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30-year-old man was admitted to our hospital with a depressed conscious level (Glasgow Coma Scale score 4/15), following an attack of generalised tonic–clonic convulsions. He had smoked 30 cigarettes a day for 5 years prior to the fit, but had not consumed alcohol. There was no history of hypertension, diabetes mellitus, jaundice, fever, bleeding diatheses, trauma or prolonged bed rest.
General examination revealed a man who was apyrexial with normal pulse rate and blood pressure and livedo reticularis of the lower limbs (figure 1). Neurological examination revealed normal sized pupils, equal and sluggishly reacting to light. Oculocephalic reflexes were absent. There was no neck stiffness or lateralising limb weakness, plantars being bilaterally extensor. Cardiovascular, respiratory and abdominal examinations were clinically normal and a detailed search for malignancy proved negative.
Cranial computed tomography (CT) showed thrombosis of the straight and superior sagittal sinuses, subsequently confirmed by magnetic resonance imaging and angiography (MRI/MRA) (figure 2). Patient had thrombocytopenia (90 × 109/l), normal erythrocyte sedimentation rate and a prolonged partial thromboplastin time (PTT). Liver function tests, whole and red blood cell counts, haemoglobin, bleeding and clotting times were normal.
He was subjected to further special investigations which clinched the diagnosis. Incidentally, the brother and sister of the patient were found to have leg ulcers and the biochemical abnormalities which the patient had on special investigations.
- What is the most likely diagnosis?
- What further investigations would establish the aetiology of cerebral venous thrombosis?
- What is the line of management to be pursued?
- What is the significance of the skin lesions?
The cerebral venous thrombosis could be the result of an underlying hypercoagulable state. The thrombocytopenia and prolonged PTT may point to the diagnosis of antiphospholipid syndrome (APLS).
APLS was confirmed in this patient by estimation of antiphospholipid antibodies in serum (anticardiolipin antibody and lupus anticoagulant). IgG and IgM anticardiolipin antibodies were markedly elevated (>5SD) and lupus anticoagulant was positive (prolonged PTT with dilute thromboplastin). Other methods of estimation of lupus anticoagulant are by Russel's viper venom time and kaolin clotting time. These antibodies are known to be present in systemic lupus erythematosus. However, antinuclear antibodies, and antibodies to double-stranded DNA and lupus cells were found to be negative, making the possibility of systemic lupus erythematosus highly unlikely. Relevant investigations to rule out other hypercoagulable states (protein C, protein S and antithrombin-III levels) were also normal. Urinary cyanide nitroprusside test for homocystinuria was negative, as was a sucrose lysis test for paroxysmal nocturnal haemoglobinuria.
Serum electrophoresis showed normal protein bands and blood for sickling, malarial parasite, leptospiral antibody titre, HIV, HbsAg and VDRL were negative. There was no evidence of DIC (normal serum fibrinogen, thrombin time and fibrin degradation products). Total red cell count and packed cell volume were normal, ruling out polycythaemia. Peripheral smear did not reveal abnormal cells. An echocardiogram showed neither clots in the cardiac chambers nor vegetations.
Anticerebral oedema measures, intravenous gamma globulin and plasmapheresis have a role in acute catastrophic APLS. Anticoagulants including aspirin are the mainstay of treatment, maintaining an INR of >3, and steroids are also recommended.
Our patient was treated initially with anti-cerebral oedema measures, aspirin, heparin and methylprednisolone, with good supportive care, switching over to warfarin, aspirin and prednisolone after 3 weeks. He is now on warfarin, aspirin and low-dose prednisolone. The anticardiolipin antibodies are positive in low titres (<2SD), and lupus anticoagulant is still positive.
Livedo reticularis has been reported to be associated with cerebrovascular accidents and antiphospholipid antibodies (Sneddon's syndrome).
After hospital treatment for about 6 weeks, he had fully recovered except for minimal bilateral sensorineural deafness (a consequence of the sagittal sinus thrombosis), detected on an audiogram. A repeat MRI showed recanalisation of the thrombosed sinuses (figure3).
Clinical features of antiphospholipid syndrome
arterial and venous thromboses
heart valve disease
recurrent spontaneous abortions
APLS, first described in 1983, is an important prethrombotic disorder associated with a specific group of antibodies.1It is more frequent in females. Hughes originally studied it in patients with systemic lupus erythematosus but found that the patients had “atypical lupus or no lupus at all”, hence the concept of primary APLS.2 B2-Glycoprotein and other such proteins are required for the binding of antibodies to phospholipids.3Treatment is with long-term anticoagulants and aspirin.4It can be further classified into primary and secondary varieties.
In 1965, Ian Bruce Sneddon, a British dermatologist, had described patients with livedo reticularis and cerebrovascular accidents which he attributed to some form of vasculitis.5 Later, this entity was found to be associated with the presence of antiphospholipid antibodies (Sneddon's syndrome).6 Its mode of inheritance is autosomal dominant and only 126 cases have been reported in the literature up to 1992. We would strongly advise investigation of a young individual with stroke and skin lesions for antiphospholipid antibodies.
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