The Antiphospholipid Syndrome as a Neurological Disease

ANTIPHOSPHOLIPID SYNDROME

The Antiphospholipid Syndrome as a Neurological Disease Yoav Arnson, MD,* Yehuda Shoenfeld, MD,† Eisen Alon, MD,* and Howard Amital, MD, MHA*

Objectives: To examine currently known and additional potential neurological manifestations of the antiphospholipid syndrome (APS) and to discuss current and experimental therapeutic options in light of the present knowledge of the disease mechanism. Methods: The PubMed database was searched for articles published between the years 1980 and 2008 for keywords referring to APS and several neurological conditions. Relevant English language articles were reviewed. Results: APS is characterized by diverse neurological manifestations. These include cerebral ischemic events, epilepsy, dementia, cognitive deficits, headaches, psychiatric disorders, chorea, multiple sclerosis-like, transverse myelitis, and ocular symptoms. Some of the symptoms can be associated with ischemia; however, other mechanisms that could lead to similar outcomes have been described, such as direct binding of antiphospholipid antibodies to neural tissue. Current treatment guidelines concern cerebrovascular events only. We propose several different therapeutic options related to the autoimmune nature of the syndrome. Conclusion: Neurological manifestations in APS are diverse and may be confused with other neurologic syndromes. This information is important for the proper diagnosis and management of patients. Experimental therapeutic alternatives expand the treatment options for patients and physicians. © 2010 Published by Elsevier Inc. Semin Arthritis Rheum 40:97-108 Keywords: APS, antiphospholipid antibodies, migraines, seizures, cerebrovascular accidents

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ntiphospholipid syndrome (APS) is manifest by venous or arterial thromboembolic events or by recurrent spontaneous abortions. A wide spectrum of neurological manifestations has been associated with APS (1). Neurologic symptoms may be the presenting features or they may emerge during the course of the disease. The pathological process underlying the neurological manifestations remains obscure. It is postulated that these manifestations arise secondary to ischemic processes involving brain tissue or direct actions of antiphospholipid antibodies (aPL) to neuronal tissue. We surveyed the existing literature regarding APS and its neurologic manifestations and present a review of the existent knowledge of the phenomena, based on human and animal studies. We also discuss current and future therapeutic options and the evidence of their effectiveness.

*Department of Medicine D, Meir Medical Center, Kfar Saba and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. †Department of Medicine B and Center for Autoimmune Diseases, and Tel Aviv University, Sackler Faculty of Medicine, Sheba Medical Center, Tel Hashomer, Israel. Address reprint requests to: Howard Amital, MD, MHA, Head of Department of Medicine D, Meir Medical Center, Tshernichovsky 59, Kfar Saba, 95847, Israel. E-mail: [email protected], [email protected].

0049-0172/10/$-see front matter © 2010 Published by Elsevier Inc. doi:10.1016/j.semarthrit.2009.05.001

METHODS The Medline database was searched, using the following medical subject heading terms both alone and in combination: antiphospholipid syndrome, Hughes syndrome, anticardiolipin, systemic lupus erythematosus, APS, aPL, and lupus anti coagulant. The terms were cross-linked with neurological manifestations, stroke, transient ischemic attack (TIA), epilepsy, dementia, cognitive impairment, hyperactivity, behavioral abnormalities, headache, migraine, psychiatric disorders, chorea, dystonia, movement disorders, multiple sclerosis, transverse myelitis, intracranial hypertension, and blindness. Available articles published in English between the years 1980 and 2008 were reviewed. References noted in relevant articles were also accessed. Preference was given to studies and surveys over case reports and to more recently published articles. Not all articles accessed are addressed in the article. RESULTS APS is defined by the occurrence of venous or arterial thrombosis, often multiple, and recurrent fetal losses in the presence of aPL, namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-␤2-glycoprotein 97

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I (␤2GPI) (2). The syndrome was first described in the 1980s, first referred to as the aCL syndrome or the Hughes syndrome (3). Wassermann and coworkers first described aPL in 1906 among patients with positive serologic test results for syphilis (4). In 1941 aCL were first identified, noted as false-positive syphilis tests (5). A major advance in understanding the syndrome was the recognition that nearly all aPL are in fact directed not against phospholipids per se, but against phospholipid-binding proteins (6). The first such cofactor identified ␤2GPI, after which many others were identified, now numbering in the dozens (7-9). APS-associated antibodies can also directly affect nervous system tissues and the blood– brain barrier, causing various neurologic manifestations. The syndrome may be an isolated autoimmune phenomenon or a manifestation of systemic disorders such as systemic lupus erythematosus (SLE). aPL are found in 30% of adults and in over 50% of pediatric lupus patients (10). The clinical sequelae of isolated (primary) APS and aPLmediated thrombosis in lupus (secondary APS) are similar. Pathogenesis The mechanisms underlying nervous tissue injury remain poorly understood. It is well established that APS is associated with hypercoagulability (11,12). aPL antibodies can induce a prothrombotic state by activating platelets or endothelial cells (13-15), by inhibiting protein C activation (16-18), or by binding to phospholipids or ␤2GPI on endothelial cells or platelet membranes resulting in their activation (19,20). aPL also induce proinflammatory signals including nuclear factor-␬B and the p38 mitogen activation protein kinase (21). Neural injury may be caused by thrombotic occlusion of brain vessels. As in other vessels, aPL can induce a proinflammatory and procoagulant state in human brain microvascular endothelial cells (22). Local ischemia due to brain microvessel thrombi opens the blood– brain barrier. aPL-triggered leukoadhesion and complement activation appear to increase blood– brain barrier permeability in lupus patients (23). Many of the central nervous system (CNS) manifestations cannot be explained solely by thrombotic events (24). The antibodies themselves can interact with the neural tissue. Interleukin-6 release is postulated to damage neuronal and astrocyte cells in APS patients as it does in neuropsychiatric lupus (25). Chapman and coworkers (26) found that aPL bind directly to neural tissue and modulate its functions, while Sun and coworkers (27) observed that aCL bind to mouse brain tissue and may inhibit astrocyte proliferation in vitro. One of the major auto-antigens in APS is ␤2GPI. Although no expressions of either ␤2GPI or of similar proteins were found on Northern blot analysis of human brain tissue, expression of ␤2GPI mRNA by astrocytes, neuronal, and endothelial cells suggest that these cells can

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be a target of autoantibodies in APS. By utilizing a standard procedure for the isolation of serum ␤2GPI, a 100-kD human brain protein was purified, which was found by peptide sequencing to have full homology with the serum protein, histidine-rich glycoprotein (HRGP). Expression of HRGP in rat and human brain tissues was established by reverse transcriptase-polymerase chain reaction studies and a partial sequence of rat brain HRGP was obtained showing 68% homology with the human protein. Immunoglobulin G (IgG) from most APS patients bind to HRGP, which shares distinct biochemical properties with ␤2GPI. It is present in the brain and may be an important auto-antigen (28). Khalili and Cooper (29) reported that patients with SLE and elevated aCL titers had avid antibody binding to myelin. aPL may interfere with endothelial cell function and promote the procoagulant activity of endothelial cells (30). Simantov and coworkers (31) demonstrated that IgG fractions from aPL patients increase mononuclear cell adhesion to human umbilical vein endothelial cells. Existing data indicate that aPL can directly affect cellular functions by attachment, ultimately resulting in pro-coagulant and pro-inflammatory actions. aPL can induce neurotoxicity in cells through overactivation of glutamate receptors (32). The contribution of animal models to the understanding of the pathogenesis of neuro-APS has been invaluable. An example of such a model utilizes immunization of BALB/c mice with monoclonal human aCL antibodies (33). These mice not only displayed elevated levels of circulating aPL, anti-␤2GPI, and antiendothelial cell antibodies but were also impaired neurologically when compared with control mice. MRL/lpr mice develop spontaneous manifestations resembling APS early in life. The symptoms include elevated aPL levels, thrombocytopenia, and increased prevalence of vascular thrombosis episodes compared with their congenic strain MRL/⫹⫹. Lack of motor coordination, reduced activity, and cognitive impairment have also been described (34). Interestingly, genetic and immunological factors interact and determine the neurologic manifestations of APS-induced mouse strains. For instance, autoantibody levels were found to be significantly higher in BALB/c, ICR, and C57BL/6 mouse strains compared with AKR and C3H. These findings were in concordance with the degree of hyperactivity, which was also recorded in the BALB/c and ICR mouse strains (35). An APS-like syndrome can be induced in animal models by immunization with ␤2GPI or aPL antibodies. Immunization of naive mice with an autoantibody results in generation of an anti-idiotypic antibody (ab2). Two to 3 months later, the mice develop anti-anti-idiotypic antibodies (ab3). Ab3 may simulate ab1 in its binding properties. Mice immunized with ␤2GPI develop high levels of aPL as well as thrombocytopenia, prolonged antiprothrombin time in blood tests, and recurrent abortions (36-38).

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Antiphospholipid Syndrome Presenting as Various Neurological Diseases Various neurological disorders have been described in patients with APS (Table 1). Some disorders originate from vascular thrombotic involvement such as cerebral ischemia and visual field defects. Other manifestations such as dementia, seizures, ocular disturbances, headaches, transverse myelitis, Guillain-Barre syndrome, and chorea result from direct injury to neuronal tissue. Accumulating data strongly imply that aPL are also associated with neuropsychiatric and cognitive disturbances (39-45). In a cohort of over 500 patients with the presence of aPL, nonthrombotic manifestations, such as epilepsy, were found in nearly 9% of these patients (46). Another study conducted in a neurological center found that nonthrombotic manifestations occurred in 40% of the patients with the presence of aPL and were often the initial occurring syndromes (47). The relative cumulative distribution of APS-related neurological pathologies is presented in Table 2 as obtained from the largest survey of APS patients to date—an example based on a population cohort of 1000 APS patients. In a study of unselected patients with acute neurological syndromes, a 15% prevalence of aPL was detected (47). The type of aPL (LA, aCL IgG, or aCL IgM) has no significant correlations with the clinical manifestations (Table 3). Stroke Strokes and TIAs are considered the third most common clinical manifestation of APS, after venous thrombosis and livedo reticularis (48-49). APS is a major, and potenTable 1 Central Nervous System Manifestations Associated With Antiphospholipid Antibodies Neurologic manifestations associated with APS Cerebrovascular events Ischemic strokes and transient ischemic attacks (49,161-166) Amaurosis fugax (167,168) Optic neuropathy (169-171) Cerebral venous thrombosis (53,172) Headache and migraine (173-175) Epilepsy (63,176-181) Chorea and dystonia (182) Cognitive dysfunction (91-93,183-187) Dementia (77,188-192) Hyperactivity and behavioral abnormalities (91,92,193,194) Psychiatric disorders Depression (102,195) Psychosis (196) Neurologic symptoms possibly associated with or possibly mimicked by APS Multiple sclerosis (120,197-199) Transverse myelitis (200) Idiopathic intracranial hypertension (201-203)

99 Table 2 The prevalence of Main Clinical Diagnoses Regarding Neuro-APS as Found at the Euro-Phospholipid Project Group (Reference 53) Diagnosis

%

Migraine Stroke Transient ischemic attack Epilepsy Multi-infarct dementia Chorea Acute encephalopathy

20.2 19.8 11.1 7.0 2.5 1.3 1.1

tially preventable, cause of stroke. aPL are found at an overall prevalence of 6.8% in stroke patients (50). In younger stroke patients (under 45 years) a prevalence of 20% has been observed (51). Many studies have linked APS with an increased stroke rate (52). In the Euro-Phospholipid Project Group, a study encompassing 1000 patients with APS (53), a total of 712 neurological events occurred throughout the patients’ lives. Approximately 400 events (56%) were related to a cerebrovascular cause (stroke, TIA, amaurosis fugax, multi-infarct dementia, and cerebral venous thrombosis). Stroke and TIA accounted for 22.9% of the initial manifestations of APS in this patient cohort. An ischemic stroke may occur as a single episode, yet it might reappear. The risk for recurrent stroke appears to be increased in active APS patients with multiple events, and particularly in a patient following the initial cerebral ischemic episode (54). The middle cerebral artery is considered to be the most affected region (55). An association between ␤2GPI-dependent aCL and the incidence of ischemic strokes and myocardial infarctions has been demonstrated. It has also been shown that ␤2GPI-positive patients have a 2-fold increase in the odds of having a stroke within 15 years of follow-up compared with aCL-negative individuals (56). Krause and coworkers (57) identified significant associations between cardiac valve lesions and CNS manifestations in a large group of APS patients. The presence of valvular vegetations was found to be associated with epilepsy and migraine, while valvular thickening, dysfunction, and other abnormalities were significantly associated with migraine. The association between ischemic cerebrovascular disease (stroke or TIA) and ischemic dermatopathy was first described in 1960 by Champion and Rook (58). This came to be known as Sneddon’s syndrome. This disease is Table 3 Correlation of the Neurological Manifestation with the Titers and Types of aPL, as Found in (Reference 204) Neurological Manifestation

LA

aCL–IgG

aCL–IgM

Thrombotic % Nonthrombotic %

61 39

65 35

57 43

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a rare, progressive disorder of unknown etiology, affecting small and medium-sized arteries of the skin and the brain (59). Acute ischemic encephalopathy has also been observed but is a rare feature in SLE patients with aPLs. Patients are acutely ill, are confused, and have asymmetrical quadriparesis, hyperreflexia, and bilateral extensor plantar responses (60). Epileptic Seizures Several reports demonstrates the linkage between aPL and epilepsy (61-63). Undiagnosed epilepsy was also shown to be present in mild forms, with subtle abnormal electroencephalogram recordings (64). Ischemic neuro-parenchymal insults can only partially elucidate the occurrence of epilepsy in APS. The prevalence of poststroke epilepsy in the general population is approximately 10%. In APS patients, the poststroke epilepsy rate is estimated to be 17%, suggesting the involvement of other factors such as a direct immune interaction with the brain (65). Different studies have shown higher titers of aCL, anti␤2GPI, and antiprothrombin antibodies in epileptic patients. The results have no relation to age, gender, or the type of seizures (66,67). In a study involving 538 patients with proven APS, an epilepsy prevalence of 8.6% was found (68). This figure is almost 20 times higher than the epilepsy rate in the general population (0.5-1%). In APS patients small foci or abnormal signals were demonstrated in the white matter using neuroimaging techniques (69). Positron emission tomography scans of APS patients with CNS manifestations may show decreased glucose metabolism in the periventricular areas, suggesting subtle ischemic insults (70). Animal models of APS have improved our understanding of the pathogenesis of epilepsy in APS. Purified IgG from APS patients has been shown to directly permeabilize and depolarize brain synaptoneurosomes (26). aPL bind neurotransmitters such as ATP, thereby interfering with neuronal function (71). It has been suggested that aPL may have a direct effect on seizure genesis through inhibition of the gamma-aminobutyric acid receptor-ion channel complex, which in turn may increase neuronal excitability (72). Dementia Cognitive disturbances and impairments are common and often worrisome manifestations of APS. An association has been observed between elevated aCL titers and either vascular dementia or Alzheimer’s disease in patients without SLE or other collagen vascular diseases (73,74). The pathogenesis of cognitive impairment in APS is not clearly understood. Mosek and coworkers (75) studied 87 patients diagnosed as having dementia and compared them with 69 healthy elderly subjects. They observed higher titers of aPL in the group of patients with dementia compared with controls. Juby and coworkers

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(76) studied the prevalence of aCL in 218 elderly patients. They discovered a significant association between aCL and both vascular dementia and Alzheimer’s disease. Chapman and coworkers (77) studied 23 patients with primary APS and found that 13 (56%) fulfilled the criteria for dementia based on the Hachinski Ischemia Score. The pathogenesis of cognitive impairment in APS is not entirely understood. Suggested mechanisms include aPL antibody-related microvascular thrombosis (78,79) or a direct effect of aPL antibodies on brain tissue (80,81). In the series of 1000 APS patients mentioned above (53), 2.5% of patients were considered to have multi-infarct dementia and no information was provided regarding less severe forms of cognitive impairment or cognitive impairment not related to ischemic pathology. Cognitive impairment has been associated with the presence of aPL in SLE (82,83). In a study involving SLE patients, a negative correlation between performance on neuropsychological testing and disease duration was found in a subgroup of patients with concomitant APS. This correlation was not detected in SLE patients without APS (84). Furthermore, in a group of otherwise healthy individuals, the presence of aPL was associated with inferior performances on neuropsychological tests (85). One of the most common complaints in these patients is poor memory, often with associated attention deficits. Some refer to these subtle changes as a probable preclinical phase of neurological involvement. Cognitive Deficits, Hyperactivity, Behavioral Abnormalities A recent study evaluating cognitive function in APS patients has shown that 42% of APS patients had cognitive deficits compared with 18% of the healthy control subjects (86). Among the most commonly involved cognitive domains were complex attention and verbal fluency. A significant association was noted between cognitive dysfunction and the presence of white matter lesions on brain magnetic resonance imaging (MRI). Kao and coworkers (87) studied 22 patients with the primary APS suffering from mild neuropsychiatric manifestations (headache, depression, personality disorders, memory loss, and cognitive function deficits) with a normal brain MRI. They found that 16 (73%) of the patients had abnormal singleemission computed tomography findings, mainly diffuse hypoperfusion lesions in the cerebral cortex. Several groups have reported hyperactivity in laboratory mice with induced APS (88). In 1 experimental model of APS, female BALB/c mice were immunized with a pathogenic monoclonal aCL antibody and developed clinical and neurological manifestations of APS. APS mice exhibited hyperactive behavior in an open field (testing spatial behavior) and displayed impaired motor coordination on a rotating bar. The main finding in mouse brain tissue examination was thrombotic occlusion of capillaries with mild inflammation (89,90).

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Immunization with ␤2GPI resulted in elevated levels of circulating antinegatively charged phospholipids and anti-␤2GPI Abs. The immunized mice exhibited hyperactive behavior, as reflected by more frequent rears (instance in which the mouse rises on hind legs to sniff the air) and a greater number of stairs climbed by the mice at specific time intervals (91). In a later study, neurological impairment was detected at an 18-week period from the induction of APS (92). Substantial evidence for the pathogenic role of aPL was achieved by intracerebroventricular administration of immunoglobulins from patients with APS that bound to normal mouse brain. IgG from an APS patient was found to bind strongly to neuronal structures in the hippocampus and cerebral cortex. Mice injected with APS-derived IgG performed worse in the water maze than control mice. These results support the hypothesis that aPL play a direct role in the pathogenesis of the neurological manifestations of APS (93). Headache and Migraine One of the most prominent complaints in APS patients is headaches. This common symptom in clinical practice can vary from classic intermittent migraines to almost continuous incapacitating headaches (94). The association between migraine and aPL has not yet been firmly established. There are widely varying results from different reports. Many authors have reported an association between migraine and LA or aCL (95), while others found no association (96-98). The controversy may be partially due to the inherent difficulty in distinguishing the transient, focal neurological events of migraine from TIA. Cuadrado and coworkers (99) reported 5 APS patients with intractable headaches who were treated with a 7-day course of anticoagulation. All 5 patients demonstrated a marked improvement in pain symptoms following the treatment. Excluding anecdotal reports, prospective studies using appropriate control groups failed to demonstrate an association between aPL and migraine in SLE patients or a higher prevalence of aPL in migraine sufferers (100,101). Psychiatric Disorders Depression and psychosis have been previously associated with aPL (102). Past reports have suggested that autoantibodies, and specifically aPL, may emerge as a response to neuroleptic treatment (103). It is also difficult to establish whether or not the psychiatric symptoms are due to a psychological reaction reflecting coping with a chronic and disabling disorder. In addition, corticosteroid therapy, mainly used in secondary APS patients, may itself produce psychiatric symptoms (104). Schwartz and coworkers (105) studied 34 untreated patients without known autoimmune disorders who were admitted with acute psychosis. aCL and LA presence were determined before and after initiation of neuroleptic

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treatment. They found that 32% of the unmedicated psychotic patients had aPL. Elevated titers of IgG aCL isotype were detected in 24% and LA was detected in 9% of unmedicated patients. No antibodies were present in the control subjects. Twenty-two patients were followed up after medication; 7 of these patients (32%) showed moderate titers of IgG-aCL, and 4 were LA positive (20%). Altogether, APL were detected in 41% of the medicated patients. No relationship was found between the presence of aCL or LA and the neuroleptic medication used. Chorea, Parkinsonism, and Dystonic Movement Disorders Chorea and dystonia are rare manifestations of SLE (106), occurring in 1 to 3% of all SLE patients. Because chorea in SLE is often unilateral, acute in onset, and frequently followed by other CNS manifestations, vascular pathogenesis is the likely cause of this phenomenon (107). A comparable mechanism may be present in patients who develop similar disorders subsequent to oral contraceptive use (108). Cervera and coworkers (109) reviewed the clinical, radiological, and immunological characteristics of 50 patients with chorea and APS. They found that 58% of the patients had defined SLE, 12% presented a “lupuslike” syndrome, and 30% of the patients had APS. In addition, 12% of the patients in the cohort developed chorea soon after initiating estrogen-containing oral contraceptives, 6% developed chorea gravidarum, and 2% developed chorea shortly after delivery. The majority of the patients (66%) had only a single episode of chorea. Computed tomography and MRI scans reported cerebral infarcts in 35% of patients. The chorea symptoms in these patients responded to treatment with a variety of medications such as corticosteroids, haloperidol, antiplatelets, anticoagulants, or a combination of these medications. Many patients responded well to haloperidol and to the discontinuation of oral contraception if this was the precipitating factor. Ocular Syndromes Ocular vaso-occlusive disease manifestations are frequently found in patients with APS (110,111). Amaurosis fugax is 1 of the most common manifestations. Optic neuropathy is a well-known ocular manifestation occurring in patients with SLE, and it remains 1 of the major causes of blindness in these patients. Bilateral optic neuropathy in SLE occurs more frequently than unilateral optic neuropathy and the associated neurological manifestation most often seen in these patients is transverse myelitis (112). On the other hand, optic neuropathy is less frequently described in APS patients without SLE and tends to be unilateral in these cases (113-115). The unilateral occurrence of optic neuropathy is considered to be a focal neurological disease due to a thrombotic event involving the ciliary vasculature. Conversely, bilateral op-

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tic nerve damage in SLE is considered to be due to different immunological mechanisms, such as vasculitis. Neurological Manifestations Possibly Associated with APS or Possibly Mimicked by APS Multiple Sclerosis or Multiple Sclerosis-like Illness Some of the manifestations of APS are similar to those of multiple sclerosis (MS). Clinical syndromes mimicking MS, such as myelitis, balance problems, and sensory problems, mainly in its relapsing–remitting pattern, are reported to occur in association with aPL (116), often leading to the mistaken diagnosis of MS. In a hospital audit, patients were asked the question, “did your doctor(s) at any stage mention a possible diagnosis of MS?” Nearly 1/3 (32%) of aPL-positive patients answered “yes” compared with 8% of controls (117). There is a controversial relationship between MS diagnosis and the presence of aPL. In 1998, Karussis and coworkers (118) screened 70 classic and 100 nonclassic MS patients, labeling as nonclassic those with features unusual for MS. They found a high proportion of aCLpositive patients in the nonclassic MS group. They speculated that these antibodies may be involved in the pathogenesis of the neurological symptoms and therefore management should include antiplatelet or even anticoagulant agents. Tourbah and coworkers (119) found that patients with MS accompanied by autoimmune features, including those with titers of an antinuclear antibody of 1:100 or less, and/or aPL, did not differ from MS patients with regard to age at onset, presenting signs and symptoms, neurological findings, or disease course. Bidot and coworkers (120) discovered that during exacerbation, up to 80% of MS subjects with the relapsing-remitting pattern had elevated titers of IgM antibodies directed against the various aPL antigens tested, but during remission, fewer than half had elevated antibody titers. Due to the small size of their cohort (24 patients), these results remain preliminary, suggesting an association between increased aPL IgM and MS exacerbations. Many reports proclaim that some APS patients may be misdiagnosed with MS, making this a crucial therapeutic point. A careful interview of the patient, a past medical history of thrombotic events, and pregnancy history in women may be useful in the differential diagnosis, favoring APS. The abruptness of onset and resolution of symptoms, especially in regard to visual symptoms (ie, amaurosis fugax), and atypical neurological features such as headache or epilepsy, strongly suggest APS rather than MS. Transverse Myelitis Transverse myelitis, a process involving the entire thickness of the spinal cord, is a rare event with an estimated incidence of 1.34 per million in the general population

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(121). Several case reports and small group studies exist that confirm the association between aPL and transverse myelitis. The prevalence of aPL is higher in SLE patients with transverse myelitis compared with SLE patients in general (122-124). Lavalle and coworkers (125) report 10 of 11 patients with transverse myelitis and SLE as being aPL positive. The pathophysiological mechanism of transverse myelitis in aPL-positive patients is uncertain, although vasculitis and arterial thrombosis resulting in ischemic cord necrosis have been suggested. Idiopathic Intracranial Hypertension The prevalence of idiopathic intracranial hypertension has not been reported for patients with primary APS, although several cases have been described (126,127). In a retrospective study, Kesler and coworkers (128) confirmed the association between idiopathic intracranial hypertension and aCL. They found a relatively high prevalence (8%) of aCL in their patients. Current and Future Management and Therapeutic Considerations Treatment of APS is generally tailored to each patient depending on the degree of symptom severity. The treatment of APS can be directed at thrombo-occlusive events using antithrombotic medications or at modulating the immune response with immunotherapy. The recommended treatment guidelines for APS patients with past thrombotic events are primarily based on treatment guidelines prescribed for venous thrombosis and ischemic stroke. Current recommendations indicate that patients with venous thrombosis and aPL should be treated with long-term warfarin anticoagulation administered to achieve an International Normal Ratio value between 2.0 and 3.0. The length of anticoagulation therapy is highly dependent on the severity of the disorder and the type of blood clotting. In general, a minimum of 6 months of anticoagulation therapy is needed and due to prevalent thrombosis recurrence rates many experts favor indefinite treatment (129). Patients with acute stroke, the most common arterial thromboembolic disorder, are managed initially based on clinical criteria. It appears that, whether or not the diagnosis of APS is known before presentation with new neurologic symptoms, therapy should be guided by well-established criteria for stroke management. If therapy can be provided within 3 hours of onset and all inclusion criteria are met, thrombolytic therapy may be indicated (130). Poststroke therapy also remains a subject of investigation and it is not clear what optimum therapy should be. Data from studies comparing warfarin versus aspirin for recurrent ischemic stroke associated with APS demonstrate that there is no difference between aspirin and warfarin in prevention of recurrent stroke (131-133). The data are mostly based on the Antiphospholipid Antibodies and Stroke Study analysis, which was based on a single

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positive aPL determination and may not generalize to APS patients with persistent and severe disease processes. Given the conflicting data regarding the importance of aPL as a risk factor for recurrent stroke, it is even less clear which patients should have aPL testing performed routinely in evaluating stroke etiology. We recommend routine testing for aPL (aCL, anti-␤2GPI, and LA) in stroke patients with any of the following features: younger than 45 years of age, concomitant diagnosis of SLE, other features of APS, thrombocytopenia, or a prolonged activated partial thromboplastin time. No data are available that address the use of any specific treatment strategies for primary prevention of aPL-associated stroke. Some experts recommend the use of aspirin (325 mg/d) for patients who have persistently positive LA or moderate- to high-titer aPL (134). We agree with that recommendation, understanding that no data support this strategy. There is no consensus of treatment of patients with APS whose symptoms present solely as neurologic disorders that were not necessarily induced by thrombosis, such as MS-like syndromes. A consensus panel concluded that aspirin therapy was a reasonable option in asymptomatic patients (135). Aspirin therapy is strongly recommended in patients with additional stroke risk factors such as lupus, hypertension, diabetes, and dyslipidemia. Anticoagulation is used in catastrophic APS and considered in aPL-positive patients with vascular dementia or focal epilepsy (77). The use of such therapies in other neurologic manifestations lacks compelling evidence and requires careful risk-benefit analysis. Statins loom as attractive agents in the treatment of APS patients. Statins may block aPL-induced endothelial cell activation and intracellular signaling. Downstream endothelial and platelet effects of this inhibition include increased nitric oxide synthase and fibrinolytic activity (136). Statin therapy improves hyperlipidemia and may inhibit ␤2GPI-induced tissue factor overexpression. Other new pharmacological strategies in APS are the inhibition of platelet activation by hydroxychloroquine (137) or the inhibition of monocyte tissue factor expression by angiotensin-converting enzyme inhibitors (138). New and Experimental Approaches for the Prevention of Thrombosis in APS Given the autoimmune nature of the syndrome, therapeutic modalities either replacing or added to anticoagulation include corticosteroids and immunosuppressive agents. An increasing number of animal model studies and case series elaborate on the beneficial contribution of intravenous immunoglobulins on the progression of APS. Yet, due to the uncontrolled nature of these reports and the publication bias naturally related to case reports and small series publications, the role of intravenous immunoglobulins is still to be determined (139-155). Mice with experimental APS were treated with mice anti-idiotypic antibodies. Treatment with the specific anti-

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idiotype or fab fragment resulted in decreased serum levels of anti-aCL antibodies and reduced symptoms; however, discontinuation of the treatment resulted in a recurrent rise in aCL antibody titer (156). Active immunization of mice with an idiotype resulted in prolonged anti-idiotype activity and decreased disease activity (157). Some groups have reported on the value of the chimeric anti-CD20 monoclonal antibody, rituximab. Rituximab is primarily used for the treatment of B-cell lymphomas and is becoming well known for its efficacy in the treatment of rheumatoid arthritis, SLE, immune thrombocytopenic purpura, and various vasculitides. Rituximb has been reported to be very effective in treating patients with APS (158). Most of the information published so far is based on a limited number of case reports, suggesting the possibility of selection bias. Recent studies conducted in experimental autoimmune models indicate that administration of peptides mimicking the binding pattern of an aPL may be beneficial. An innovative approach based on peptides sharing similar characteristics to bacterial antigens and to a specific region of the ␤2GPI molecule that inhibits its binding to cardiolipin was shown to reverse aPL-mediated thrombosis in mice (159,160). DISCUSSION Neurological symptoms are significant manifestations of APS. These symptoms can range in severity from mild to life-threatening and disabling. The presenting symptoms can vary immensely. The underlying mechanism can be related to ischemic damage to brain tissue or to direct damage to brain tissue produced by circulating antibodies. This article reviewed several neurologic conditions that have been either directly associated with APS or mentioned due to a high prevalence of aCL titers. This potential association is important for therapeutic decision-making and patient outcomes. Several reports that discussed anticoagulation treatment for neurologic manifestations such as epilepsy and migraine have been reviewed. Anticoagulation is the current standard of treatment for preventing thrombotic phenomena; however, new approaches inhibiting the inflammatory aspects of the disease may provide additional benefits. REFERENCES 1. Hughes GR. The antiphospholipid syndrome: ten years on. Lancet 1993;342:341-4. 2. Bertolaccini ML, Khamashta MA, Hughes GR. Diagnosis of antiphospholipid syndrome. Nat Clin Pract Rheumatol 2005;1: 40-6. 3. Hughes GR. The anticardiolipin syndrome. Clin Exp Rheumatol 1985;3:285-6. 4. Lowy I. Scientific facts and their public: the history of the diagnosis of syphilis. Rev Synth 1995;116:27-54. 5. Conley CL, Rathbun HK, Orse WI, Onibson JE Jr. Circulating anticoagulants as a cause of hemorrhagic diathesis in man. Bull Johns Hopkins Hosp 1948;83:288-93.

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