Fig. 18.72 Principles of botulinum toxin chemodenervation in  left sixth nerve palsy - see text    • To assess the potential for BSV in a patient with a constant  manifest squint by straightening the eyes temporarily. The  deviation can then be corrected surgically if appropriate. A  small proportion of patients maintain BSV long-term after  the effects of the toxin have worn off.   • In lateral rectus palsy botulinum toxin can be injected into  the ipsilateral medial rectus to give symptomatic relief during  recovery and to see whether there is any lateral rectus action  when there is medial rectus contracture (Fig. 18.72A). The  temporary paralysis of the muscle causes relaxation so that  the horizontal forces on the globe are more balanced, thus  allowing assessment of lateral rectus function (Fig. 18.72B).   A similar approach can be used for fourth nerve palsy, with  injection into the ipsilateral inferior oblique or contralateral  inferior rectus.   • Patients with a cosmetically poor deviation who have  undergone multiple squint operations can be treated by  repeated BT injections, which may reduce in frequency with  time.    NEUROIMAGING 774  Computed tomography 774  Magnetic resonance imaging 775  Angiography 776   Visual evoked potential 779  Signs of optic nerve dysfunction 780  Classification of optic neuropathy by  cause 781  Optic atrophy 781  Classification of optic neuritis 782  Demyelinating optic neuritis 783  Parainfectious optic neuritis 785  Infectious optic neuritis 785  Non-infectious optic neuritis 785  Neuroretinitis 785   Non-arteritic anterior ischaemic optic  neuropathy 786  Arteritic anterior ischaemic optic  neuropathy 787  Posterior ischaemic optic  neuropathy 790  Diabetic papillopathy 790  Leber hereditary optic neuropathy 790  Miscellaneous hereditary optic  neuropathies (atrophies) 791  Nutritional optic neuropathy 792  Papilloedema 793   Afferent pupillary defect 807  Horner syndrome (oculosympathetic  palsy) 807  Adie pupil 810  Miscellaneous pupillary  abnormalities 811   CHIASM 812  Anatomy 812  Physiology 814  Pituitary adenomas 815  Pituitary apoplexy 818  Craniopharyngioma 818  Meningioma 818   Conjugate eye movements 830  Abnormalities of horizontal gaze 831  Vertical gaze palsy 832  Skew deviation 832    NYSTAGMUS 832  Introduction 832  Physiological nystagmus 833  Vestibular nystagmus 834  Infantile (congenital) nystagmus 835  Acquired nystagmus 835  Treatment of nystagmus 837  Nystagmoid movements 838   Myasthenia gravis 838  Myotonic dystrophy 840  Chronic progressive external  ophthalmoplegia 841   Computed tomography (CT) uses X-ray beams to obtain tissue  density values from which detailed cross-sectional images are  formed by a computer. Tissue density is represented by a grey  scale, white being maximum density (e.g. bone) and black being  minimum density (e.g. air). Advanced CT scanners are able to  acquire thinner slices leading to improved spatial resolution,  together with faster examination times, without a proportionate  increase in radiation dose. Images are acquired in an axial form  and can be viewed in any plane using computer reconstruction.  This multiplanar information can be an advantage over magnetic  resonance (MR) with regard to anatomical detail. CT is widely    available, easy to perform, relatively inexpensive and quick, but  unlike MR exposes the patient to ionizing radiation.   Iodinated contrast material improves sensitivity and specificity  but is contraindicated in patients allergic to iodine and in those  with renal failure. Contrast is not indicated in acute haemorrhage,  bony injury or localization of foreign bodies because it may mask  visualization of these high density structures.   • Orbital trauma, for the detection of bony lesions such as  fractures (Fig. 19.lA), blood, herniation of extraocular  muscles into the maxillary sinus and surgical emphysema.   • Evaluation of the extraocular muscles in thyroid eye disease  (Fig. 19.1B); CT and MR (see below) have complementary  advantages in the assessment of orbital disease.   Fig. 19.1 CT scans. (A) Coronal image showing blow-out fractures of the left orbital floor and medial wall with orbital  emphysema; (B) axial image showing bilateral enlargement of extraocular muscles and right proptosis; (C) axial image  showing an acute parenchymal haematoma in the right temporal lobe; (D) axial image showing extensive subarachnoid  blood in the basilar cisterns, and the Sylvian and interhemispheric fissures   (Courtesy of N Sibtain - figs A, C and D; A Pearson - fig. B)   • Bony involvement of orbital tumours is better assessed  using CT than MR.   • Orbital cellulitis for assessment of intraorbital extension  and subperiosteal abscess formation.   (Fig. 19.1D) haemorrhage, which is harder to visualize on  MR within the first few hours of onset.   Magnetic resonance imaging (MRI) depends on the rearrange¬  ment of positively charged hydrogen nuclei (protons) when a  tissue is exposed to a short electromagnetic pulse. When the pulse  subsides, the nuclei return to their normal position, re-radiating  some of the absorbed energy. Sensitive receivers pick up this elec¬  tromagnetic echo. Unlike CT, it does not subject the patient to  ionizing radiation. The signals are analyzed and displayed as a  cross-sectional image that may be axial, coronal or sagittal.   Weighting refers to two methods of measuring the relaxation  times of the excited protons after the magnetic field has been  switched off. Various body tissues have different relaxation times  so that a given tissue may be Ti- or T2-weighted (i.e. best visual¬  ized on that particular type of image). In practice, both types of  scans are usually performed. It is easy to tell the difference between  CT and MR images because bone appears white on CT but is not  clearly demonstrated on MR.   • Ti-weighted images are generally optimal for viewing  normal anatomy. Hypointense (dark) structures include  cerebrospinal fluid (CSF) and vitreous. Hyperintense  (bright) structures include fat, blood, contrast agents and  melanin (Figs 19.2A and C).   • T2-weighted images, in which water is shown as  hyperintense, are useful for viewing pathological changes  because oedematous tissue (e.g. inflammation) will display a  brighter signal than normal surrounding tissue. CSF and  vitreous are hyperintense as they have high water content.  Blood vessels appear black on T2 imaging unless they are  occluded (Figs 19.2B and D).   • Gadolinium contrast acquires magnetic moment when  placed in an electromagnetic field. Administered  intravenously, it remains intravascular unless there is a  breakdown of the blood-brain barrier. It is only visualized  on Ti-weighted images, and enhancing lesions such as  tumours and areas of inflammation will appear bright.   Ideally MR is performed both before (Fig. 19.3A) and after  (Fig. 19.3B) administration of gadolinium for most clinical    indications. Special head or surface coils can also be used to  improve spatial definition of the image. Adverse effects with  gadolinium are uncommon and usually relatively innocuous.   • Fat-suppression techniques are useful for imaging the orbit  because the bright signal of orbital fat on conventional  Ti-weighted imaging frequently obscures other orbital  contents. Fat suppression eliminates this bright signal and  better delineates normal structures (optic nerve and  extraocular muscles) as well as tumours, inflammatory  lesions and vascular malformations. The two types of  fat-suppression sequence used for orbital imaging are:   o Ti fat saturation used with gadolinium allows areas  suspicious using other techniques to be enhanced, e.g.  suppressing orbital fat signal to visualize optic nerve  sheath lesions (Figs 19.3C and D).   O STIR (short Ti inversion recovery) is the optimal sequence  for detecting intrinsic lesions of the intraorbital optic nerve  (e.g. optic neuritis - Fig. 19.3E). STIR images have very low  signal from fat but still have high signal from water.   • FLAIR (fluid-attenuated inversion recovery) sequences  suppress the bright CSF on T2-weighted images to allow  better visualization of adjacent pathological tissue such as  periventricular plaques of demyelination (Fig. 19.3F).   • DWI/ADC (diffusion-weighted imaging and apparent  diffusion coefficient). DWI measures aberrance in expected  Brownian motion of free water, and is useful in acute  ischaemic stroke to identify abnormalities at a very early  stage - within minutes - and in distinguishing ischaemic  damage reversible with treatment from irreversible damage  such that intervention (e.g. with a thrombolytic agent) is  unlikely to be of benefit.   • FIESTA and CISS (fast imaging employing steady-state  acquisition, and constructive interference in steady-state) are  newer high-resolution sequences. In neuro-ophthalmology, a  particular application may be the investigation of cranial  nerve palsy.   • Recent haemorrhage is not detected, so MRI is inappropriate  in patients with suspected acute intracranial bleeding.   • It cannot be used in patients with magnetic foreign objects  (e.g. cardiac pacemakers, intraocular foreign bodies and  ferromagnetic aneurysm clips).   • Substantial patient cooperation is required, including  remaining motionless; it is poorly tolerated by  claustrophobic patients as it involves lying in an enclosed  space for many minutes.   MRI is the technique of choice for lesions of the intracranial visual   • The optic nerve is best visualized on coronal STIR images in  conjunction with coronal and axial Ti fat saturation  post-gadolinium images. Axial Ti images are useful for    Fig. 19.2 MR scans. (A) Tl-weighted coronal image through the globe in which vitreous is hypointense (dark) and orbital fat  is hyperintense (bright); (B) T2-weighted axial image in which vitreous and cerebrospinal fluid (CSF) are hyperintense;   (C) Tl-weighted midline sagittal image through the brain in which the CSF in the third ventricle is hypointense;   (D) T2-weighted axial image through the brain in which the CSF in the lateral ventricles is hyperintense    displaying normal anatomy. MRI can detect lesions of the  intraorbital part of the optic nerve (e.g. neuritis, glioma) as  well as intracranial extension of optic nerve tumours.   • Optic nerve sheath lesions (e.g. meningioma) are of similar  signal intensity to the nerve on Ti- and T2-weighted images  but enhance avidly with gadolinium.   • Sellar masses (e.g. pituitary tumours) are best visualized by  Ti-weighted contrast-enhanced studies. Coronal images  optimally demonstrate the contents of the sella turcica as  well as the suprasellar and parasellar regions and are usually  supplemented by sagittal images.   • Cavernous sinus pathology is best demonstrated on coronal  images; contrast may be required.   • Intracranial lesions of the visual pathways (e.g.  inflammatory, demyelinating, neoplastic and vascular). MRI    allows further characterization of these lesions as well as  better anatomical localization.   Magnetic resonance angiography (MRA) is a non-invasive method  of imaging the intra- and extracranial carotid and vertebrobasilar  circulations (Fig. 19.4A) to demonstrate abnormalities such as ste¬  nosis, dissection, occlusion, arteriovenous malformations and  aneurysms. The motion sensitivity of MR is utilized to visualize  blood flow within vessels and does not require contrast. However,  because of the reliance on active flow, thrombosed aneurysms may   Fig. 19.3 Enhancement techniques. (A) Pre-contrast sagittal Tl-weighted image of a meningioma; (B) post-contrast image  showing enhancement of the tumour; (C) coronal STIR image showing an intermediate signal intensity mass surrounding  the left optic nerve consistent with an optic nerve sheath meningioma compared to STIR; (D) Tl-weighted fat saturated  coronal image of the same patient as (C) showing avid homogeneous enhancement of the meningioma; (E) coronal STIR  image of right retrobulbar neuritis showing a high signal within the optic nerve with enlargement of the nerve sheath  complex; (F) sagittal FLAIR image showing multiple periventricular plaques of demyelination   (Courtesy of D Thomas - figs A and B; N Sibtain - figs C-F)   Fig. 19.4 Cerebral angiography. (A) Normal MRA of the external carotid and vertebral circulation; (B) MRI venogram, axial  view, demonstrating narrowing of the left transverse sinus (arrow) in idiopathic intracranial hypertension; (C) CT angiogram  shows a left posterior communicating aneurysm (arrows); (D) conventional catheter angiogram with subtraction shows an  aneurysm arising from the internal carotid artery at its junction with the posterior communicating artery (arrow)   (Courtesy of N Sibtain - figs A and C; G Liu, N Volpe and S Galetta, from Neuro-Ophthalmology Diagnosis and Management, Saunders 2010 - fig. B; JD Trobe,  from ‘Neuro-Ophthalmology ', in Rapid Diagnosis in Ophthalmology, Mosby 2008 - fig. D)    be missed and turbulent flow may lead to difficulties in interpreta¬  tion. The technique has limited facility in the detection of very  small aneurysms. MRA adds about 10 minutes to the standard  MRI acquisition time.   Over recent years increasing attention has been paid to intracra¬  nial venous system pathology, particularly dural sinus occlusion  and stenosis. Historically, the venous phase of conventional digital    subtraction angiography (DSA) has been used for intracranial  venous assessment, and still offers high sensitivity and specificity.  However, both CT and MRI can be used to similar purpose and  are relatively non-invasive and low-risk compared to DSA; tech¬  nological advances have conferred greatly improved accuracy.  Whilst CTV (see below) is generally faster and offers high spatial  resolution, it entails a significant radiation dose and always  requires contrast for image acquisition. Magnetic resonance  venography (MRV) can be used with contrast or using non¬  contrast enhanced techniques, among other indications making   it suitable for patients to whom contrast cannot be given. Substan¬  tial advances in MRV pulse sequences now allow excellent visuali¬  zation of the venous system (Fig. 19.4B), and increasing reliance  on MRV seems to be evident. However, local resource availability,  experience and expertise are critical in determining the choice of  technique.   Computed tomographic angiography (CTA) has been emerging  as the method of choice in the investigation of intracranial aneu¬  rysms (Fig. 19.4C). It enables acquisition of extremely thin slice  images of the brain following intravenous contrast. Images of the  vessels can be reconstructed in three dimensions and viewed from  any direction, aiding the approach to treatment. The investigation  is safe and quick and does not carry the 1% risk of stroke associated  with conventional catheter angiography.   Computed tomographic venography (CTV) is a fast high-  resolution technique in which patient motion artefact is of lesser  importance than with MRV. CTV is believed to be at least as sensi¬  tive as MRV in the diagnosis of cerebral venous thrombosis; both  techniques may provide complementary findings in difficult diag¬  nostic situations. However, contrast is always required and a sig¬  nificant radiation dose is delivered. Visualization of skull base  structures is limited by bony artefact relative to MRV. The tech¬  nique is similar to that of CTA.   Conventional intra-arterial catheter angiography is usually per¬  formed under local anaesthetic. A catheter is passed via the femoral  artery into the internal carotid and vertebral arteries in the neck  under fluoroscopic guidance. Following contrast injection, images  are acquired in rapid succession. Digital subtraction results in  images of the contrast-filled vessels with the exclusion of back¬  ground structures such as bone (Fig. 19.4D). Until recently, this  technique was the first-line investigation in the diagnosis of intra¬  cranial aneurysms but may now be reserved for cases where CTA  is equivocal or negative.   • Afferent fibres. The optic nerve carries approximately 1.2  million afferent nerve fibres, each of which originates in a  retinal ganglion cell. Most of these synapse in the lateral  geniculate body, although some reach other centres, notably  the pretectal nuclei in the midbrain. Nearly one-third of the  fibres subserve the central 5 0 of the visual field. Within the    optic nerve itself the nerve fibres are divided into about 600  bundles by fibrous septae derived from the pia mater.   o The innermost layer is the delicate and vascular pia  mater.   o The outer sheath comprises the arachnoid mater and  the tougher dura mater which is continuous with  the sclera; optic nerve fenestration involves incision  of this outer sheath. The subarachnoid space is  continuous with the cerebral subarachnoid space and  contains CSF.   The optic nerve is approximately 50 mm long from globe to   • Intraocular segment (optic nerve head) is the shortest, being  1 mm deep and approximately 1.5 mm in vertical diameter.  The ophthalmoscopically visible portion is called the optic  disc (Fig. 19.5D).   • Intraorbital segment is 25-30 mm long and extends from  the globe to the optic foramen at the orbital apex. Its  diameter is 3-4 mm because of the addition of the myelin  sheaths to the nerve fibres. At the orbital apex the nerve is  surrounded by the tough fibrous annulus of Zinn, from  which originate the four rectus muscles.   • Intracanalicular segment traverses the optic canal and  measures about 6 mm. Unlike the intraorbital portion, it is  fixed to the canal, since the dura mater fuses with the  periosteum.   • Intracranial segment joins the chiasm and varies in length  from 5 to 16 mm (average 10 mm). Long intracranial  segments are particularly vulnerable to damage by adjacent  lesions such as pituitary adenomas and aneurysms.   • Principle (Fig. 19.6). Visual (visually) evoked potential  (VEP) tests record electrical activity of the visual cortex  created by retinal stimulation. The most common  indications in ophthalmology are the monitoring of visual  function in babies and the investigation of optic neuropathy,  particularly when associated with demyelination. It can also  be used to monitor macular pathway function, and to  investigate functional (non-physiological) visual loss.   • Technique. The stimulus is either a flash of light (flash VEP)  or a black-and-white checkerboard pattern on a screen that  periodically reverses polarity (pattern VEP). Several tests are  performed and the average potential is calculated.   • Interpretation. Latency (delay) and amplitude are assessed.  In optic neuropathy both parameters are affected, with  prolongation of latency and a decrease in amplitude.  Threshold VEP (by using different sized check stimuli) can  detect early or subclinical dysfunction as smaller check size  responses may become abnormal earlier than responses to  larger stimuli.   Fig. 19.5 Structure of the optic nerve. (A) Transverse section, P = pia, A = arachnoid, D = dura; (B) longitudinal section, LC =  lamina cribrosa; arrow points to a fibrous septum; (C) surrounding sheaths and pial blood vessels; (D) clinical appearance  of the normal optic disc   • Reduced visual acuity for distance and near is common, but  is non-specific; acuity may be relatively preserved in some  conditions.   • Dyschromatopsia is impairment of colour vision, which in  the context of optic nerve disease mainly affects red and  green. A simple way of detecting a monocular colour vision  defect is to ask the patient to compare the colour of a red  object using each eye in turn.   • Diminished light brightness sensitivity, often persisting  after visual acuity returns to normal, for instance following  the acute stage of optic neuritis.   • Visual field defects, which vary with the underlying  pathology, include diffuse depression of the central visual  field, central scotomas, centrocaecal scotomas, nerve fibre  bundle and altitudinal (Table 19.1).   • Inflammatory. Optic neuritis, including demyelinating,  parainfectious, infectious and non-infectious, and  neuroretinitis.   • Ischaemic. Anterior non-arteritic, anterior arteritic,  posterior ischaemic and diabetic papillopathy.   Optic atrophy refers to the late stage changes that take place in the  optic nerve resulting from axonal degeneration in the pathway  between the retina and the lateral geniculate body, manifesting  with disturbance in visual function and in the appearance of the  optic nerve head. It can be classified in several ways, including by  whether axonal death is initiated in the retina (anterograde) or  more centrally (retrograde), and by cause. Optic ‘atrophy’ is not  true atrophy, a term that strictly refers to involutional change  secondary to lack of use. A classification according to ophthalmo¬  scopic appearance is set out below.   Primary optic atrophy occurs without antecedent swelling of the  optic nerve head. It may be caused by lesions affecting the visual    pathways at any point from the retrolaminar portion of the optic  nerve to the lateral geniculate body. Lesions anterior to the optic  chiasm result in unilateral optic atrophy, whereas those involving  the chiasm and optic tract will cause bilateral changes.   o Reduction in the number of small blood vessels on the  disc surface.   o Attenuation of peripapillary blood vessels and thinning of  the retinal nerve fibre layer (RNFL).  o The atrophy may be diffuse or sectoral depending on the  cause and level of the lesion. Temporal pallor of the optic  nerve head may indicate atrophy of fibres of the  papillomacular bundle, and is classically seen following  demyelinating optic neuritis. Band atrophy is a similar  phenomenon caused by involvement of the fibres  entering the optic disc nasally and temporally; it occurs  in lesions of the optic chiasm or tract and gives nasal as  well as temporal pallor.   o Toxic and nutritional optic neuropathies; these may give  temporal pallor, particularly in early/milder cases when  the papillomacular fibres are preferentially affected (Fig.  19.7B).  o Trauma.   Secondary optic atrophy is preceded by long-standing swelling of  the optic nerve head.   o Slightly or moderately raised white or greyish disc with  poorly delineated margins due to gliosis (Fig. 19.7C).  o Obscuration of the lamina cribrosa.  o Reduction in the number of small blood vessels on the  disc surface.   O Peripapillary circumferential retinochoroidal folds,  especially temporal to the disc (Paton lines - see Fig.   • Causes include chronic papilloedema, anterior ischaemic  optic neuropathy and papillitis. Intraocular inflammatory  causes of marked disc swelling are sometimes considered  to cause secondary rather than consecutive atrophy (see  below).   Consecutive optic atrophy is caused by disease of the inner retina  or its blood supply. The cause is usually obvious on fundus exami¬  nation, e.g. extensive retinal photocoagulation, retinitis pigmen¬  tosa or prior central retinal artery occlusion. The disc appears  waxy, with reasonably preserved architecture (Fig. 19.7D).   Fig. 19.7 Optic atrophy. (A) Primary due to compression; (B) primary due to nutritional neuropathy - note predominantly  temporal pallor; (C) secondary due to chronic papilloedema - note prominent Paton lines (see text); (D) consecutive due to  vasculitis   normal, at least initially, because the optic nerve head is not    involved. It is the most common type in adults and is  frequently associated with multiple sclerosis (MS).   • Papillitis is characterized by hyperaemia and oedema of the  optic disc, which may be associated with peripapillary  flame-shaped haemorrhages (Fig. 19.8). Cells maybe seen in  the posterior vitreous. Papillitis is the most common type of  optic neuritis in children, but can also affect adults.   • Neuroretinitis is characterized by papillitis in association  with inflammation of the retinal nerve fibre layer and a  macular star figure (see below). It is the least common type  and is only rarely a manifestation of demyelination.   • Infectious. This may be sinus-related, or associated with  conditions such as cat-scratch disease, syphilis, Lyme disease,  cryptococcal meningitis and herpes zoster.   • Non-infectious causes include sarcoidosis and systemic  autoimmune diseases such as systemic lupus erythematosus,  polyarteritis nodosa and other vasculitides.   Demyelination is a pathological process in which normally myeli¬  nated nerve fibres lose their insulating myelin layer. The myelin is  phagocytosed by microglia and macrophages, subsequent to  which astrocytes lay down fibrous tissue in plaques. Demyelinat¬  ing disease disrupts nervous conduction within the white matter  tracts of the brain, brainstem and spinal cord. Demyelinating con¬  ditions that may involve the visual system include the following:   • Isolated optic neuritis with no clinical evidence of  generalized demyelination, although in a high proportion of  cases this subsequently develops.   • Multiple sclerosis (MS), by far the most common  demyelinating disease (see below).   • Devic disease (neuromyelitis optica), a very rare disease that  may occur at any age, characterized by bilateral optic  neuritis and the subsequent development of transverse  myelitis (demyelination of the spinal cord) within days or  weeks.   • Schilder disease, a very rare relentlessly progressive  generalized disease with an onset prior to the age of 10 years  and death within 1-2 years. Bilateral optic neuritis without  subsequent improvement may occur.   • Presentation is typically in the third-fourth decades,  generally with relapsing/remitting demyelination that may  switch later to an unremitting pattern, and less commonly  with progressive disease from the outset.   o Cerebral, e.g. hemiparesis, hemianopia, dysphasia,  o Psychological, e.g. intellectual decline, depression,  euphoria.   o Transient features, e.g. the Lhermitte sign (electrical  sensation on neck flexion) and the Uhthoff phenomenon  (sudden worsening of vision or other symptoms on  exercise or increase in body temperature).   o Common. Optic neuritis (usually retrobulbar),  internuclear ophthalmoplegia, nystagmus,  o Uncommon. Skew deviation, ocular motor nerve palsies,  hemianopia.   o Lumbar puncture shows oligoclonal bands on protein  electrophoresis of cerebrospinal fluid in 90-95%.  o MRI almost always shows characteristic white matter  lesions (plaques - Fig. 19.9 and see Fig. 19.3F).    o VEPs are abnormal (conduction delay and a reduction in  amplitude) in up to 100% of patients with clinically  definite MS.   • The overall 15-year risk of developing MS following an acute  episode of optic neuritis is about 50%; with no lesions on  MRI the risk is 25%, but over 70% in patients with one or  more lesions on MRI; the presence of MRI lesions is  therefore a very strong predictive factor.   • A substantially lower risk of developing MS when there are  no MRI lesions is conferred by the following factors,  providing critical support in deciding whether to commence  immunomodulatory MS-prophylactic treatment following  an optic neuritis episode:   o Absence of a viral syndrome preceding the optic neuritis,  o Optic disc swelling, disc/peripapillary haemorrhages or  macular exudates.   o Vision reduced to no light perception,  o Absence of periocular pain.   • Optic neuritis is the presenting feature of MS in up to 30%.   • Optic neuritis occurs at some point in 50% of patients with  established MS.   o Subacute monocular visual impairment,  o Usual age range 20-50 years (mean around 30).  o Some patients experience tiny white or coloured flashes  or sparkles (phosphenes).   O Discomfort or pain in or around the eye is present in  over 90% and typically exacerbated by ocular movement;  it may precede or accompany the visual loss and usually  lasts a few days.   o Frontal headache and tenderness of the globe may also be  present.   o Visual acuity (VA) is usually 6/18-6/60, but may rarely be  worse.   o The optic disc is normal in the majority of cases   o Temporal disc pallor may be seen in the fellow eye (see  Fig. 19.7B for similar appearance), indicative of previous  optic neuritis.   o Diffuse depression of sensitivity in the entire central 30°  is the most common.   Fig. 19.10 Visual field defects in optic neuritis. (A) Central  scotoma; (B) centrocaecal scotoma; (C) nerve fibre bundle;  (D) altitudinal    o Focal defects are frequently accompanied by an element  of superimposed generalized depression.   • Course. Vision worsens over several days to 3 weeks and  then begins to improve. Initial recovery is fairly rapid and  then slower over 6-12 months.   o More than 90% of patients recover visual acuity to 6/9 or  better.   o Subtle parameters of visual function, such as colour  vision, may remain abnormal,  o A mild relative afferent pupillary defect may persist,  o Temporal optic disc pallor or more marked optic atrophy  may ensue.   o About 10% develop chronic optic neuritis with slowly  progressive or stepwise visual loss.   • Indications for steroid treatment. When visual acuity  within the first week of onset is worse than 6/12, treatment  may speed up recovery by 2-3 weeks and may delay the  onset of clinical MS over the short term. This may be  relevant in the patients with poor vision in the fellow eye or  those with occupational requirements, but the limited  benefit must be balanced against the risks of high-dose  steroids. Therapy does not influence the eventual visual  outcome and the great majority of patients do not require  treatment.   • Steroid regimen. Intravenous methylprednisolone sodium  succinate 1 g daily for 3 days, followed by oral prednisolone   (1 mg/kg daily) for n days, subsequently tapered over 3 days.  Oral prednisolone may increase the risk of recurrence of  optic neuritis if used without prior intravenous steroid.   • Immunomodulatory treatment (IMT) reduces the risk of  progression to clinical MS in some patients, but the risk  versus benefit ratio has not yet been fully defined with the  options available, which include interferon beta,  teriflunomide and glatiramer. A decision should be  individualized, based on risk profile - particularly the  presence of brain lesions - and patient preference; most do  not commence IMT until a second episode of clinical  demyelination has occurred, though there may be an  increasing tendency towards a lower threshold.   Optic neuritis may be associated with viral infections such as  measles, mumps, chickenpox, rubella, whooping cough and glan¬  dular fever, and may also occur following immunization. Children  are affected much more frequently than adults. Presentation is  usually 1-3 weeks after a viral infection, with acute severe visual  loss generally involving both eyes. Bilateral papillitis is the rule;  occasionally there may be a neuroretinitis or the discs may be  normal. The prognosis for spontaneous visual recovery is very  good, and treatment is not required in the majority of patients.  However, when visual loss is severe and bilateral or involves an  only seeing eye, intravenous steroids should be considered, with  antiviral cover where appropriate.   • Sinus-related optic neuritis is uncommon and is sometimes  characterized by recurrent attacks of unilateral visual loss  associated with severe headache and spheno-ethmoidal  sinusitis. Possible mechanisms include direct spread of  infection, occlusive vasculitis and mucocoele. Treatment is  with systemic antibiotics and, if appropriate, surgical  drainage.   • Cat-scratch fever (benign lymphoreticulosis) is usually  caused by Bartonella henselae inoculated by a cat scratch or  bite (see below and also Ch. 11). Numerous ophthalmological  features have been described, notably neuroretinitis.   • Syphilis may cause acute papillitis or neuroretinitis during  the primary or secondary stages (see Ch. 11).   • Lyme disease (borreliosis) is a spirochaetal infection caused  by Borrelia burgdorferi transmitted by a tick bite (see Ch. 11).  It may cause neuroretinitis and occasionally acute  retrobulbar neuritis, which may be associated with other  neurological manifestations and can mimic MS.   • Cryptococcal meningitis in patients with acquired  immunodeficiency syndrome (AIDS) may be associated with  acute optic neuritis, which may be bilateral (see Ch. 11).   • Varicella zoster virus may cause papillitis by spread from  contiguous retinitis (i.e. acute retinal necrosis, progressive  retinal necrosis - see Ch. 11) or associated with herpes zoster  ophthalmicus. Primary optic neuritis is uncommon but may    occur in immunocompromised patients, some of whom may  subsequently develop viral retinitis.   Optic neuritis affects 1-5% of patients with neurosarcoid. It may  occasionally be the presenting feature of sarcoidosis but usually  develops during the course of established systemic disease. The  optic nerve head may exhibit a lumpy appearance suggestive of  granulomatous infiltration and there may be associated vitritis  (Fig. 19.11). The response to steroid therapy is often rapid, though  vision may decline if treatment is tapered or stopped prematurely,  and some patients require long-term low-dose therapy. Meth¬  otrexate may also be used as an adjunct to steroids or as mono¬  therapy in steroid-intolerant patients.   Autoimmune optic nerve involvement may take the form of ret¬  robulbar neuritis or anterior ischaemic optic neuropathy (see  below). Some patients may also experience slowly progressive  visual loss suggestive of compression. Treatment is with systemic  steroids and other immunosuppressants.   Neuroretinitis refers to the combination of optic neuritis and signs  of retinal, usually macular, inflammation. Cat-scratch fever is  responsible for 60% of cases. About 25% of cases are idiopathic   Fig. 19.11 Sarcoid granuloma of the optic nerve head with  overlying vitreous haze   • Symptoms. Painless unilateral visual impairment, usually  gradually worsening over about a week.   o VA is impaired to a variable degree,  o Signs of optic nerve dysfunction are usually mild or  absent, as visual loss is largely due to macular  involvement.   o A macular star (Fig. 19.12B) typically appears as disc  swelling settles; the macular star resolves with a return to  normal or near-normal visual acuity over 6-12 months.   Fig. 19.12 Progression of neuroretinitis. (A) Severe papillitis;  (B) later stage in a different patient showing macular star   (Courtesy of P Saine - fig. A; L Merin - fig. B)    o Venous engorgement and splinter haemorrhages may be  present in severe case.   • Optical coherence tomography (OCT) demonstrates  sub- and intraretinal fluid to a variable extent.   • Fluorescein angiography (FA) shows diffuse leakage from  superficial disc vessels.   • Blood tests may include serology for Bartonella and other  causes according to clinical suspicion (see also Ch. 11).   This is specific to the cause, and often consists of antibiotics.  Recurrent idiopathic cases may require treatment with steroids  and/or other immunosuppressants.   Non-arteritic anterior ischaemic optic neuropathy (NAION) is  caused by occlusion of the short posterior ciliary arteries resulting  in partial or total infarction of the optic nerve head. Predisposi¬  tions include structural crowding of the optic nerve head so that  the physiological cup is either very small or absent, hypertension  (very common), diabetes mellitus, hyperlipidaemia, collagen vas¬  cular disease, antiphospholipid antibody syndrome, hyperhomo-  cysteinaemia, sudden hypotensive events, cataract surgery, sleep  apnoea syndrome and erectile dysfunction. Patients are usually  over the age of 50, but are typically younger than those who  develop arteritic ION (see below).   o Sudden painless monocular visual loss; this is frequently  discovered on awakening, suggesting a causative role for  nocturnal hypotension.   o VA is normal or only slightly reduced in about 30%. The  remainder has moderate to severe impairment,  o Visual field defects are typically inferior altitudinal but  central, paracentral, quadrantic and arcuate defects may  also be seen.   o Dyschromatopsia is usually proportional to the level of  visual impairment, in contrast to optic neuritis in which  colour vision may be severely impaired when VA is  reasonably good.   o Disc swelling gradually resolves and pallor ensues 3-6  weeks after onset.   Investigation should include blood pressure, a fasting lipid  profile and blood glucose. It is also very important to exclude    occult giant cell arteritis (see below) with symptomatic  enquiry and testing as appropriate. Atypical features may  prompt special investigations, such as neuroimaging.   • Prognosis. Improvement in vision is common although  recurrence occurs in about 6%. About 50% of eyes achieve  6/9 or better, though 25% will only reach 6/60 or worse.   • Fellow eye. Involvement of the fellow eye occurs in about  10% of patients after 2 years and 15% after 5 years. When the  second eye becomes involved, optic atrophy in one eye and  disc oedema in the other gives rise to the ‘pseudo-Foster  Kennedy syndrome’.   • Optic nerve fenestration has not been shown to be of  benefit.   • Although aspirin is effective in reducing systemic vascular  events and is frequently prescribed in patients with NAION,  it does not appear to reduce the risk of involvement of the  fellow eye.   Arteritic anterior ischaemic optic neuropathy (AAION) is caused  by giant cell arteritis (GCA). About 50% of patients with GCA  have polymyalgia rheumatica (PMR) at diagnosis, while around  20% of PMR patients will develop GCA. PMR is characterized by  pain and stiffness in proximal muscle groups, typically the shoul¬  ders and biceps, that is worse on waking. Symptoms can be severe  but generally respond dramatically to a low-medium dose (ini¬  tially 15-20 mg daily) of oral prednisolone. The causative relation¬  ship between GCA and PMR remains uncertain, though many  suspect them to be different presentations of the same underlying  entity.   GCA is a granulomatous necrotizing arteritis (Fig. 19.14A) with a  predilection for large and medium-size arteries, particularly the  major aortic branches and the superficial temporal (STA), oph¬  thalmic, posterior ciliary and proximal vertebral arteries. The  severity and extent of involvement are associated with the quantity  of elastic tissue in the media and adventitia and intracranial arter¬  ies are usually spared as they possess little elastic tissue. Smoking,  low body mass index and early menopause may be independent  risk factors. Patients are usually elderly (average 70 years) and the  condition is extremely rare under the age of 50. Women are  affected four times more commonly than men. The diagnosis of  both GCA and PMR is essentially clinical; the American College  of Rheumatology criteria may be helpful in diagnostic decision¬  making (Table 19.2).   o Scalp tenderness, first noticed when combing the hair, is  common.   o Headache, which may be localized to the frontal, occipital  or temporal areas or be more generalized.   o Jaw claudication (cramp-like pain on chewing), caused by  ischaemia of the masseter muscles, is virtually  pathognomonic.   o Non-specific symptoms such as weight loss, fever, night  sweats, malaise and depression are common.   o Superficial temporal arteritis is characterized by  thickened, tender, inflamed and nodular arteries (Fig.  19.14B), though the signs may be subtle.   o Pulsation is initially present, but later ceases, a sign  strongly suggestive of GCA, since a non-pulsatile  superficial temporal artery is highly unusual in a normal  individual.   O Ocular motor palsies, including a pupil-involving third  nerve palsy, can manifest.   5. Abnormal artery biopsy: biopsy specimen showing  vasculitis characterized by a predominance of  mononuclear cell infiltration or granulomatous  inflammation, usually with multinucleated giant cells   For purposes of classification, a patient shall be said to  have giant cell (temporal) arteritis if at least three of  these five criteria are present   Fig. 19.14 Giant cell arteritis. (A) Histology shows transmural granulomatous inflammation, disruption of the internal elastic  lamina, proliferation of the intima and gross narrowing of the lumen; (B) the superficial temporal artery is often pulseless,  nodular and thickened; (C) pale swollen disc in arteritic ischaemic optic neuropathy; (D) ischaemic optic neuropathy and  cilioretinal artery occlusion   (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2002 - fig. A; S Farley T Cole and L Rimmer - fig. B; SS Hayreh  - figs C and D)    o Rare complications include dissecting aneurysms, aortic  incompetence, myocardial infarction, renal failure and  brainstem stroke.   o Erythrocyte sedimentation rate (ESR) is often very high,  with a level of >60 mm/hr, although in approximately  20% of patients it is normal, even low-normal,  o C-reactive protein (CRP) is invariably raised and may be  helpful when ESR is equivocal,  o Full blood count: elevated platelets and normocytic  normochromic anaemia are commonly present.    o Liver function tests are abnormal in one-third,  o Autoantibodies are normal.   o Temporal artery biopsy (TAB) should be performed if  GCA is suspected. Steroid treatment (see below) should  never be withheld pending biopsy, which should ideally  be performed within 3 days of commencing steroids.  Systemic steroid administration of duration greater than  7-10 days may suppress histological evidence of active  arteritis although this is not invariable. In patients with  ocular involvement it is advisable to take the biopsy from  the ipsilateral side. The ideal location is the temple   because it lessens the risk of major nerve damage. At least  2.5 cm of artery should be collected and serial sections  examined because of the phenomenon of ‘skip’ lesions in  which inflamed segments of arterial wall are interspersed  with histologically normal areas. A negative TAB should  not prevent ongoing treatment in the presence of a  convincing clinical picture of GA as 15% have normal  histology; a contralateral biopsy may be positive in 5%  following a negative initial biopsy.   o Colour Doppler and duplex ultrasonography shows a  hypoechoic halo around the superficial temporal artery  lumen in around 75% due to oedema in the artery wall,  and may be pathognomonic. There is some evidence that  this provides a valid non-invasive alternative to TAB.  Doppler imaging is also a useful aid to locating the artery  for biopsy when it cannot be palpated.   o Extracranial large vessel imaging. Aortic imaging with  ultrasonography, MRA or positron emission tomography  (PET) scanning may be used to exclude aortic aneurysm  or dissection due to aortitis. Serial long-term imaging is  increasingly being advocated to exclude these potentially  life-threatening complications, the risk of which has now  been demonstrated to be substantially increased in and  following GCA.   particular inflammatory features in the shoulder joints on  MRI and ultrasonography may be useful diagnostically in  PMR.   Treatment in the absence of visual symptoms is with oral pred¬  nisolone. An initial dose of 1 mg/kg/day is typical, the subsequent  duration of treatment being governed by the response of symp¬  toms and the level of the ESR or CRP; symptoms may recur  without a corresponding rise in ESR or CRP and vice versa. Most  patients need treatment for 1-2 years, although some may require  indefinite maintenance therapy. Rapid tapering should generally  not occur, with added caution when the dose is reduced to below  about 10 mg a day. CRP may play an important role in monitoring  disease activity, as the level seems to fall more rapidly than the ESR  in response to treatment.   Arteritic anterior ischaemic optic neuropathy (AAION) affects  30-50% of untreated patients with GCA, of whom one-third  develop involvement of the fellow eye, usually within a week of  the first. Posterior ischaemic optic neuropathy is much less  common.   o Sudden, profound unilateral visual loss not uncommonly  preceded by transient visual obscurations (amaurosis  fugax) and sometimes by double vision.   o Other GCA symptoms are common; most cases of  AAION occur within a few weeks of the onset of GCA,   o Simultaneous bilateral involvement is rare but rapid  involvement of the second eye, with resultant total  blindness, should always be regarded as a substantial risk.   19.14C) is particularly suggestive of GCA.  o Over 1-2 months, the swelling gradually resolves and  severe optic atrophy ensues.   Prognosis is very poor. Visual loss is usually permanent,  although, very rarely, prompt administration of systemic  steroids may be associated with partial recovery.   Treatment is aimed at preventing blindness of the fellow  eye, as visual loss in the index eye is unlikely to improve  even with immediate treatment; the second eye may still  become involved in 25% despite early steroid administration.  The regimen is as follows:   o Intravenous methylprednisolone, 500 mg to 1 g/day for 3  days followed by oral prednisolone 1-2 mg/kg/day. After 3  more days the oral dose is reduced to 50-60 mg (not less  than 0.75 mg/kg) for 4 weeks or until symptom resolution  and ESR/CRP normalization. A typical subsequent  regimen consists of reducing the daily dose by 10 mg/day  every 2 weeks until 20 mg/day is reached, with tapering  afterwards titrated against ESR/CRP and symptoms, e.g. a  2.5 mg reduction every 2-4 weeks to 10 mg then a 1 mg  reduction every 1-2 months,  o Enteric-coated prednisolone may be appropriate,   particularly in patients with a history of peptic ulceration,  o Steroid treatment should be accompanied by bone and  gastrointestinal protection, e.g. a weekly bisphosphonate,  calcium/vitamin D supplementation and a proton pump  inhibitor.   o Monitoring should be performed by a physician with  appropriate training and should look particularly for  steroid-related complications. A full blood count, ESR/  CRP, urea and electrolytes, random glucose and blood  pressure should be checked at each visit. Every 1-2 years,  a chest X-ray or more sophisticated imaging should be  performed to exclude an aortic aneurysm and bone  mineral density should be assessed,  o Antiplatelet therapy, e.g. aspirin 600 mg stat then  100 mg/day should be commenced as this has been  shown to reduce the risk of visual loss and stroke,  o Any significant symptomatic relapse should be treated  with an aggressive increase in steroid dose; intravenous  methylprednisolone should be given if visual disturbance  occurs.   o Immunosuppressives such as methotrexate may be used  as adjuncts in steroid-resistant cases or as steroid-sparing  agents when extended treatment is required, though with  caution as their benefit is considerably less proven than  that of steroids.    o Biological blockers have not been shown to have a  definite protective effect.   • Cilioretinal artery occlusion may be combined with AAION  (Fig. 19.14D).   • Central retinal artery occlusion is often combined with  occlusion of a posterior ciliary artery - with resultant  choroidal hypoperfusion - as the two can arise from the  ophthalmic artery by a common trunk.   • Ocular ischaemic syndrome due to involvement of the  ophthalmic artery is rare.   Posterior ischemic optic neuropathy (PION) is much less common  than the anterior variety. It is caused by ischaemia of the retrolam-  inar portion of the optic nerve supplied by the surrounding pial  capillary plexus, which in turn is supplied by pial branches of the  ophthalmic artery; only a small number of capillaries actually  penetrate the nerve and extend to its central portion among the  pial septae. The diagnosis of PION should be made only after other  causes of retrobulbar optic neuropathy, such as compression or  inflammation, have been excluded. Initially, the optic disc appears  normal but pallor develops over weeks.   • Operative (perioperative) PION develops following a variety  of surgical procedures, most notably involving the heart and  the spine. It occurs in about 0.02% of these procedures. The  major risk factors appear to be anaemia and intraoperative  hypovolaemic hypotension. Bilateral involvement is  common and the visual prognosis is typically poor. Prompt  blood transfusion and treatment of facial/orbital swelling  may be of benefit.   • Arteritic PION is associated with giant cell arteritis and  carries a poor visual prognosis.   • Non-arteritic PION is associated with the same systemic risk  factors as NAION, but is not associated with a crowded  optic disc. The visual prognosis is similar to NAION. Some  practitioners prescribe a short course of high-dose systemic  steroid in early cases.   Leber hereditary optic neuropathy (LHON) is a rare ganglion cell  degeneration; the papillomacular bundle is particularly affected.  The condition is caused by maternally inherited mitochondrial  DNA point mutations, most frequently (50-90%) at nucleotide  position 11778 (G to A) in the MT-ND4 gene. The condition    typically affects males between the ages of 15 and 35 years, although  in atypical cases the condition may affect females and present at  any age between 10 and 60 years. The diagnosis of LHON should  therefore be considered in any patient with bilateral optic neu¬  ropathy, irrespective of age.   • Symptoms. Typically acute or subacute severe painless  unilateral (50%) loss of central vision. In initially unilateral  cases, the fellow eye becomes similarly affected within weeks  or months.   • Signs during the acute stage are often subtle and easily  overlooked, and in some patients the disc may be entirely  normal.   o Colour vision is likely to be subnormal,  o There is often a relative afferent pupillary defect,  o In typical cases there is disc hyperaemia with obscuration  of the disc margins (Fig. 19.15A).  o Dilated capillaries on the disc surface; these may extend  onto adjacent retina (telangiectatic microangiopathy  - Fig. 19.15B).   o Dilatation and tortuosity of posterior pole vasculature,  o Subsequently, the vessels and pseudo-oedema regress,  and severe optic atrophy supervenes (Fig. 19.15C), with  nerve fibre layer dropout most pronounced in the  papillomacular bundle.   o Telangiectatic microangiopathy may be present in  asymptomatic female relatives,  o Surprisingly, the pupillary light reactions may remain  fairly brisk.   • LHON plus refers to rare variants with additional  manifestations such as neuromuscular dysfunction.   • Prognosis is poor, although some visual recovery may  occur in a minority of cases even years later. Most patients  suffer permanent bilateral visual loss with a final VA of  6/60 or less. The 11778 mutation carries the worst prognosis.   • OCT. Patients show peripapillary retinal thinning;  unaffected carriers frequently show variable thickening of  the temporal retinal nerve fibre layer, perhaps due to  compensatory mitochondrial accumulation.   • Visual field defects usually consist of central or centrocaecal  scotomas, with preserved peripheral vision.   • FA shows no leakage from the disc or microangiopathic  vessels.   • Genetic testing to look for the three common causative  mutations.   • Apart from symptomatic measures such as low vision aids,  treatment is generally ineffective.   • Various vitamins and co-factors, idobenone, creatine and  others have been tried with anecdotal success, and  subspecialist prescription of one or more of these may be    Fig. 19.15 Leber hereditary optic neuropathy. (A) Acute stage  showing hyperaemic disc swelling with blurring of margins;  (B) marked telangiectatic microangiopathy; (C) late -  atrophic appearance   worthwhile, particularly in early disease or prior to second  eye involvement. Counterintuitively, the cyanocobalamin  (but not the hydroxocobalamin) form of vitamin B 12 has  been reported to worsen outcomes.   • Dietary deficiencies should be avoided, particularly of B 12 .    • Smoking and excessive alcohol consumption should be  discouraged, theoretically in order to minimize  mitochondrial stress.   This heterogeneous group of rare disorders are characterized pri¬  marily by bilateral optic atrophy. There is no effective treatment,  though the measures described above for LHON may be tried.   Dominant optic atrophy (Kjer type optic  atrophy, optic atrophy type 1)   • Inheritance is autosomal dominant (AD); this is the most  common hereditary optic neuropathy with an incidence of  around 1:50 000; it is frequently due to a mutation in the  OPAi gene on chromosome, which causes mitochondrial  dysfunction, but other genes can be responsible and  X-linked and autosomal recessive (AR) forms have been  reported. There is usually high penetrance but variable  expressivity in the dominant forms.   • Presentation is typically, though not always, in childhood  with insidious visual loss. There is usually a family history,  but the course may be variable even within the same family.   • Optic atrophy may be subtle and temporal (Fig. 19.16A) or  diffuse (Fig. 19.16B). There may be enlargement of the cup.   • Prognosis is variable (final VA 6/12-6/60) with considerable  differences within and between families. Very slow  progression over decades is typical.   • Systemic abnormalities. Twenty per cent develop  sensorineural hearing loss; other features are less common.   • Prognosis is variable, with moderate to severe visual loss  and nystagmus.   Wolfram syndrome is also referred to as DIDMOAD (diabetes  insipidus, diabetes mellitus, optic atrophy and deafness).   • Inheritance. Three genetic forms are recognized, caused by a  variety of mutations in WFSi, which gives Wolfram  syndrome 1, CISD2 - Wolfram syndrome 2 - and probably a  form caused by a mitochondrial DNA mutation, with  inheritance being AR, AD or via the maternal mitochondrial  line.   • Presentation is usually between the ages of 5 and 21 years;  diabetes mellitus is typically the first manifestation, followed  by visual problems.   Fig. 19.16 Hereditary optic atrophy. (A) Bilateral temporal disc pallor; (B) bilateral diffuse pallor    • Optic atrophy is diffuse and severe and may be associated  with disc cupping.   • Systemic abnormalities (apart from DIDMOAD) are highly  variable, presumably in part due to genetic heterogeneity,  and may include anosmia, ataxia, seizures, mental handicap,  short stature, endocrine abnormalities and elevated CSF  protein. Life expectancy is usually substantially reduced.   Nutritional optic neuropathy (tobacco-alcohol amblyopia) is an  apparently uncommon but likely underdiagnosed acquired optic  neuropathy. The mechanism is thought to be deficient mitochon¬  drial function, similar to that of the heritable optic neuropathies,  and like these the papillomacular bundle is preferentially affected.  In Western developed countries the condition typically affects  individuals with high alcohol and tobacco consumption. Most    patients have neglected their diet, and the features are most likely  to be due principally to deficiency in the B-complex vitamins,  particularly cyanocobalamin (B 12 ) and thiamine (BJ, but also ribo¬  flavin (B 2 ), niacin (B 3 ) and pyridoxine (B 6 ). Copper, folic acid and  protein deficiency may also be important, and direct toxic effects  of alcohol and tobacco may also be significant. A strict vegan diet  can also be causative, as can dietary deficiency in elderly patients.  A similar clinical picture may be seen due to toxicity from medica¬  tion or environmental (e.g. occupational) toxins. In under¬  resourced geographic regions, nutritional aetiological factors due  to inadequate dietary intake predominate, and nutritional optic  neuropathy can be epidemic. Pernicious anaemia sufferers may  develop the condition due to reduced vitamin B 12 absorption.   The possibility of a range of causes, particularly alternative optic  neuropathies and macular pathology, should be borne in mind.   o The insidious onset of painless bilateral central blurring  associated with abnormal colour vision.   o Enquiry should be made about potentially causative  medication (see Ch. 20), environmental toxin exposure  and a vegan diet.   o Peripheral neurological symptoms (sensory loss, gait  disturbance) raise the suspicion of a peripheral  neuropathy.   o The discs at presentation are normal in most cases, but  some patients show subtle pallor, often temporal,  splinter-shaped haemorrhages on or around the disc, or  minimal oedema.   o The pupil reactions are often normal, but may respond  weakly in more severe cases,  o Other ocular and systemic features of nutritional   deficiency should be sought (and investigations carried  out accordingly), e.g. Korsakoff syndrome, Wernicke  disease, pernicious anaemia; xerophthalmia and beriberi  should be considered in developing nations.   • Colour vision testing. A reduction in colour vision is  disproportionate to the reduction in acuity. Red desaturation  is likely to be present. Ishihara chart testing is a simple,  moderately quantitative test that is widely available.   • Visual field defects are bilateral, relatively symmetrical,  centrocaecal scotomas. The margins of the defects are  difficult to define with a white target but are more  substantive with a red target.   • OCT may show peripapillary retinal nerve fibre  layer thickening and will help to exclude macular  pathology.   • Fundus autofluorescence (FAF) should be performed if  available to exclude macular changes suggesting a cone or  cone-rod dystrophy that may present with colour deficiency  and central scotomata.   • Prognosis is good in early cases provided patients comply  with treatment although visual recovery may be slow; colour  perception returns more slowly than measured acuity. In  advanced cases there is likely to be a substantial permanent  deficit, but it is highly unusual for complete loss of useful  vision to occur, with preservation of peripheral field usual  even in quite severe cases.   • Blood tests. B 12 (cobalamin) and folate (serum and red cell)  and possibly other vitamin levels such as B x (thiamine) and  B 2 , a full blood count and film (macrocytic anaemia) and  serum protein levels. Some authorities advocate routine  syphilis serology. Screening for specific toxins or for FHON  (see above) mutations may be indicated. A high serum  methylmalonate and/or homocysteine level may be an  indicator of potentially functional B 12 deficiency, even in the  presence of a low-normal B 12 .   • VEP. The P100 amplitude is markedly reduced but with  normal or near-normal latency.   • MRI is commonly considered to rule out mimicking  intracranial pathology, particularly with an atypical clinical   • Dietary revision with formal nutritional advice,  incorporating increased fruit and leafy green vegetable intake.   • Abstention from alcohol and tobacco; reduction in  consumption may be all that is practically possible.   • Vitamins. A daily multivitamin preparation, plus thiamine  (100 mg twice daily) and folate (1 mg daily). In someone  who is both folate and B 12 deficient, it is prudent to correct  the B 12 deficiency first to avoid precipitating subacute  combined degeneration of the cord.   • Intramuscular hydroxocobalamin (vitamin B 12 ) injections.  The use of injected B 12 has become less common in recent  years, as evidence shows that even in malabsorption states  oral treatment may be as effective. Some work suggests that  hydroxocobalamin injections improve vision in tobacco-  alcohol amblyopia, including when smoking continues,  perhaps by reversing cyanide toxicity; their use may  therefore still be considered in severe or unresponsive cases,  noting also that intramuscular treatment bypasses  compliance failure. Regimens range from 1 mg weekly for 8  weeks to monthly for several months; injections every 3  months are typically continued for life.   • Exposure to the identified agent should be discontinued  immediately in cases due to medication or environmental  toxicity.   Papilloedema is swelling of the optic nerve head secondary to  raised intracranial pressure (ICP). ‘Disc swelling’ and ‘disc  oedema’ are non-specific terms that include papilloedema but also  a disc swollen from other causes. All patients with papilloedema  should be suspected of harbouring an intracranial mass. Not all  patients with raised ICP will develop disc swelling. Causes of a  swollen-appearing optic disc are given in Table 19.3.   o Cerebrospinal fluid (CSF) is formed by the choroid  plexus in the ventricles of the brain,  o It leaves the lateral ventricles to enter the third ventricle  through the foramina of Munro.  o From the third ventricle, it flows through the Sylvian  aqueduct to the fourth ventricle,  o From the fourth ventricle, the CSF passes through the  foramina of Fuschka and Magendie to enter the    • Visual symptoms are commonly absent in mild or early  raised ICP.   o Transient visual obscurations lasting up to 30 seconds in  one or both eyes are frequent in established  papilloedema, and are sometimes precipitated by  bending, coughing or the Valsalva manoeuvre; disc  swelling due to other causes is usually associated with  more persistent visual impairment,  o Horizontal diplopia due to sixth nerve palsy caused by  stretching of one or both abducens nerves over the  petrous tip (Fig. 19.18); this is a false localizing sign,  o Vision is generally normal or minimally reduced.   Significant reduction is a late feature in conjunction with  secondary optic atrophy.   distinguishing between papilloedema and other causes of  a swollen or apparently swollen  (pseudopapilloedematous) optic disc with 80-90%    subarachnoid space, flowing around the spinal cord and  bathing the cerebral hemispheres,  o Absorption is into the cerebral venous system through  the arachnoid villi.   • Normal CSF pressure on lumbar puncture (not upright) is  10-18 cmH 2 0 in adults.   O Idiopathic intracranial hypertension,  o Obstruction of the ventricular system by congenital or  acquired lesions.   O Impairment of CSF absorption due to meningitis,  subarachnoid haemorrhage or trauma,  o Cerebral venous sinus thrombosis,  o Cerebral oedema from blunt head trauma,  o Severe systemic hypertension.   o Hypersecretion of CSF by a choroid plexus tumour (very  rare).   • Headaches, which characteristically occur early in the  morning and may wake the patient from sleep, although less  commonly they can occur at any time of day. The pain may  be generalized or localized, and may intensify with head  movement, bending or coughing. They tend to get  progressively worse over time. Very rarely, headache may be  absent.   • Nausea, often episodic and with associated projectile  vomiting; may occur as an isolated feature or may precede  the onset of headaches.   • Deterioration of consciousness as severity increases, initially  with drowsiness and somnolence. A dramatic deterioration  in concscious level may be indicative of brainstem distortion  and requires immediate attention.   Fig. 19.17 (A) Circulation of cerebrospinal fluid; (B) causes of  raised intracranial pressure - see text (FM = foramen  magnum; LV = lateral ventricle; AQ = aqueduct of Sylvius)   Fig. 19.18 Mechanism of sixth nerve palsy due to raised  intracranial pressure    sensitivity and specificity by measuring the external  diameter of the optic nerve sheath (ONSD), which is  substantially distended (5.0-5.7 mm or greater at 3.0 mm  behind the globe - Fig. 19.19A). The nerve must be  scanned axially for the measurement to be accurate, and  there is a degree of operator dependence. In contrast to  spontaneous venous pulsation (SVP - see below), ONSD  does not normalize with short-term ICP fluctuation. The  ‘crescent sign’ (Fig. 19.19B) refers to an echolucent area in  the anterior intraorbital nerve thought to represent  increased separation of the nerve and its sheath. Lateral  gaze (‘thirty degree test’) commonly leads to a 10%  reduction in diameter on A-scan measurement in the  presence of excess fluid (Figs 19.19C and D), but not if  normal or if increased ONSD is due to infiltration.  Fluid-related ONSD can also be caused by other  pathology, such as inflammation and trauma.   o MRI to exclude a space-occupying lesion and/or enlarged  ventricles; MRI can also be used to measure ONSD  (average normal diameter approximately 5.5 mm ± 1 mm  on MRI).   o In certain cases vascular imaging may be performed, such  as venography to rule out cerebral venous sinus  thrombosis.   o Lumbar puncture (LP) must not be carried out until  imaging has excluded a space-occupying lesion that  might cause downwards herniation of the intracranial  contents towards the LP-induced low-pressure area.  Clotting abnormality, including therapeutic  anticoagulation, is also a contraindication unless reversed  prior to the LP.   o Mild disc hyperaemia with preservation of the optic cup.  o Indistinct peripapillary retinal nerve striations and disc  margins.   o SVP is absent in about 20% of normal individuals and  may be difficult to identify even when present. An  identifiable venous pulsation in at least one eye means  that the ICP is normal at that point in time, bearing in  mind that diurnal fluctuation can occur.   indistinct margins and absence of the physiological cup.  o Venous engorgement, peripapillary flame haemorrhages  and frequently cotton wool spots,  o As the swelling increases, the optic nerve head appears  enlarged.   o Circumferential retinal folds (Paton lines) may develop,  especially temporally (see Fig. 19.7C).  o Macular fan: in younger patients small vesicles may form  in the superficial retina, converging on the fovea in a fan  shape with the apex at the fovea; this is not to be  confused with a macular star, composed of exudates,  o Enlarged blind spot.   o VA is variable and the visual fields begin to constrict,  o Disc elevation; cotton wool spots and haemorrhages are  characteristically no longer present,  o Optociliary shunts (see Ch. 13) and drusen-like crystalline  deposits (corpora amylacea) may be present on the disc  surface.   o The optic discs are grey-white, slightly elevated, with few  crossing blood vessels and indistinct margins.   Idiopathic intracranial hypertension, previously known as benign  intracranial hypertension or pseudotumour cerebri, is character¬  ized by elevated ICP that by definition has no identifiable cause;  obese young adult women are the most commonly affected group.  Various medications including the contraceptive pill have been  implicated (strictly ‘secondary intracranial hypertension’ if a cause  is identified), as well as a range of conditions such as systemic  lupus erythematosus, Lyme disease and sleep apnoea syndrome.   • Symptoms and signs are those of papilloedema, with  headache in over 90%; pulsatile tinnitus may be experienced,   Fig. 19.19 Ultrasonography in papilloedema. (A) Optic nerve sheath diameter of 7.1 mm, 3 mm posterior to the globe;   (B) transverse B-scan showing crescent sign (arrowheads); (C) A-scan in primary position with retrobulbar nerve diameter  of 4.8 mm; (D) in lateral gaze diameter reduces to 3.5 mm - positive 30° test   (Courtesy of M Stone, from American Journal of Emergency Medicine 2009;27:376.el-376.e2 - fig. A; L Lystad, B Hayden, A Singh, from Ultrasound Clinics  2008;3:257-66 - figs B-D)    and cranial nerve palsies and occasionally other symptoms  may occur. The long-term visual prognosis is usually good,  but up to a quarter will have a degree of permanent  impairment.   • Investigation is as for papilloedema: ONSD is increased and  MRI may show slit-like ventricles and flattening of the  pituitary gland (‘empty sella’ sign). MRV is usually carried  out to exclude cerebral venous sinus thrombosis or stenosis.  Additional investigation for an occult cause should be  considered, especially in patients who do not fit the usual  profile.   • Weight loss, including via bariatric surgery, can be very  effective and formal dietary intervention is strongly  recommended.   • Other options include acetazolamide, furosemide, digoxin  and analgesia, and in unresponsive cases optic nerve   • Steroids are controversial, but a short course is sometimes  used in severe papilloedema.   • Intravenous mannitol or a lumbar puncture are usually  reserved for acute severe exacerbations.   • The ophthalmologist’s role is usually confined to diagnosis  and the monitoring of visual function with VA, colour  vision and fields, and optic nerve appearance/photography.   A tilted optic disc is a common anomaly, usually bilateral, describ¬  ing an apparently oblique entry of the optic nerve into the globe.  It is strongly associated with myopia and astigmatism. A suggested  definition regards tilting as present when the ratio of the longest    diameter of the disc to the shortest (ovality index) is greater than  1.3 (Fig. 19.21A), but this will not include many subjectively appar¬  ently tilted discs (Fig. 19.21B). A major implication of tilting is  difficulty in excluding superimposed glaucomatous damage, as the  temporal, particularly the inferotemporal, neuroretinal rim is fre¬  quently very thin.   • Signs. Small, oval or D-shaped disc: the axis is most   o The disc margin is indistinct where retinal nerve fibres  are elevated.   O Peripapillary chorioretinal thinning may be marked, and  situs inversus may be present: the temporal vessels  deviate nasally before turning temporally (Fig. 19.21C).    • Perimetry may show superotemporal defects; these do not  respect the vertical midline.   • OCT may demonstrate sectoral peripapillary retinal nerve  fibre layer thinning, but macular ganglion cell complex  analysis is often - but not always - normal so may provide a  more useful parameter for the exclusion of coexistent  glaucomatous damage.   A torsional (torsioned) disc is said to be present when its long axis   is inclined at more than 15 0 from the vertical meridian, a line at   Fig. 19.21 (A) Tilted disc; (B) borderline tilted disc with thin  inferotemporal neuroretinal rim; (C) markedly tilted - and  torsional - disc with situs inversus and associated  inferonasal chorioretinal thinning    90° to a horizontal line connecting the foveola to the centre of the  optic disc (see Fig. 19.21C). It is often present in association with  tilting, and is also associated with myopia.   o VA is normal in the absence of complications,  o The disc is often larger than normal and contains a  greyish round or oval pit of variable size, usually  temporal (Fig. 19.22A) but occasionally central or  elsewhere; pits are bilateral in 10-15%.  o Visual field defects are common and may mimic  glaucoma; central defects may indicate a macular  detachment.   • Serous macular detachment (Fig. 19.22B) develops in about  half of eyes with non-central disc pits (median age 30 years).  The source of the fluid remains speculative.   o A schisis-like retinal separation that extends from the pit  is followed by serous detachment of the outer retinal  layers (Fig. 19.22C). It is important to examine the optic  disc carefully in all patients with central serous  chorioretinopathy.   o FA does not usually show hyperfluorescence of the  detachment, which is demonstrated well on FAF (Fig.  19.22D) and OCT.   • Management. Long-term review (including Amsler grid use)  for the development of complications is prudent, as it is  possible that early treatment of macular detachment may  confer a better visual outcome. Options when macular  detachment develops include:   o Observation for spontaneous resolution, which occurs in  up to 25%, but may worsen the eventual outcome,  o Laser may be considered if vision is deteriorating. Light  burns are applied along the temporal aspect of the disc.  The success rate is 25-35%.   o Vitrectomy with air-fluid exchange and postoperative  prone positioning may be considered if laser is  unsuccessful.   Disc drusen are deposits, usually calcified, within the substance of  the optic nerve head that are present in up to 2% of the popula¬  tion, often bilaterally (75%). They are usually sporadic but in some  cases have AD inheritance. They are thought to consist of focal  collections of axonal metabolic products.   • Symptoms are usually absent, but some patients may  experience episodic blurring, possibly due to transient  ischaemia related to a crowding effect.   • Buried drusen. Particularly in childhood, drusen may be  obscured beneath the disc surface (Figs 19.23A and B); this is  a common cause of pseudopapilloedema. A lumpy disc  appearance, an absent cup and anomalous vascular patterns  including proximal branching, an increased number of  major vessels and tortuosity suggest drusen, as well as a lack  of papilloedematous features such as hyperaemia and vessel    Fig. 19.22 (A) Optic disc pit; (B) optic disc pit and macular detachment; (C) macular detachment; (D) fundus autofluorescence  image of the eye in (B)   • Exposed drusen. Drusen at or close to the disc surface  appear as whitish pearl-like lesions of a range of sizes  (Figs 19.23C and D). They tend to enlarge slowly over  many years.   • Visual field defects of a range of configurations are present  in up to 75% and are often progressive, though a substantial  impact on sight is rare. No definitive treatment is  recognized, though reducing IOP and other speculative  measures may be tried in selected cases.   • Associations include retinitis pigmentosa and angioid  streaks; disc drusen are present in 90% of patients with  Alagille syndrome.    • Complications (rare) include juxtapapillary choroidal  neovascularization (Fig. 19.23E), vitreous haemorrhage and  vascular occlusions, particular anterior ischaemic optic  neuropathy.   o FAF usually demonstrates drusen extremely well (see Figs  19.23B and D).   o Ultrasonography (US) shows calcified drusen as highly  reflective foci (Fig. 19.23F). US optic nerve features  distinguishing raised ICP are discussed above,  o OCT. Diffuse or focal RNFL thinning; OCT can be used  for monitoring.   radiation dose and so is not indicated solely to confirm  drusen.    Fig. 19.23 Optic disc drusen. (A) Buried disc drusen; (B) fundus autofluorescence image of eye in (A); (C) exposed disc  drusen; (D) fundus autofluorescence of eye in (C); (E) drusen with secondary choroidal neovascularization; (F) B-scan shows  high acoustic reflectivity   (Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 - fig. E; P Gili - fig. F)   The embryonic fissure of the developing eye is located inferiorly  and slightly nasally, and extends from the optic nerve to the  margin of the pupil; a coloboma is a defect in one or more  ocular structures due to the fissure’s incomplete closure. The  defect may be unilateral or bilateral and usually occurs sporadi¬  cally in otherwise normal individuals, though numerous systemic  associations have been described, e.g. chromosomal abnormali¬  ties, CHARGE syndrome, Goldenhar syndrome and central  nervous system abnormalities. An AD variety is caused by a muta¬  tion in the gene PAX6.   o VA is often decreased; amblyopia and refractive error  may be present.   decentred inferiorly so that the inferior neuroretinal rim  is thin or absent and normal disc tissue is confined to a  superior wedge of variable size depending on severity  (Figs 19.24A and B).   o A disc coloboma may be associated with, or even  continuous with, a large chorioretinal coloboma (Figs  19.24C and D).   o A disc pit is sometimes associated (Fig. 19.24E); pit-like  excavations are sometimes seen with disc colobomata  (Fig. 19.24F)   • Ocular associations include microphthalmos, microcornea  and coloboma of other structures such as the iris or   Fig. 19.24 Optic disc coloboma. (A) Small disc coloboma; (B) large disc coloboma; (C) disc coloboma continuous with a  chorioretinal coloboma; (D) isolated chorioretinal coloboma;   Fig. 19.24, Continued (E) associated disc pit and coloboma; (F) pit-like excavation associated with a small coloboma   (Courtesy of P Gili - fig. B; L Merin - fig. E; S Chen and T Roberts - fig. F)    • Complications (rare) include serous retinal detachment,  progressive neuroretinal rim thinning and choroidal  neovascularization.   Morning glory anomaly is a rare, usually unilateral and sporadic  condition that has a spectrum of severity. Bilateral cases, which  are rarer still, may be hereditary. As in coloboma, a PAX6 gene  mutation can be responsible. Systemic associations are uncom¬  mon; the most important is frontonasal dysplasia, characterized  by mid-facial anomalies, a basal encephalocele and other midline  brain malformations, including pituitary insufficiency.   o VA may be normal or impaired to a variable extent,  o A large disc with a funnel-shaped excavation   o A white tuft of glial tissue overlies the central portion and  represents persistent hyaloid vascular remnants,  o The blood vessels emerge from the rim of the excavation  in a radial pattern like the spokes of a wheel. They are  increased in number and it may be difficult to distinguish  arteries from veins.   The hypoplastic optic nerve, unilateral or bilateral, carries a  diminished number of nerve fibres. Its frequency seems to be  increasing, though it remains relatively rare. Young maternal age,  primiparity and maternal exposure to various agents have been    linked. It may occur as an isolated anomaly in an otherwise normal  eye, but systemic associations are common (see below).   o Severe bilateral cases present with blindness in early  infancy with roving eye movements or nystagmus.   o Unilateral or less severe bilateral cases usually present  with squint.   o A relative afferent pupillary defect may be present; both  pupils may have sluggish light responses in bilateral cases.   O Mild hypoplasia consists simply of a smaller than normal  disc (Fig. 19.26A); a foveola-disc centre distance of three  or more times the disc diameter strongly suggests  hypoplasia.   o Further along the hypoplastic spectrum, a small grey  disc is seen, with central cupping-like deficiency of  neural tissue and disc vessels emerging in a radial  configuration (Fig. 19.26B). The vessels are sometimes  tortuous.   o The double-ring sign is characteristic, and consists of a  white ring of visible sclera surrounding a pigmented  band thought to consist of migrated pigment epithelium  (Fig. 19.26C). A thin outer pigmented line may also be  seen.   Fig. 19.26 (A) Mildly hypoplastic disc; (B) moderately hypoplastic  absence of the corpus callosum   (Courtesy of R Bates - fig. B; A Moore - fig. C; K Nischal - fig. D)    • Ocular associations include astigmatism, amblyopia, field  defects, foveal hypoplasia, aniridia, and microphthalmos.   • Systemic associations. Optic disc hypoplasia is associated  with a wide variety of developmental midline brain defects;  pituitary and hypothalamic deficits are common.  Historically, the most frequent association has been  considered to be ‘septo-optic dysplasia’ (de Morsier  syndrome) - bilateral optic nerve hypoplasia, absent septum  pellucidum, corpus callosum dysgenesis (Fig. 19.26D) and  hypopituitarism - but it is now believed that this complex  does not exist as a specific entity.   • Investigation. All affected children should be screened for  systemic associations, especially hormonal deficiencies and  developmental delay.   Occasionally myelination of ganglion cell axons extends beyond  the cribriform plate and is visible on retinal examination in about  1% of the population: myelinated or medullated nerve fibres  (MNF). The condition is usually congenital and stable but both  progression and an acquired form have been reported. MNF is  occasionally familial. Systemic associations are very rare.   o VA is likely to be reduced if the central macula is  involved; perimetry may show an absolute scotoma  corresponding to the involved area of retina,  o One or more whitish striated patches with feathery  borders; the location and size are variable (Figs 19.27 and  19.28); two-thirds are not contiguous with the optic disc.    o Retinal vessels in the involved area are obscured,  o Between 5 and 10% of cases are bilateral,  o The appearance can be mimicked by neoplastic  infiltration and other conditions.   • Imaging. FAF shows hypoautofluorescence, and there is  masking of background fluorescence on FA. The RNFL is  hyper-reflective on OCT.   • Treatment consists of addressing refractive error, amblyopia  and squint if present.   Aicardi syndrome consists of a range of central nervous system  and other malformations in association with multiple bilateral  depigmented chorioretinal lacunae clustered around a hypoplas¬  tic, colobomatous or pigmented optic disc (Fig. 19.29); other  ocular features can include cataract and coloboma. Inheritance is  X-linked dominant; the condition is lethal in utero for males.  Death usually occurs within the first few years of life in affected  girls.   This relatively common anomaly consists of remnants of the  hyaloid vessels (Fig. 19.30); see also Chs 12 and 17.   • Peripapillary staphyloma is a non-hereditary, usually  unilateral condition in which a relatively normal disc sits at  the base of a deep excavation whose walls, as well as the  surrounding choroid and retinal pigment epithelium (RPE),  show atrophic changes (Fig. 19.31A). VA is markedly reduced    Fig. 19.29 The ocular fundus in Aicardi syndrome. (A) Right  eye; (B) left eye    and local retinal detachment may be present. Unlike other  excavated optic disc anomalies, it is rarely associated with  other congenital defects or systemic diseases.   • Papillorenal (renal-coloboma) syndrome is an AD genetic  condition caused in most cases by a mutation in PAX2 and  characterized by renal and optic disc dysplasia. The discs do  not exhibit true hypoplasia, but a failure of angiogenesis.  They are normal in size with central excavation and  replacement of the central retinal vasculature by cilioretinal  vessels (Fig. 19.31B).   Fig. 19.30 Bergmeister papilla. (A) and (B) Small bilateral  lesions; (C) larger example   (Courtesy of D Taylor and CS Hoyt, from Pediatric Ophthalmology and  Strabismus, Elsevier 2005 - fig. B)    • Optic disc dysplasia is a descriptive term for a markedly  deformed disc that does not conform to any recognizable  category (Fig. 19.31C).   • Megalopapilla is a typically bilateral condition in which  both the horizontal and vertical disc diameters are 2.1 mm  or more, or the disc area is greater than 2.5 mm 2 . Although  the cup-to-disc ratio is greater than normal, the cup should  retain its normal configuration with no evidence of focal  neuroretinal rim loss. Although OCT may show peripapillary  retinal nerve fibre layer thinning, macular ganglion cell  complex imaging is typically normal.   • Optic nerve aplasia is an extremely rare condition in which  the optic disc is absent or rudimentary and retinal vessels are  absent or few in number and abnormal. There may be  retinal pigmentary disturbance, especially at the site where    the optic disc might have been. Other ocular and systemic  developmental defects may be present.   The light reflex is mediated by the retinal photoreceptors and  subserved by four neurones (Fig. 19.32).   • First (sensory) connects each retina with both pretectal  nuclei in the midbrain at the level of the superior colliculi.  Impulses originating from the nasal retina are conducted by    fibres that decussate in the chiasm and pass up the opposite  optic tract to terminate in the contralateral pretectal nucleus.  Impulses originating in the temporal retina are conducted by  uncrossed fibres (ipsilateral optic tract) that terminate in the  ipsilateral pretectal nucleus.   • Second (internuncial) connects each pretectal nucleus to  both Edinger-Westphal nuclei. Thus a uniocular light  stimulus evokes bilateral and symmetrical pupillary  constriction. Damage to internuncial neurones is responsible  for light-near dissociation in neurosyphilis and pinealomas.   • Third (preganglionic motor) connects the Edinger-Westphal  nucleus to the ciliary ganglion. The parasympathetic fibres  pass through the oculomotor nerve, enter its inferior  division and reach the ciliary ganglion via the nerve to the  inferior oblique muscle.   • Fourth (postganglionic motor) leaves the ciliary ganglion  and passes in the short ciliary nerves to innervate the  sphincter pupillae. The ciliary ganglion is located within the  muscle cone, just behind the globe. It should be noted that,  although the ciliary ganglion serves as a conduit for other  nerve fibres, only the parasympathetic fibres synapse there.   The near reflex, a synkinesis rather than a true reflex, is activated  when gaze is changed from a distant to a near target (see also Ch.  18). It comprises accommodation, convergence and miosis. Vision  is not a prerequisite and there is no clinical condition in which the  light reflex is present but the near response absent. Although the  final pathways for the near and light reflexes are identical (i.e. third  nerve, ciliary ganglion, short ciliary nerves), the centre for the near  reflex is ill-defined. There are probably two supranuclear    influences: the frontal and occipital lobes. The midbrain centre for  the near reflex is probably located more ventrally than the pretec¬  tal nucleus and this may explain why compressive lesions such as  pinealomas, preferentially involving the dorsal internuncial  neurones involved in the light reflex, spare the near reflex fibres  until later.   An absolute afferent pupillary defect (amaurotic pupil) is caused  by a complete optic nerve lesion and is characterized by the  following:   • The involved eye is completely blind (i.e. no light perception).   • When the affected eye is stimulated by light neither pupil  reacts.   • When the normal eye is stimulated both pupils react  normally.   A relative pupillary defect (Marcus Gunn pupil) is caused by an  incomplete optic nerve lesion or severe retinal disease, but never  by a dense cataract. The clinical features are those of an amaurotic  pupil but more subtle. Thus the pupils respond weakly to stimula¬  tion of the diseased eye and briskly to that of the normal eye. The  difference between the pupillary reactions of the two eyes is high¬  lighted by the ‘swinging flashlight test’ in which a light source is  alternatively switched from one eye to the other and back, thus  stimulating each eye in rapid succession. A right relative defect is  characterized by the following:   • When the normal left eye is stimulated, both pupils constrict  (Fig. 19.33A).   • When the light is swung to the diseased right eye, the  stimulus delivered to the constriction mechanism is reduced  and both pupils dilate instead of constricting (Fig. 19.33B).   • When the normal left eye is again stimulated, both pupils  constrict once more (Fig. 19.33C).   • When the diseased right eye is stimulated, both pupils dilate  (Fig. 19-33D).   It should be remembered that in afferent (sensory) lesions, the  pupils are equal in size; anisocoria (asymmetrical pupil diameter)  implies disease of the efferent (motor) nerve or the iris itself.   (Courtesy of ES Rosen, P Eustace, HS Thompson and WJK Cumming, from  Neuro-ophthalmology, Mosby 1998)    ciliospinal centre of Budge, in the intermediolateral horn of  the spinal cord, located between C8 and T2.   • Second (preganglionic) passes from the ciliospinal centre to  the superior cervical ganglion in the neck. During its long  course, it is closely related to the apical pleura where it may  be damaged by bronchogenic carcinoma (Pancoast tumour)  or during surgery on the neck.   • Third (postganglionic) ascends along the internal carotid  artery to enter the cavernous sinus where it joins the  ophthalmic division of the trigeminal nerve. The  sympathetic fibres reach the ciliary body and the dilator  pupillae muscle via the nasociliary nerve and the long ciliary  nerves.   The causes of Horner syndrome are shown in Table 19.4. Most  commonly, isolated (without additional neurological features)  postganglionic Horner syndrome is microvascular in aetiology,  but this cannot be assumed.   The majority of cases are unilateral. Causes of bilateral involve¬  ment include cervical spine injuries and autonomic diabetic neu¬  ropathy. Painful Horner syndrome, especially of acute onset,  should raise the possibility of carotid dissection.   • Mild ptosis (usually 1-2 mm) as a result of weakness of  Muller muscle, and miosis due to the unopposed action of  the sphincter pupillae with resultant anisocoria (Fig. 19.35A).   • A key examination finding is that anisocoria is accentuated  in dim light, since in contrast to a normal fellow pupil the  Horner pupil will dilate only very slowly; the dark-induced   • Brainstem disease - commonly stroke (e.g. lateral  medullary infarction), but also tumour,  demyelination   • Miscellaneous neck lesions (thyroid tumour,  enlarged lymph nodes, trauma, postsurgical)   • Hypochromic heterochromia (irides of different colour, the  Horner being lighter) may be seen if congenital or long¬  standing (Fig. 19.35B).   • Slight elevation of the inferior eyelid (inferior ptosis) as a  result of weakness of the inferior tarsal muscle.   (B) heterochromia iridis associated with a left congenital  Horner syndrome in a child    • Reduced ipsilateral sweating, but because the sudomotor  fibres supplying the skin of the face run along the external  carotid artery this occurs only if the lesion is below the  superior cervical ganglion; patients may mistakenly interpret  the normal side to be sweating excessively.   Ti - grip strength), as well as the neck and regional  lymph nodes should be examined, if necessary by a  neurologist.   Apraclonidine or cocaine is used to confirm the diagnosis, the  latter now less commonly (see below). Hydroxyamphetamine and  adrenaline maybe used to differentiate a preganglionic (abnormal  first- or second-order neurone) from a postganglionic lesion  (abnormal third-order neurone), though as the distinction may  not alter investigation - carotid lesions may cause either pre- or  postganglionic disease, for instance - some authorities limit phar¬  macological testing to confirmation of the presence of Horner  syndrome.   • Apraclonidine 0.5% or 1.0%. One drop is instilled into both  eyes to confirm or refute the presence of Horner syndrome.  The pupils should be checked at 30 minutes and, if negative,  rechecked at 45 minutes. Apraclonidine penetrates the  blood-brain barrier, so should be used only with great  caution in infants under one year of age. It can have an  extended duration of action, so subsequent pharmacological  tests should not be performed for 3-5 days.   o Result: A Horner pupil will dilate but a normal pupil  is essentially unaffected. The ptosis commonly also  improves. Sensitivity is around 90% (it will detect  most cases) and specificity close to 100% (it will very  rarely falsely identify abnormality that is not actually  present).   o Explanation: Alpha-i receptors are upregulated in the  denervated dilator pupillae.   • Cocaine 4% is instilled into both eyes; as cocaine is less  readily available than apraclonidine, this test is now not  commonly performed and may be reserved for acute lesions  (apraclonidine testing probably takes at least 14 days to  become positive) or those in which apraclonidine testing is  equivocal but clinical suspicion is high.   o Result: The normal pupil will dilate but the Horner pupil  will not; anisocoria of as little as 0.8 mm in a dimly lit  room is significant.   o Explanation: Cocaine blocks the re-uptake of  noradrenaline secreted at the postganglionic nerve  ending, which accumulates and causes dilatation of  a normal pupil. In Horner syndrome, there is no  noradrenaline being secreted, so cocaine has no  effect.   • Phenylephrine 1% is more readily available than  hydroxyamphetamine (see next) and adrenaline and is  approximately as accurate, so has to a large extent replaced  them in testing to distinguish pre- and postganglionic   (B) bilateral mydriasis following instillation of  hydroxyamphetamine into both eyes - ptosis has also  been partially relieved    lesions. It is typically prepared by dilution of commonly  available 2.5% or 10% solution.   o Result: In an established (10 days) postganglionic lesion,  the Horner pupil will dilate and ptosis may be  temporarily relieved. A central or preganglionic Horner  pupil and a normal pupil will not dilate or will dilate  minimally.   O Explanation: In postganglionic Horner syndrome the  dilator pupillae muscle develops denervation  hypersensitivity to adrenergic neurotransmitters due to  its dysfunctional local motor nerve.   • Hydroxyamphetamine 1%. Two drops are instilled into each  eye. It may be slightly more sensitive than phenylephrine  testing.   O Result: A normal or preganglionic Horner pupil will  dilate (Fig. 19.36), but a postganglionic Horner will not.  o Explanation: Hydroxyamphetamine potentiates the  release of noradrenaline from functioning postganglionic  nerve endings. In a lesion of the third-order neurone  (postganglionic) there is no release of noradrenaline from  the dysfunctional nerve.   • Adrenaline 0.1% has an action similar to that of  phenylephrine.   Specialist neurological or neuro-ophthalmological assessment  should be sought for a confirmed Horner syndrome; an acute  presentation should be regarded as an emergency. In contrast, if  the features have been present for over a year and there are no    other localizing signs then the likely diagnostic yield from further  investigation is very low. The mainstay of investigation is imaging;  CT or MR angiography examining the region from the aortic arch  to the circle of Willis will facilitate exclusion of neck (including  carotid), apical lung, thyroid and skull base lesions. MR may be  utilized if greater soft tissue definition is required, such as to  exclude a brainstem stroke. Plain X-rays and carotid ultrasound  imaging have limited utility.   Any identified cause should be addressed as appropriate. The  ptosis of Horner syndrome is mild but surgery can be considered  at the patient’s discretion; apraclonidine may be helpful as a tem¬  porizing measure.   An Adie pupil (tonic pupil, Adie syndrome) is caused by denerva¬  tion of the postganglionic parasympathetic supply to the sphincter  pupillae and the ciliary muscle, and may follow a viral illness. It is  occasionally inherited in an AD pattern. Sites of dysfunction are  presumed to be the ciliary ganglion, and, in wider Holmes-Adie  syndrome, the dorsal root ganglion involved in reflex pathways. It  typically affects young women and presents in one eye in 80%,  though involvement of the second eye typically develops within  months or years.   • Symptoms. Patients may notice anisocoria, or may have  blurring for near due to impaired accommodation.   o The direct light reflex is absent or sluggish (Fig. 19.37B).  o On slit lamp examination, vermiform movements of the  pupillary border are typically seen.   O Constriction is also absent or sluggish in response to light  stimulation of the fellow eye (consensual light reflex  - Fig. 19.37C).   o The pupil responds slowly to near, following which  re-dilatation is also slow.   O Accommodation may manifest similar tonicity, with  slowed and impaired focusing for near and prolonged  re-focusing in the distance.   • Associations include diminished lower limb deep tendon  reflexes (Holmes-Adie syndrome - Fig. 19.37D) and other  features of autonomic nerve dysfunction such as excessive  sweating (Ross syndrome), orthostatic hypotension and  occasionally bowel obstruction or urinary retention. Typical  Adie-type pupils are often present in generalized  dysautonomias, with a wide range of aetiologies.    Fig. 19.37 Right Adie pupil. (A) Large right pupil; (B) absent or sluggish direct light reflex; (C) consensual light reflex is similar;  (D) diminished deep tendon reflex   (Courtesy of DM Albert and FA Jakobiec, from Principles and Practice of Ophthalmology, Saunders 1994 - figs A-C; MA Mir ; from Atlas of Clinical Diagnosis,  Saunders 2003 - fig. D)    • Pharmacological testing. Instillation of 0.1-0.125%  pilocarpine into both eyes leads to constriction of the  abnormal pupil due to denervation hypersensitivity, with the  normal pupil unaffected. Some diabetic patients may also  show this response and very occasionally both pupils  constrict in normal individuals.   • Syphilis serology (see Ch. 11) should usually be checked in  patients with bilateral tonic pupils.   Treatment is not generally required, but reading glasses may be  used to address near vision difficulties and sunglasses or low-  concentration pilocarpine drops can be used to improve photo¬  phobia. Thoracic sympathectomy can be considered for excessive  sweating.   • Physiological anisocoria (Fig. 19.38). Anisocoria of around  1 mm is present in around 20% of the normal population.  The asymmetry persists to the same proportion under  differing levels of illumination. Exceptionally, apraclonidine  or cocaine testing may be needed to exclude Horner  syndrome.    • Pharmacological mydriasis (Fig. 19.39). Dilatation of one or  both pupils due to instillation of a mydriatic agent can be  inadvertent (e.g. use of eye drops prescribed for someone  else, rubbing the eye after touching a car sickness  scopolamine skin patch) or deliberate for the purpose of  malingering. The pupil does not constrict in bright light or  on accommodation and there is no response to any  concentration of pilocarpine. There are no other  neurological features.   • Argyll Robertson pupils (Fig. 19.40) are caused by  neurosyphilis, and have been attributed to a dorsal midbrain  lesion that interrupts the pupillary light reflex pathway but  spares the more ventral pupillary near reflex pathway   - light-near dissociation results. In dim light both pupils are  small and may be irregular. In bright light neither pupil  constricts, but on accommodation (near target) both  constrict. The pupils do not dilate well in the dark, but  cocaine induces mydriasis unless marked iris atrophy is  present. After instillation of pilocarpine 0.1% into both eyes,  neither pupil constricts, distinguishing Argyll Robertson  pupils from bilateral long-standing tonic pupils. Other  causes of light-near dissociation are shown in Table 19.5.   • Tectal (dorsal midbrain) pupils (Fig. 19.41). This  phenomenon is a component of dorsal midbrain syndrome   Fig. 19.38 Right physiological anisocoria. (A) In dim light the  right pupil is slightly larger than the left; (B) in bright light  both pupils constrict normally, but the right pupil is still  fractionally larger than the left; (C) both pupils dilate with  instillation of cocaine 4%   (Courtesy of JJ Kanski , from Signs in Ophthalmology: Causes and Differential  Diagnosis, Mosby 2010)    (see later). The pupils are dilated in both dim and bright  light. There is light-near dissociation. Pilocarpine 0.1% has  no effect.   idiopathic condition (Fig. 19.42) occurs most commonly in  otherwise healthy young women and may represent a  migrainous phenomenon or a range of heterogeneous  aetiologies. Mydriasis tends to last for minutes or hours  before resolving completely. There may be mild associated  blurring and headache. The need for further investigation  should be assessed on an individual basis. There is no - or   Fig. 19.39 Right pharmacological mydriasis. (A) Right  mydriasis in dim illumination; (B) in bright light the right  pupil does not constrict; (C) on accommodation the right  pupil does not constrict; (D) neither pupil constricts after  instillation of pilocarpine 0.1% into both eyes; (E) after  instillation of 1% pilocarpine into both eyes the left pupil  constricts but the right does not   (Courtesy of JJ Kanski , from Signs in Ophthalmology: Causes and Differential  Diagnosis, Mosby 2010)    limited - response to light or accommodation. Pilocarpine  o.i% induces no change, but pilocarpine i% to both eyes  gives bilateral miosis.   The sella turcica (Turkish saddle) is a deep saddle-shaped depres¬  sion in the superior surface of the body of the sphenoid bone in   Fig. 19.40 Argyll Robertson pupils. (A) In dim light both pupils  are small and may be irregular; (B) in bright light neither  pupil constricts; (C) on accommodation to a near target  both pupils constrict - light-near dissociation; (D) neither  pupil constricts on instillation of pilocarpine 0.1% into both  eyes   (Courtesy of JJ Kanski, from Signs in Ophthalmology: Causes and Differential  Diagnosis, Mosby 2010)    which the pituitary gland lies (Fig. 19.43). The roof of the sella is  formed by a fold of dura mater, the diaphragma sellae, which  stretches from the anterior to the posterior clinoids. The optic  nerves and chiasm lie above the diaphragma sellae; posteriorly, the  chiasm is continuous with the optic tracts and forms the anterior  wall of the third ventricle. A visual field defect in a patient with a  pituitary tumour therefore generally indicates suprasellar exten¬  sion. Tumours less than 10 mm in diameter (microadenomas)  tend to remain confined to the sella, whereas those larger than  10 mm (macroadenomas) often extend outside. Table 19.6 lists  causes of chiasmal disease.   • Venous. The cavernous sinuses lie lateral to the sella so that  horizontally extending pituitary tumours affect the  cavernous sinus and may damage the intracavernous parts of  the third, fourth and sixth cranial nerves. Conversely,  aneurysms arising from the intracavernous part of the  internal carotid artery may erode into the sella and mimic  pituitary tumours.   Fig. 19.41 Tectal (dorsal midbrain) pupils. (A) In dim light  there is bilateral mydriasis, which may be asymmetrical;   (B) in bright light neither pupil constricts; (C) on  accommodation both pupils constrict normally - light-near  dissociation; (D) neither pupil constricts on instillation of  pilocarpine 0.1% into both eyes   (Courtesy of JJ Kanski , from Signs in Ophthalmology: Causes and Differential  Diagnosis, Mosby 2010)    Fig. 19.42 Right benign episodic unilateral mydriasis (BEUM).  (A) In dim light the right pupil is larger than the left; (B) in  bright light the right pupil does not constrict; (C) on  accommodation the right pupil does not constrict; (D)  instillation of pilocarpine 0.1% to both eyes fails to  constrict either pupil; (E) instillation of pilocarpine 1% to  both eyes induces bilateral miosis; (F) after 24 hours both  pupils are equal   (Courtesy of JJ Kanski, from Signs in Ophthalmology: Causes and Differential  Diagnosis, Mosby 2010)    • Arterial (Fig. 19.44). The internal carotid arteries curve  posteriorly and upwards from the cavernous sinus and lie  immediately below the optic nerves, following which they  ascend vertically along the lateral aspect of the chiasm. The  precommunicating portion of the anterior cerebral artery is  closely related to the superior surface of the chiasm and    Fig. 19.43 Anatomy of the chiasm in relation to the pituitary  gland    optic nerves, so an aneurysm in this region can compress  either or both the optic nerve or chiasm.   The lobules of the anterior part of the pituitary gland are com¬  posed of six cell types. Five of these secrete hormones and the sixth  (follicular cell) has no secretory function. Pituitary adenomas of  mixed-cell type are common; any of the six cell types may prolifer¬  ate to produce an adenoma; the current classification of pituitary  tumours is discussed further below.   • The anterior pituitary lobe is under the control of various  inhibiting and promoting factors synthesized in the    hypothalamus, passing to the pituitary through the  hypothalamo-hypophyseal portal system:  o Human growth hormone (HGH or GH) or  somatotropin.   O Thyroid-stimulating hormone (TSH).  o Adrenocorticotrophic hormone (ACTH), which regulates  blood cortisol levels,  o Beta-endorphin.   Tumour classification is based on the type of hormone secreted;  about 25% of primary pituitary tumours do not secrete any hor¬  mones and may be asymptomatic, cause hypopituitarism and/or  ophthalmic features. An older classification system divided pitui¬  tary tumours into acidophilic, basophilic and chromophobic types  based on their histological staining characteristics, but is now not  commonly used.   Large pituitary lesions may first present to ophthalmologists, often  with vague visual symptoms, and a low threshold should be  adopted for visual field assessment in chronic headache of any  sort. It is also important to perform a careful visual field assess¬  ment on both eyes in patients with unexplained unilateral central  visual impairment.   o Headache may be prominent due to local effects but does  not have the usual features associated with raised ICP,  and diagnostic delay is therefore common,  o Visual symptoms may be vague; they usually have a   gradual onset and may not be noticed by the patient until  well established.   • Colour desaturation across the vertical midline of the  uniocular visual field is an early sign of chiasmal  compression.   o The patient is asked to compare the colour and intensity  of a red pin or pen top as it is moved from the nasal to  the temporal visual field in each eye.   targets in precisely symmetrical parts of the temporal and  nasal visual fields, and to ask if the colours appear the  same.   • Optic atrophy is present in approximately 50% of cases with  field defects. When optic atrophy is present the prognosis  for visual recovery after treatment is guarded. When nerve  fibre loss is confined to fibres originating in the nasal retina  (i.e. nasal to the fovea) only the nasal and temporal aspects   o Visual field defects depend on the location and direction  of enlargement of a compressive lesion, as well as the  anatomical relationship between the pituitary and chiasm  (Fig. 19.45 and see below). Patients may not present until  central vision is affected from pressure on macular fibres,  o Lower nasal optic nerve fibres traverse the chiasm  inferiorly and anteriorly, hence the upper temporal  quadrants of both visual fields are affected first by most  expanding pituitary lesions, giving a bitemporal superior  quadrantanopia progressing to the classic chiasmal visual  field lesion, a bitemporal hemianopia (Fig. 19.46). Field    Fig. 19.46 Typical progression of bitemporal visual field  defects caused by compression of the chiasm from below  by a pituitary adenoma. LE = left eye; RE = right eye   posteriorly and therefore are involved first by a lesion  such as a craniopharyngioma that arises above the chiasm  (Fig. 19.48). If the lower temporal quadrants of the visual  field are affected more profoundly than the upper, a  pituitary adenoma is unlikely.   o A lesion compressing the anterior chiasm, such as a  pituitary adenoma in conjunction with a postfixed  chiasm, may give rise to a ‘junctional scotoma’ - the  syndrome of a central or paracentral defect on the side of  optic nerve involvement together with a contralateral  superotemporal defect (see Fig. 19.53). The precise  mechanism is disputed, but is commonly attributed to  simultaneous involvement of the fibres of one of the  optic nerves together with contralateral inferonasal fibres  looping forward into the nerve in the putative knee of  Wilbrand.   Fig. 19.48 Progression of bitemporal visual field defects  caused by compression of the chiasm from above by a  craniopharyngioma. LE = left eye; RE = right eye   o Macular fibres decussate throughout the chiasm, but are  concentrated posteriorly. A lesion that preferentially  compresses the posterior chiasm, such as a pituitary  adenoma in conjunction with a prefixed chiasm, may  therefore cause bitemporal hemianopic changes  predominantly affecting the central and paracentral fields.  Predominant involvement of the optic tracts by a  posterior lesion can give a homonymous hemianopia.  o Extensive loss of the temporal visual field in both eyes  can disrupt sensory fusion, decompensating a phoria and  causing problems with near vision. ‘Postfixation  blindness’ refers to the presence of a non-seeing area  distal to the fixation point due to the overlap of two  blind hemifields (Fig. 19.49); despite the similar  terminology, it is not linked to a postfixed chiasm.  Patients may complain of difficulty with fine close-up   (Courtesy of G Liu, N Volpe and S Ga/etta, from Neuro-Ophthalmology  Diagnosis and Management, Saunders 2010)   tasks such as threading a needle and cutting fingernails,  and near visual acuity measured binocularly may be  worse than when measured with each eye individually.  Double vision may result from slippage of the two fields  with fusional failure (‘hemifield slide’); diplopia may also  result from cranial nerve palsy (see next),  o Differential diagnosis of bitemporal defects includes   dermatochalasis, tilted discs, optic nerve colobomas, nasal  retinoschisis, nasal retinitis pigmentosa and functional  (‘non-physiological’) visual loss.   • Extraocular muscle paresis due to disruption of the cranial  nerves traversing the cavernous sinus.   • MR with gadolinium contrast (Fig. 19.50) utilizing multiple  planes and thin sections demonstrates the relationship  between a mass lesion and the chiasm, and is usually the  preferred imaging modality. Adenomas are typically  hypointense on Ti and hyperintense on T2 images.   • Endocrinological evaluation is complex, particularly as  combined hormonal over- and under-secretion may be  present, and is usually undertaken by an endocrinologist.   Fig. 19.50 Tl-weighted gadolinium-enhanced MR of a  pituitary adenoma. (A) Sagittal and (B) coronal images   Lactotrophic adenoma or prolactinoma (formerly known as  chromophobe adenoma, though lesions can be weakly acido¬  philic) is the most common pituitary adenoma. Patients are typi¬  cally young to middle-aged adults. In women excessive prolactin  secretion leads to the infertility-amenorrhoea-galactorrhoea syn¬  drome, and in men may cause hypogonadism, impotence, sterility,  decreased libido, and occasionally gynaecomastia and galactor-  rhoea. Up to 95% remain as microadenomas, though those that  do not may present initially with visual features.   A corticotrophic adenoma (a variant of basophil adenoma)  secretes ACTH and causes Cushing disease (Cushing syndrome  refers to the clinical picture of increased blood cortisol from  any cause), which may include central obesity and moon face,  cutaneous striae, pigmentation and other features such as  hypertension.   Somatotrophic (acidophil) tumours secrete excessive GH, causing  acromegaly in adults (once bone elongation has been completed)  and gigantism in children. Presentation is in middle age with  features including enlargement of the head, hands, feet and  tongue, coarseness of features with prominent supraorbital ridges  and nasiolabial folds (Fig. 19.51), enlargement of the jaw with  dental malocclusion, and hirsutism in females. There are many  complications, including diabetes mellitus, hypertension, cardio¬  myopathy and carpal tunnel syndrome.   • Observation may be appropriate for incidentally discovered  and clinically silent tumours.   • Medical therapy is usually the initial step and consists of the  reduction in tumour size and secretion using agents such as  dopamine agonists (e.g. cabergoline and the older  bromocriptine) and somatostatin analogues such as  octreotide, with supplementary hormonal correction as  appropriate.   • Surgery consists of tumour debulking rather than complete  excision and is usually carried out endoscopically via a  trans-sphenoidal approach through a gum incision behind  the upper lip. Indications include the failure or intolerance  of medical management and sometimes decompression for  acute visual loss (see below). Visual field improvement is  fastest in the earliest weeks and months following surgery.   • Radiotherapy is rarely employed due to the risk of  complications, but is utilized in some circumstances. Newer  techniques include intensity-modulated radiation therapy  and stereotactic radiosurgery.   • Monitoring. Long-term ophthalmological review is required,  with serial assessment of visual function.   Pituitary apoplexy (PA) is caused by acute haemorrhage into or  infarction of the pituitary gland, and is usually associated with a  previously undiagnosed adenoma; Sheehan syndrome is infarction  of the pituitary usually associated with childbirth and is generally  regarded as a form of PA. PA typically manifests with the sudden  onset of a severe headache, nausea and vomiting, sometimes with  meningism and occasionally reduced consciousness or stroke.  There is often reduced visual acuity and/or a bitemporal hemiano-  pia depending on the anatomical effects of the lesion. Double  vision due to compromise of the adjacent ocular motor nerves is  common. Acute hormonal insufficiency can lead to life-threatening  complications such as an Addisonian crisis. Investigations include  MR, urgent visual field testing, and hormonal assessment. Acute  medical management, including hormone administration and  surgical decompression, may be necessary.   Craniopharyngioma is a slow-growing tumour arising from ves¬  tigial remnants of the Rathke pouch along the pituitary stalk.  Affected children frequently present with dwarfism, delayed sexual  development and obesity due to interference with hypothalamic  function. Adults usually present with visual impairment.   Visual field defects are complex and may be due to involvement  of the optic nerves, chiasm or tracts.   The initial defect frequently involves both inferotemporal fields  because the tumour compresses the chiasm from above and  behind, damaging the upper nasal fibres (see Fig. 19.48). MRI  shows a solid tumour that appears isointense on Ti images (Fig.  19.52). Cystic components appear hyperintense on Ti images.  Treatment is mainly surgical, but recurrences are common.   Fig. 19.52 Sagittal Tl-weighted MR image of a  craniopharyngioma with secondary hydrocephalus   Visual field defects and clinical signs depend on the location of the   • Tuberculum sellae meningiomas often produce a junctional  scotoma (see above and Fig. 19.53) due to their location.   • Sphenoidal ridge tumours compress the optic nerve early if  the tumour is located medially and late if the lateral aspect  of the sphenoid bone and middle cranial fossa are involved  (Fig. 19.54A). A classic finding in the latter is fullness in the  temporal fossa due to hyperostosis (Fig. 19.54B).   Fig. 19.53 Examples of optic nerve compression by  meningioma; a junctional scotoma resulting from a  tuberculum sellae lesion is also shown    Fig. 19.54 Sphenoid ridge meningioma. (A) CT axial image;  (B) reactive hyperostosis    • Olfactory groove meningioma may cause loss of the sense of  smell, as well as optic nerve compression.   • Treatment usually consists of surgery, but radiotherapy is  sometimes required. Observation alone may be adequate.   Retrochiasmal pathology results in partial or total binocular visual  field defects involving contralateral visual space. This hemianopia  (hemianopsia) involving the same side of the field in both eyes is    homonymous, in contradistinction to the bitemporal hemianopia  seen in chiasmal compression, which produces heteronymous  loss, with opposite sides of the visual field affected in each eye.   A homonymous hemianopia may be incomplete or complete. In  the context of incomplete hemianopia, congruity refers to how  closely the extent and pattern of field loss in one eye matches that  of the other. Almost identical field defects in either eye are  therefore highly congruous, while mismatching right and left  visual field defects are incongruous. Hemianopia secondary to  pathology in the anterior retrochiasmal visual pathways is charac¬  teristically incongruous, while that due to pathology further back  (e.g. the posterior optic radiations) manifests a higher degree of  congruity.   o The optic tracts arise at the posterior aspect of the chiasm,  diverge and extend posteriorly around the cerebral  peduncles, to terminate in the lateral geniculate bodies,  o Each optic tract contains crossed fibres from the   contralateral nasal hemiretina, and uncrossed fibres from  the ipsilateral temporal hemiretina.   O Nerve fibres originating from corresponding retinal  elements are, however, not closely aligned,  o Homonymous hemianopia caused by optic tract lesions is  therefore characteristically incongruous,  o Lesions of the lateral geniculate body also produce  asymmetrical hemianopic defects,  o The causes of optic tract disease are similar to those  affecting the chiasm but the tract is particularly  vulnerable when the chiasm is prefixed (see above).   o The optic tracts contain both visual and pupillomotor  fibres. The visual fibres terminate in the lateral geniculate  body but the pupillary fibres leave the optic tract anterior  to the lateral geniculate body, projecting through the  brachium of the superior colliculus to terminate in the  pretectal nuclei.   o An optic tract lesion may therefore give rise to an afferent  pupillary conduction defect.   o Characteristically, the pupillary light reflex will be normal  when the unaffected hemiretina is stimulated, and absent  when the involved hemiretina is stimulated (i.e. light is  shone from the hemianopic side),  o In practice, this Wernicke hemianopic pupillary reaction  is difficult to elicit because of scatter of light within the  eye - a fine beam should be used.   • Optic atrophy may occur when the optic tracts are damaged  because their fibres are the axons of the retinal ganglion  cells. The ipsilateral disc manifests atrophy of the superior  and inferior aspects of the neuroretinal rim (fibres from the  temporal retina), while the contralateral disc manifests a  c bow tie’ pattern (nasal and nasal macular fibres).   Fig. 19.55 Visual field defects caused by lesions of the optic radiations and visual cortex    • Contralateral pyramidal signs may occur when an optic  tract lesion also damages the ipsilateral cerebral peduncle.   The optic radiations extend from the lateral geniculate body to  the striate cortex, which is located on the medial aspect of the  occipital lobe, above and below the calcarine fissure (Fig. 19.55).  As the radiations pass posteriorly, fibres from corresponding  retinal elements lie progressively closer together. For this reason,  incomplete hemianopia caused by posterior radiation lesions are  more congruous than those involving the anterior radiations.  Because these fibres are third-order neurones that originate in the  lateral geniculate body, lesions of the optic radiations do not  produce optic atrophy. The optic radiations and visual cortex have  a dual blood supply from the middle and posterior cerebral  arteries.   • Visual field defect consists of a contralateral superior  homonymous quadrantanopia ( c pie in the sky’), because the  inferior fibres of the optic radiations, which subserve the  upper visual fields, first sweep anteroinferiorly (Meyer loop)  into the temporal lobe around the anterior tip of the  temporal horn of the lateral ventricle (see c a’ in Fig. 19.55).   • Associated features are likely to include contralateral  hemisensory disturbance and hemiparesis, because the  temporal radiations pass very close to the sensory and motor  fibres of the internal capsule before passing posteriorly and  rejoining the superior fibres. Other features of temporal lobe  disease include paroxysmal olfactory and gustatory    hallucinations (uncinate fits), formed visual hallucinations  and seizures, with receptive dysphasia if the dominant  hemisphere is involved.   • Visual field defect consists of a contralateral inferior  homonymous quadrantanopia ( c pie on the floor’) because  the superior fibres of the radiations, which subserve the  inferior visual fields, proceed directly posteriorly through the  parietal lobe to the occipital cortex. However, a lesion  involving only the anterior parietal part of the radiations is  rare. Hemianopia resulting from a parietal lobe lesion tends  to be relatively congruous (see c b’ in Fig. 19.55).   • Associated features of dominant parietal lobe disease  include acalculia, agraphia, left-right disorientation and  finger agnosia. Non-dominant lobe lesions may cause  dressing and constitutional apraxia and spatial neglect.   Deep in the parietal lobe, the optic radiations lie just external to  the trigone and the occipital horn of the lateral ventricle. Lesions  in this area usually cause a complete homonymous hemianopia  (see C c’ in Fig. 19.55).   • Optokinetic nystagmus (OKN), elicited with a rotating  striped optokinetic drum, may be useful in localizing the  cause of an isolated homonymous hemianopia.   o Physiological OKN involves smooth pursuit of a target,  followed momentarily by a saccade in the opposite  direction to fixate on the next target,  o If a homonymous hemianopia is due to a lesion in the  parietal lobe, the smooth pursuit pathways towards the  side of the lesion are likely to be affected, making this  component of OKN defective. OKN will therefore be  asymmetrical: erratic when the drum is rotated towards   the side of the lesion, but regular when the drum is  rotated away from the side of the lesion,  o If the lesion is in the occipital lobe, the smooth pursuit  pathways are intact and OKN will be symmetrical - this  is the Cogan dictum, which also states that the parietal  lobe lesion is more likely to be a tumour and the occipital  lesion an infarction.   o In the striate cortex the peripheral visual fields are  represented anteriorly. This part of the occipital lobe is  supplied by a branch of the posterior cerebral artery,  o Central macular vision is represented posteriorly just  lateral to the tip of the calcarine cortex, an area supplied  mainly by a branch of the middle cerebral artery.  Occlusion of the posterior cerebral artery will therefore  tend to produce a macular-sparing congruous  homonymous hemianopia (see c d’ in Fig. 19.55).  o Damage to the tip of the occipital cortex, as might occur  from a head injury, tends to give rise to congruous,  homonymous, macular defects (see c e’ in Fig. 19.55),  although macular sparing may sometimes occur with  vascular lesions of the occipital lobe,  o The anteriormost part of the calcarine cortex subserves  the temporal extremity of the visual field of the  contralateral eye, the area of visual space that extends  beyond the field of binocular single vision and is  perceived monocularly. A lesion in this area may  therefore give rise to a monocular temporal field defect in  the contralateral eye, known as a temporal crescent.   • Associated features of visual cortex disease (cortical  blindness) include formed visual hallucinations, denial of  blindness (Anton syndrome) and the Riddoch phenomenon  (only moving visual targets perceived).   • Stroke in the territory of the posterior cerebral artery is  responsible for over 90% of homonymous hemianopia with  no other neurological deficit.   a range of uncommon inflammatory (including autoimmune  and infective), degenerative and toxic disorders can also be  causative, but will usually manifest with more widespread  neurological features; imaging and lumbar puncture are  typically key to diagnosis. Mimicking by retinal disease such  as acute zonal occult outer retinopathy (AZOOR) may occur.   often referred to as a visual variant of Alzheimer disease. Patients    field defects, visual agnosia, alexia and acalculia. The diagnosis is  commonly missed; other degenerative conditions often exhibiting  early occipital cortical involvement include Alzheimer and Creut-  zfeldt-Jakob disease; presentation in the latter can be with acute  visual symptoms only. Electroretinography may be abnormal. In  immunocompromised states, including drug-induced, progres¬  sive multifocal leukoencephalopathy can present with isolated  occipital features.   Balint syndrome refers to the combination of simultanagnosia  (inability to discern the overall impression of an image whilst  distinguishing individual components), optic ataxia (defective  visually-directed reaching) and ocular apraxia (impairment of vol¬  untary saccades). It is typically due to parieto-occipital disease,  with a range of causes reported.   Posterior reversible encephalopathy syndrome (PRES) or revers¬  ible posterior leukoencephalopathy syndrome refers to a clinical  presentation thought to result from vascular endothelial dysfunc¬  tion seen in patients with malignant hypertension or eclampsia,  treatment with some drugs (e.g. tacrolimus, ciclosporin) and  rarely other associations such as autoimmune disease. Cortical  visual deficits can occasionally be the presenting feature, others  including headache and seizures.   The nuclear complex of the third (oculomotor) nerve is situated  in the midbrain at the level of the superior colliculus, ventral to  the Sylvian aqueduct (Fig. 19.56). It is composed of the following  paired and unpaired subnuclei:   • Levator subnucleus is an unpaired caudal midline structure  that innervates both levator muscles. Lesions confined to  this area will therefore give rise to bilateral ptosis.   Postr. communicating artery  Oculomotor nerve (III)  Trochlear nerve (IV)  Postr. cerebral artery  Supr. cerebellar artery  Basilar artery  Abducent nerve (VI)    Fig. 19.56 Dorsal view of the course of the third nerve    • Superior rectus subnuclei are paired: each innervates the  respective contralateral superior rectus. A nuclear third  nerve palsy will therefore spare the ipsilateral, and affect the  contralateral, superior rectus.   • Medial rectus, inferior rectus and inferior oblique  subnuclei are paired and innervate their corresponding  ipsilateral muscles. Lesions confined to the nuclear complex  are relatively uncommon. The most frequent causes are  vascular disease, primary tumours and metastases.  Involvement of the paired medial rectus subnuclei cause a  wall-eyed bilateral internuclear ophthalmoplegia (WEBINO),  characterized by exotropia with defective convergence and  adduction. Lesions involving the entire nucleus are often  associated with involvement of the adjacent and caudal  fourth nerve nucleus.   The fasciculus consists of efferent fibres that pass from the third  nerve nucleus through the red nucleus and the medial aspect of  the cerebral peduncle. They then emerge from the midbrain and  pass into the interpeduncular space. The causes of nuclear and  fascicular lesions are similar, except that demyelination may affect  the fasciculus.   • Benedikt syndrome involves the fasciculus as it passes  through the red nucleus and is characterized by ipsilateral  third nerve palsy and contralateral extrapyramidal signs such  as hemitremor.   • Weber syndrome involves the fasciculus as it passes through  the cerebral peduncle and is characterized by ipsilateral third  nerve palsy and a contralateral hemiparesis.   • Nothnagel syndrome involves the fasciculus and the  superior cerebellar peduncle and is characterized by  ipsilateral third nerve palsy and cerebellar ataxia.   • Claude syndrome is a combination of Benedikt and  Nothnagel syndromes.   The basilar part starts as a series of ‘rootlets’ that leave the mid¬  brain on the medial aspect of the cerebral peduncle, before    Fig. 19.58 Compression of the third nerve by a posterior  communicating aneurysm   coalescing to form the main trunk. The nerve then passes between  the posterior cerebral and superior cerebellar arteries, running  lateral to and parallel with the posterior communicating artery  (Fig. 19.57). As the nerve traverses the base of the skull along its  subarachnoid course unaccompanied by any other cranial nerve,  an isolated third nerve palsy is commonly basilar. The following  are important causes:   • Aneurysm of the posterior communicating artery at its  junction with the internal carotid artery (Fig. 19.58), typically  presents acutely as a pupil-involving painful third nerve palsy.   • Head trauma, resulting in extradural or subdural  haematoma, may cause a tentorial pressure cone with  downward herniation of the temporal lobe. This compresses  the third nerve as it passes over the tentorial edge (Fig.   19.59), initially causing irritative miosis followed by  mydriasis and complete third nerve palsy.   The third nerve then enters the cavernous sinus by piercing the  dura just lateral to the posterior clinoid process. Within the sinus,   Fig. 19.60 Location of the cranial nerves in the cavernous  sinus viewed from behind   the third nerve runs in the lateral wall above the fourth nerve (Fig.  19.60). In the anterior part of the cavernous sinus, the nerve  divides into superior and inferior branches that enter the orbit  through the superior orbital fissure within the annulus of Zinn.  The following are potential causes of intracavernous third nerve  palsy:   • Miscellaneous pathology such as aneurysm, meningioma,  carotid-cavernous fistula and granulomatous inflammation  (Tolosa-Hunt syndrome). Because of its close proximity to  other cranial nerves, intracavernous third nerve lesions are  likely to be associated with involvement of the fourth and  sixth nerves and the first division of the trigeminal nerve.   • Inferior division innervates the medial rectus, the inferior  rectus and the inferior oblique muscles. The branch to the  inferior oblique also contains preganglionic parasympathetic  fibres from the Edinger-Westphal subnucleus, which  innervate the sphincter pupillae and the ciliary muscle.  Lesions of the inferior division are characterized by limited  adduction and depression, together with a dilated pupil.   Both superior and inferior division palsies are commonly  traumatic or vascular.   Between the brainstem and the cavernous sinus, the pupillomotor  parasympathetic fibres are located superficially in the superome-  dial part of the third nerve (Fig. 19.61). They derive their blood  supply from the pial blood vessels, whereas the main interior trunk  of the nerve is supplied by the vasa nervorum. Involvement or   • ‘Surgical’ lesions such as aneurysms, trauma and uncal  herniation characteristically involve the pupil by  compressing the pial blood vessels and the superficially  located pupillary fibres.   • ‘Medical’ lesions such as occur in hypertension and diabetes  usually spare the pupil. This is because the microangiopathy  associated with medical lesions involves the vasa nervorum,  causing ischaemia of the main trunk of the nerve, leaving  the superficial pupillary fibres intact.   These principles are not infallible; pupillary involvement may be  seen in some microangiopathic palsies, while pupillary sparing  does not invariably exclude aneurysm or other compressive lesion.  Pupillary involvement may develop a few days after the onset of  diplopia as an aneurysm expands. Exceptionally, pupillary involve¬  ment may be the only sign of third nerve palsy (basal meningitis,  uncal herniation). Like other features of third nerve palsy, pupil¬  lary involvement may be complete or partial, so mild pupillary  signs may be clinically significant.   Partial involvement will give milder degrees of ophthalmoplegia.  The other cranial nerves and peripheral nervous system should  always be examined.   • Profound ptosis due to weakness of the levator muscle (Fig.  19.62A), so that diplopia may not be volunteered.   • Abduction and depression in the primary position (‘down  and out’ - Fig. 19.62B) due to unopposed action of the  lateral rectus and superior oblique muscles. The intact  superior oblique muscle also causes intorsion of the eye at  rest, which increases on attempted downgaze.   • Normal abduction as the lateral rectus is intact (Fig. 19.62C).   • Limited elevation due to weakness of the superior rectus  and inferior oblique (Fig. 19.62E).   Fig. 19.61 Location of pupillomotor fibres within the trunk of  the third nerve   Fig. 19.62 Right third nerve palsy. (A) Total right ptosis; (B) right exotropia and depression in the primary position; (C) normal  abduction; (D) limitation of adduction; (E) limitation of elevation; (F) limitation of depression    • Limited depression due to weakness of the inferior rectus  (Fig. 19.62F).   Aberrant regeneration may follow acute traumatic and compres¬  sive, but not vascular, third nerve palsies. This is because the  endoneural nerve sheaths, which may be breached in traumatic  and compressive lesions, remain intact with vascular lesions.  Bizarre defects in ocular motility such as elevation of the upper  eyelid on attempted adduction or depression (the pseudo-Graefe  or pseudo-von Graefe phenomenon), are caused by misdirected  regenerating axons that re-innervate the incorrect extraocular  muscle. The pupil may also be involved.   Clinical evaluation and imaging facilitates identification of a cause  in most cases.    • Microvascular disease associated with systemic risk factors  such as hypertension and diabetes is the most common  cause of third nerve palsy. Marked periorbital pain is often  associated, which is therefore not helpful in distinguishing  an aneurysmal cause. In diabetes-related paresis, motility  disturbance is typically profound, but there is usually (75%)  relative or complete pupil sparing and when pupillary  involvement does occur some degree of reaction to light is  almost always preserved.   • Aneurysm of the posterior communicating artery at its  junction with the internal carotid is a very important cause  of isolated third nerve palsy with involvement of the pupil.  Pain is often though not invariably present, and the extent  of pupillary involvement characteristically exceeds the  severity of motility dysfunction. An aneurysm of the internal  carotid within the cavernous sinus tends to also involve  other cranial nerves (see above).   • Trauma, both direct and secondary to subdural haematoma  with uncal herniation. However, the development of third  nerve palsy following relatively trivial head trauma should    alert the clinician to the possibility of an underlying  aneurysm or tumour.   • Miscellaneous uncommon causes include tumour,  inflammatory disease such as syphilis, Lyme disease and  sarcoidosis, giant cell arteritis and vasculitis associated with  collagen vascular disorders.   • Episodic. Brief episodes of third nerve dysfunction with  spontaneous recovery may be idiopathic or occur with  migraine, compression, ischaemia and alterations in  intracranial pressure. Myasthenia gravis may mimic  intermittent pupil-sparing third nerve paresis.   • Vascular risk factor assessment similar to that for retinal  arterial disease (see Ch. 13). Supplementary investigation  may be required if a rarer aetiology such as infection (e.g.  syphilis, Lyme disease) or vasculitis (including giant cell  arteritis) is suspected; this may include a lumbar puncture.   • CT angiography should be performed with great urgency if  the clinical features are suspicious of an expanding  aneurysm, especially if there is marked pupillary  involvement with milder motility dysfunction and only  partial ptosis.   • MRI brain and orbits with venography, including specific  exclusion of a brainstem stroke or tumour, cavernous sinus  or orbital apex lesion.   micro vascular cases; the majority will resolve over weeks or  months. Temporary (e.g. Fresnel stick-on) prisms may be  useful if the angle of deviation is small, but uniocular  occlusion may be necessary to avoid diplopia if the ptosis  component is partial or recovering. Botulinum toxin  injection into the uninvolved lateral rectus muscle is  sometimes used to prevent its contracture when recovery  time is prolonged.   • Surgical treatment of the ocular motility element and ptosis  should be contemplated only after spontaneous  improvement has ceased, usually not earlier than 6-12  months from onset. Numerous innovative surgical  techniques have been described.   The fourth (trochlear) cranial nerve (Fig. 19.63) supplies only the  superior oblique muscle.   o It is a very long and slender nerve, increasing its  vulnerability.   o It is the only cranial nerve to emerge from the dorsal  aspect of the brain.   Oculomotor nerve (III)  Abducent nerve (VI)  Posterior cerebral artery  Superior cerebellar artery    Fig. 19.63 Dorsal view of the course of the fourth nerve   o It is the only decussated (crossed) cranial nerve besides  the optic nerve, innervating the superior oblique muscle  contralateral to its nucleus,  o It has the fewest axons of any of the cranial nerves.   • The nucleus is located at the level of the inferior colliculi  ventral to the Sylvian aqueduct. It is caudal to, and  continuous with, the third nerve nuclear complex.   • The fasciculus consists of axons that curve posteriorly  around the aqueduct and decussate completely in the  anterior medullary velum.   • The trunk leaves the brainstem on the dorsal surface, just  caudal to the inferior colliculus. It then curves laterally  around the brainstem, runs forwards beneath the free edge  of the tentorium, and like the third nerve passes between the  posterior cerebral artery and the superior cerebellar artery. It  then pierces the dura and enters the cavernous sinus.   • The intracavernous part runs in the lateral wall of the sinus,  inferior to the third nerve and above the first division of the  fifth. In the anterior part of the cavernous sinus it rises and  passes through the superior orbital fissure above and lateral  to the annulus of Zinn.   • Idiopathic lesions are common, and many of these are  thought to be congenital although symptoms may not  develop until decompensation occurs in adult life due to  reduced fusional ability. In contrast to acquired lesions  patients are not usually aware of the torsional aspect, but  may develop vertical double vision that is often appreciated  as of sudden or subacute onset. Examination of old  photographs for the presence of a compensatory head  posture may be helpful, as is the presence of an increased  vertical prism fusional range. Occasionally cataract surgery  can be associated with decompensation.    Fig. 19.64 Left fourth nerve palsy. (A) Left hypertropia  (left over right) in the primary position; (B) increase in left  hypertropia on right gaze due to left inferior oblique  overaction; (C) limitation of left depression in adduction;  (D) normal left abduction; (E) normal left elevation    • Trauma frequently causes bilateral fourth nerve palsy. The  long and slender nerves are particularly vulnerable as they  decussate in the anterior medullary velum, through impact  with the tentorial edge. Care must be taken not to mistake a  bilateral palsy for a unilateral lesion, particularly when  corrective surgery is contemplated.   • Microvascular lesions are relatively common, this aetiology  often being presumed when appropriate systemic risk factors  are present in the absence of features of congenital onset.   The acute onset of vertical diplopia in the absence of ptosis, com¬  bined with a characteristic head posture, strongly suggests fourth  nerve disease. The main actions of the superior oblique are intor¬  sion (incyclotorsion), and depression in adduction. Peripheral  lesions cause ipsilateral and nuclear lesions contralateral superior  oblique weakness; left paresis is characterized by:   • Left hypertropia (‘left over right’) in the primary position  (Fig. 19.64A), increasing on right gaze (Fig. 19.64B).   • A compensatory head posture (Fig. 19.65) avoids diplopia:  vertical, torsional and worse on downgaze. To compensate  for weakness of intorsion there is contralateral head tilt to  the right. To alleviate the weakened depression of the eye  the chin is slightly depressed; as this is most marked in  adduction, the face may also be turned slightly to the  right.   • Bilateral involvement should always be excluded,  particularly following head trauma.   o Right hypertropia in left gaze and left hypertropia in right  gaze, though orthophoria may be present,  o Greater than io° of cyclodeviation (measured using  double Maddox rods or by synoptophore - see Ch. 18).  o C V’ pattern esotropia is often present,  o Bilaterally positive Bielschowsky head tilt test (see  below).    Fig. 19.65 Compensatory head posture in left fourth nerve  palsy; head tilt to right, face turn to the right and chin  depressed   This clinical test allows isolation of a single weak muscle in patients  with vertical diplopia of acute onset; it is inaccurate in some cir¬  cumstances, including prior extraocular muscle surgery.   • Step one. In the primary position, the hypertropic eye is  identified, narrowing the affected muscle to one of the  depressors of the hypertropic eye (superior oblique or  inferior rectus) or one of the elevators of the hypotropic eye  (superior rectus or inferior oblique). In a fourth nerve palsy,  the involved eye is higher (see Fig. 19.64A).   • Step two. The eyes are examined in right and left gaze to  determine where the hypertropia is greater, thus assigning  the weakness to the two of the four previously identified  muscles having the greatest vertical action in that position.   In superior oblique weakness (see Fig. 19.64B) the deviation  is worse on opposite gaze - WOOG.   o The Bielschowsky head tilt test (BHTT) is performed  with the patient fixating on a target directly ahead,  optimally at 3 metres.   o The head is tilted to each side in turn in order to assess  the muscles responsible for cyclotorsion, with observation    to determine the position in which the hypertropia is  worse. On tilt to one side, the superior oblique and  superior rectus (note that both are superior) muscles of  the eye of that same side correctively intort, and the  inferior rectus and inferior oblique (note both are  inferior) of the contralateral eye correctively extort. From  the two muscles previously isolated, one can be  eliminated.   o In fourth nerve palsy the deviation is better on opposite  tilt - BOOT (Fig. 19.66); in practice, as the three-step test  is almost always employed to confirm a fourth nerve  palsy, the BHTT alone is often sufficient for a working  diagnosis.   Vascular investigation is sometimes indicated; neuroimaging is  not required routinely for an isolated non-progressive fourth  nerve palsy, but should be considered if improvement does not  occur.   Fig. 19.66 Positive Bielschowsky test in left fourth nerve  palsy. (A) No hypertropia on right head tilt; (B) marked  hypertropia on left head tilt    Fig. 19.68 The pons at the level of the sixth nerve nucleus    Strabismus surgery is not infrequently required for traumatic  and childhood cases, in the former for troublesome diplopia and  the latter for a substantial compensatory head posture; the  approach depends on the pattern and severity of weakness.   • A small hypertropia under 15 prism dioptres can usually be  treated either by inferior oblique weakening or by superior  oblique tucking, though surgery to other muscles might be  required in some circumstances.   • A moderate-large deviation may be treated by ipsilateral  inferior oblique weakening combined with, or followed by,  ipsilateral superior rectus weakening and/or contralateral  inferior rectus weakening if required; defective elevation is a  potential complication.   • Excyclotorsion may need to be addressed, particularly in  bilateral cases; the Harada-lto procedure involves splitting  and anterolateral transposition of the lateral half of the  superior oblique tendon (Fig. 19.67).   The nucleus of the sixth (abducens or abducent) nerve lies at the  mid-level of the pons, ventral to the floor of the fourth ventricle  (Fig. 19.68). The fibres (fasciculus) leave the brainstem ventrally at  the pontomedullary junction.   • Nuclear lesion. A nuclear sixth nerve lesion also causes a  failure of horizontal gaze towards the side of the damage due  to involvement of the adjacent horizontal gaze centre  (paramedian pontine reticular formation). Facial (seventh)  nerve fibres wrap around the sixth nerve nucleus, so  ipsilateral lower motor neurone (LMN) facial nerve palsy is  also common. Isolated sixth nerve palsy is never nuclear in  origin.   • Foville (inferior medial pontine) syndrome is most  frequently caused by vascular disease or tumours  involving the dorsal pons. It is characterized by ipsilateral  involvement of the fifth to eighth cranial nerves, central   • Millard-Gubler (ventral pontine) syndrome involves the  fasciculus as it passes through the pyramidal tract and is  most frequently caused by vascular disease, tumours or  demyelination. As well as ipsilateral sixth nerve palsy, there  is contralateral hemiplegia and often an ipsilateral LMN  facial nerve palsy.   The basilar part of the nerve enters the prepontine basilar cistern,  passes upwards close to the base of the skull and is crossed by the  anterior inferior cerebellar artery (Fig. 19.69). It pierces the dura  below the posterior clinoids and angles forwards over the tip of  the petrous bone, passing through or around the inferior petrosal  sinus, through the Dorello canal (underneath the petroclinoid  ligament), to enter the cavernous sinus.   • An acoustic neuroma may damage the sixth nerve at the  pontomedullary junction (Fig. 19.70); the first symptom of  an acoustic neuroma is hearing loss, and the first sign  diminished corneal sensitivity. Hearing and corneal   Fig. 19.69 Lateral view of the course of the sixth nerve    Fig. 19.70 MRI with gadolinium enhancement - coronal  image of an acoustic neuroma    sensation should be checked in all patients with sixth nerve  palsy.   • Nasopharyngeal tumours may invade the skull and its  foramina and damage the nerve during its basilar course.   • Raised intracranial pressure may cause a downward  displacement of the brainstem. This may stretch one or both  sixth nerves over the petrous tip, when paresis is a false  localizing sign.   • Gradenigo syndrome, most frequently caused by mastoiditis  or acute petrositis, may result in damage of the sixth nerve  at the petrous tip. The latter is frequently accompanied by  facial weakness and pain, and hearing difficulties.   • The intracavernous section runs below the third and fourth,  and the first division of the fifth nerves. The sixth nerve is  the most medially situated and runs through the middle of  the sinus in close relation to the internal carotid artery.  Occasionally, intracavernous sixth nerve palsy is  accompanied by a postganglionic Horner syndrome  (Parkinson syndrome) due to damage to the paracarotid  sympathetic plexus. The causes of intracavernous sixth nerve  and third nerve lesions (see above) are similar.   • The intraorbital part enters the orbit through the superior  orbital fissure within the annulus of Zinn to innervate the  lateral rectus.   • Symptoms. Double vision is characteristically worse for a  distant target and less or absent for near fixation. A careful    review of systems should be conducted, including enquiry  about other neurological symptoms, giant cell arteritis,  trauma and symptoms of ear disease.   • Esotropia in the primary position due to relatively  unopposed action of the medial rectus (Figs 19.71A and  19.72A); the deviation (and symptomatic description) is  characteristically worse for distance than near fixation.   • Limitation of abduction on the side of the lesion (Figs  19.71B and 19.72B).   • Bilateral acute sixth nerve paresis (Fig. 19.73) is  considerably less common than unilateral; the causes are  broadly similar, but elevated intracranial pressure should be  excluded as a priority.   • A compensatory face turn is towards the side of the  paralysed muscle in unilateral palsy.   • Neurological examination. The other cranial nerves and the  peripheral nervous system should be examined, if necessary  by an appropriate specialist. In a child or any patient with  relevant symptoms, an otorhinolaryngological review may be  sought.   Idiopathic and presumed microvascular lesions are common (up  to 60%) in older patients, but a wide range of causes has been  reported and a low threshold should be adopted for neuroimaging  and other investigations even with isolated paresis; these should  be performed broadly as for third nerve palsy. Also as with third  nerve palsy, improved imaging has led to increasingly common  identification of a cause in lesions that might previously have been  categorized as idiopathic. In contrast to fourth nerve palsy, a  decompensated congenital aetiology is thought to be rare. The   Fig. 19.71 Acute left sixth nerve palsy in a child. (A) Left  esotropia in the primary position; (B) marked limitation of  left abduction   Fig. 19.72 Left sixth nerve palsy in an adult. (A) Slight left  esotropia in the primary position; (B) limitation of left  abduction; (C) normal left adduction    presence of bilateral paresis, additional relevant clinical findings  or presentation in children and younger adults should prompt  aggressive investigation.   • Observation with monocular occlusion or prismatic (e.g.  temporary Fresnel stick-on) correction of diplopia is  appropriate in idiopathic and presumed microvascular  lesions; up to 90% will recover spontaneously, usually over  weeks to several months. Young children should be treated  with alternate patching to prevent amblyopia.   • Botulinum toxin injection into the ipsilateral medial rectus  may be used to prevent contracture, assess residual function  and sometimes to facilitate prismatic correction with a large  deviation (see Fig. 18.72); it is rarely curative.   • Surgery should be considered only when adequate  time has been allowed for maximal spontaneous   o Partial palsy (paresis) is treated by adjustable medial  rectus recession and lateral rectus resection in the affected  eye, aiming for a small exophoria in the primary position  to maximize the field of binocular single vision,  o Complete palsy is treated by transposition of the superior  and inferior recti to positions above and below the  affected lateral rectus muscle (see Fig. 18.70), coupled  with weakening of the ipsilateral medial rectus  (sometimes with injection of botulinum toxin - ‘toxin  transposition’). Three rectus muscles should not be  detached from the globe at the same procedure because  of the risk of anterior segment ischaemia.   • Permanent prism. Troublesome but mild residual deviation  may be treated with a prism incorporated into spectacles as  an alternative to surgery.   Conjugate eye movements (versions) are binocular movements in  which the eyes move synchronously and symmetrically in the same  direction. The main types are saccades, smooth pursuit and non-  optical reflex movements. Saccadic and pursuit movements are  supranuclear in origin, controlled at both cerebral and brainstem  levels. Non-optical reflex function helps to stabilize the visual field  with respect to head position. Disturbance of supranuclear eye  movement function causes gaze palsy.   • Function. Rapid voluntary or reflex alignment of the fovea  with a target image, including transferral of fixation from  one target to another.   • Pathway. There are separate horizontal and vertical  pathways. Many cortical areas and the superior colliculi are  involved in saccade generation, but classically initiation  occurs in the premotor cortex frontal eye fields, from where  impulses for horizontal movement pass to the contralateral  paramedian pontine reticular formation (PPRF) - the  horizontal gaze centre (Fig 19.74). Each frontal lobe initiates  contralateral saccades. Vertical pathways are less well  mapped (see below).   • Function. To maintain fixation on a target with slow  smooth movements once it has been located by the saccadic  system. The stimulus is image movement near the fovea.   • Pathway. This is complex, involving several cortex regions  as well as the PPRF, the superior colliculi, cerebellum and  other structures. The pathways are ipsilateral, the cortex on  one side controlling pursuit to the same side.    Fig. 19.74 Anatomical pathways for horizontal eye  movements (LR = lateral rectus; MLF = medial longitudinal  fasciculus; MR = medial rectus; PPRF = paramedian  pontine reticular formation)   • Function. The maintenance of eye position without  conscious input following a change of head or body  position. Other, visually directed (i.e. optical) mechanisms  are also concerned with visual field stability; both may be  active in the doll’s eye (oculocephalic) reflex, in which when  the head of an unconscious patient is rotated, the eyes move  in the opposite direction to preserve the image position on  the retina.   • Pathway. Movements are mediated mainly via the vestibular  system. Signals originate in the inner ear labyrinths and in  proprioceptors that provide information concerning head  and neck movements. For horizontal movements, afferent  fibres synapse in the vestibular nuclei and pass to the  horizontal gaze centre.   After initiation horizontal eye movements are generated in the  horizontal gaze centre (PPRF - see Fig. 19.74) and mediated via a  common pathway. From here, impulses travel (i) directly to the  ipsilateral sixth nerve nucleus and (ii) indirectly via internuclear  neurones that cross the midline at the level of the pons and pass  up the contralateral medial longitudinal fasciculus (MLF), to  motor neurones in the medial rectus subnucleus of the contralat¬  eral third nerve complex. Stimulation of the horizontal gaze centre  on one side therefore causes a conjugate movement of the eyes to  the same side.   A lesion of the horizontal gaze centre in the PPRF gives ipsilateral  horizontal gaze palsy, with an inability to look in the direction of  the lesion.   A lesion in the MLF is responsible for the clinical syndrome of  internuclear ophthalmoplegia (INO); causes include demyelina-  tion, stroke and tumours. Strabismus surgery can be performed  for persistent diplopia.   • Unilateral INO (Fig. 19.75). Double vision is not typically a  complaint.   o Straight eyes in the primary position,  o Defective adduction of the eye on the side of the lesion  and nystagmus of the contralateral eye on abduction;  note that the side of the lesion is named for the side of  the adduction deficit.   o Gaze to the side of the lesion is normal,  o Convergence is intact if the lesion is anterior and discrete  but impaired if the lesion is posterior or extensive.   o Limitation of left adduction and ataxic nystagmus of the  right eye on right gaze.   o Limitation of right adduction and ataxic nystagmus of  the left eye on left gaze.   Fig. 19.75 Left internuclear ophthalmoplegia. (A) Straight in  the primary position; (B) limitation of left adduction on right  gaze; (C) normal left abduction on left gaze   Fig. 19.76 Bilateral internuclear ophthalmoplegia. (A)  Limitation of left adduction on right gaze; (B) less severe  limitation of right adduction on left gaze; (C) convergence is  intact    o Convergence may be intact or impaired,  o A rostral midbrain lesion may give an associated  convergence deficit with resultant bilateral exotropia  and abducting nystagmus: ‘wall-eyed bilateral INO’ -  WEBINO.   combined on the same side give rise to the ‘one-and-a-half  syndrome’ characterized by a combination of ipsilateral gaze  palsy and INO. The only residual movement is abduction of  the contralateral eye, which exhibits abduction nystagmus.   Vertical eye movement initiation in the frontal lobes is simultane¬  ously bilateral, with impulses mediated via the vertical gaze centre  in the midbrain (rostral interstitial nucleus of the MLF). From the  vertical gaze centre, impulses pass to the subnuclei of the eye  muscles controlling vertical gaze in both eyes. Cells subserving    upward and downward eye movements are intermingled in the  vertical gaze centre, although selective paralysis of upgaze and  downgaze may occur in spite of this.   O Straight eyes in the primary position,  o Supranuclear upgaze palsy (Fig. 19.77A).  o Defective convergence (Fig. 19.77B).  o Large pupils with light-near dissociation (see Fig. 19.41).  o Lid retraction (Collier sign),  o Convergence-retraction nystagmus.   o The elderly: midbrain vascular accidents, mass lesions  involving the periaqueductal grey matter and posterior  fossa aneurysms.   Progressive supranuclear palsy (Steele-Richardson-Olszewski  syndrome) is a severe degenerative disease presenting in old age.  Clinical features include:   • Supranuclear gaze palsy, initially primarily of downgaze and  subsequently upgaze.   • Horizontal movements subsequently become impaired, with  eventual global gaze palsy.   Skew deviation is an uncommon supranuclear motility disorder  in which the eyes are deviated vertically and often exhibit cyclo-  torsional disturbance. Three categories have been described, cor¬  responding to differing motility patterns and lesion sites; both eyes  can be deviated upwards, or one can be hypertropic and one  hypotropic. The most frequent cause is a brainstem or cerebellar  stroke, which it is thought leads to dysfunction of a primordial  field stabilization mechanism.   Nystagmus is an involuntary oscillation of the eyes that can be a  physiological (e.g. following the rotation of an optokinetic drum)  or pathological phenomenon. In pathological nystagmus, each  cycle of movement is usually initiated by an involuntary,   (Courtesy of ES Rosen, P Eustace, HS Thompson and WJK Cumming, from  Neuro-ophthalmology, Mosby 1998)   defoveating drift of the eye away from the target, followed by a  refixating saccadic movement.   • Amplitude refers to the extent of excursion: fine or coarse.   • Frequency describes how rapidly the eyes oscillate: high,  moderate or low.   A schematic such as that shown in Fig. 19.79 can be used for   • Jerk nystagmus is saccadic with a slow defoveating ‘drift’  movement and a fast corrective refoveating saccadic  movement. The direction of nystagmus is described in terms  of the direction of the fast component: right, left, up, down  or rotatory.   • Pendular nystagmus is non-saccadic in that both the  foveating and defoveating movements are slow (i.e. the  velocity of nystagmus is equal in both directions).   • Mixed nystagmus consists of pendular nystagmus in the  primary position and jerk nystagmus on lateral gaze. 
KanskisClinicalOphthalmology8th2016_201901 Kanski's Clinical Ophthalmology 8th-2016_djvu.txt