A number of ophthalmological complications are associated with Marfan \200\231s syndrome. A pproximately 60 % have ectopia lentis which is managed with miotic drugs to constrict the p upil and refractive lenses. Patients frequently have strabismus, requiring treatment to pre vent amblyopia. There is an increased risk of retinal detachment as the globe is elongated. Kyphosis and scoliosis may develop during childhood. A scoliosis beyond 40 may contribut e to restrictive lung disease, resulting in cor pulmonale, and require corrective surgery. Pectus excavatum may require surgery in early adulthood as the reduced spinal \200\223stern um diameter may lead to cardiac complications. Pectus cari- natum rarely causes medical com plications but may be repaired for cosmetic reasons. Figure 12.1 shows an MRI of a marked thoracolumbar scoliosis in Marfan \200\231s syndrome, convex to the right. Dural ectasia is a dilation of the dural sac, usually at the L5 \200\223S1 level of the spi ne (Fig. 12.2 ) and can occur in two-thirds of adults with Marfan \200\231s syndrome. It ty pi- cally presents with unremitting headache or spinal pain and may cause peripheral neurol ogical symptoms due to nerve root pressure, such as referred pain, weak- ness, or loss of b ladder control. It may be treated conservatively with gabapentin, physiotherapy, and hydro- therapy, but ma y require neurosurgical repair of the dura for symptomatic relief. 5. What advice regarding sport should be given to a patient with Marfan \200\231s syndrome? Low to moderate degrees of activity are advised for patients with Marfan \200\231s syn- dro me depending on the presence of risk factors, and a reduction of physical and haemodynamic stress may be advised for those with cardiopulmonary or ophthal- mological disease. Patient s are advised about the dangers associated with some sports and to avoid those that involve blows to the head and eye such as boxing and some racquet sports. Contact sports and high diving should be avoided because of the risks of aortic dissection and lens dislocation. Pa tients who have undergone aortic root or valve replacements may need further caution, parti cularly if receiv- ing anticoagulation. Diving should be avoided because of the risk of spo ntaneous pneumothorax. 73 CASE 12 Fig. 12.1 T 1 -weighted MRI scan of the spine in a patient with Marfan \200\231s syndrome. Fig. 12.2 Dural ectasia with a large cystic cerebrospinal fluid (CSF) out-pouching extendin g through the left S2 exit foramen. (Note: this is not the same patient as in Fig. 12.1 ). 74 CASE HISTORIES IN RHEUMATOLOGY Follow-up This patient developed dyspnoea and bilateral pedal oedema due to mitral valve prolapse whe n she was 25 years old and underwent a 33 mm Bjork \200\223Shiley tilting mitral valve repl acement. Regular echocardiograms demonstrated aortic root dilatation of 6 cm at the age of 30 years and she underwent an aortic root replacement. Further reading de Paepe A , Devereux RB , Dietz HC , Hennekam RC , Pyeritz RE ( 1996 ). R evised diagnosti c criteria for the Marfan syndrome. Am J Med Genet ; 62 : 417 \200\223 26. Ho NCY , Tran JR , Bektas A ( 2005 ). Marfan \200\231s syndrome. Lancet ; 366 : 1978 \200 \223 81. Summers KM , Wes JA , Peterson MM , Stark D , McGill JJ , West MJ ( 2006 ). Challe nges in the diagnosis of Marfan syndrome . Med J Aust ; 184 : 627 \200\223 31. 75 CASE 13 Case 13 A 12-year-old girl presented with a 4-week history of involuntary choreiform movements when walking, initially affecting her right arm, progressing to involve her left arm, legs, and subsequently her face, head, and trunk. It interfered with dressing and feeding herself. S he had dysphasia and was noted to have easy bruising. There was no past medical history, bu t her paternal grandmother had Sydenham \200\231s chorea as a child. She had normal cardiov ascular, respiratory, and abdominal examinations, and normal eye movements and fundoscopy. She had small widespread bruises and a mottled rash on her legs (Fig. 13.1 ). A full blood count showed her to have a throm- bocytopenia with platelets of 58 \227 10 9 /L. 76 CASE HISTORIES IN RHEUMATOLOGY Fig. 13.1 (See also Plate 9) Rash on patient \200\231s legs. 77 CASE 13 Questions 1. What is the differential diagnosis of choreiform movements? 2. What investigations would narrow the differential and elucidate the diagnosis? 3. What is the most likely diagnosis? 4. What is the significance of the rash (Fig. 13.1 ), the chorea, and the thrombo- cytopenia? 5. How would you treat her at this stage? How may this change in the future? 78 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis of choreiform movements? Choreiform movements are likely to result from basal ganglia pathology. The differential di agnosis includes the following: \227\206 Infection-related: viral \200\224 varicella, HIV, measles, mumps, herpes simplex, Epstein \200\223Barr, cyto megalovirus pertussis, diphtheria Sydenham \200\231s chorea bacterial endocarditis Lyme disease mycoplasma. \227\206 Autoimmune/vasculitis: SLE APS BD sarcoid. \227\206 Vascular: arteriovenous malformation basal ganglia infarction or hemorrhage. \227\206 Endocrine: hyperthyroidism hypoparathyroidism, pseudo-hypoparathyroidism. \227\206 Metabolic: hypocalcaemia hypoglycaemia renal failure hypomagnesaemia hypo- or hypernatraemia. \227\206 Neoplastic: primary and metastatic brain tumor primary CNS lymphoma paraneoplastic syndrome. \227\206 Drug-related: anticholinergics anticonvulsants 79 CASE 13 antidopaminergics antihistamines CNS stimulants dopamine agonists lithium. \227\206 Epilepsy \227\206 Inherited conditions e.g. Wilson \200\231s disease. 2. What investigations would narrow the differential and elucidate the diagnosis? \227\206 Infection screen including viral studies, blood cultures, throat swab, antistrep- tolysin-O titre (ASOT), and an echocardiogram. \227\206 Autoantibodies to include antinuclear antibody (ANA), extractable nuclear antigen (ENA), complement, immunoglobulins, anticardiolipin antibody(aCL), and anti- 2 -glycopr otein-I antibody \227\206 Clotting studies, lupus anticoagulant (LA) \227\206 Urine dipstick for protein and blood, microscopy for casts \227\206 MRI brain \227\206 Lumbar puncture Investigations showed the following: \227\206 Hb 10.6 g/dL; MCV 79 fL; platelets 58 \227 109/L; WCC 6.8 \227 109/L with lymphocytes 2.2 \227 109/L; ESR 4 mm/h \227\206 Prolonged clotting: PT 15.4 s; activated partial thromboplastin time (APTT) 66.7 s \227\206 Positive LA; aCL 27 IU/ml \227\206 Positive ANA and negative ENA; C3 88 mg/dL (65 \200\223190); C4 11.8 mg/dL (14 \200\22340) \227\206 CRP <8 mg/L \227\206 Renal and liver function were normal \227\206 Viral studies and ASOT were negative \227\206 Echocardiogram showed mild mitral regurgitation with minor thickening of atrium m itral leaflet and absence of left ventricular or left atrial enlargement. \227\206 MRI excluded focal lesions in the basal ganglia. 3. What is the most likely diagnosis? What is the significance of the rash (Figure 13.1 ), the chorea, and the thrombocytopenia? This patient had positive LA and antiphospholipid, with clinical manifestations of anti-pho spholipid syndrome (APS), but did not satisfy the classification criteria for the syndrome since she did not have a history of arterial or venous thrombosis. APS is a non-inflammatory autoimmune disease characterized by recurrent arte- rial and veno us thrombosis and pregnancy-related complications for mother and 80 CASE HISTORIES IN RHEUMATOLOGY Table 13.1 Sapporo Classification Criteria for the antiphospholipid syndrome Clinical criteria 1. Vascular thrombosis \200\224 arterial, venous, or small vessel thrombosis in any tissue or organ 2. Pregnancy morbidity, when other causes have been excluded: one or more unexplained deaths at or beyond the 10th week gestation one or more premature b irths before the 34th week of gestation due to eclampsia, severe pre-eclampsia, or placenta l insufficiency three or more consecutive spontaneous abortions before the 10th week of ges tation Laboratory criteria \200\224 present on two or more occasions at least 12 weeks apart, in titre > 99th percentile 1. Lupus anticoagulant (LA) present in plasma 2. Anticardiolipin (aCL) antibody of IgG and/ or IgM isotype in serum or plasma 3. Anti- 2 -glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma fetus, and the presence of antiphospholipid antibodies. It can occur as primary APS but is also associated with other autoimmune conditions, most commonly SLE. It occurs mainly in yo ung women, with a male-to-female ratio of 1:3.5 for primary disease and 1:7 in patients wit h SLE. The Sapporo criteria (Table 13.1 ) classify APS as being present if at least one clinical a nd one laboratory criterion are met. A diagnosis requires the presence of laboratory criter ia on two separate occasions 12 weeks apart because only persist- ent abnormalities are cli nically relevant. Although the criteria are not validated in children, they are used for di agnosis as in adults. An international registry of pae- diatric APS patients has demonstrat ed 50 % as having an underlying autoimmune disease. Her rash (Fig. 13.1) was livedo reticularis, which is more prevalent among APS patients with SLE and in females. Non-criteria clinical manifestations of APS include (percentages taken from the Euro-Phospholipid Project): \227\206 livedo reticularis (24 % ) \227\206 thrombocytopenia (30 % ) \227\206 neurological manifestations (epilepsy 10 % , chorea 1.3 % ) \227\206 heart valve disease (14 % ) \227\206 nephropathy (3 % ). Livedo reticularis is a violaceous reticular or mottled pattern of the skin on the trunk, a rms, or legs. In APS, it occurs predominantly in females with SLE. Histology shows partial or complete occlusion of small to medium-sized arteries and arterioles with no perivascular inflammatory infiltrate and negative direct immunofluores- cence examination. The lesions can lead to ischaemia and tissue infarction, termed livedo vasculitis, which manifest as pu rpura, nodules, and painful ulcers. Thrombocytopenia is a well-recognized feature of APS, being present in a third of patients. Patients with APS associated with SLE more frequently exhibit 81 CASE 13 thrombocytopenia and leucopenia. Platelet levels are seldom low enough to be associated wit h hemorrhage and usually function well. Evan \200\231s syndrome occurs in some patients wit h APS and thrombocytopenia who also develop haemolytic anae- mia with a positive direct Coo mbs \200\231 test. The most common neurological manifestations of APS, such as stroke, transient ischaemic att ack, and cerebral venous sinus thrombosis are caused by thrombosis. In some cases this may be caused by emboli from cardiac valve vegetations. Not all neurological manifestations are clearly linked to thrombosis; these include chorea, transverse myelopathy, Guillain \200 \223Barr syndrome, psychosis, and migraine. Antiphospholipid antibodies may also have spe cific non-thrombogenic effects on peripheral and central nervous system tissues; for exampl e, anti- 2 -glycoprotein-I has been shown to bind to neuronal and astrocyte membranes. Heart valve lesions in the form of sessile vegetations or valve thickenings occur in 30 \200\22350 % patients with APS. This can cause stenosis or regurgitation. Valvular thickeni ng tends to be diffuse, in contrast with the localized thickening of rheu- matic heart dise ase. Cardiac valvular disease contributes to the risk of stroke. Antiphospholipid antibodies are associated with a renal small artery vasculopathy and chronic renal ischaemia. SLE should also be considered as a diagnosis in this case. It is important to deter- mine w hether an autoimmune disorder is present, as complications such as thrombosis or pregnancy losses may be caused by factors other than those related to APS. Clinical and laboratory fe atures of APS are the same in both APS and APS associated with SLE. The presence of antipho spholipid is frequent in pediatric SLE (55 % ) and represents a risk factor for thrombosis and poor prognosis overall. This patient had a positive ANA, aCL, LA, and thrombocytopenia, in keeping with SLE, but she did not completely satisfy the criteria for the disease. Late r, she developed a malar rash, Raynaud \200\231s triad, and a raised anti-double-stranded D NA, supporting a diagnosis of SLE. 4. How would you treat her at this stage? How may this change in the future? Coexisting risk factors for thrombosis should be identified in every case and used to asses s risk. These include increased age ( > 55 years in men and > 65 years in women), inherited thrombophilias, nephrotic syndrome, malignancy, immobiliza- tion, surgery, and other cardi ovascular risk factors (hypertension, diabetes mellitus, elevated LDL or low HDL cholestero l, smoking, family history of premature car- diovascular disease, body mass index (BMI) > 3 0 kg/m 2 , microalbuminuria, reduced estimated GFR of <60mL/min). VTE with APS should be treated with unfractionated or low molecular weight heparin for at l east 5 days overlapped with warfarin adjusted to a target interna- tional normalized ratio (INR) of 2 \200\2233. The expert consensus view is to anticoagulate these patients indefini tely because of the high rate of recurrence after discontinua- tion of warfarin. Arterial thromboembolism most commonly involves the cerebral circulation in the form of str oke or transient ischaemia. The Antiphospholipid Antibodies and