Antiphospholipid antibodies syndrome in 'Stroke in young'.
Antiphospholipid antibodies syndrome has emerged as an important entity responsible for stroke in young. Seven cases of young stroke (< 40 years of age) with mean age of 30.1 years (age range 25-39 years, 2 males and 5 females), who tested positive for antiphospholipid antibodies are being reported. All subjects had completed strokes. Six had arterial ischaemic and one patient had venous stroke. One patient suffered from four episodes, three ischaemic and one intracerebral haemorrhage. Two patients suffered from foetal loss. Generalised tonic clonic seizures occurred in three patients. Deep vein thrombosis was observed in one case. Thrombocytopenia was not observed in any case. All the patients had elevated anticardiolipin antibodies (aCL) IgM or IgG, while Lupus anticoagulant (LA) was elevated in 4 cases. Six cases belonged to primary antiphospholipid antibodies syndrome and one to lupus like illness. Oral anticoagulants were administered to maintain a high intensity international normalized ratio (INR). No recurrences were observed during a follow up period of 6-18 months.
Last decade has witnessed emergence of antiphospholipid antibodies syndrome (APLAS) as one of the important treatable causes of stroke in young. This is characterized by systemic venous and arterial thrombosis, the latter occurring most often in the cerebral circulation, foetal loss, seizures, thrombocytopenia and pulmonary hypertension. Antiphospholipid antibodies (APLA) are a part of heterogenous group of circulating serum polyclonal immunoglobulins (IgG, IgM, IgA or mixed) that bind negatively charged or neutral phospholipid component of cell membrane and may cause increased tendency for thrombosis. Anticardiolipin antibodies (aCL) and lupus anticoagulant (LA) are the most important members of this family, leading to both venous and arterial thrombosis. APLAS is strongly associated with systemic lupus erythematosis (SLE) and is labeled as secondary APLAS. In the absence of any autoimmune disease, the syndrome including the presence of APLA and thrombotic events is called primary APLA syndrome. A link between APLA and ischaemic cerebrovascular disease is now well recognized. Moreover, other neurological disorders with an established or presumed vascular pathogenesis including amaurosis fugax, acute ischaemic encephalopathy, multi-infarct dementia, chorea, migraine and transverse myelitis have been reported to be associated with APLAS. Seven cases of young stroke that tested positive for antiphospholipid antibodies are being reported.
During February 1996 to July 1997, seven patients of stroke were detected to be positive for APLA. Patients with very apparent cause of stroke, long standing hypertension, ischaemic heart disease, rheumatic heart disease, meningitis, renal or hepatic dysfunction were excluded from the study.
The diagnosis of stroke was confirmed by CT scan or MRI of the brain. Routine haemogram, urine analysis, x-rays chest, ECG, liver and renal function tests, collagen profile, lipid profile, ultrasonography of abdomen, syphilis and HIV serology, echocardiography, carotid duplex scanner or magnetic resonance angiography were performed in every case. In 12 patients, where no apparent cause of stroke could be found, special investigations like platelet count, anticardiolipin antibodies (aCL) IgG and IgM, lupus anticoagulant and baseline INR were conducted. Anticardiolipin antibodies were tested by ELISA and quantification was done as units per ml. The quantitative estimation of anticardiolipin antibodies was done by Varelisa cardiolipin kit (Pharmacia & Upjohn, Freiburg, Germany). IEMA-Solid Phase technology was used to measure the titre of antibodies. aCL titres were categorized into negative (<10 MPL or GPL units), low positive (10-20 MPL or GPL units), moderately positive (21-60 MPL or 21-100 GPL units) and highly positive (>60 MPL or 100 GPL units).1 Dilute Russell Viper venom time (dRVVT) selectively activates factor X to factor Xa which activates prothrombin II to thrombin II with phospholipids and factor V. By this method LA titre can be measured. Pooled normal plasma serves as control. Russell Viper venom from Diagnostica Stago was used. Normal value of dRVVT is approximately 25 seconds. Activated Partial thromboplastin time (APTT) is a good screening test for diagnosing coagulation disorders. Citrated plasma was added to APTT reagent and incubated for 3 minutes at 37O C. Calcium chloride solution was added and the time required to form a clot was measured.
Results of standard workup of a case of stroke in young and special investigations are highlighted in [Table I]. Out of the 7 cases tested positive for aCL, three had mild elevation, while four revealed moderate elevation of antibodies. Three patients had moderate to severe anaemia. None showed evidence of thrombocytopaenia. Case no.1 experienced one haemorrhagic stroke in addition to three ischaemic strokes. Case no 5 had an infiltrating lung lesion in the middle zone on left side, which was thought to be tubercular but didn't improve on rigorous antitubercular therapy for a period of 3 months.
In 1983, Hughes described for the first time a syndrome comprising of thrombosis, abortion, cerebral disease and the lupus anticoagulant, therefore it is also called Hughes syndrome. The syndrome, embracing venous and arterial thrombosis, livedo reticularis hypertension, cerebral involvement (with a marked propensity to cerebral infarction), recurrent miscarriages, thrombocytopaenia, among others were described in detail by Harris et al. As stated above, APLAS is associated with either arterial or venous thrombotic phenomenon. All of our cases had ischaemic stroke but one patient also had a haemorrhagic stroke, although bleeding complications are extremely rare among LA patients. The occurrence of haemorrhagic stroke is not reported, moreover, LA was negative in this case. The antiphospholipid antibody in stroke study (APASS) group demonstrated that aCL may be risk factor for cerebral ischaemia and stroke not only in the young but also in the elderly.
Case controlled studies suggest a prevalence of APLA of 4.3% in healthy people. Nagaraja et al (1997) in a study of sixty healthy Indian subjects, reported elevated levels of aCL in 3.2%. We could not do case control study since this test is expensive and patients had to bear the cost. APLA have been reported in 1% to 46 % of stroke patients,, depending on the design and criteria of studies and the age distribution of patients. APASS indicated an average incidence of 10 %. Nagaraja et al (1997) in a study of 60 cases of young stroke found elevated aCL in 14 patients (23%). In our study, one patient had recurrent venous infarcts and another had deep vein thrombosis of calf muscles, while Nagaraja et al didn't observe any case of venous thrombosis. Katrak and Ramteke reported elevated levels of aCL in 5/14 cases of cerebral venous thrombosis, in a study of 62 cases with an age range of 7-70 years. Further details about such a high incidence are not mentioned. Before 1997, there were only anecdotal reports of description of APLAS in the Indian literature., Pulmonary hypertension has been reported in APLAS but the infiltrating lung lesions (as in one of our cases) have not been reported. This may be a chance association but investigations were undertaken to rule out other common causes like tuberculosis and collagen vascular diseases etc. Moderate to severe anaemia of normocytic normochromic type may be one of the manifestations of wider spectrum, not reported in the western literature. APLAS occurring in association with autoimmune disorders, especially SLE or malignancies, is labeled as secondary APLAS. In the absence of any associated condition as mentioned above, the condition is labelled as primary APLAS. In our study, we had 6 cases of primary APLAS and one case of lupus like illness, who had malar rash and fever, but didn't meet the criteria of SLE as laid down by American Rheumatism Association.
APLA lead to a hypercoagulable state by several distinct mechanisms like endothelial anticoagulant dysfunction, abnormalities of prostacyclin, antithrombin III, placental anticoagulant protein, protein C and protein S, and complement activation, any of which could lead to thrombosis. In addition to these factors, various studies have shown that b2-GP1 may be the key immunogen in the APLAS. APLA may occur during ingestion of various drugs, including phenytoin, quinidine, hydralazine, procainamide, phenothiazines, alpha-interferon and cocaine. Thus while collecting blood sample, the patient should be off the above mentioned drugs. A low prevalence of recognised risk factors for stroke and atherosclerosis has been reported in stroke patients with aCL. One patient each had hypercholestrolaemia and mild hypertension of recent origin respectively. Both these patients had no evidence of carotid occlusive disease or atherosclerotic manifestations elsewhere in the body.
Newer associations with APLAS are being described. Some of the conditions where high titre of aCL has been found are Sneddon's syndrome, Budd-Chiari syndrome, Chronic hepatitis C, eosinophilia myalgia and toxic oil syndrome.
Several therapeutic approaches including corticosteroids, immunosuppressives, plasma exchange, antiplatelets and anticoagulants have been tried with variable outcomes. Khamashta et al in a study of 147 cases with 947 patient years of follow up demonstrated a clear benefit of high intensity INR (international normalized ratio >3) with long term warfarin therapy as compared to low intensity INR or aspirin. The patients with APLAS should remain on life long anticoagulants to prevent recurrences.
To conclude, cases with recurrent miscarriages, deep vein thrombosis of any site, unexplained thrombocytopaenia, venous or arterial ischaemic stroke etc should be investigated for antiphospholipid antibodies. This is a treatable condition, and can be prevented with long term anticoagulation. All young patients with stroke where no aetiology is found, must be investigated for APLAS.