Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

Neurologic disorders are among the most prominent clinical manifestations associated with the antiphospholipid syndrome. Such neurologic disorders are predominantly related to focal central nervous system thrombo-occlusive events. This review summarizes the latest data regarding the clinical aspects of stroke and other neurologic manifestations associated with antiphospholipid antibodies.

Antiphospholipid (aPL) antibodies have been associated with a variety of neurologic manifestations (Table 1). In patients with systemic lupus erythematosus (SLE) and in those with lupus-like disease and the primary antiphospholipid syndrome (APS), aPL antibodies are strongly associated with central nervous system (CNS) disease [1, 2].

Neurologic disorders are mainly, but not exclusively, linked to focal cerebral or ocular thrombo-occlusive events. One of the most prominent and grave features associated with aPL is cerebral ischemia, which manifests as single or multiple ischemic strokes or transient ischemic attacks (TIAs). Thrombo-occlusive events may manifest indirectly in various ways, such as with seizures or multi-infarct dementia secondary to arterial thrombosis, or with intracranial hypertension secondary to cerebral venous thrombosis (CVT). Rarely, an acute ischemic encephalopathy may manifest, particularly as part of the catastrophic APS [3, 4]. Additional nonthrombotic mechanisms likely underlie other neurologic manifestations. For example, direct reactivity of aPL with nervous tissue was demonstrated and may be relevant to some neurologic disorders [5, 6]. However, aPL antibodies are identified in 2% to 7% of healthy young people and in higher rates among the elderly [7], complicating interpretation of associations with different neurologic manifestations.

Thrombotic events associated with aPL are venous in approximately two thirds of the cases; the other third is arterial. The specificity of different aPL to thrombosis in the venous or arterial circulation needs to be investigated. The cerebral arterial tree is the most common arterial bed affected among patients with aPL. Rosove and Brewer [8] observed that the site of the first arterial or venous event tended to predict the site of subsequent events.

Several studies suggest that the presence of high titers of anticardiolipin (aCL) immunoreactivity correlate with an increased risk of thrombosis [9**, 10, 11]. Generally, titers of IgG aCL antibodies are greater than 40 IgG phospholipid units (GPL), although this is a somewhat arbitrary cut-off point that depends on nonstandardized test systems. IgG is the aCL isotype mainly implicated in thrombosis. Tuhrim et al. [12**] recently found in a large case-controlled study of patients enrolled in the Minorities Risk Factors and Stroke Study that IgM aCL antibodies are also associated with increased stroke risk [12**]. In addition to the lupus anticoagulant (LA) and aCL, antibodies against antiphosphatidyl serine, antiphosphatidylinositol, and anti-b2-glycoprotein I (b2-GPI) were also associated with increased risk of ischemic stroke [13, 14, 15, 16].

Physicians should maintain a high index of suspicion for the presence of aPL antibodies in patients with ischemic neurologic disease. aPL antibodies should be assessed in patients with clinical or serologic manifestations of the APS (such as recurrent miscarriages, venous thrombosis, and livedo reticularis), in young patients after stroke, in any patient after recurrent strokes, and in patients with thrombo-occlusive events of undetermined origin.

• Focal Cerebral Ischemia

Antiphospholipid antibodies are common among children or young adults with ischemic stroke [14, 17, 18]. Among unselected patients with stroke, prevalence rates of aPL proteins ranged from 1% to 38% [7, 11,12,19, 20, 21,22**, 23, 24, 25, 26]. There are conflicting results between the studies regarding whether aPL antibodies constitute an independent risk factor for ischemic stroke in such a population [11, 12, 13,21, 22**, 23, 24, 25, 26]. aPL positivity among patients with ischemic stroke may also be a marker of higher mortality [19, 27].

In the Antiphospholipid Antibodies in Stroke Study (APASS) conducted at 15 medical centers, 255 consecutive patients with first ischemic stroke and 255 age- and sex-matched hospitalized patients without stroke were evaluated for aCL [22**]. Positive aCL was present in 9.7% of stroke patients and 4.3% of controls. aCL antibodies were significantly associated with incident ischemic stroke, with odds ratio of 2.3 after adjusting for other traditional vascular risk factors. In the largest study of its kind, Tuhrim et al. [12**] demonstrated among 524 hospitalized patients with acute stroke and 1020 community controls enrolled in the Minorities Risk Factors and Stroke Study, that aCL constitutes an independent stroke risk factor, conferring a fourfold increased risk of ischemic stroke. IgG and IgM isotype aCL were shown to be associated with increased stroke risk.

In several case-control studies and in two studies using nested case-controlled designs, aCL did not constitute an independent risk factor. No significant differences in aCL titers were found when comparing 100 apparently healthy adult men subsequently developing an ischemic stroke with 100 well-matched controls; whereas aCL titers were significantly associated with subsequent deep vein thrombosis and pulmonary embolism in the Physician’s Health Study [11]. More recently, in an incident case-referent study nested within the MONICA and Swedish Västerbotten cohort, IgM isotype aCL was found to be associated with future stroke but did not constitute an independent risk factor after adjusting for conventional vascular risk factors [26].

The risk of recurrent thrombo-occlusive events in patients with focal cerebral ischemia and aPL was estimated in several studies, although these studies have limited statistical power. In a 2-year follow-up of first ischemic stroke patients included in APASS, aCL positivity (>10 GPL) was not an independent, significant risk factor for subsequent thrombo-occlusive events or death [28]. In a prospective study of consecutively identified patients with focal cerebral ischemia and aPL, more than 50% of the cohort had at least one recurrent thrombo-occlusive event during the 7-year follow-up [29]. Patients with the highest IgG aCL titers had the shortest times to subsequent thrombo-occlusive events. In another study, patients with aCL titers >40 GPL had subsequent thrombo-occlusive events occur sooner and more often after focal cerebral ischemia associated with IgG aCL. In addition, more of them subsequently died 10]. These issues are addressed in the WARSS-APASS collaborative study [30]. Patients with first ischemic stroke enrolled in the Warfarin Aspirin Recurrent Stroke Study (WARSS) had baseline aPL status determined at the time of a recurrent thrombo-occlusive event, and then yearly if the results were positive. Results of this prospective, carefully conducted study may be valuable in assessing the clinical implications of the presence of aPL among patients with ischemic stroke, and in assessing the efficacy of warfarin versus aspirin for secondary prevention in such a population.

There is no unique clinical presentation of aPL-associated ischemic stroke. Infarcts are caused by small- or large-vessel occlusive disease, and may be cortical, subcortical, or deep. Cerebral angiography results are normal or reveal large-vessel occlusion or stenosis without changes suggestive of vasculitis [31]. Patients with only transient dysfunction generally have normal radiologic study results, including angiography. Transient or permanent visual symptoms secondary to retinal or optic nerve ischemia are common [32, 33]. Relatively young patients have frequent multiple, yet minor, cerebrovascular events associated with high positive aCL (>100 GPL with no disability-titer correlation). These events are often associated with tobacco abuse, hyperlipidemia, LA, systemic ischemic events, and occult cardiac disease [34].

Echocardiographic studies have demonstrated heart valve abnormalities, which may be a cause for cardioembolism, in approximately a third of patients with the APS. Valvular lesions associated with aPL occur as valve masses (nonbacterial vegetations) or thickening [35, 36]. aCL and other prothrombotic states are common in patients with cryptogenic ischemic stroke and a patent foramen ovale [37], possibly with paradoxic embolism as an underlying cause.

Data suggest that immunologic factors may contribute to thrombosis and atherosclerosis, mediated by aPL. When human plaques were studied, b2-GPI were found to reside in the subendothelial regions and colocalize with CD4 lymphocytes [38]. Thus, the immune response toward b2-GPI may play an important role in atherogenesis, serving as a possible target for antigen-specific therapies. aPL can contribute to atheroma development by targeting some of the sequential steps that constitute early atherogenesis [39]. Antibody response to phospholipids, oxidized LDL, b2-GPI, prothrombin, and endothelial cells partially overlap and may reflect a broadening spectrum of autoantibody-associated atherothrombotic disease.

Unselected patients with ischemic stroke are often elderly with multiple vascular risk factors, diffuse atherosclerosis, and cardiac impairment, and thus may have multiple underlying mechanisms for thromboembolism. Cardiovascular risk factors are associated with substantially higher rates of IgG isotype aCL and higher immunoreactivity, and may complicate interpretation of a positive assay in such a population [40*]. The interaction of aPL with conventional vascular risk factors remains unclear. There should be a distinction between patients with the primary or secondary APS (ie, characterized by recurrent thrombotic events, fetal loss, livedo reticularis, and thrombocytopenia) and older patients with multiple cardiovascular risk factors who are found to have positive serology for aCL but who do not demonstrate the other features of the syndrome. In both groups, aPL may predispose to thromboembolism, representing the sole causative factor in the patients with primary or secondary APS. However, in older patients, aPL may potentially be one of the many predisposing factors.

• Cerebral Venous Thrombosis

Cerebral venous thrombosis is an infrequent condition with a variety of underlying causes, including acquired or congenital varieties of thrombophilia. CVT has been described with aCL or other aPL [41, 42, 43]. aCL may be an important factor contributing to the development of CVT but is mostly associated with other predisposing factors. Onset of aCL-related CVT was reported to occur at a relatively young age and with relatively more extensive superficial and deep cerebral venous system involvement than CVT unrelated to aCL [42]. aCL antibodies were identified in patients developing idiopathic intracranial hypertension, through mechanisms related or unrelated to major venous thrombosis [44,45].

• Dementia

An association between dementia and aPL is probably explained mostly by multiple brain infarcts. Similar to other patients with vascular dementia, these patients may show other neurologic findings of focal cerebral disease or history of clear-cut cerebrovascular events. Infarct features favoring vascular dementia include bilaterality, multiplicity (>1), location in the dominant hemisphere, and location in the limbic structures (fronto- and mediolimbic). Extensive white matter lesions may also cause vascular dementia [46].

Mosek et al. [47] found that five of 87 demented elderly patients (6%) had elevated aPL. All except for one (who had mixed dementia) were diagnosed clinically as having dementia of the Alzheimer type, compared with zero of 69 normal age-matched controls. However, aPL antibodies are probably not a common cause for dementia in the general population. In addition, the relationship to degenerative dementia is unclear. aPL may be associated with cognitive deterioration by other mechanisms, as suggested by a 22-year-old woman with depression, dementia, and chorea gradually developing over an 8-month period who had a negative work-up except for aPL. A favorable response to a regimen of prednisone, hydroxychloroquine, and aspirin cleared the dementia. Such a remarkable response to immunosuppressive therapy strongly implies a nonthrombotic/ischemic pathogenesis [48].

Up to 40% of the patients with Sneddon’s syndrome (characterized by livedo reticularis and cerebrovascular disease) have elevated aPL levels, suggesting an association between APS and Sneddon’s syndrome [49]. Despite the similarities in the clinical and MRI findings between patients with the APS and those with Sneddon’s syndrome, patients with Sneddon’s syndrome generally have a progressive clinical course with increasing disability and cognitive deterioration. However, patients with APS have a more benign course. Patients with APS may have infarcts in territories of the main cerebral arteries, whereas patients with Sneddon’s syndrome more commonly have leukoaraiosis and small lacunar infarcts [50].

Studies assessing for an association between subtle neuropsychological dysfunction and aPL in normal adults demonstrated that increased aCL titers in normal elderly persons may be associated with subtle neuropsychological dysfunction. The studies also demonstrated that these changes may be part of a subclinical phase of neurologic involvement and may prove to be the most sensitive markers of the syndrome [51, 52]. Single photon emission computed tomography (SPECT) may reveal areas of lesion in patients with the APS [53].

• Myelopathy

Several cases of transverse myelopathy (TM) associated with aPL have been published, most of them in patients with SLE [54, 55]. TM presents with acute or subacute onset of paraparesis or quadriparesis, sphincter abnormalities, and a sensory level, depending on the level, extension, and severity of the spinal cord involved.

The age of the patients with myelopathy ranges from childhood to the 80s. The spinal MRI may show the cord to be thickened with areas of hyperintensity on proton density- and T2-weighted images and with inconsistent contrast enhancement. Several patients have been observed who had recurrent episodes, with recurring hyperintensities and eventually cord atrophy [56]. Most patients responded to steroid pulse therapy with or without anticoagulation and some showed further response to cyclophosphamide [57]. Four of our patients have been treated with steroids in the acute phase and then by pulses of cyclophosphamide with continued improvement over 1 year.

• Chorea

Chorea is a well-known phenomenon in SLE, shown to be strongly related to the presence of aPL. Chorea in several patients, most of whom are children, has been described in association with primary APS. The chorea, which is generalized or involved with only one side of the body (hemichorea), evolves within a couple of weeks, may last weeks to 1 month, and may sometimes persist beyond a month. Except for symptomatic response to dopamine receptor-blocking agents (haloperidol, the most commonly used), chorea usually responds to immunosuppressive treatment, including high doses of glucocorticoids and cyclophosphamide.

In many cases, an ischemic brain lesion can be found in the caudate nucleus or the putamen. In a few patients who had functional brain imaging with SPECT or fluorodeoxyglucose and positron emission tomography (PET), a decreased circulation in the basal ganglia and in the medial parts of both temporal lobes or an increase in lentiform and caudate nucleus metabolism prevailing on one side was shown. After treatment, these changes were completely normalized [58, 59].

Cervera et al. [60], in a review of the clinical, radiologic, and immunologic characteristics of 50 patients with chorea and the APS from 1985 through 1995, demonstrated that 96% of the patients were female, approximately two thirds had SLE or lupus-like syndrome, and approximately one third had primary APS. The mean age of the patients was 23 years (range 6-77 years), with onset of chorea occurring in childhood (6-14 years) in 20% and at 60 years of age or later in 4%. Many patients developed chorea after additional exposure, such as oral contraceptive use or pregnancy, but most (66%) had only one episode. Chorea was bilateral in 55% of the patients. CT and MRI scans reported cerebral infarcts in one third of the patients [60].

• Migraine

Migraine headaches have been reported in patients with the APS. The prevalence of aPL is not increased in patients with migraine, either with or without SLE. This has been shown in children and adults [61, 62**]. The study by Tietjen et al. [62**], which included patients with transient focal neurologic events (TFNE) (518 in the TFNE group with migraine with aura, 497 in the TFNE group with migraine without aura and 366 controls), found no association between aPL and migraine or TFNE. aPL antibodies were found in six of 16 patients with migrainous stroke, suggesting the possible role of aPL in the pathogenesis of the rare cases of migrainous stroke [63].

• Other Neurologic Manifestations

  • Psychosis

Antiphospholipid antibodies have been found in patients with SLE with CNS involvement, including psychiatric disturbances [2]. Schwartz et al. [64] studied the prevalence of aPL in 34 psychiatric patients. They found that 32% of nonmedicated patients with acute psychosis had aPL, most of which were IgG-aCL isotype, and 90% had LA compared with 20 normal controls, none of whom tested positive, and 9% had LA.

•  Seizures

In patients with SLE, there is a higher rate of seizures in those with aPL antibodies [65]. The etiology for seizures in primary APS or aPL associated with SLE is probably vascular. A consecutive series of 23 children with cryptogenic partial epilepsy were observed for an association between aPL and cryptogenic seizures; an association was found in three, with no clinical or serologic evidence for SLE [66]. Inzelberg and Korczyn [67] found LA in four patients who had late-onset epileptic seizures of whom three had no clinical or electroencephalographic evidence of focality and all of whom had no significant cerebral pathologic findings on cranial CT. The frequency of aPL in patients with cryptogenic seizures is unclear.

•  Multiple sclerosis (MS) or MS-like disease

The association between MS and MS-like disease and aPL has been studied. Karussis et al. [68**] isolated a subgroup of 20 patients (eight males and 12 females) from a cohort of 100 patients with MS (diagnosed according to PoserQrspuo;s criteria) who were consistently positive for aCL. Most of the patients (15 of 20) had a slowly progressive myelopathy, and six of 20 had optic neuropathy. Headache was a dominant symptom in eight of the 20 patients. Less common symptoms included cognitive and psychiatric disorders and chronic fatigue. Oligoclonal bands in the cerebrospinal fluid were detected in only three of the 20 patients. The neurologic deterioration was slower than expected in MS. They concluded that for these patients, other mechanisms, presumably vascular, may be involved in the pathogenesis of the neurologic symptoms and that management should include antiplatelet or anticoagulant agents [68**]. Cuadrado et al. [69] analyzed the clinical, laboratory, and imaging findings of MS-like expression in a cohort of patients with APS. Twenty-seven patients with the diagnosis of probable or definite MS with symptoms suggesting an underlying connective tissue disease, uncommon findings for MS on MRI, atypical evolution of MS, or aPL positivity were studied and compared with patients with MS only. The neurologic signs or symptoms did not differ between the patient groups. In addition, the laboratory findings were not useful in distinguishing APS from MS. Patients with MS had significantly increased severity score in white matter lesions (and in the pons and cerebellum), whereas patients with APS had significantly increased scores in the putamen. Most of the patients with APS showed a good response to oral anticoagulant treatment. In patients with secondary APS, the outcome was poorer [69].

•  Transient global amnesia

Transient global amnesia has been associated with aPL [70]. This transitory memory disturbance remains an enigma from a pathogenic point of view and may be caused by ischemia, seizure discharge, or migraine.

•  Polymyositis or dermatomyositis

Sherer et al. [71] assessed the association between aPL and polymyositis or dermatomyositis in their patients, and found that three had both conditions, two of whom had SLE.

•  Guillain Barré syndrome

Antiphospholipid antibodies were found in sera of patients with the Guillain-Barré syndrome (GBS). However, these autoantibodies are probably produced as a result of the myelin damage rather than being the cause of the demyelination. [72,73].

• Conclusions

There is compelling evidence demonstrating the strong association between aPL and neurologic manifestations in patients with the primary or secondary APS. Central nervous system thrombo-occlusive events underlie most neurologic disorders, but additional nonthrombotic mechanisms likely underlie some other manifestations. The clinical role of aPL in the general stroke population is unclear but may be elucidated by ongoing large clinical studies.

---

References

1. Asherson RA, et al.: Cerebrovascular disease and antiphospholipid antibodies in systemic lupus erythematosus, lupus-like disease, and the primary antiphospholipid syndrome. Am J Med 1989, 86:391-399.

2. Toubi E, et al.: Association of antiphospholipid antibodies with central nervous system disease in systemic lupus erythematosus. Am J Med 1995, 99:397-401.

3. Briley DP: Neurological disease associated with antiphospholipid antibodies. Ann Neurol 1989, 25:221-227.

4. Asherson, RA: The catastrophic antiphospholipid syndrome, 1998: a review of the clinical features, possible pathogenesis and treatment. Lupus 1998, 7:S55-S62.

5. Caronti B, et al.: Serum anti-beta2-glycoprotein I antibodies from patients with antiphospholipid antibody syndrome bind central nervous system cells. J Autoimmun 1998, 11:425-429.

6. Kent MN, et al.: Ultrastructural localization of monoclonal antiphospholipid antibody binding to rat brain. Exp Neurol 2000, 163:173-179.

7. Tanne D: Epidemiology of antiphospholipid antibodies and vascular disease. In Clinical Approach to Antiphospholipid Antibodies. Edited by Levine SR and Brey R. Woburn, MA: Butterworth-Heinemann; 2000: 1-18.

8. Rosove MH: Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992, 117:303-308.

9. Finazzi G, et al.: Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a 4-year prospective study from the Italian registry. Am J Med 1996, 100:530-536.

In this multicenter Italian prospective study, 360 patients with antiphospholipid antibodies were observed for 4 years. Previous thrombosis and aCL > 40 GPL were found to be independent predictors of future thrombosis.

10. Levine SR, et al.: IgG anticardiolipin antibody titer > 40 GPL and the risk of subsequent thrombo-occlusive events and death: a prospective cohort study. Stroke 1997, 28:1660-1665.

11. Ginsburg KS, et al.: Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med 1992, 117:997-1002.

12. Tuhrim S, et al.: Elevated anticardiolipin antibody titer is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity. Stroke 1999, 30:1561-1565.

This is the largest case-control study to date, demonstrating that aCL constitutes an independent stroke risk factor, conferring a fourfold increased risk of ischemic stroke. IgG and IgM aCL were shown to be associated with increased stroke risk.

13. Tuhrim S, et al.: Antiphosphatidyl serine antibodies are independently associated with ischemic stroke. Neurology 1999, 53:1523-1527.

14. Toschi V, et al.: High prevalence of antiphosphatidylinositol antibodies in young patients with cerebral ischemia of undetermined cause. Stroke 1998, 29:1759-1764.

15. Fiallo P, et al.: Antibodies to beta(2)-glycoprotein I in ischemic stroke. Cerebrovasc Dis 2000, 10:293-297.

16. Tanne D: Antiphospholipid-protein antibodies and ischemic stroke: not just cardiolipin any more. Stroke 1998, 29:1755-1758.

17. deVeber G, et al.: Prothrombotic disorders in infants and children with cerebral thromboembolism. Arch Neurol 1998, 55:1539-1543.

18. Kenet G, et al.: Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischemic stroke in children. Stroke 2000, 31:1283-1288.

19. Chakravarty KK, et al.: Antibodies to cardiolipin in stroke: association with mortality and functional recovery in patients without systemic lupus erythematosus. Q J Med 1991, 79:397-405.

20. Montalban J, et al.: Antiphospholipid antibodies in cerebral ischemia. Stroke 1991, 22:750-753.

21. Camerlingo M, et al.: Anticardiolipin antibodies in acute non-hemorrhagic stroke seen within six hours after onset. Acta Neurol Scand 1995, 92:69-71.

22. The Antiphospholipid Antibodies in Stroke Study (APASS) Group: Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. Neurology 1993, 43:2069-2073.

In this multicenter, case-control study, positive aCL levels were present in 9.7% of stroke patients and 4.3% of controls. The odds ratio for stroke status, given aCL positivity, was 2.31 after adjusting for conventional vascular risk factors, suggesting that aCL appears to be an independent risk factor for stroke in these patients.

23. Zielinska J, et al.: Anticardiolipin antibodies are an independent risk factor for ischemic stroke. Neurol Res 1999, 21:653-657.

24. Muir KW, et al.: Anticardiolipin antibodies in an unselected stroke population. Lancet 1994, 344:452-456.

25. Metz LM, et al.: The frequency of phospholipid antibodies in an unselected stroke population. Can J Neurol Sci 1998, 25:64-69.

26. Ahmed E, et al.: Anticardiolipin antibodies are not an independent risk factor for stroke: an incident case-referent study nested within the MONICA and Vasterbotten cohort project. Stroke 2000, 31:1289-1293.

27. Tanne D, et al.: Anticardiolipin antibodies and mortality in patients with ischemic stroke: a prospective follow-up study. 2001: Submitted for publication.

28. The Antiphospholipid Antibodies and Stroke Study Group: Anticardiolipin antibodies and the risk of recurrent thrombo-occlusive events and death. Neurology 1997, 48:91-94.

29. Levine SR, et al.: Recurrent stroke and thrombo-occlusive events in the antiphospholipid syndrome. Ann Neurol 1995, 38:119-124.

30. WARSS, APASS, PICSS, and HAS Study Groups: The feasibility of a collaborative double-blind study using an anticoagulant: the Warfarin-Aspirin Recurrent Stroke Study (WARSS), the Antiphospholipid Antibodies and Stroke Study (APASS), the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), and the Hemostatic System Activation Study (HAS). Cerebrovasc Dis 1997, 7:100-112.

31. Levine SR, et al.: Cerebrovascular and neurologic disease associated with antiphospholipid antibodies: 48 cases. Neurology 1990, 40:1181-1189.

32. Castanon C, et al.: Ocular vaso-occlusive disease in primary antiphospholipid syndrome. Ophthalmology 1995, 102:256-262.

33. Demirci FY, et al.: Ocular involvement in primary antiphospholipid syndrome. Int Ophthalmol 1998, 22:323-329.

34. Verro P: Cerebrovascular ischemic events with high positive anticardiolipin antibodies. Stroke 1998, 29:2245-2253.

35. Hojnik M, et al.: Heart valve involvement (Libman-Sacks endocarditis) in the antiphospholipid syndrome. Circulation 1996, 93:1579-1587.

36. Espinola-Zavaleta N, et al.: Echocardiographic evaluation of patients with primary antiphospholipid syndrome. Am Heart J 1999, 137:973-978.

37. Chaturvedi S: Coagulation abnormalities in adults with cryptogenic stroke and patent foramen ovale. J Neurol Sci 1998, 160:158-160.

38. George J, et al.: Immunolocalization of beta2-glycoprotein I (apolipoprotein H) to human atherosclerotic plaques: potential implications for lesion progression. Circulation 1999, 99:2227-2230.

39. Harats D, et al.: Atheroma: links with antiphospholipid antibodies, Hughes syndrome and lupus. QJM 1999, 92:57-59.

40. Tanne D, et al.: Anticardiolipin antibodies and their associations with cerebrovascular risk factors. Neurology 1999, 52:1368-1373.

A study demonstrating that the presence of multiple cerebrovascular risk factors is associated with substantially higher rates of positive IgG isotype aCL and with higher immunoreactivity. These findings caution against overdiagnosis of the antiphospholipid syndrome, and consequent changes in management among patients with multiple cerebrovascular risk factors.

41. Deschiens MA, et al.: Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis. Stroke 1996, 27:1724-1730.

42. Carhuapoma JR: Cerebral venous thrombosis and anticardiolipin antibodies. Stroke 1997, 28:2363-2369.

43. Christopher R, et al.: Anticardiolipin antibodies: a study in cerebral venous thrombosis. Acta Neurol Scand 1999, 99:121-124.

44. Mokri B: Pseudotumor syndrome associated with cerebral venous sinus occlusion and antiphospholipid antibodies. Stroke 1993, 24:469-472.

45. Leker RR: Anticardiolipin antibodies are frequently present in patients with idiopathic intracranial hypertension. Arch Neurol 1998, 55:817-820.

46. Erkinjuntti T, et al.: Imaging of static brain lesions in vascular dementia: implications for clinical trials. Alzheimer Dis Assoc Disord 1999, 13:S81-S90.

47. Mosek A, et al.: Dementia and antiphospholipid antibodies. Dement Geriatr Cogn Disord 2000, 11:36-38.

48. Van Horn G: Reversible dementia and chorea in a young woman with the lupus anticoagulant. Neurology 1996, 46:1599-1603.

49. Frances C, et al.: Sneddon syndrome with or without antiphospholipid antibodies: a comparative study in 46 patients. Medicine 1999, 78:209-219.

50. Fetoni V, et al.: Clinical and neuroradiological aspects of SneddonQrspuo;s syndrome and primary antiphospholipid antibody syndrome: a follow-up study. Neurolog Sci 2000, 21:157-164.

51. Schmidt R, et al.: Anticardiolipin antibodies in normal subjects: neuropsychological correlates and MRI findings. Stroke 1995, 26:749-754.

52. Jacobson, MW, et al.: Neuropsychological deficits associated with antiphospholipid antibodies. J Clin Exp Neuropsychol 1999, 21:251-264.

53. Kao CH, et al.: Evaluation of regional cerebral blood flow with 99mTc-HMPAO in primary antiphospholipid antibody syndrome. J Nucl Med 1999, 40:1446-1450.

54. Lavalle C, et al.: Transverse myelitis: a manifestation of systemic lupus erythematosus strongly associated with antiphospholipid antibodies. J Rheumatol 1990, 17:34-37.

55. Kovacs B, et al.: Transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and review of the literature. Ann Rheum Dis 2000, 59:120-124.

56. Campi A, et al.: Recurrent acute transverse myelopathy associated with anticardiolipin antibodies. AJNR Am J Neuroradiol 1998, 19:781-786.

57. Aziz A, et al.: Acute optic neuropathy and transverse myelopathy in patients with antiphospholipid antibody syndrome: favorable outcome after treatment with anticoagulants and glucocorticoids. Lupus 2000, 9:307-310.

58. Masala C, et al.: Chorea in primary antiphospholipid syndrome. Clin Neurol Neurosurg 1996, 98:247-248.

59. Kiechl-Kohlendorfer U: Chorea as the presenting clinical feature of primary antiphospholipid syndrome in childhood. Neuropediatrics 1999, 30:96-98.

60. Cervera R, et al.: Chorea in the antiphospholipid syndrome: clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature. Medicine 1997, 76:203-212.

61. Verrotti A, et al.: Lack of association between antiphospholipid antibodies and migraine in children. Int J Clin Lab Res 2000, 30:109-111.

62. Tietjen GE, et al.: Role of anticardiolipin antibodies in young persons with migraine and transient focal neurologic events: a prospective study. Neurology 1998, 50:1433-1440.

This is a large case-control study in which aCL positivity was assessed for 645 patients with transient focal neurologic events, 518 patients with transient focal neurologic events with migraine with aura, 497 patients with migraine without aura, and 366 controls. aCL positivity did not differ significantly between the groups, demonstrating that aCL is not associated with migraine.

63. Silvestrini M, et al.: Migrainous stroke and the antiphospholipid antibodies. Eur Neurol 1994, 34:316-319.

64. Schwartz M, et al.: High association of anticardiolipin antibodies with psychosis. J Clin Psychiatry 1998, 59:20-23.

65. Herranz MT, et al.: Association between antiphospholipid antibodies and epilepsy in patients with systemic lupus erythematosus. Arthritis Rheum 1994, 37:568-571.

66. Angelini L, et al.: Partial seizures associated with antiphospholipid antibodies in childhood. Neuropediatrics 1998, 29:249-253.

67. Inzelberg R: Lupus anticoagulant and late onset seizures. Acta Neurol Scand 1989, 79:114-118.

68. Karussis D, et al.: A subgroup of multiple sclerosis patients with anticardiolipin antibodies and unusual clinical manifestations: do they represent a new nosological entity? Ann Neurol 1998, 44:629-634.

The authors isolated a subgroup of 20 patients from a cohort of 100 patients with MS who are consistently positive for aCL and characterized them clinically and by ancillary laboratory test results. These patients showed a slower progression and had some atypical features for MS, such as persistent headaches and absence of oligoclonal bands in the cerebrospinal fluid, suggesting involvement of other pathogenetic mechanisms.

69. Cuadrado MJ, et al.: Can neurologic manifestations of Hughes (antiphospholipid) syndrome be distinguished from multiple sclerosis? Analysis of 27 patients and review of the literature. Medicine 2000, 79:57-68.

70. Montalban J, et al.: Transient global amnesia and antiphospholipid antibodies. Clin Exp Rheumatol 1989, 7:85-87.

71. Sherer Y, et al.: Dermatomyositis and polymyositis associated with the antiphospholipid syndrome: a novel overlap syndrome. Lupus 2000, 9:42-46.

72. Gilburd B, et al.: Autoantibodies to phospholipids and brain extract in patients with the Guillain-Barré syndrome: cross-reactive or pathogenic? Autoimmunity 1993, 16:23-27.

73. Marchiori PE, et al.: Cerebrospinal fluid and serum antiphospholipid antibodies in multiple sclerosis, Guillain-Barré syndrome and systemic lupus erythematosus. Arq Neuropsiquiatr 1990, 48:465-468.