Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 46, Num. 4, 2000, pp. 258-261

Journal of Postgraduate Medicine, Vol. 46, No. 4, October-December, 2000, pp. 258-261

Antiphospholipid Antibody Positive Young Stroke: An Analysis of 12 Cases

Panagariya A, Garg A, Sureka RK

Department of Neurology, SMS Medical College & Hospital, Jaipur - 302 004, India
Address for Correspondence: Ashok Panagariya, DM, 7, Raj Niketan, Moti Doongri Road, Jaipur, India E-mail: rsureka@usa.net

Code Number: jp00087

Abstract:

AIMS AND OBJECTIVES: To study clinico-investigative profile of 12 young (<45 years) patients with stroke who tested positive for anti phospholipid antibodies (APLA). SUBJECTS AND METHODS: The diagnostic, clinical, laboratory and radiologic features in 12 APLA positive young patients who presented with stroke were studied. The APLA analysis included estimation of anticardiolipin (aCL) antibodies and lupus anticoagulant (LA). Other relevant tests included anti-nuclear antibody, human immunodeficiency virus, Venereal Diseases Research Laboratory, platelet count, echocardiography and carotid Doppler. APLA positive strokes were those cases where either the immunoglobulin G (IgG) and immunoglobulin M (IgM) were raised or LA was positive, and other known causes were excluded. RESULTS: Levels of IgG (aCL) was raised in 11 cases (mild 7, moderate 1, high 3), IgM was elevated in all the 12 cases (moderate 2, high 10). Of the two LA positive cases both were IgM positive but in one IgG was negative. Five patients showed small multiple bilateral cerebral infarcts on computerised tomography (CT) scan. 5 patients had history of recurrent strokes. Hemiparesis was more frequent than hemiplegia. None presented with dense hemiplegia. All patients recovered to normal functional capacity and did not have recurrence on drugs. CONCLUSION: A preliminary study on APLA positive young strokes showed certain clinical and radiological features, mild to moderate stroke, pre-treatment recurrences, multiple smaller infarcts on CT, which could be clustered in a subgroup of stroke in young. Incidentally these patients showed a good prognosis in terms of long term outcome. (J Postgrad Med 2000; 46:258-261)

Key Words: Antiphospholipid antibody, ischaemic stroke, antiplatelet therapy.

Anti phospholipid antibodies (APLA) are a part of heterogeneous group of circulating serum polyclonal immunoglobulins (IgG, IgM, IgA or mixed) that bind negatively charged or neutral phospholipid component of cell membranes and cause increased tendency to venous or arterial thrombosis.¹ There has been a dramatic surge of interest in APLA and associated clinical disorders especially focal ischaemic cerebrovascular diseases.² They are probably present in up to 50% of the young persons with stroke and perhaps even in higher prevalence with recurrent ischaemic and diseases like systemic lupus erythematosous (SLE).³ Due to unexplained aetiology in large number of young stroke patients and absence of conventional predisposing risk factors like hypertension, diabetes, atherosclerosis etc., the importance of APLA estimation may increase many fold.

Twelve young patients of stroke with APLA positivity were assessed in detail to analyse whether they form an independent subgroup having specific pattern of occlusive disease.

Subjects and Methods

Ninety-four young patients (<45 years) with stroke admitted in neurology department, SMS Medical College, Jaipur between March '96 and June '98 were studied. Apart from computerised tomography (CT) and Magnetic Resonance Imaging (MRI) (where ever necessary) all the routine and related specific investigations like haemogram, platelet count, activated partial thromboplastin time (aPTT), prothrombin time, chest x-ray, electrocardiogram, liver function and renal function tests, lipid profile, ultrasonography, echocardiography, carotid Doppler studies, anti-nuclear antibody (ANA), VDRL, HIV, were done. Aetiology was established in 64 (68%) cases. These included haemorrhagic stroke due to HT and aneurysm, cerebral venous thrombosis (CVT) related with pregnancy and puerperium, and thrombo-embolic stroke associated with hypertension, diabetes mellitus and valvular heart disease. In the remaining 30 patients where the aetiology could not be established, APLA were tested by anticardiolipin (aCL) antibodies and lupus anticoagulant (LA) estimation⁴ on admission (third to tenth day of stroke). aCL was tested by enzyme linked immunosorbent assay (Varelisa cardiolipin kit). Solid phase enzyme immuno essay technology (IEMA) was used to measure titre of antibodies. aCL titres were categorised into negative (<10MPL or GPL units), low positive (10-20MPL or GPL units), moderately positive (21-60MPL or 21-100 GPL units) and highly positive (>60MPL or 100GPL units).⁵ LA titre was estimated by dilute Russell viper venom technique (DRVVT). In 11 patients aCL antibodies (both IgG & IgM) were found to be positive in different titres and in one patient LA was positive along with high IgM. This sub group of 12 APLA positive cases was subsequently analysed. Various causes of secondary APLA like SLE, adult/juvenile rheumatoid arthritis, auto-immune thrombocytopaenic purpura, dermatomyositis, polymyositis, syphilis, leprosy, tuberculosis, HIV infections and drugs like chlorpromazine, phenothiazine, phenytoin etc. were excluded by relevant history and investigations. Anti ds-DNA was not done, as facilities were not available.

Results

The salient features are shown in Table 1. While IgG was raised in 11 cases (mild 7, moderate 1, high 3), IgM was elevated in all the 12 cases (moderate 2, high 10). Of the two LA positive cases both were IgM positive but in one IgG was negative. Five patients showed small multiple bilateral cerebral infarcts on CT scan. Five patients had history of recurrent strokes. Hemiparesis was a more frequent occurrence than hemiplegia. None presented with dense hemiplegia. Case 4 had suffered more than two episodes of foetal loss. Case 12 had cerebral venous thrombosis with cortical infarcts. All the 12 patients responded well to treatment with anti-platelets, aspirin or ticlopidine (in cases of single stroke) and anticoagulants (in cases of recurrent strokes).

Discussion

APLA have been reported in 1% to 46% of stroke patients and 1-4% in normal controls,⁶ depending on the design and criteria of studies and the age distribution of the patients.^6-8 Nagaraja et al⁹ in a study of 60 cases of young stroke found elevated aCL in 23% patients. The anti phospholipid antibodies in stroke study⁵ (APASS) indicated an average incidence of 10%. The mean age in the present study was 36.8 years., which is about two decades younger than average age of thromboembolic patients. The predisposing risk factors for stroke like diabetes, hypertension, atherosclerosis and hyperlipidaemia were absent in these patients. Similar low prevalence of recognised risk factors has also been reported in stroke patients with APLA in other studies.¹⁰ The available data so far suggest that APLA should be suspected in young stroke patients with history of previous thrombotic event, deep venous thrombosis, thrombocytopaenia and women with history of recurrent foetal loss.¹¹

In the present study, level of aCL both IgG and IgM were raised, while Levine¹² suggested that IgG is the aCL most commonly seen with APLA positive stroke. In the recent study by Tuhrim et al¹³ aCL antibodies conferred a four fold increased risk of ischaemic stroke. Young stroke patients tend have higher levels of APLA and multiple infarcts than general stroke population.¹⁰ Whether elevated cardiolipin antibody titre is an independent risk factor is still not conclusive.^13,14 Patients with migraine headache with or without aura have had APLA and some of these patients had suffered cerebral infarcts.¹¹ The occurrence of vascular headache in three cases in the present series is consistent with this association, although the mechanism is uncertain. Incidentally, none of the patients in the present study had thrombocytopaenia. Five patients in present series had multiple (two or more) infarcts and in one patient cerebral venous thrombosis was found. Nagraja et al⁹ did not observe any case of venous thrombosis while in a study conducted by Mehndiratta et al¹⁶ one out of seven patients had venous stroke. Feldmann and Levine² in 1995 also suggested that high titres of APLA are associated with a relatively high risk of recurrent thrombotic events, especially stroke. Five patients in our series had recurrent strokes, but its correlation with high titres of APLA could not be established. The lack of availability of follow up values of aCL is the limitation of the study. On comparing the APLA positive and APLA negative stroke patients in the present study, we found APLA positive stroke group had an average age of 36.8 years which was younger than average age for APLA negative group. More over multiple strokes/TIA episodes were more frequent in APLA positive group than the APLA negative group. These findings are in collaboration with other studies.¹⁵

APLA leads to a hypercoagulable state by several different mechanisms like endothelial anticoagulant dysfunction, abnormalities of prostacyclin, anti-thrombin III, placental anticoagulant protein, protein C and protein S and complement activation any of which would lead to thrombosis.¹⁰ In addition to these factors, various studies have shown that a₂-glycoprotein I (a₂ GPI) may be the key immunogen in the APLAS. LA also requires a co-factor identified as lipid bound prothrombin to interact with negatively charged phospholipids.¹⁷ In this reaction the LA recognizes an epitope that becomes exposed upon calcium mediated binding of prothrombin to phospholipid. The LA by reacting with proteins at these or other sites, may interfere with the normal haemostatic system and contribute to a prothrombotic environment by binding to thrombine activated platelets inhibiting thrombin mediated endothelial cell prostacycline release or inhibitory protein C activation.

Therapeutic options in patients with stroke and APLA include antithrombotics and immune based treatments. Antithrombotics include anticoagulants, subcutaneous heparin or low molecular weight heparin and antiplatelet agents aspirin and ticlopidine. Immune based therapies include corticosteroids and immunosuppressants¹¹. In our series, patients with first episode of stroke were put on aspirin or ticlopidine and were followed fortnightly with total blood counts. Patients with recurrent events were put on oral anticoagulant. All patients recovered to normal functional capacity and did not have recurrence. Our findings are in agreement with other study by Munther et al.¹⁸ It is difficult to make any recommendation about preferred therapy as the number of cases with follow up is too small. Besides drug therapy recent studies have indicated that calcium intake in dairy milk has inverse relation with risk for ischaemic stroke.¹⁹ There are no clear recommendations about the duration of the therapy but consensus could favour the life long treatment with antiplatelet drugs or anticoagulants to prevent recurrences.¹⁶

Though the study comprises of a small sample certain inferences can be drawn. The APLA positive young stroke cases may constitute an independent subgroup with certain clinical, investigatory and prognostic predictors. Thus, they have mild to moderate strokes, more often multiple smaller infarcts on CT/MRI, history of pretreatment recurrences and relatively better, immediate and long term outcome.

References

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