137 CASE 23 mycophenolate mofetil. Earlier withdrawal of maintenance therapy is associated with a high rate of relapse. In addition, chronic nasal carriage of Staph.aureus has been associated wi th higher rates of relapse. Prophylactic use of co-trimoxazole may be useful in this settin g. Prednisolone should ideally be tapered and stopped by the time maintenance therapy is co mmenced, but if this is not possible owing to persistent low-grade disease, it should be co ntinued at the lowest possible dose. Patients with WG are at two- to threefold increased ri sk of cardiovascular morbidity, so modifiable risk factors such as smoking, dyslipidaemia, and hypertension should be addressed. Bone protection with calcium, vitamin D, and bisphosp honates should be considered in patients at increased risk of osteoporotic fracture, especi ally those who require ongoing glucocorticoid therapy, are post-menopausal, and/or have low baseline BMD. Additional Reading Jayne D , Rasmussen N , Andrassy K , et al . ( 2003 ). A randomized trial of maintenance th erapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies . N Engl J M ed ; 349 ( 1 ): p. 36 \200\223 44 . Jayne DR , Gaskin G , Rasmussen N , et al . ( 2007 ). Randomized trial of plasma exchange o r high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis . J Am S oc Nephrol ; 18 : 2180 \200\223 8 . Jennette JC , Falk RJ , Andrassy K , et al . ( 1994 ). Nomenclature of systemic vasculitide s. Proposal of an international consensus conference . Arthritis Rheum ; 37 : 187 \200\223 92 . Hudson BG , Tryggvason K , Sundaramoorthy M , et al . ( 2003 ). Alport \200\231s syndrome, Goodpasture \200\231s syndrome, and type IV collagen . N Engl J Med ; 348 : 2543 \200\223 56 . Koldingsnes W , Nossent H ( 2002 ). Predictors of survival and organ damage in Wegener \200 \231s granulomatosis . Rheumatology ; 41 : 572 \200\223 81 . Mukhtyar C , Flossmann O , Hellmich B , et al . ( 2008 ). Outcomes from studies of antineut rophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force . Ann Rheum Dis ; 67 : 1004 \200\223 10 . 138 CASE HISTORIES IN RHEUMATOLOGY Case 24 A 31-year-old woman presented to the rheumatology department with a 2-year history of arthr algia of her hands, wrists, and ankles, associated with early morning stiffness. Her past m edical history included mild asthma and depression. She smoked 15 cigarettes a day. There w as no family history of arthritis or autoimmune disease. On examination, she had swelling of the small joints of her hands and wrists, with wasting of the intrinsic muscles and reduced grip strength. There was a small nodule at her left el bow. The CXR was unremarkable, and her hand X-rays suggested carpal crowding and periarticu lar osteopenia, with possible small erosion at the distal end of her proximal phalanx. The diagnosis of rheumatoid arthritis was made, and she was treated with intramuscular steroid, methotrexate, and hydroxychloroquine. The following year, she presented with shortness of breath on exertion. Her meth- otrexate was stopped, but the shortness of breath progressed and she developed orthopnoea. On admiss ion, she was found to be tachycardic and hypertensive. The CXR (Fig. 24.1 ) demonstrated an increase in the cardiac silhouette. An echocardiogram demonstrated a pericardial effusion, as well as a severely dilated left atrium, mitral regurgitation, and a reduced ejection fr action at 49 % . An MRI gadolinium cardiac scan showed left ventricular hypertrophy, a dila ted left atrium, a pericardial effusion, moderate mitral regurgitation, and a thrombus in t he left apex. It also demonstrated endomyocardial inflammation or fibrosis (Fig. 24.2 ). Fig. 24.1 CXR showing increased cardiac silhouette. 139 CASE 24 Questions 1. Give a differential diagnosis at her initial presentation with joint pains. 2. What are the current recommendations for management of rheumatoid arthritis (RA)? 3. What are the causes of shortness of breath in RA? Give a differential diagnosis based on the CXR findings. 4. What is the differential diagnosis for the endomyocardial inflammation or fibrosis? 5. What are the current NICE guidelines for starting biological therapy in RA? Fig. 24.2 The echocardiogram: (a) asterisk, left ventricular hypertrophy; arrow, pericardia l effusion; (b) thin arrow, thrombus in apex; thick arrow, endomyocardial enhancement demon strating inflammation or fibrosis; (c), (d), (e) arrows show the endomyocardial enhancement pattern. The patient had a coronary angiogram which was normal, excluding an ischaemic cause. The patient was commenced on warfarin for the apical thrombus. Her hematology data was reviewed and she was found to have an eosinophilia of 37 % (normally <5 % ). Oral corticosteroids were given and an infliximab infusion commenced because of ongoing high DAS and lack of efficacy of multiple DMARDs. 140 CASE HISTORIES IN RHEUMATOLOGY Answers 1. Give a differential diagnosis for the initial presentation of joint pains The most likely diagnosis is nodular rheumatoid arthritis because there was a sym- metrical small-joint polyarthritis with wrist involvement, wasting of the intrinsic muscles, and a nodule at the elbow. There is periarticular osteopenia on X-ray. These are consistent with a the diagnosis of RA. Other causes of a polyarthritis include the following: \227\206 Psoriatic arthritis \227\206 Reactive arthritis \227\206 Osteoarthritis \227\206 Connective tissue disease (e.g. SLE) \227\206 Vasculitis \227\206 Sarcoidosis \227\206 Malignancy (e.g. leukemia). These are less likely given the absence of other supporting features such as a rash, histor y of preceding infection, family history, erythema nodosum, or marked constitutional upset. 2. What are the current recommendations for management of rheumatoid arthritis? The BSR guidelines for the management of new-onset disease suggest the following: \227\206 Refer patients with suspected persistent synovitis of undetermined cause for spec ialist opinion. Patients should be offered ongoing access to the multidisci- plinary team, including specialist physiotherapist and occupational therapist. \227\206 Offer a combination of DMARDs, including methotrexate and at least one other DMAR D, plus short-term glucocorticoids as first-line treatment as soon as possible. \227\206 To monitor disease, use CRP and the key components of DAS. The DAS is a combined index that was developed in Nijmegen in the 1980s to measure the dise ase activity in patients with RA. It has been validated for use in clinical trials in combi nation with the EULAR response criteria. There are DAS calculators that make it easy to use , and thus it is possible to collect information about the disease activity and response to treatment. The DAS takes into account the number of swollen and tender joints, the ESR or CRP, and a V isual Analog Score (VAS) of perceived patient disease activity. The score is between 0 and 10 and indicates how active the RA is at the time of measurement. The DAS has been used to define thresholds for disease activity: high disease activity (>3.7); moderate (2.4<DAS<3.7); low (<2.4); remission (<1.6) 141 CASE 24 3. What are the causes of shortness of breath in RA? What does the CXR in Fig. 24.1 show? Give a differential diagnosis based on the CXR finding s The causes of shortness of breath in rheumatoid arthritis are as follows. \227\206 Pulmonary: non-specific interstitial pneumonia (NSIP) idiosyncratic allergic alveolitis associated with drugs such as methotrexate, leflunomide, salazopyrine pulmonary fibrosis pleural effusion pulmonary hypertension. \227\206 Cardiac: pericarditis pericardial effusion cardiac amyloid. \227\206 Hematological: anemia. The CXR demonstrates a significant increase in the cardiac silhouette size. The differentia l diagnosis of this includes: \227\206 left ventricular failure \227\206 pericardial effusion \227\206 left ventricular hypertrophy \227\206 dilated cardiomyopathy \227\206 hypertrophic cardiomyopathy. 4. What is the differential diagnosis for the endomyocardial inflammation or fibrosis? The differential diagnoses for the endomyocardial inflammation or fibrosis are: \227\206 cardiac amyloid \227\206 hypertensive heart disease \227\206 ischaemic heart disease \227\206 rare side effects of DMARDs \227\206 eosinophilic myocarditis. Other causes of myocarditis might include: \227\206 infective (viral \200\224 adenovirus, parvovirus, human herpes virus 6, HIV) \227\206 connective tissue disorders (e.g. SLE, scleroderma) \227\206 sarcoidosis. 142 CASE HISTORIES IN RHEUMATOLOGY The pattern of endomyocardial enhancement seen on echocardiography in this case was conside red to be typical of eosinophilic myocarditis rather than amyloidosis. There is a documented association between RA and eosinophilia. This was first described in the 1970s. It was later recognized that there are two patterns of eosi- nophilia: one relat ed to the disease process itself, and the other related to therapy (e.g. gold, penicillamin e). The extra-articular features of RA, such as pericarditis, pulmonary fibrosis, and rheum atoid nodules, are more common in patients with eosinophilia. The relationship between tiss ue eosinophilia and RA is less well known. There are documented cases of RA with eosinophil ic pneumonia, eosinophilic enteritis, and even eosinophilic meningoencephalitis, where no o ther cause for the eosinophilia is found. Eosinophils are known to be harmful to the myocardium. Chronic eosinophilia has been associ ated with endomyocardial fibrosis and myocardial damage. This tissue injury is a direct res ult of degranulation of toxic eosinophilic granule proteins. Other causes of eosinophilic myocarditis include \227\206 idiopathic hypereosinophilia syndrome \227\206 parasites \227\206 rejected heart transplant \227\206 drug reactions \227\206 vasculitis (Churg \200\223Strauss syndrome (CSS)). The patient was successfully immunosuppressed with infliximab and this normalized her eosin ophilic count. She showed improvement in her cardiac function, including a reduction in lef t ventricular mass, a rise in ejection fraction from 46 % to 74 % , and a reduction of the endomyocardial enhancement demonstrated previously. 5. What are the current NICE guidelines for starting biological therapy in RA? The current NICE guidelines for starting biological therapy in RA are as follows (Table 24. 1 ). \227\206 The TNF- inhibitors (adalimumab, etanercept and infliximab) are recom- me nded as options for treatment in those with active RA as measured by the DAS, i.e. > 5.1 on at least two occasions, or those who have undergone trials of two DMARDs (usually for a mi nimum of 6 months). \227\206 Rituximab in combination with methotrexate is recommended as an option for the tr eatment of severe RA in those who have had an inadequate response or intoler- ance to other DMARDs, including treatment with at least one TNF- inhibitor. 143 CASE 24 Table 24.1 NICE/BSR guidelines for anti-TNF therapy TA130 Time DAS Start > 5.1 6 months Falls by 1.2 or is <3.2 Subsequently > 1.2 below initial level Source: NICE Technology Appraisal TA130 ( http://guidance.nice.org.uk/TA130 ). Further reading Funovits J , Aletaha D , Bykerk V , et al. ( 2010 ). The 2010 American College of Rheumatol ogy/ European League Against Rheumatism classification criteria for rheumatoid arthritis: m ethodological report phase I . Ann Rheum Dis ; 69 : 1589 \200\223 95. Luqmani R , Hennell S , Estrach C , et al . ( 2009 ). British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of rheumatoid art hritis (after the first 2 years) . Rheumatology ; 48 : 436 \200\223 9 . 144 CASE HISTORIES IN RHEUMATOLOGY Case 25 Part 1 A 72-year-old Caucasian female presented with rapid-onset, painful, and disabling dactyliti s of both second toes (Fig. 25.1 ). She had a past history of mechanical low back pain. Sin ce the development of dactylitis she suffered general malaise, pain all over, and night swe ats . On examination she was distressed and anxious, afebrile, and nor- motensive, with wid espread hyperalgesia but no significant abnormality apart from dactylitis of both second to es. In particular, there were no skin, hair, or nail lesions. During the following few mont hs the dactylitis migrated between different toes, but was always present in at least two t oes. The pain, fever, and malaise troubled her to such an extent that she became depressed. She was treated with paracetamol, NSAIDs, amitriptyline, and morphine sulfate, all of whic h were ineffective. Intravenous methylprednisolone had a transient effect on the inflammato ry response. DMARDs (methotrexate, leflunomide, and sulfasalazine) were also ineffective. Investigations showed the following: 10.1 g/dL after 4 months (MCV 88 fL) 856 \227 10 9 /L after 4 months \227\206 Hb 12.7 g/dL initially \227\206 Platelets 430 \227 10 9 /L initially \227\206 CRP 80 mg/L initially \227\206 WCC 14.5 \227 10 9 /L initially \227\206 Lympho cytes 7.2 \227 10 9 /L initially 160 mg/L after 4 months 22.1 \227 10 9 /L after 4 months 11.7 \227 10 9 /L after 4 months \227\206 Urinalysis was unremarkable throughout. Fig. 25.1 (See also Plate 12) Dactylitis of left second toe. 145 CASE 25 Questions \200\224Part 1 1. What is the differential diagnosis for dactylitis? 2. What other investigations would you undertake in this case? 146 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis for dactylitis? Dactylitis is the inflammation of a finger or toe, affecting any of the structures within a digit. There are many causes, the most common of which is an association with inflammatory arthritis, sarcoidosis, or sickle cell disease. With increasing glo- balization, infection -related dactylitis associated with tuberculosis and congenital syphilis should be consider ed. Blistering dactylitis associated with group A -haemolytic streptococci or Staphyloco ccus aureus infection is a rare complication of these ubiquitous infections. \227\206 Dactylitis associated with inflammatory arthritis, particularly seronegative spon dyloarthritis, is a diffuse painful swelling of a digit caused by a combination of flexor t enosynovitis, soft tissue oedema, synovitis, enthesitis, and bone oedema. It is most common ly seen in psoriatic arthritis (up to one-third of patients), but also occurs with all sero negative spondyloarthritides and reactive arthritis. Often dactylitis manifests as \200 \230sausage-like \200\231 digits and involves a few fingers or toes asymmetrically. Clinica l examination is usually sufficient for diagnosis, but in severe cases the dactylitis may r esemble cellulitis or osteomyelitis. Most cases are self-limiting and DMARD treatment is re served for persistent cases or those with associated arthritis. \227\206 Sarcoid dactylitis is a rare manifestation of sarcoidosis, occurring in about 0.2 % of patients, and is often associated with lupus pernio. Non-caseating granulomas invade the bones and adjacent soft tissue, leading to fusiform swellings which are usually bilater al, asymmetrical, and painless. Serum angiotensin-converting enzyme (ACE) level may be rais ed and there may be associated hypercalcaemia and hilar lymphadenopathy. Diagnosis is confi rmed by tissue biopsy from the digit or other skin lesions. \227\206 Sickle cell disease dactylitis is caused by infarction of bone marrow during pain - ful vaso-occlusive crises. It most commonly occurs during early childhood and is sometime s the first manifestation of the disease. Clinically, it is characterized by sudden onset o f a warm tender global swelling of the hands or feet, often with fever and leucocytosis. X- ray appearance may resemble that of osteomyelitis, with a \200\230moth-eaten \200\231 peri ostitis and focal osteosclerosis. Hemoglobin electro- phoresis is used to test for sickle c ell disease. \227\206 Tuberculous dactylitis is a rare extrapulmonary manifestation of tuberculosis cau sed by osteomyelitis extending into digit soft tissue. It usually presents as a painful sof t tissue swelling around the diaphysis of the involved bone. An abnormal CXR points towards the diagnosis, which may need to be confirmed by tissue biopsy. \227\206 Syphilitic dactylitis is a manifestation of congenital syphilis resulting from tr ans- placental transmission of Treponema pallidum . The spirochetes invade peri- chondrium, periosteum, cartilage, bone marrow, and sites of active endochondral ossification. The dac tylitis is bilateral and symmetric. Syphilis is confirmed by screening tests for syphilis ( IgM/IgG combined enzyme immunoassay (EIA), VDRL, or Treponema pallidum haemagglutination (T PHA) tests). 147 CASE 25 \227\206 Blistering distal dactylitis is an infection of the anterior fat pad of the volar surface of the distal part of the finger or toe, most often caused by group A -haemolyt ic streptococci and occasionally staphylococcus aureus. It characteristically manifests as a tense bulla which covers the anterior fat pad, proximal and lateral nail folds. Usually t here are no constitutional symptoms, and treatment is with excision, drainage. Systemic ant ibiotics are usually given to prevent spread of the infection. 2. What other investigations would you undertake in this case? This woman \200\231s painful dactylitis in association with systemic symptoms and raised in flammatory markers meant that investigations were needed to exclude an underly- ing seroneg ative inflammatory arthritis, connective tissue disease, vasculitis, and the infectious cau ses of dactylitis. The level of constitutional upset and inflammatory response, which was d isproportionate to the clinical signs, prompted a search for occult malignancy. Further normal tests were: \227\206 liver function, renal function, serum calcium, bone biochemistry \227\206 ANA, ANCA, rheumatoid factor \227\206 serum ACE, QuantiFERON test for tuberculosis \227\206 immunoglobulin, electrophoresis, and urine for Bence-Jones proteins \227\206 infection screen \200\224 blood, urine, throat culture \227\206 echocardiogram. Imaging was as follows: \227\206 MRI spine to look for spinal infection, metastatic disease, and infection. Screening for occult malignancy involved: \227\206 CT of chest, abdomen and pelvis \227\206 upper and lower GI endoscopy \227\206 breast screening \227\206 pelvic ultrasound. All investigations in this patient were normal except for the blood movie which showed a pe rsistent lymphocytosis. Peripheral blood leucocyte immunophenotyp- ing revealed a neoplasti c B-cell clone, consistent with a diagnosis of chronic lym- phocytic leukemia (CLL). A diag nosis of paraneoplastic syndrome was proposed. She was treated with chlorambucil and her da ctylitis symptoms and inflammatory response settled as her white cell count normalized. Questions \200\224Part 2 3. What are the rheumatological manifestations of paraneoplastic syndromes? 4. How should a patient with suspected paraneoplastic arthritis be managed? 5. What is the prognosis of a patient with paraneoplastic arthritis? 148 CASE HISTORIES IN RHEUMATOLOGY Answers 3. What are the rheumatological manifestations of paraneoplastic syndromes? Malignant disease can affect the musculoskeletal system by direct invasion, metastasis, syn ovial reaction to juxta-articular masses, and indirectly by the effects of a distant tumor. A wide variety of paraneoplastic syndromes can occur involving multiple organ systems, inc luding the musculoskeletal system. The paraneoplastic syndromes are thought to be caused by a humoral response to a malignancy, and can be defined by the following criteria: \227\206 They occur during the course of an identified malignant disease or precede clinic al evidence of a malignancy. \227\206 Symptoms cannot be the result of direct tumor invasion or compression. \227\206 Symptoms improve with treatment of the underlying neoplasm. Presentation is often atypical with a rapid onset, and symptoms and signs may be migratory. The systemic inflammatory response may be disproportionate to the arthritis as in this pat ient \200\231s case. Autoantibody screening tests are usually negative, and response to cor ticosteroids and immunosuppressive agents is poor. Inflammatory myopathies, seronegative rheumatoid arthritis, and some atypical vasculitides are the most frequently reported paraneoplastic rheumatological dis- eases, although parane oplastic scleroderma-like and lupus-like syndromes, erythema nodosum, and Raynaud \200\231s syndrome have also been described. Adult patients presenting with inflammatory myositis (dermatomyositis and polymyositis) hav e a significant malignancy association. Patients presenting with PMR symptoms who are young er than age 50 with an ESR <40 or > 100, and who respond poorly to corticosteroids, should be considered for age-appropriate malig- nancy screening. 4. How should a patient with suspected paraneoplastic arthritis be managed? Paraneoplastic arthritis is not common but it often presents before the malignancy itself, on average by 3 months. Therefore it is important to undertake age-specific screening for m alignancy in anyone in whom it is suspected. Treatment of the malignancy often leads to a r esolution of the rheumatological disease. In one case series, 12 out of the 13 patients wit h paraneoplastic arthritis had resolution of their joint symptoms with chemotherapy or tumo r resection. The mean age of initial presentation was 58 years (range 28 \200\22385 years). Sixty per cent of paraneoplastic arthritis is caused by adenocarcinoma of the lung; theref ore it is important to have a higher index of suspicion with smokers. Although both solid a nd hematological malignancies can cause paraneoplastic arthritis, it is more common with so lid malignancies. There is no relation between the type of arthritis and the underlying tum or type. 149 CASE 25 3. What is the prognosis of a patient with paraneoplastic arthritis? The prognosis is linked to the progression of the malignancy. With a high index of suspicio n, malignancies occurring as part of paraneoplastic arthritis tend to be detected at an ear lier stage than usual. Therefore the chances of survival are often higher for patients with paraneoplastic arthritis than for those without. In this case a recurrence of the patient \200\231s lymphocytosis was heralded by a recurren ce of the dactylitis. It is important to be aware of this, as rheumatological symptoms can serve as an early warning for tumor recurrence, with early detection leading to an improved treatment outcome. However, not all cases of tumor relapse involve a recurrence of the rhe umatological symptoms. Further reading Racanelli V , Marcella P , Minoia C , Favoino E , Perosa F ( 2008 ). Rheumatic disorders as paraneoplastic syndromes Autoimmun Rev ; 7 : 352 \200\223 8. Morel J , Deschamps V , Toussirot E , et al . ( 2008 ). Characteristics and survival of 26 patients with paraneoplastic arthritis . Ann Rheum Dis ; 67 : 244 \200\223 7 . Olivieri E , Scarano A , Padula V ( 2006 ). Dactylitis : a term for different digit disease s . Scand J Rheumatol ; 35 : 333 \200\223 40 . 150 CASE HISTORIES IN RHEUMATOLOGY Case 26 A 40-year-old male presented with a 3-week history of multiple transient focal neuro- logic al events. On the first occasion, he woke up with left-sided weakness and incoherent speech lasting for a few minutes. This was followed within a few days by episodes of right hemipa resis and expressive dysphasia lasting up to 30 minutes. These symptoms were associated wit h a constant occipital headache, worse towards the end of day, which was helped with analge sia. He had no relevant past medical history and had never smoked. On examination, his bloo d pressure was 135/85 mmHg. He had minimal ataxia on heel \200\223toe walking, but his neur ological examination was otherwise normal. Investigations showed the following: \227\206 Normal hematological and biochemical studies \227\206 Normal inflammatory markers \227\206 Negative ANA, ANCA, RF, cryoglobulins, normal complement \227\206 Negative thrombophilia screen \227\206 Normal CXR \227\206 ECG: normal sinus rhythm \227\206 Normal transthoracic echocardiogram \227\206 MRI and MRA of the brain are shown in Figs 26.1 and 26.2 \227\206 CSF: opening p ressure 8 cmH 2 O, glucose 3.8 mmol/L (blood 5.8 mmol/L), protein 477 mg/L, lymphocytes 20 /mm 3 , no red cells, and no oligoclonal bands. Fig. 26.1 T 2 -weighted MR images of the brain with gadolinium. 151 CASE 26 Fig. 26.2 Magnetic resonance angiogram. Questions 1. What does the MRI and MRA brain (Figs 26.1 and 26.2 ) show? 2. What is the differential diagnosis? 3. What other investigations should be considered? 4. How would you treat this condition? 152 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What does the MRI and MRA brain (Figs 26.1 and 26.2 ) show? The MR images with gadolinium demonstrate small focal enhancing parenchymal lesions (Fig. 2 6.3 , arrows). There were multiple lesions of varying ages in the left posterior putamen, i nternal capsule, and right basal ganglia. The MRA shows reduced caliber of the left middle cerebral artery (Fig. 26.4 , arrow). Fig. 26.3 T 2 -weighted MR images of brain with gadolinium demonstrating small focal enhanc ing parenchymal lesions (arrows). 153 CASE 26 Fig. 26.4 MRA angiogram showing reduced caliber of left middle cerebral artery (arrow). 2. What is the differential diagnosis? This patient has vascular disease affecting a number of vessels of varying caliber and caus ing lesions of different ages. The differential diagnoses are: \227\206 primary angiitis of the CNS (PACNS) \227\206 reversible cerebral vasoconstrictive syndromes (RCVSs) \227\206 secondary CNS vasculitis. Secondary forms of CNS vasculitis may occur in many conditions including the following: \227\206 Infections: HIV, varicella zoster virus (VZV), hepatitis C, syphilis. \227\206 Drugs: amphetamines, cocaine, heroin, ephedrine, phenylpropanolamine. \227\206 Lymphoproliferative disease: Hodgkin \200\231s and non-Hodgkin \200\231s lymphoma . \227\206 Systemic vasculitis: PAN, MPA, BD, WG, CSS. \227\206 Connective tissue diseases: SLE, Sj gren \200\231s syndrome. \227\206 Other: radiation, graft versus host disease. 154 CASE HISTORIES IN RHEUMATOLOGY Infections of the CNS with HIV, VZV, hepatitis C, and syphilis may result in a similar clin ical picture to that of primary CNS vasculitis. VZV cerebral angiitis generally affects old er patients and may be preceded by a clinical zoster infection. Diagnosis is confirmed by a positive VZV IgM in the CSF. HIV may be the primary infection causing a CNS vasculitis or associated with an opportunistic infection such as neurosyphilis. Hepatitis C may cause a C NS vasculitis without cryoglobuli- naemia. Other infections causing a CNS vasculitis are Bo rrelia burgdorferi , Bartonella , Mycobacterium tuberculosis , and cysticercosis. Most systemic vasculitides may involve the CNS, but the most commonly report- ed are PAN, BD, and the ANCA-associated vasculitides. Results of investigations so far did not support a diagnosis of systemic inflamma- tory dis ease, lymphoproliferative disorder, APS, infection, metabolic disorder, or a thromboembolic disease. RCVSs are an important differential and may present with similar clinical and radiological features to CNS vasculitis. Young female patients characteristically present with a severe acute ( \200\230thunderclap \200\231) headache with or without neurological signs but witho ut evidence of a subarachnoid hemorrhage. CSF analysis is usually normal. Multifocal segmen tal cerebral artery vasoconstriction is best demonstrated on angiography showing multiple v essel involvement in multiple beds, and the changes are reversible within 12 weeks. It is t wice as common in females, and tends to occur in the 20 \200\22340-year-old age group. MRI scans may be normal but can show infarction resulting from hypoperfusion and small subarach noid hemorrhages resulting from reperfusion. It is a self-resolving condition, but may be t reated with calcium-channel blockers and occasionally high-dose steroids. It is less likely in this case where the disease onset is insidious and the CSF is abnormal. PACNS is a rare form of vasculitis and is of unknown cause. Evidence of systemic inflammati on is characteristically absent. Presentation can be extremely variable but generally inclu des multifocal neurological signs and symptoms with headache or altered mental states. Diag nostic criteria for PACNS were proposed by Calabrese and Malleck in 1998, and include all o f the following: \227\206 An acquired neurological deficit that remains unexplained after thorough evaluation. \227\206 Either high-probability angiographic evidence or histopathologic demonstration of angiitis within the CNS. \227\206 No evidence of systemic vasculitis or any other condition to which the angiograph ic or pathological condition could be attributed. Clinical subsets of PACNS comprise granulomatous angiitis of the CNS (GACNS), which account s for 20 % of cases, spinal cord and mass lesion presentations, and atypical cases where gr anulomatous angiitis is associated with GCA, sarcoidosis, and amyloidosis. GACNS is more common in males with a male-to-female ratio of 3:2 and a median age of 50 yea rs. It has a variable onset and is often associated with a 3 \200\2236-month pro- dromal il lness. The major symptoms include headache, strokes, or encephalopathy, but presentation ma y include recurrent transient ischaemic attacks, seizures, cognitive 155 CASE 26 or behavioral changes, myelopathy, and ataxia. The CSF is abnormal in 80 \200\22390 % of pa tients with PACNS with mild to moderate leucocytosis and elevated protein. This case was most likely to be a presentation of PACNS in view of the multiple focal neuro logical events with headache, the CSF findings, demonstration of multiple vessel involvemen t on MRI, and absence of any other abnormal investigations. 3. What other investigations should be considered? A brain and leptomeningeal biopsy is the gold standard investigation for the diag- nosis of PACNS. The histological features consist of granulomatous inflammation, fibrinoid necrosis of vessel walls, or lymphocytic infiltrates. Sensitivity may be low due to skip lesions an d sampling error but can be improved by using MRI to select enhancing lesions. Further imaging studies include formal cerebral angiography, computed tomog- raphy angiogra phy, and 18-fluorodeoxyglucose positron emission tomography. Cerebral angiography can demon strate disease of larger and medium-sized vessels (e.g. stenosis and aneurysms), but it is less sensitive for disease in smaller vessels although it has higher resolution than MRA. Angiography may be normal in 40 % of cases where the diseased vessel is small and is termed high probability in 40 % of cases where vessels show definite involvement. Serum and CSF studies should be performed to detect viral, bacterial, and atypical infections. 4. How would you treat this condition? There have been no randomized controlled trials of the treatment of CNS vasculitis, and man agement is based on extrapolation of protocols for other systemic vasculitides with severe organ involvement. This patient should be managed in collaboration with a neurologist. Curr ent practice is to use pulse cyclophosphamide and gluco- corticoid regimens to achieve remi ssion followed by azathioprine, methotrexate, or mycophenolate mofetil for maintenance. Adj uvant treatment includes prevention of opportunistic infection and osteoporosis. This patient responded well to a course of pulsed cyclophosphamide and oral corticosteroids , with resolution of symptoms and return to normal function. He started maintenance treatme nt with mycophenolate mofetil and has been carefully followed up as the relapse rate of the condition is estimated at 25 % . Early recognition of disease and prompt treatment is like ly to improve outcome. Further reading Birnbaum J , Hellmann DB ( 2009 ). Primary angiitis of the CNS . Arch Neurol ; 66 : 704 \200\223 9. Calabrese LH , Malleck JA ( 1988 ). Primary angiitis of the central nervous sys tem . Medicine ; 67 : 20 \200\223 39. Calabrese LH ( 2007 ). Narrative review: reversible cerebral vasoconstriction syndromes. Ann Int Med ; 146 : 34 \200\223 44. 156 CASE HISTORIES IN RHEUMATOLOGY Calabrese LH , Duna GF ( 2008 ). Vasculitis of the central nervous system . In: Ball E , Br idges SL (eds) Vasculitis ( 2 nd edn). Oxford : Oxford University Press . Hajj-Ali RA, Calabrese LH ( 2009 ). Central nervous system vasculitis . Curr Opin Rheumatol ; 21 : 10 \200\223 18. K ker W ( 2007 ). Cerebral vasculitis: imaging signs revisited . Neuroradiology ; 49 : 471 \200\223 9. 157 CASE 27 Case 27 A 26-year-old woman, who had been working part-time as a waitress and training to be a beau ty therapist, was referred to the rheumatology outpatient department with severe pain and w eakness in her legs. The patient stated that her leg symptoms occurred as a result of a fal l at her workplace 6 months previously when she slipped on wet tiles in the restaurant. The re was initial bruising of her left calf and thigh. Her employers were not sympathetic, den ying that the floor was wet. She was in the process of taking legal action against them. Sh e had not been able to work since because her legs were too painful; her mobility was sever ely affected and she was confined to her home. Her parents were present during the consulta tion and they provided the history. The patient was tearful and did not say very much, but complained of fatigue and pain. There was no past medical history apart from migraines and dysmenorrhea. On examination the patient was noted to be overweight. She could not walk without her fathe r assisting her. Both legs had normal tone; there was a global weakness of her legs related to pain. The skin was cool, especially below her knees, and she described marked hyperalge sia of the skin from the mid-thigh downwards. Reflexes were normal and the joints were norm al apart from exquisite pain on movement. Questions 1. What is the diagnosis? 2. Would the presence of more widespread trigger points and sleep disturbance change the diagnosis? 3. What is the approach to management? 4. What is the role of pharmacotherapy for neuropathic pain? 5. What are the risk factors for this patient having a poor outcome? 158 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the diagnosis? The working diagnosis is that of a complex regional pain syndrome (CRPS). This condition en compasses a diversity of painful conditions, often following trauma, coupled with abnormal regulation of blood flow and sweating, trophic changes, and oedema of the skin. The excruci ating pain and autonomic dysfunction is dis- proportionate to any inciting event. CRPS type I is formally identified as reflex sympathetic dystrophy. CRPS type II is the term that de scribes the condition when it coexists with documented nerve injury. CRPS I may follow trivial injury. Clinical features include allodynia, hyperalge- sia, oede ma, pseudo-motor and vasomotor abnormalities, and subsequent trophic changes. This results in a diminution in quality of life and overall reduction in health. There is an interplay w ith the organic features of the reflex sympathetic dystrophy and the non-organic pain modul ation disorder. A physical trauma is often the precipitating event and becomes a point of f ixation, particularly when there is a legal claim or compensation is sought. 2. Would the presence of more widespread trigger points and sleep disturbance change the diagnosis? The presence of widespread trigger points and sleep disturbance with fatigue would raise th e possibility that the patient had developed fibromyalgia. The definition encompasses pain and tenderness that affects muscles and tendons over the whole body and continues for more than 3 months. It is called a \200\230syndrome \200\231 because it is a collection of symp toms, rather than a disease. It is almost always present in association with non-restorativ e sleep. There is evidence that in these patients \200\231 psychological conditions, includ ing depression, panic disorders, anxiety, and post-traumatic stress, may play a part. Genet ic factors may also play a role in the pathogenesis of a fibromyalgia syndrome. Personality factors may also be involved. Buskila and col- leagues have analyzed coping styles of fibr omyalgia patients with specific emphasis on the differences between those patients with and without post-traumatic stress. The psychological concept of \200\230suppression \200\231 as a coping style is significantly more common in fibromyalgia patients with comorbid post- traumatic stress. 3. What is the approach to management? Management of CRPS I requires a clear therapeutic plan which needs the full par- ticipation and cooperation of the patient and family. Understanding the process and its presentation is paramount to the success of treatment. The physiotherapist often leads in the management . A graded exercise program, training the patient to use their legs fully, should be commen ced as soon as possible. Altering sensory stimuli such as hot, cold, light touch, and vibra tion are helpful in re-training nerves. Balance and proprioception are often lost early and need to be worked on. There is some evidence that mirror therapy may be helpful in CRPS I. 159 CASE 27 The primary tool of mirror therapy is a mirror from which the patient receives visual feedb ack in order to \200\230train \200\231 the brain to configure a new \200\230body map \200 \231. This so-called map is the mental representation that allows a person to be aware of w here each component of the body is at all times, even in complete darkness. The feedback th at is gained from the normal limb is used to train the painful limb. Clinical psychology and pain-management strategies need to proceed alongside the physical t herapies. The losses to self-esteem, work, and health need to be addressed, and their meani ng to the patient needs to be explored. Acupuncture and transcutaneous electrical nerve sti mulation (TENS) may have some value in the relief of pain, but the evidence base for these treatments is poor. 4. What is the role of pharmacotherapy for neuropathic pain? Pharmacotherapy has a role in the management of neuropathic pain. Drugs such as tricyclic a ntidepressants and serotonin reuptake inhibitors may be useful. Noradrenaline and serotonin are important mediators of descending inhibition of noxious signaling and are important in stress response pathways. Meta-analyzes have demonstrated the efficacy of tricyclic antide pressants in fibromyalgia. Selective serotonin reuptake inhibitors have limited efficacy. A nticonvulsants such as gabap- entin and pregabalin, which affect calcium flux and the relea se of excitatory amino acids, have been shown to be useful. The analgesic tramadol, which i s a -opioid receptor agonist inhibiting noradrenaline and serotonin reuptake, has been s hown to be useful. There has been some role for the use of bisphosphonates and also regional nerve blocks, in particular guanethidine. 5. What are the risk factors for this patient having a poor outcome?