Cerebral microembolism, a disease marker for ischemic cerebrovascular events in the antiphospholipid syndrome of systemic lupus erythematosus?

OBJECTIVES: We investigated whether the detectability of microembolic Doppler signals (MES) in the intracranial circulation may help to define the individual cerebrovascular risk in systemic lupus erythematosus (SLE) with antiphospholipid syndrome (APS). MATERIAL AND METHODS: Retrospective cross-sectional study of 70 patients with SLE with or without APS, and 30 controls with a history of cerebral ischemia of unknown cause. Of all patients, 38 had a clinical history of APS and 32 did not. RESULTS: 15 patients with APS (39%) showed MES. In contrast, all patients without APS and 29 of 30 controls were microemboli-negative. MES were more strongly associated with cerebrovascular symptoms than with APS, antiphospholipid antibodies, or cardiac pathology. The time elapsed since the last ischemic cerebrovascular symptom was significantly shorter in microemboli-positive patients than in microemboli-negative patients (P<0.001). CONCLUSION: MES may be related to disease activity in patients with SLE and APS. Their detection may help to assess individual cerebrovascular risk and contribute to therapeutic decision making and therapeutic monitoring.

Microsphere embolism-induced elevation of nerve growth factor level and appearance of nerve growth factor immunoreactivity in activated T-lymphocytes in the rat brain.

Changes in nerve growth factor (NGF) level and type of cells producing NGF were investigated in the rat brain after sustained cerebral embolism. The NGF level was determined by a two-site enzyme immunoassay specific for NGF. The cerebral cortex, striatum, and hippocampus of the embolized hemisphere maximally contained 2.4-, 2.4-, and 1.7-times higher NGF levels than the corresponding regions of the nonembolized hemisphere. A significant increase was transiently observed for 1 week in the cerebral cortex and striatum, whereas the increase was longer lasting, at least of 4 weeks' duration, in the hippocampus. To examine the localization of NGF-like immunoreactivity (NGF-LI), we used a newly developed anti-NGF peptide antiserum that specifically recognized a 30-kDa molecule(s) in the hippocampal extracts or in NGF cDNA-transfected cells, suggesting that the antibody predominantly reacted with the putative NGF precursor protein(s). NGF-LI, which was localized in neurons of the normal or non-embolized hemisphere, was reduced, and on the embolized side new signals emerged in small non-neuronal cells having a round shape. These included cells with common leukocyte antigen CD45 and T-lymphocyte antigen CD3, which did not appear in the normal or non-embolized hemisphere. NGF-LI and CD3 were colocalized in a substantial number of the cells, suggesting that some activated T-lymphocytes produce NGF for neuronal regeneration after sustained cerebral embolism.

The presence of infection-related antiphospholipid antibodies in infective endocarditis determines a major risk factor for embolic events.

OBJECTIVES: The impact of infection-associated antiphospholipid antibodies (APA) on endothelial cell activation, blood coagulation and fibrinolysis was evaluated in patients with infective endocarditis with and without major embolic events. BACKGROUND: An embolic event is a common and severe complication of infective endocarditis. Despite the fact that APAs are known to be associated with infectious diseases, their pathogenic role in infective endocarditis has not been clearly defined. METHODS: The relationship among the occurrence of major embolic events, echocardiographic vegetation size, endothelial cell activation, thrombin generation, fibrinolysis and APA was examined in 91 patients with definite infective endocarditis, including 26 patients with embolic events and 65 control subjects without embolic events. RESULTS: Overall, 14.3% of patients exhibited elevated APA levels. Embolic events occurred more frequently in patients with elevated levels of APA than in patients without (61.5% vs. 23.1%; p = 0.008). Patients with elevated levels of APA showed higher levels of prothrombin-fragment F1 +2 (p = 0.005), plasminogen-activator inhibitor 1 (p = 0.0002), von Willebrand factor (p = 0.002) and lower levels of activated protein C (p = 0.001) than patients with normal levels of APA. Thrombin generation and endothelial cell activation were both positively correlated with levels of APA. The occurrence of elevated APA levels was frequently associated with structural valve abnormalities (p = 0.01) and vegetations >1.3 cm (p = 0.002). CONCLUSIONS: Infection-associated elevated APA levels in patients with infective endocarditis are related to endothelial cell activation, thrombin generation and impairment of fibrinolysis. This may contribute to the increased risk for major embolic events in these patients.

Anticardiolipin antibodies: a study in cerebral venous thrombosis.

OBJECTIVES: Anticardiolipin antibodies (aCL) have been recognized as a marker for an increased risk of thrombosis. There are no documented reports from India on the prevalence of aCL in patients with cerebral venous thrombosis (CVT). Our study aimed at establishing the prevalence of these antibodies in patients with CVT and evaluating their clinical significance. SUBJECTS AND METHODS: Thirty-one patients with CVT diagnosed by angiography and/or cranial CT were investigated for the presence of aCL along with 31 age- and sex-matched normal controls. All subjects had no overt evidence of systemic lupus erythematosis or related autoimmune disorders. The titres of IgG and IgM type of aCL were estimated in the sera using a solid phase enzyme-linked immunosorbent assay. RESULTS: Anticardiolipin antibodies were detected in 22.6% of CVT patients compared to 3.2% of normal controls (95% confidence interval (CI) 1.01 to 75.65). Five CVT patients had both IgG and IgM antibodies, and 2 had only IgG antibodies. The aCL positive group did not differ from the aCL-negative group with respect to the clinical characteristics and the demographic and risk factor profile. CONCLUSION: The findings suggest that anticardiolipin antibodies are a risk marker for cerebral venous thrombosis. Further studies on a larger group of patients are needed to establish the role of aCL in the pathogenesis of CVT.

Cerebrovascular ischemic events with high positive anticardiolipin antibodies.

BACKGROUND AND PURPOSE: The aim of our study was to characterize the patient profile and prognostic value associated with high positive IgG (>100 GPL) anticardiolipin antibodies (aCL). METHODS: We studied the clinical, laboratory, radiological, and prospective historical features of ischemic cerebrovascular disease in patients with >100 GPL titers. From our neurology department, 27 consecutive patients were prospectively identified and followed up (mean follow-up time, 34 months). RESULTS: The mean age of our cohort was 41 years. Lupuslike illness occurred in 3; 23 had primary antiphospholipid syndrome, including 3 who met criteria for Sneddon's syndrome; 1 patient had progressive systemic sclerosis. Cerebral infarcts occurred in 74% and were recurrent in 37%. Systemic ischemic events, most commonly deep vein thrombosis, occurred in 37%. Tobacco use was documented in 85%, hyperlipidemia in 74%, hypertension in 44%, and diabetes mellitus in 7% of patients. A prominent headache history was present in 67%. Lupus anticoagulant (LA) was present in 72%, approximately one half had positive antinuclear antibodies and thrombocytopenia, and one quarter had a false-positive VDRL. We compared mean GPL levels in patients testing positive for specific laboratory features of antiphospholipid syndrome with those testing negative for these parameters. Only the LA(+) group had a significantly higher mean GPL than the LA(-) group (P=0.006). Brain imaging showed nonlacunar infarcts in 73% and lacunes in 12%. Of 19 cerebral angiograms, 5 (26%) showed large-vessel occlusive disease and 6 (32%) branch obstruction. Echocardiograms were abnormal in 75%: thickened left-sided valves in 33% and vegetations in 12%. Recurrent cerebrovascular ischemic events were observed in 96%, with transient events (mean rate, 25%/y) occurring 5 times more frequently than strokes (mean rate, 5%/y). Using a standardized disability scale blinded to aCL titer, neurological impairment was severe in 7%, moderate in 30%, and mild or nonexistent in 63%, and unrelated to mean GPL value (P=0.567). Titers fluctuated greatly for individual patients, and most did not consistently test as highly positive. An analysis of fluctuation in symptom severity with concurrent GPL values did not show a statistically significant correlation. Compared with historical controls having a wide range of positive titers, the presence of high IgG aCL titers did not confer a worse prognosis for disability and recurrent ischemic events. CONCLUSIONS: Our data suggest that cerebrovascular events associated with high positive GPL are frequently multiple and minor (with no disability-titer correlation), present in relatively young patients, and often associated with tobacco abuse, hyperlipidemia, LA, systemic ischemic events, and occult cardiac disease.

Acute stroke in a young female with anti-human beta2-glycoprotein I antibodies.

We report the case of a woman who, at the age of 27, developed a cerebral arterial occlusion. The laboratory investigations showed an anti-human beta2-glycoprotein I antibody, but no other biological sign of antiphospholipid antibody syndrome or autoimmune disorders. The patient otherwise presented with diabetes and moderate obesity. The species specificity of anti-beta2-glycoprotein I antibodies probably explains the discrepancy between false negative results for antiphospholipid antibodies assayed by clotting and ELISA studies and positivity for anti-human beta2-glycoprotein I. Further studies will be important to evaluate the frequency of such antibodies, as well as their value as a risk factor for venous and arterial thrombosis, and their signification within the antiphospholipid antibody syndrome.

Vascular cell adhesion molecule-1 mRNA is expressed in immune-mediated and ischemic injury of the rat nervous system.

In this study we used nonradioactive in situ hybridization for the cellular localization of vascular cell adhesion molecule-1 (VCAM-1) mRNA in immune-mediated, ischemic and degenerative diseases of the rat nervous system. In the acute phase of experimental autoimmune encephalomyelitis and neuritis VCAM-1 mRNA was expressed not only on the luminal surface of inflamed vessels but also in perivascular cells suggesting a functional role of VCAM-1 in both endothelial adhesion and local restimulation of autoantigen-specific T cells. Accordingly, perivascular T cell accumulation was most pronounced at sites of local VCAM-1 mRNA expression. In addition, VCAM-1 mRNA was detected in the border zone around photochemically induced cerebral infarcts which is the predeliction site of T cell infiltration and expression of immune activation markers during the first week after ischemia. VCAM-1 mRNA was absent from the center of the infarcts as well as axotomized central and peripheral nerves undergoing Wallerian degeneration. These data indicate that VCAM-1-mediated adhesion processes are involved in immune-mediated and ischemic diseases of the nervous system but not in T cell-independent macrophage recruitment during Wallerian degeneration.

Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis.

BACKGROUND AND PURPOSE: Cerebral venous thrombosis (CVT) is an infrequent condition with a large variety of causes. However, in 20% to 35% of cases, no cause is found. We studied coagulation parameters, including activated protein C resistance associated with factor V gene mutation (factor V Leiden) and anticardiolipin antibodies, in a large series of patients with CVT with or without identified cause or risk factor. METHODS: Forty patients (30 women and 10 men) aged 19 to 71 years (mean age, 36.2 years) with CVT diagnosed by angiography and/or MRI were studied 1 to 18 years after thrombosis. No known cause was found in 10 idiopathic cases. Coagulation studies included the following tests: fibrinogen, antithrombin, protein C, protein S, plasminogen, anticardiolipin antibodies, activated protein C resistance, and factor V Leiden. RESULTS: Six cases of thrombophilia (15%) were found: 1 protein C deficiency, 1 protein S deficiency, and 4 activated protein C resistance with heterozygous factor V Leiden mutation (10%). Only 1 case (protein S deficiency) was found in the group of 10 patients with idiopathic CVT. In the other 5, there was another cause or risk factor. Three patients (8%) had increased anticardiolipin antibodies: 1 with systemic lupus and 2 with primary antiphospholipid syndrome; 2 of these 3 patients also had factor V Leiden mutation. CONCLUSIONS: Although present in a number of CVT cases, acquired (anticardiolipin) or congenital varieties of thrombophilia (factor V Leiden being the most frequent) are almost invariably associated with other predisposing factors. This suggests that (1) these abnormalities should be looked for in patients with CVT, whether a cause is found or not, and (2) their presence should not deter the search for other potential causes. The detection of such abnormalities has major practical consequences on the long-term management of patients to prevent further thrombotic episodes.

Elevated levels of anticardiolipin antibodies and epilepsy in lupus patients.

To examine the association between anticardiolipin (aCL) antibodies and epilepsy, we investigated the serum titers of aCL antibodies in a total 252 systemic lupus erythematosus (SLE) patients recruited in a prospective study. Twenty-one cases with epilepsy which were not attributable to any causes other than SLE were identified after being followed-up for five years. The clinical manifestations were recorded and blood samples were tested for the presence of aCL antibodies (IgG, IgM and IgA isotypes). Among 21 patients with epilepsy, 12 (57.1%), 2 (9.5%) and 2 (9.5%), respectively, had elevated baseline serum levels of IgG, IgM and IgA aCL antibodies. There was a dose-response relationship between risk of seizure and the baseline serum level of aCL antibodies (P < 0.01). The odds ratio of developing seizure were 3.7 for those who had a high level of aCL antibodies compared with those without a detectable level of aCL antibodies as the referent. Our results indicate that epilepsy as a primary neuropsychiatric event among lupus patients is associated with a high titer of aCL antibodies.

Gender influences the magnitude of the inflammatory response within embolic cerebral infarcts in young rats.

BACKGROUND AND PURPOSE: The inflammatory response within cerebral infarcts may have an influence on tissue damage. Since old animals with an impaired immune response have decreased inflammation after experimental cerebral infarction, we postulated that female animals with an increased immune response will have an increased inflammatory response after cerebral infarction. METHODS: Embolic cerebral infarcts were produced by photochemical irradiation of the right carotid artery in 12 female Fischer rats. The inflammatory response within 4-day-old infarcts was quantitated by histology with the use of computer-assisted image analysis and compared with that in 12 male rats from a previous series. RESULTS: Severe infarcts had the most pronounced inflammatory response. Female rats had an increased inflammatory response in infarcts of all severity, which was statistically significant in severe cerebral infarcts even after adjustment for infarct size. Severe infarcts in males were significantly larger than those in females. CONCLUSIONS: Gender influences the outcome of embolic cerebral infarcts after photochemical damage to the carotid artery, both in terms of the magnitude of the inflammatory response and infarct size. There are numerous gender-related differences in neurochemicals, cytokine production, and drug metabolism that may influence tissue damage after stroke and responsiveness to therapeutic intervention. The preponderance of male animals in stroke research may produce results not applicable to female stroke patients. The use of female animals will be required to provide adequate models for the study of stroke in women.

Cerebral microembolism in patients with Sneddon's syndrome.

BACKGROUND: The pathogenesis of Sneddon's syndrome is unclear. This study addresses the question whether cerebral thromboembolism may be involved in the pathogenesis of the neurologic complications of the disorder. The study consisted of 13 patients with Sneddon's syndrome defined by both generalized livedo reticularis and a history of one or more cerebrovascular ischemic events; none had clinical or Doppler ultrasonographic evidence of atherosclerosis. METHODS: Transcranial Doppler microembolic monitoring of the middle cerebral artery; blood screening for antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies). RESULTS: Five patients (38%) showed clinically silent microembolism at transcranial Doppler monitoring, with individual microembolic event rates of the middle cerebral artery between 2 per hour and 33 per hour. In this group, the time since the last ischemic symptom was significantly shorter than in the eight patients without microemboli. Antiphospholipid antibodies were detected in three patients (23%), all of whom belonged to the microemboli-positive group. CONCLUSIONS: These data suggest that the detectability of both clinically silent cerebral microembolism and antiphospholipid antibodies may provide paraclinical evidence of active disease in patients with Sneddon's syndrome. The results support the notion that an immune-mediated prothrombotic state facilitating the formation of arterial thrombi with subsequent cerebral embolization, and/or triggering in situ thrombosis of cerebral vessels, plays a pathogenetic role in the neurologic manifestations of this disorder.

Value of immunologic testing in stroke patients. A prospective multicenter study.

BACKGROUND AND PURPOSE: The aims of this prospective and multicenter study were to determine the frequency of anticardiolipin and antinuclear antibodies in an unselected ischemic and hemorrhagic stroke population and to evaluate the clinical significance of these autoantibodies. METHODS: Over a 1-year period, we collected plasma from 481 consecutive patients with ischemic or hemorrhagic stroke attending four different hospitals. Blood (10 mL) was drawn from each subject into a citrated glass tube. Plasma was obtained immediately by centrifugation and was stored at -70 degrees C until use. Concentrations of IgM and IgG anticardiolipin antibodies were measured at room temperature in normal (not heat-treated) plasma by standardized enzyme-linked immunosorbent assay. All sera were treated by indirect immunofluorescence on mouse liver and kidney sections for antinuclear antibodies. RESULTS: A total of 481 patients (325 men, 156 women) 16 to 90 years in age (mean age, 61 years) were studied. Anticardiolipin antibodies were present in 5 of 481 (1.04%) patients. One patient was IgG positive and four patients were IgM positive. Of 481 patients, 35 (7.2%) were positive for antinuclear antibodies. Anti-DNA antibodies were not demonstrable in any patient. CONCLUSIONS: The frequency of anticardiolipin antibodies in a heterogeneous stroke population is possibly lower than reported. The routine screening of anticardiolipin and antinuclear antibodies in a stroke population is of questionable value.

Anticardiolipin and acquired protein S deficiency in early childhood.

A 27 month old child presented with left hemiplegia and was found to have deep cerebral venous thrombosis. The deep cerebral venous thrombosis resolved on warfarin. Elevated and fluctuating anticardiolipin antibodies as well as protein S deficiency were detected.

Antisteroid immune complexes and vascular thrombosis during steroid hormone therapy.

To test an immunological hypothesis proposed to explain the pathogenesis of cerebrovascular thrombosis in steroid users, circulating immune complexes were assayed in the sera from 6 control subjects, 14 ever users of oral contraceptive having developed a neurological ischaemic accident, and 7 patients with the same clinical history during use of other sex steroid not containing ethinylestradiol. Beaumont's ammonium sulfate and polyethylene glycol precipitation methods, together with a specific method of isolation of circulating immune complexes using affinity chromatography on Protein A, were used. Radioactivity from labeled ethinylestradiol added to the sera before precipitation was monitored in the precipitates to detect anti-ethinylestradiol antibodies. There were no significant differences for these parameters in the three groups. However, protein content and 3H-EE activity in the precipitates were equally and dramatically reduced after affinity chromatography in the three groups. These latter results do not support the presence of antibodies against ethinylestradiol in steroid users with cerebrovascular thrombosis. Moreover, our data suggest a lack of specificity of Beaumont's method for the isolation of immune complexes containing anti-ethinylestradiol antibodies.

Sneddon's syndrome, anti-cardiolipin antibody and glomerular thrombosis.

Sneddon's syndrome, cerebrovascular thrombosis and livedo reticularis, is often a variant of the "primary" anti-phospholipid syndrome (PAPS). We report a woman with PAPS, presenting as Sneddon's syndrome, with renal impairment and glomerular thrombosis on renal biopsy. An IgG anti-cardiolipin antibody (aCL) was identified. The aCL was purified by affinity chromatography, gel filtration chromatography and ion-exchange chromatography, assayed in a modified ELISA and found to be of the type that requires the plasma protein beta 2-GPI to bind aCL. As beta 2-GPI has anticoagulant properties it is postulated that its interaction with aCL has a pathogenic role in the thrombotic lesions associated with aCL.

[Importance of antiphospholipid antibodies in cerebral ischemia]. / Bedeutung der Antiphospholipidantikörper bei zerebralen Ischämien.

The association between cerebrovascular complications and detection of antiphospholipid antibodies (aPA) has been under clinical and immunological investigation during the last ten years. The occurrence of aPA in coincidence with recurrent thrombosis, miscarriages and thrombocytopenia is termed "primary antiphospholipid syndrome". The most important neurological symptoms are recurrent cerebral arterial and venous ischemias. Especially in the case of young patients with a history of recurrent infarcts, migraine-like headaches and the absence of classical risk factors should lead to a determination of these antibodies. Although the pathogenetic importance of these antibodies is still unclear, patients positive for them seem to carry a higher cerebrovascular risk and should be observed more cautiously. More studies are necessary to define the origin of these antibodies and their role in thrombogenesis. To develop standards for therapeutic management a multicenter study is desirable.

[Antiphospholipid syndrome: a new clinical entity? Part 2: pathophysiological aspects and treatment possibilities]. / Das Antiphospholipid-Syndrom: Eine neue klinische Entität? Teil 2: Pathophysiologische Aspekte und Behandlungsmöglichkeiten.

Antiphospholipid antibodies are immunoglobulins of the IgG, IgM or rarely IgA class directed against phospholipids or phospholipid-protein complexes of the coagulation cascade. They were first described in patients with systemic lupus erythematosus, but are also frequent in other autoimmune diseases, lymphoproliferative and malignant disorders, some bacterial and viral infections, and after drug exposure. Their mechanism of action is considered multiple, disturbing various natural inhibitory pathways of coagulation. Clinically they have been associated with a thrombotic tendency without a proven direct causal role. Both arterial and venous thromboses, as well as habitual abortion in pregnant women, are reported. A variety of treatment measures have been tried against these associated clinical manifestations.

Migraine in patients with stroke and antiphospholipid antibodies.

The association between migraine and antibodies against antiphospholipids is controversial. We investigated the prevalence and the clinical feature of migraine in patients with ischemic stroke and antiphospholipid antibodies. Data were obtained from the medical records of 162 consecutive patients with ischemic stroke over a 2-year period. Ten patients with antiphospholipid antibodies were prospectively identified. A history of migraine was present in 6 of these patients and in only 5 of the 152 patients with negative results for antiphospholipid antibodies (chi-square = 47.68; P < .0001). In the former, migraine had been for a long time the only clinical problem before the occurrence of the ischemic stroke. These findings suggest that migraine is frequent and can be an early and a prominent symptom in the antiphospholipid antibodies syndrome. Further studies are needed to fully elucidate the association of migraine and antiphospholipid antibodies. A better knowledge of this association could allow an early identification of patients at high risk of stroke.

Antiphospholipid antibodies and ischemic stroke.

Antibodies directed against phospholipids are highly associated with episodes of venous and arterial thrombosis, which are often recurrent. There seems to be a skewed frequency of cerebral thrombosis when the arterial circulation is affected. Clinical clues that should lead to evaluation for aPL include stroke in a young adult, recurrent thrombosis or miscarriage, and thrombocytopenia. Associated laboratory abnormalities include a biologically false-positive test for syphilis, abnormal antinuclear antibody titers, and a high erythrocyte sedimentation rate. If the activated partial thromboplastin time is prolonged on routine screening and does not correct with mixing studies, a lupus anticoagulant should be suspected. However, more sensitive and specific tests are usually necessary to detect aPL. Many in vitro and more recently in vivo systems strongly suggest that aPL may be directly implicated in the pathogenesis of thrombosis. Optimal management of patients with aPL-associated thrombosis is unknown. The use of aggressive therapeutic management schemes with such agents as warfarin or corticosteroids is sometimes required.

Prevalence of anticardiolipin antibody in isolated mitral or aortic regurgitation, or both, and possible relation to cerebral ischemic events.

Anticardiolipin antibodies (acLa) are associated with a thrombotic tendency (often involving cerebral ischemic events), are frequently present with systemic lupus erythematosus and have been found together with cardiac valve abnormalities. Previous studies evaluated patients characterized by the presence of acLa or lupus, precluding assessment of the frequency of acLa in those with valvular disease. This study aims to establish the prevalence of acLa in patients with valve disease in the absence of lupus and, furthermore, to determine the influence of acLa on the risk of cerebral events in valve disease. Eighty-seven consecutive patients with mitral or aortic regurgitation, or both, prospectively underwent enzyme-linked immunosorbent assay testing for immunoglobulin G (IgG) and M acLa, as did 24 normal subjects. AcLa values greater than or equal to 3 SD above the normal mean were considered "positive." Prior cerebral events were defined retrospectively. Of 87 patients with valvular disease, 26 had positive IgG acLa levels compared with 0 of 24 normal subjects (p less than 0.01). AcLa values did not vary with valve disease etiology. Focal cerebral events had occurred in 8 patients and were embolic or probably embolic in 7, including 7 of 26 IgG acLa-positive and 1 of 60 IgG acLa-negative patients (p less than 0.001). In the absence of lupus, IgG acLa is highly prevalent among patients with aortic or mitral regurgitation, or both; this association may indicate a relatively high risk for cerebral emboli.