935

Antiphospholipid Antibodies: Neuropsychiatric Presentations Jean-Christophe Gris, MD, PhD1

Benjamin Brenner, MD2

1 Department of Haematology, University Hospital, Nîmes and

University of Montpellier, France 2 Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel

Address for correspondence Jean-Christophe Gris, MD, PhD, Department of Haematology, University Hospital, Nîmes and University of Montpellier, GHU Caremeau, Place du Pr. Robert Debré, 30029 Nîmes, France (e-mail: [email protected]).

Abstract

Keywords

► antiphospholipid antibodies ► neurology ► psychiatry

Antiphospholipid antibodies (aPL) are associated with a wide range of neurological, psychological, and psychiatric manifestations. In addition to clearly delineated purely thrombotic manifestations, which define the neurological contribution to the antiphospholipid syndrome, the strength of the other described associations is highly variable, and the underlying pathophysiological mechanisms are not fully understood. Some indications seem to support a psychiatric impact of aPL. The magnitude of the association and cellular and molecular mechanisms involved need to be further elucidated.

Antiphospholipid antibodies (aPL) include a wide range of autoantibodies, and their number and categorization have strikingly broadened over recent years. While the initial description of aPL was limited to reaction with anionic phospholipids (PLs), their characteristics progressively matured from false-positive Wassermann reaction for syphilis to two more circumscribed markers, that is, the emblematic lupus anticoagulant (LA) activity and anticardiolipin antibodies (aCL). aPL reactions with other PLs, for instance the zwitterionic phosphatidylethanolamine, have been lately highlighted. The antiphospholipid syndrome (APS) was defined by precise clinical criteria (strictly delimited thrombotic and/or obstetric morbidities) and persistently positive LA or aCL.1,2 Clinically relevant aPL were thereafter described recognizing glycoproteins bound on anionic PLs (the so-called aPL cofactors), β2-glycoprotein I (β2GP1)3,4 anti-β2GP1 (aβ2GP1), as specified by the current APS criteria,5 by prothrombin6 (FII), and by annexin A5.7 Neurologic symptoms have been early described in APS,8 with a wide spectrum of manifestations involving the central nervous system (CNS), from neurologic to psychiatric syndromes9,10 (►Table 1). Although only stroke and transient ischemic attack (TIA) are included in the formal APS diagnostic criteria, more complex neurological manifestations are recognized and multifocal white matter lesions on brain

magnetic resonance imaging (MRI) are common.11–14 Besides thrombotic mechanisms involved in neurologic APS, other nonthrombotic mechanisms have been recently evaluated, leading to the definition of a non-APS, aPL-associated neuropsychiatric disease, which may call for specific therapeutic developments.

published online October 15, 2013

Copyright © 2013 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

Issue Theme Coagulation and the Brain; Guest Editors, Benjamin Brenner, MD, and Jean-Christophe Gris, MD, PhD.

Pathophysiology Little is known about the pathogenesis of nonvascular, aPLrelated neuropsychiatric, manifestations. The nonspecific white matter changes evidenced in some patients are generally anticipated as being ischemic or inflammatory,11–14 but biopsy specimens are hardly available. Animal models of experimental APS could provide, to some extent, keys for better understanding of human pathology.15 Histology evidences perivascular and meningeal inflammation processes. Rabbits with experimental APS develop inflammatory infiltrates within the meningeal and perivascular areas together with thrombotic vascular occlusions in the brain tissue,16,17 associating with thrombonecrotic foci and macrophage clusters surrounded by mononuclear cells and small perivascular infiltrates consisting of lymphocytes predominantly located within the white matter of brain hemispheres and cerebellum.18 In mice immunized with a pathogenic aPL

DOI http://dx.doi.org/ 10.1055/s-0033-1357488. ISSN 0094-6176.

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Semin Thromb Hemost 2013;39:935–942.

Antiphospholipid Antibodies

Gris, Brenner

Table 1 Associations between antiphospholipid antibodies and central nervous system morbidities 1. Neurologic syndromes • Thrombotic mechanism: APS syndrome  Stroke  Early-onset multi-infarct dementia  Transient ischemic attack – Amaurosis fugax – Transient paresthesias  Cerebral vein thrombosis • Other nonsystemic thrombosis-related mechanisms  Optic neuropathy/atrophy  Epilepsy  Chorea and dystonia  Cognitive dysfunction  Nonvascular dementia 2. Psycho-psychiatric syndromes • Hyperactivity and behavioral abnormalities • Depression and mania: bipolar disorders • Psychosis 3. Neurologic symptoms possibly associated with or mimicked by aPL • Multiple sclerosis • Transverse myelitis • Idiopathic intracranial hypertension Abbreviation: APS, antiphospholipid syndrome.

monoclonal antibody, thrombotic occlusion of capillaries in combination with mild inflammation localized mainly in the meninges is the main finding.19 The immunization of mice against β2GP1 is related to thrombosis and brain inflammation20: This associates with high levels of proinflammatory cytokines, such as tumor necrosis factor-α (TNFα), with perivascular infiltrates of lymphocytes and macrophages, and with microglial activation detected in the cortex, parahippocampal areas, and the hippocampus,20 but this does not associate with microscopic infarcts. The latter fact is concordant with the results obtained in the study of mice immunized with an aPL monoclonal antibody,19 in which electron microscopy was needed to reveal microthrombi. Coagulation inhibitors such as protease nexin-1 (PN-1) and protease nexin-2 (PN-2, i.e., amyloid precursor protein APP), appear to be involved in CNS experimental APS20: The APS brain is likely to be exposed to high levels of thrombin, causing consumption of these intrinsic brain inhibitors of coagulation. Enhanced thrombin generation in the brain tissue can cause brain tissue dysfunction and neuronal cell death21–23 and changes in thrombin metabolism have been described in experimental autoimmune encephalomyelitis, an experimental inflammatory brain disease.24–26 The major role for specific aPL interacting with brain tissues and causing neurodegenerative and inflammatory pathologies is thus suspected. Antibodies against β2GP1 can bind to various cells in the CNS: neurons, astrocytes, and endothelial cells.27,28 Toll-like receptors and apolipoprotein E receptor-2, two types of cell-surface receptors for β2GP1 involved in APS-related cell activation induced by aβ2GP1–β2GP1 complexes, have been described on neuronal Seminars in Thrombosis & Hemostasis

Vol. 39

No. 8/2013

cells, but direct evidence for β2GP1 binding is lacking.29,30 Human aPL and aβ2GP1 can also directly permeabilize and depolarize brain synaptosomes.31 Histological examination shows aPL binding to both neuronal and white matter.32,33 Monoclonal antiphosphatidylserine antibodies were found to react with myelinated fibers in gray and white matters of brain and spinal cord from normal cat and mouse in a pattern virtually identical to myelin basic protein.32 Immunogold electron microscopy technique revealed aPL reacting with myelin, mainly with the major dense line formed by the cytoplasmic apposition of the oligodendrocyte plasma membrane.33 A limiting step of the direct antibody effects on the CNS is their passage through the blood–brain barrier (BBB). Vascular endothelial cells, pericytes, and astrocytes are cellular components of the neurovascular unit, with endothelial cells playing the central role in the BBB permeability. The effects of aPL on brain endothelial cells may induce inflammatory and hypercoagulation effects on the brain tissues. The aPLmediated endothelial activation can perpetuate the prothrombotic state of APS, resulting in procoagulant and proinflammatory phenotypes.34 The aPL activate brain endothelial cells35 and may, thus, induce adhesion receptors, tissue factor,36–38 cytokines like TNFα39,40 and therefore also enhancing vascular leakage. The cytoprotective-activated protein C pathway, which protects vascular integrity and the BBB,41 can also be inhibited by aPL.42 Endothelial cell activation is likely to disrupt the BBB, facilitating the diffusion of pathogenic antibodies, pathogenic coagulation, and inflammatory factors into the brain tissues. The direct effect of the autoantibodies on neurons, glia, oligodendrocytes, and microglia may induce the behavioral changes observed in the APS mice. Putative effects of aPL on signal transduction mechanisms have been described, including MAPK p38 and NF-κB,37,43,44 but data on brain cells are lacking. Mice immunized with aβ2GP1 meet all the major clinical and biological criteria of APS,45,46 particularly BALB/c mice, who also develop behavioral and cognitive impairments, including hyperactivity and anxiety/explorative behavior, memory and learning deficits. Using a staircase apparatus as the test device, the APS mice very progressively develop both higher stair-climbing activity and rearing in the months following immunization,47 a fact that can be reproduced in various strains of mice, but always after a 4- to 5-month exposure to the systemic antibodies.48,49 Mice immunized with a pathogenic monoclonal antibody also develop a similar hyperactive syndrome in an open-field paradigm, which tests spatial behavior.50 High systemic levels of aPL induced by β2GP1 immunization are associated with memory and learning deficits best displayed in the T-maze alternation test performed 4 to 5 months after a single immunization.49 Mice directly injected with APS immunoglobulin G (IgG) in cerebral ventricles develop memory and learning deficit in the Morris water maze.51 This effect can be reproduced in several mice and associates with antibodies binding to specific areas of the mouse brain, especially the hippocampus, the cortex, and the choroids plexus.51 For some APS mice sera, the binding pattern was predominantly evidenced in the

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

936

white matter of the limbic system, including the white matter tracts in the hippocampus, stria medullaris, stria terminalis, fornix, olfactory tract, internal capsule, cerebral peduncle, and white matter tracts in the hypothalamus, suggesting target sites within CNS with which aPL can react.15 In female BALB/c mice immunized once with β2GP1 and developing behavioral abnormalities in the absence of vessel occlusion or infarcts, lymphocytic infiltration and activation of glia and macrophages were checked by immunohistochemistry. Alterations in ligand binding densities of various neurotransmitter receptors (NMDAR [N-methyl-D-aspartate receptor]; AMPAR [a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor]; GABA AR: g-aminobutiric acid receptor; 5HT1AR [5-hydroxytryptamine 1A receptor]) were evaluated using in vitro receptor autoradiography.52 Neither activation of astrocytes or microglia nor accumulation of macrophages was found. Binding values of excitatory and inhibitory neurotransmitters were largely unchanged. Ligand-binding densities of the modulatory serotonergic 5-HT1A receptors in the hippocampus and in the primary somatosensory cortex were upregulated, which may induce the behavioral abnormalities observed.52

Neurologic Manifestations Stroke and TIA Strokes and TIAs are considered to be the third most common clinical manifestation of APS, after venous thrombosis and livedo reticularis.53,54 APS is a major, and potentially preventable, cause of stroke. An overall aPL prevalence of 6.8% has been described in patients with stroke55 and a prevalence of 20% has been observed in patients with stroke younger than 45 years.56 In the RATIO study focused on women younger than 50 years, who were admitted to hospital with first ischemic stroke or myocardial infarction in the Netherlands, LA was found in 17% of the patients with ischemic stroke, the related mean odds ratio reaching 43, with the one for women positive for aβ2GP1 being only 2.3.57 Stroke and TIA accounted for 22.9% of initial manifestations of APS in the Euro-Phospholipid Project Group, in a cohort of 1,000 patients with APS.58 Cerebral manifestations including infarcts were observed in 62% of the 250 patients in the European Catastrophic Antiphospholipid Antibody Syndrome (CAPS) registry, with stroke inducing death in 13% of the 114 deaths in this registry.59 Stroke recurrence is increased in patients with active APS and with several previous symptomatic events, more particularly in case of an initial cerebral ischemic event.60 The β2GP1-dependent aCL-IgG positive patients had a twofold increase in the risk of developing a stroke within 15 years of follow-up compared with β2GP1dependent aCL negative individuals.61 In women with an initial purely obstetric APS, the risk of subsequent cerebrovascular arterial events is roughly doubled, despite chronic low-dose aspirin prophylaxis (mean annual rate: 0.32%).62 Conflicting data exist in APS patients regarding the favorable effect of a patent “foramen ovale” on the ischemic stroke risk.63,64 The association between stroke or TIA and ischemic dermatopathy, first described in 1960,65 currently known as

Gris, Brenner

the Sneddon syndrome, is a rare, progressive disorder of unknown etiology, affecting small- and medium-sized arteries of the brain and the skin.66 Acute ischemic encephalopathy has also been observed but is a rare feature in systemic lupus erythematosus (SLE) patients with aPL, who are acutely ill, confused, have asymmetrical quadriparesis, hyperreflexia, and bilateral extensor plantar responses.67 Ocular vasoocclusive manifestations are frequent in patients with APS, amaurosis fugax being one of the most common presentations.68,69 Optic neuropathy, remaining one of the major causes of blindness in SLE patients, which is less frequently described in APS patients without SLE, but tends to be unilateral in these cases, is considered to be a focal neurological disease due to a thrombotic event involving the ciliary vasculature, whereas bilateral optic nerve damage in SLE is considered to be due to different immunological mechanisms, such as vasculitis.70–72

Epilepsy Epileptic seizures have been associated with aPL and purely electric undiagnosed mild forms have even been reported as frequent in APS. The prevalence of aPL, is apparently greater in patients with epilepsy, including newly diagnosed seizure disorders, the increased prevalence of autoantibodies being more strongly associated with epilepsy than with antiepileptic drugs, perhaps indicating that immune dysregulation may be commonly associated with epilepsy.73 A study involving more than 500 patients with APS described an epilepsy prevalence of 8.6%, which is roughly 10 times higher than the normal epilepsy rate.43 It has been suggested that aPL may have a direct effect on seizure genesis through inhibition of the GABA receptor-ion channel complex, which in turn may increase neuronal excitability.74 Surprisingly, administering fluvastatin (40 mg) to a patient with CAPS to diminish the endothelial activation induced by aPL, also induced focal seizures, which disappeared after discontinuation of this treatment.75

Dementia Studies focusing on aCL testing in patients without SLE or any other systemic inflammatory disease, led to description of an association of elevated titers with both vascular dementia and Alzheimer disease.76,77 In the European series of 1,000 APS patients, 2.5% had multi-infarct dementia.58 Normal healthy individuals demonstrated inferior performances in case of aCL positivity.78 A negative correlation between performance on neuropsychological testing and disease duration was found in a subgroup of SLE patients with concomitant APS, but not in the subgroup of aPL-negative SLE patient.79 The presence of aPL in SLE patients is classically associated with cognitive impairment.80,81 The pathogenesis of cognitive alterations in APS patients has not been elucidated. In the absence of a typical multiinfarct dementia feature, a direct effect of aPL on brain cells or an aPL-mediated microthrombotic vascular mechanism can be suggested but cannot be certified in individual patients. The ABICMA study (Antiphospholipid Antibodies, Brain Infarcts, and Cognitive and Motor Decline in Aging study) Seminars in Thrombosis & Hemostasis

Vol. 39

No. 8/2013

937

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Antiphospholipid Antibodies

Antiphospholipid Antibodies

Gris, Brenner

began in late 2009 and will test the hypothesis that aPL are associated with an increased risk of pathologically proven brain infarcts and are related to cognitive and motor decline in aging.82

Chorea and Dystonia The review of the characteristics of 50 APS patients with chorea, 29 with SLE and 15 with primary APS, evidenced a striking female preponderance (96%), 6 developing chorea soon after starting estrogen-containing oral contraceptives, 3 during pregnancy, and 1 shortly after delivery. The majority (66%) had only one episode of chorea. Computed tomographic scan and nuclear MRI (NMRI) demonstrated cerebral infarcts in 35% of the patients. LA was positive in 92% of the patients. Therapies usually prescribed in the presence of other manifestations of SLE or APS were efficient; however, many patients responded well to haloperidol and to the discontinuation of oral contraceptives if it was the precipitating factor.83 Because chorea is often unilateral, acute in onset, and frequently followed by other CNS manifestations in SLE patients, a vascular pathogenesis is likely even if brain imaging does not systematically evidence recent infarcts.

Migraines The most frequent symptom reported by patients with APS is headache, especially migraine.58 The recent analysis of a random cohort of 284 consecutive migraineurs (225 women) demonstrated an excess of aPL-positive patients (12 vs. 3%), 2 patients having triple positivity for LA, aβ2GP1 and aCL, 1 patient—double positivity for LA and aβ2GP1, with none of the controls showing multiple positivity. An association between aPL and migraine was suggested, and migraine was proposed to be an early sign for identifying aPL positive individuals.84 Conflicting data are, however, available and previous prospective studies with carefully designed control groups failed to demonstrate an association between aCL positivity and migraine in SLE patients or a higher prevalence of aPL in migraine sufferers.85,86

Cognitive and Psychiatric Manifestations The presence of cognitive dysfunction in 60 patients with APS, none of them being diagnosed as having dementia, and its association with clinical (neuropsychological assessment), laboratory, and cerebral MRI characteristics was examined in a case–control study.14 Of the 60 patients with APS, 25 (42%) had cognitive deficits compared with 11 (18%) healthy control subjects. The most commonly involved cognitive domains were complex attention and verbal fluency. No difference was found in cognitive performance between patients with primary APS and those with SLE-related APS. No relationship was detected between cognitive dysfunction and prior CNS disease. A significant association was evidenced between cognitive dysfunction and livedo reticularis as well as between cognitive dysfunction and the presence of white matter lesions on the findings of brain MRI. An evaluation of the regional cerebral blood flow was performed in 22 women with primary APS using 99mTcSeminars in Thrombosis & Hemostasis

Vol. 39

No. 8/2013

hexamethylpropyleneamine oxime single-photon emission computed tomography. All these patients suffered from mild neuropsychiatric manifestations (headache, depression, personality disorders, memory loss, and cognitive function deficits) with a normal brain NMRI. Abnormal findings, mainly diffuse hypoperfusion lesions in the cerebral cortex, were found in 16 (73%) patients.87 The presence of aPL in depressed patients was investigated in a case–control study involving 22 minor, 23 simple major, and 20 melancholic depressives.88 A large number of depressed patients were positive, with a significant discrimination between melancholic individuals and healthy controls. This higher expression of aPL during depression and the incidence of positive patients were, however, lower than in classical autoimmune disorders. The first case report of an acute manic episode in association with APS was published in 200889 and the first APS patient with habit or impulse control disorders was described in 2011 as a long-lasting pathological gambling case.90 After separate reports in patients with depressive and maniac episodes, appearance of a publication of a case associating APS with bipolar disorder is not so much surprising.91 Bipolar disorders are a heterogeneous group of illnesses; among these, there is evidence of a vascular component of physiopathology, particularly in relatively late-onset cases.92,93 The risk factors for “vascular mania” are systemic disorders that increase the probability of developing cerebrovascular diseases.94 The first case of APS psychiatric morbidity during pregnancy, by itself a vascular risk factor, was described in a 34-year-old pregnant woman with no previous medical, obstetrical, or psychiatric history.95 At 18 weeks of gestation, she experienced a fetal death, related to APS with a strong triple positivity for LA, aCL, and aβ2GP1, which was preceded by an acute depressed mood, feelings of anxiety, and insomnia with a strong premonitory sense of upcoming loss of pregnancy, symptoms of depression, slowed ideation, and apprehension persisting for at least 2 months after fetal demise. Patients suffering from schizophrenia on and off neuroleptic medications have been found seropositive for aPL.96–100 Studies on unmedicated psychotic patients have also reported increased levels of aCL as well as LA in these individuals.101,102 These data are in line with findings of dysregulated immune functions and cytokine activity in patients with psychiatric disorders.103 Psychosis can be a presenting symptom for primary APS, even in young children.104,105 A first comprehensive and comparative study on aPL in blood and cerebrospinal fluid (CSF) obtained from 100 medicated patients with psychosis having hallucinations and/ or delusions showed specificity and isotype discordances between CSF and blood aPL, implicating a CNS independent autoimmune process with intrathecal synthesis, that may have an underlying association with the pathophysiology of their disease.106 The large multicenter Canadian study “1000 Faces of Lupus,” focusing on SLE, found variable prevalence and factors associated with neuropsychiatric SLE depending on the definition used, the association with aPL being

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

938

Antiphospholipid Antibodies

Other Controversial Neurological Manifestations Idiopathic Intracranial Hypertension A retrospective limited study performed on 37 patients described an association between idiopathic intracranial hypertension and aPL with a relatively high prevalence of aCL (8%).109 No similar data are available for patients with primary APS.

Transverse Myelitis This very rare disease (incidence: roughly one per million) involves the entire thickness of the spinal cord. Only case reports and very limited series are available. SLE patients with transverse myelitis have a higher prevalence of positive aPL than nonaffected SLE patients.110–112 The work on 11 SLE patients with transverse myelitis found 10 of them to be aPL positive.110

Multiple Sclerosis-Like Presentation It is sometimes difficult to differentiate APS from multiple sclerosis (MS), as some initial clinical presentations of APS can mimic MS, which often leads to a mistaken diagnosis. Nearly a third of aPL-positive patients heard their doctor mentioning at any stage a possible diagnosis of MS in a hospital audit.56 The presence and role of aPL in MS diagnosis is highly controversial. The screening of 70 classic MS and 100 nonclassic MS cases with unusual clinical features revealed a high proportion of aCL-positive patients in the nonclassic MS group.113 The authors speculated on the pathogenic role of these antibodies, concluding that management should include antiplatelet or even anticoagulant agents. MS can thus be associated with positivity for aPL. However, in the study of 161 MS cases, aPL-positive MS patients did not seem to differ from aPL-negative MS patients in terms of age at onset, presenting signs and symptoms, neurological findings, or disease course.114 A recent study in 85 Polish patients with MS and clinically isolated syndrome did not find an increased frequency of positive aCL, while aβ2GP1 were more frequent in patients with secondary progressive MS.115 Nonthrombotic neurological manifestations of APS remain difficult to distinguish from MS associated with aPL positivity.116 NMRI findings of primary APS are difficult to differentiate from those of MS, although MRI reveals more profound injury in patients with MS than in those with primary APS.117 An observational study of 143 consecutive MS patients pointed out the absence of evidence for misdiagnosis of APS in aPLpositive MS patients, if care was based on NMRI and longterm follow-up.118

939

APS Therapies Antithrombotic therapy, while useful for primary and secondary prevention of vascular events,119,120 has not been evaluated in neuropsychiatric settings of APS patients. Steroids occasionally used in APS may aggravate neuropsychiatric presentations.121 Likewise, antimalarial medications can sometimes induce aPL and neuropsychiatric manifestations.122

Conclusions aPL are associated with a wide range of neurological, psychological, and psychiatric manifestations. Along with clearly delimited purely thrombotic manifestations, defining the neurological contribution to APS, precise interactions between various antiphospholipid/cofactor autoantibodies, for instance, aβ2GP1, antiprothrombin and antiannexin A5, and cell-surface receptors on brain endothelial cells, neurons, astrocytes, and glial cells remain to be elucidated, together with the relevant induced modifications of cell functions. Some indications seem to support a psychiatric impact of aPL, which should be systematically studied, focusing on the categorization of psychiatric syndromes according to molecular pathogenesis. These data may pave the way to new therapeutic developments.

References 1 Asherson RA, Khamashta MA, Ordi-Ros J, et al. The “primary”

2

3

4

5

6

7

8 9 10 11

antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore) 1989;68(6):366–374 Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42(7):1309–1311 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990;87(11):4120–4124 Galli M, Comfurius P, Maassen C, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990;335(8705):1544–1547 Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4(2): 295–306 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991;66(6):629–632 Lieby P, Poindron V, Roussi S, et al. Pathogenic antiphospholipid antibody: an antigen-selected needle in a haystack. Blood 2004; 104(6):1711–1715 Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed) 1983;287(6399):1088–1089 Muscal E, Brey RL. Antiphospholipid syndrome and the brain in pediatric and adult patients. Lupus 2010;19(4):406–411 Brey RL, Muscal E, Chapman J. Antiphospholipid antibodies and the brain: a consensus report. Lupus 2011;20(2):153–157 Molad Y, Sidi Y, Gornish M, Lerner M, Pinkhas J, Weinberger A. Lupus anticoagulant: correlation with magnetic resonance imaging of brain lesions. J Rheumatol 1992;19(4):556–561 Seminars in Thrombosis & Hemostasis

Vol. 39

No. 8/2013

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

globally positive, but variable by ethnicity (highest prevalence in Aboriginals). This association was found to be no more significant when patients with thromboembolic events were removed from the study.107 Recommendations from the European League Against Rheumatism (EULAR) state that aPL is a strong risk factor for neuropsychiatric SLE manifestations.108

Gris, Brenner

Antiphospholipid Antibodies

Gris, Brenner

12 Provenzale JM, Barboriak DP, Allen NB, Ortel TL. Patients with

31 Chapman J, Cohen-Armon M, Shoenfeld Y, Korczyn AD. Anti-

antiphospholipid antibodies: CT and MR findings of the brain. AJR Am J Roentgenol 1996;167(6):1573–1578

phospholipid antibodies permeabilize and depolarize brain synaptoneurosomes. Lupus 1999;8(2):127–133 Kent M, Alvarez F, Vogt E, Fyffe R, Ng AK, Rote N. Monoclonal antiphosphatidylserine antibodies react directly with feline and murine central nervous system. J Rheumatol 1997;24(9): 1725–1733 Kent MN, Alvarez FJ, Ng AK, Rote NS. Ultrastructural localization of monoclonal antiphospholipid antibody binding to rat brain. Exp Neurol 2000;163(1):173–179 Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011;7(6):330–339 Aronovich R, Gurwitz D, Kloog Y, Chapman J. Antiphospholipid antibodies, thrombin and LPS activate brain endothelial cells and Ras-dependent pathways through distinct mechanisms. Immunobiology 2005;210(10):781–788 Todorova M, Baleva M. Some recent insights into the prothrombogenic mechanisms of antiphospholipid antibodies. Curr Med Chem 2007;14(7):811–826 Vega-Ostertag M, Casper K, Swerlick R, Ferrara D, Harris EN, Pierangeli SS. Involvement of p38 MAPK in the up-regulation of tissue factor on endothelial cells by antiphospholipid antibodies. Arthritis Rheum 2005;52(5):1545–1554 Williams FM, Parmar K, Hughes GR, Hunt BJ. Systemic endothelial cell markers in primary antiphospholipid syndrome. Thromb Haemost 2000;84(5):742–746 Berman J, Girardi G, Salmon JE. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol 2005;174(1):485–490 Forastiero RR, Martinuzzo ME, de Larrañaga GF. Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprosy related antiphospholipid antibodies. Lupus 2005;14(2):129–136 Griffin JH, Zlokovic BV, Mosnier LO. Protein C anticoagulant and cytoprotective pathways. Int J Hematol 2012;95(4):333–345 Urbanus RT, de Laat B. Antiphospholipid antibodies and the protein C pathway. Lupus 2010;19(4):394–399 López-Pedrera C, Buendía P, Cuadrado MJ, et al. Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF-kappaB/Rel proteins via the p38 mitogenactivated protein kinase pathway, and of the MEK-1/ERK pathway. Arthritis Rheum 2006;54(1):301–311 Vega-Ostertag ME, Ferrara DE, Romay-Penabad Z, et al. Role of p38 mitogen-activated protein kinase in antiphospholipid antibody-mediated thrombosis and endothelial cell activation. J Thromb Haemost 2007;5(9):1828–1834 Blank M, Faden D, Tincani A, et al. Immunization with anticardiolipin cofactor (beta-2-glycoprotein I) induces experimental antiphospholipid syndrome in naive mice. J Autoimmun 1994; 7(4):441–455 Gharavi AE, Sammaritano LR, Wen J, Elkon KB. Induction of antiphospholipid autoantibodies by immunization with beta 2 glycoprotein I (apolipoprotein H). J Clin Invest 1992;90(3): 1105–1109 Katzav A, Pick CG, Korczyn AD, et al. Hyperactivity in a mouse model of the antiphospholipid syndrome. Lupus 2001;10(7): 496–499 Katzav A, Litvinjuk Y, Pick CG, et al. Genetic and immunological factors interact in a mouse model of CNS antiphospholipid syndrome. Behav Brain Res 2006;169(2):289–293 Shrot S, Katzav A, Korczyn AD, et al. Behavioral and cognitive deficits occur only after prolonged exposure of mice to antiphospholipid antibodies. Lupus 2002;11(11):736–743 Ziporen L, Shoenfeld Y, Levy Y, Korczyn AD. Neurological dysfunction and hyperactive behavior associated with

13 Sanna G, Bertolaccini ML, Cuadrado MJ, et al. Neuropsychiatric

32

manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol 2003; 30(5):985–992 14 Tektonidou MG, Varsou N, Kotoulas G, Antoniou A, Moutsopoulos

HM. Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic resonance imaging findings. Arch Intern Med 2006;166(20): 2278–2284

33

34

15 Katzav A, Shoenfeld Y, Chapman J. The pathogenesis of neural

injury in animal models of the antiphospholipid syndrome. Clin Rev Allergy Immunol 2010;38(2–3):196–200

35

16 Nowacki P, Ronin-Walknowska E, Ossowicka-Stepińska J. Central

nervous system involvement in pregnant rabbits with experimental model of antiphospholipid syndrome. Folia Neuropathol 1998;36(1):38–44

36

17 Nowacki P, Ronin-Walknowska E, Ossowicka-Stepińska J. Neuro-

pathological changes within the brain of rabbits with experimental model of antiphospholipid syndrome in different time after immunization. Folia Neuropathol 1999;37(4):269–272

37

18 Nowacki P, Ossowicka-Stepińska J, Ronin-Walkanowska E, Tabaka

J. The antiphospholipid syndrome in pregnant rabbits and their offspring. Neuropathological aspects. Folia Neuropathol 2005; 43(1):15–22

38

19 Ziporen L, Polak-Charcon S, Korczyn DA, et al. Neurological

39

dysfunction associated with antiphospholipid syndrome: histopathological brain findings of thrombotic changes in a mouse model. Clin Dev Immunol 2004;11(1):67–75

40

20 Tanne D, Katzav A, Beilin O, et al. Interaction of inflammation,

thrombosis, aspirin and enoxaparin in CNS experimental antiphospholipid syndrome. Neurobiol Dis 2008;30(1):56–64 21 de Castro Ribeiro M, Badaut J, Price M, et al. Thrombin in ischemic

neuronal death. Exp Neurol 2006;198(1):199–203 22 Maggio N, Shavit E, Chapman J, Segal M. Thrombin induces long-

term potentiation of reactivity to afferent stimulation and facilitates epileptic seizures in rat hippocampal slices: toward understanding the functional consequences of cerebrovascular insults. J Neurosci 2008;28(3):732–736

41 42 43

23 Xue M, Del Bigio MR. Acute tissue damage after injections of

thrombin and plasmin into rat striatum. Stroke 2001;32(9): 2164–2169 24 Beilin O, Gurwitz D, Korczyn AD, Chapman J. Quantitative meas-

44

urements of mouse brain thrombin-like and thrombin inhibition activities. Neuroreport 2001;12(11):2347–2351 25 Beilin O, Karussis DM, Korczyn AD, et al. Increased thrombin

inhibition in experimental autoimmune encephalomyelitis. J Neurosci Res 2005;79(3):351–359

45

26 Beilin O, Karussis DM, Korczyn AD, et al. Increased KPI containing

amyloid precursor protein in experimental autoimmune encephalomyelitis brains. Neuroreport 2007;18(6):581–584

46

27 Caronti B, Calderaro C, Alessandri C, et al. Serum anti-beta2-

glycoprotein I antibodies from patients with antiphospholipid antibody syndrome bind central nervous system cells. J Autoimmun 1998;11(5):425–429

47

28 Caronti B, Pittoni V, Palladini G, Valesini G. Anti-beta 2-glycopro-

tein I antibodies bind to central nervous system. J Neurol Sci 1998;156(2):211–219

48

29 Tang SC, Arumugam TV, Xu X, et al. Pivotal role for neuronal Toll-

like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci U S A 2007;104(34):13798–13803

49

30 Myant NB. Reelin and apolipoprotein E receptor 2 in the embry-

onic and mature brain: effects of an evolutionary change in the apoER2 gene. Proc Biol Sci 2010;277(1680):345–351 Seminars in Thrombosis & Hemostasis

Vol. 39

No. 8/2013

50

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

940

Antiphospholipid Antibodies

51 Shoenfeld Y, Nahum A, Korczyn AD, et al. Neuronal-binding

antibodies from patients with antiphospholipid syndrome induce cognitive deficits following intrathecal passive transfer. Lupus 2003;12(6):436–442 52 Frauenknecht K, Katzav A, Grimm C, Chapman J, Sommer CJ.

Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic 5-HT1A receptors. Immunobiology 2013;218(4):517–526 53 Krause I, Leibovici L, Blank M, Shoenfeld Y. Clusters of disease

manifestations in patients with antiphospholipid syndrome demonstrated by factor analysis. Lupus 2007;16(3):176–180 54 Shah NM, Khamashta MA, Atsumi T, Hughes GR. Outcome of

patients with anticardiolipin antibodies: a 10 year follow-up of 52 patients. Lupus 1998;7(1):3–6 55 Montalbán J, Rio J, Khamastha M, et al. Value of immunologic

testing in stroke patients. A prospective multicenter study. Stroke 1994;25(12):2412–2415 56 Hughes GR. Migraine, memory loss, and “multiple sclerosis”.

Neurological features of the antiphospholipid (Hughes’) syndrome. Postgrad Med J 2003;79(928):81–83 57 Urbanus RT, Siegerink B, Roest M, Rosendaal FR, de Groot PG,

Algra A. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. Lancet Neurol 2009;8(11):998–1005 58 Cervera R, Piette JC, Font J, et al; Euro-Phospholipid Project Group.

70 Giorgi D, Gabrieli CB, Bonomo L. The clinico-ophthalmological

spectrum of antiphospholipid syndrome. Ocul Immunol Inflamm 1998;6(4):269–273 71 Reino S, Muñoz-Rodriguez FJ, Cervera R, Espinosa G, Font J,

Ingelmo M. Optic neuropathy in the “primary” antiphospholipid syndrome: report of a case and review of the literature. Clin Rheumatol 1997;16(6):629–631 72 Giorgi D, Balacco Gabrieli C. Optic neuropathy in systemic lupus

erythematosus and antiphospholipid syndrome (APS): clinical features, pathogenesis, review of the literature and proposed ophthalmological criteria for APS diagnosis. Clin Rheumatol 1999;18(2):124–131 73 Peltola JT, Haapala A, Isojärvi JI, et al. Antiphospholipid and

antinuclear antibodies in patients with epilepsy or new-onset seizure disorders. Am J Med 2000;109(9):712–717 74 Liou HH, Wang CR, Chou HC, et al. Anticardiolipin antisera from

lupus patients with seizures reduce a GABA receptor-mediated chloride current in snail neurons. Life Sci 1994;54(15): 1119–1125 75 Miesbach W, Chapman J, Scharrer I. Focal seizures after treatment

with fluvastatin in a patient with a history of catastrophic antiphospholipid syndrome. J Neurol Sci 2005;238(1–2):93–95 76 Jacobson MW, Rapport LJ, Keenan PA, Coleman RD, Tietjen GE.

Neuropsychological deficits associated with antiphospholipid antibodies. J Clin Exp Neuropsychol 1999;21(2):251–264 77 Mosek A, Yust I, Treves TA, Vardinon N, Korczyn AD, Chapman J.

Dementia and antiphospholipid antibodies. Dement Geriatr Cogn Disord 2000;11(1):36–38

Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46(4):1019–1027

78 Schmidt R, Auer-Grumbach P, Fazekas F, Offenbacher H, Kapeller

59 Bucciarelli S, Espinosa G, Cervera R. The CAPS Registry: morbidity

79 Whitelaw DA, Spangenberg JJ, Rickman R, Hugo FH, Roberts M.

and mortality of the catastrophic antiphospholipid syndrome. Lupus 2009;18(10):905–912

The association between the antiphospholipid antibody syndrome and neuropsychological impairment in SLE. Lupus 1999; 8(6):444–448

60 Levine SR, Salowich-Palm L, Sawaya KL, et al. IgG anticardiolipin

antibody titer > 40 GPL and the risk of subsequent thromboocclusive events and death. A prospective cohort study. Stroke 1997;28(9):1660–1665 61 Brey RL, Abbott RD, Curb JD, et al. beta(2)-Glycoprotein 1-

P. Anticardiolipin antibodies in normal subjects. Neuropsychological correlates and MRI findings. Stroke 1995;26(5):749–754

80 Menon S, Jameson-Shortall E, Newman SP, Hall-Craggs MR, Chinn

R, Isenberg DA. A longitudinal study of anticardiolipin antibody levels and cognitive functioning in systemic lupus erythematosus. Arthritis Rheum 1999;42(4):735–741

dependent anticardiolipin antibodies and risk of ischemic stroke and myocardial infarction: the Honolulu Heart Program. Stroke 2001;32(8):1701–1706

81 Olazarán J, López-Longo J, Cruz I, Bittini A, Carreño L. Cognitive

62 Gris JC, Bouvier S, Molinari N, et al. Comparative incidence of a

82 Arvanitakis Z, Brey RL, Rand JH, et al. Antiphospholipid anti-

first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood 2012;119(11):2624–2632

bodies, brain infarcts, and cognitive and motor decline in aging (ABICMA): design of a community-based, longitudinal, clinicalpathological study. Neuroepidemiology 2013;40(2):73–84

63 Rajamani K, Chaturvedi S, Jin Z, et al; PICSS-APASS Investigators.

83 Cervera R, Asherson RA, Font J, et al. Chorea in the antiphospho-

Patent foramen ovale, cardiac valve thickening, and antiphospholipid antibodies as risk factors for subsequent vascular events: the PICSS-APASS study. Stroke 2009;40(7):2337–2342

lipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature. Medicine (Baltimore) 1997;76(3):203–212

64 Tanaka Y, Ueno Y, Miyamoto N, et al. Patent foramen ovale and

84 Cavestro C, Micca G, Molinari F, et al. Migraineurs show a high

atrial septal aneurysm can cause ischemic stroke in patients with antiphospholipid syndrome. J Neurol 2013;260(1):189–196

prevalence of antiphospholipid antibodies. J Thromb Haemost 2011;9(7):1350–1354

65 Champion RH, Rook A. Livedo reticularis. Proc R Soc Med 1960;

85 Tietjen GE, Day M, Norris L, et al. Role of anticardiolipin antibodies

53:961–962 66 Schellong SM, Weissenborn K, Niedermeyer J, et al. Classification

of Sneddon’s syndrome. Vasa 1997;26(3):215–221

dysfunction in systemic lupus erythematosus: prevalence and correlates. Eur Neurol 2009;62(1):49–55

in young persons with migraine and transient focal neurologic events: a prospective study. Neurology 1998;50(5):1433–1440 86 Sanna G, Bertolaccini ML, Cuadrado MJ, Khamashta MA,

associated with antiphospholipid antibodies. Ann Neurol 1989; 25(3):221–227

Hughes GR. Central nervous system involvement in the antiphospholipid (Hughes) syndrome. Rheumatology (Oxford) 2003;42(2):200–213

68 Wiechens B, Schröder JO, Pötzsch B, Rochels R. Primary anti-

87 Kao CH, Lan JL, Hsieh JF, et al. Evaluation of regional cerebral blood

phospholipid antibody syndrome and retinal occlusive vasculopathy. Am J Ophthalmol 1997;123(6):848–850

flow with 99mTc-HMPAO in primary antiphospholipid antibody syndrome. J Nucl Med 1999;40(9):1446–1450

69 Nahum A, Levy Y, Shoenfeld Y. Ocular manifestations in the

88 Maes M, Meltzer H, Jacobs J, et al. Autoimmunity in depression:

antiphospholipid syndrome [in Hebrew]. Harefuah 1999; 136(1):50–53

increased antiphospholipid autoantibodies. Acta Psychiatr Scand 1993;87(3):160–166

67 Briley DP, Coull BM, Goodnight SH Jr. Neurological disease

941

Seminars in Thrombosis & Hemostasis

Vol. 39

No. 8/2013

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

antiphospholipid antibodies. A mouse model. J Clin Invest 1997; 100(3):613–619

Gris, Brenner

Antiphospholipid Antibodies

Gris, Brenner

89 Raza H, Epstein SA, Pao M, Rosenstein DL. Mania: psychiatric

90

91

92 93

94

95

96

97

98

99

100

101

102

103

104

105

106

manifestations of the antiphospholipid syndrome. Psychosomatics 2008;49(5):438–441 Barros S, de Carvalho J. Pathological gambling and primary antiphospholipid (Hughes) syndrome: a unique neuropsychiatric association. Lupus 2011;20(10):1086–1089 Avari JN, Young RC. A patient with bipolar disorder and antiphospholipid syndrome. J Geriatr Psychiatry Neurol 2012;25(1): 26–28 Shulman KI, Herrmann N. The nature and management of mania in old age. Psychiatr Clin North Am 1999;22(3):649–665, ix Steffens DC, Krishnan KR. Structural neuroimaging and mood disorders: recent findings, implications for classification, and future directions. Biol Psychiatry 1998;43(10):705–712 Lyness J, Caine E. Cerebrovascular risk factors and depression: data, deductions and directions. In: Chiu E, Ames D, Katona C, eds. Vascular Disease and Affective Disorders. London, UK: Martin Dunitz Ltd; 2002:161–170 Spyropoulou AC, Tsartsara EI, Angelopoulou A, Zervas IM. Psychiatric manifestations preceding fetal death in antiphospholipid syndrome. Gen Hosp Psychiatry 2010;32(2):225–227 Canoso RT, de Oliveira RM, Nixon RA. Neuroleptic-associated autoantibodies. A prevalence study. Biol Psychiatry 1990;27(8): 863–870 Lillicrap DP, Pinto M, Benford K, Ford PM, Ford S. Heterogeneity of laboratory test results for antiphospholipid antibodies in patients treated with chlorpromazine and other phenothiazines. Am J Clin Pathol 1990;93(6):771–775 Schwartz M, Silver H. Lymphocytes, autoantibodies and psychosis —coincidence versus etiological factor: an update. Isr J Psychiatry Relat Sci 2000;37(1):32–36 Sirota P, Schild K, Firer M. The diversity of autoantibodies in schizophrenic patients and their first degree relatives: analysis of multiple case families. Biol Psychiatry 1990;27(Suppl 1):118A Strous RD, Shoenfeld Y. Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. J Autoimmun 2006;27(2):71–80 Schwartz M, Rochas M, Weller B, et al. High association of anticardiolipin antibodies with psychosis. J Clin Psychiatry 1998;59(1):20–23 Chengappa KN, Carpenter AB, Keshavan MS, et al. Elevated IGG and IGM anticardiolipin antibodies in a subgroup of medicated and unmedicated schizophrenic patients. Biol Psychiatry 1991; 30(7):731–735 Arolt V, Rothermundt M, Peters M, Leonard B. Immunological research in clinical psychiatry: report on the consensus debate during the 7th Expert Meeting on Psychiatry and Immunology. Mol Psychiatry 2002;7(8):822–826 Lai JY, Wu PC, Chen HC, Lee MB. Early neuropsychiatric involvement in antiphospholipid syndrome. Gen Hosp Psychiatry 2012; 34(5):579 e571–573 Shabana M, Shalaby M, Alhumayed S, Alshehri A. Paediatric case report: primary antiphospholipid syndrome presented with nonthrombotic neurological picture psychosis; treat by antidepressants alone? Int J Rheum Dis 2009;12(2):170–173 Sokol DK, O’Brien RS, Wagenknecht DR, Rao T, McIntyre JA. Antiphospholipid antibodies in blood and cerebrospinal fluids

Seminars in Thrombosis & Hemostasis

Vol. 39

No. 8/2013

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121 122

of patients with psychosis. J Neuroimmunol 2007;190(1–2): 151–156 Borowoy AM, Pope JE, Silverman E, et al. Neuropsychiatric lupus: the prevalence and autoantibody associations depend on the definition: results from the 1000 faces of lupus cohort. Semin Arthritis Rheum 2012;42(2):179–185 Bertsias GK, Ioannidis JP, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 2010;69(12):2074–2082 Kesler A, Ellis MH, Reshef T, Kott E, Gadoth N. Idiopathic intracranial hypertension and anticardiolipin antibodies. J Neurol Neurosurg Psychiatry 2000;68(3):379–380 Lavalle C, Pizarro S, Drenkard C, Sánchez-Guerrero J, AlarcónSegovia D. Transverse myelitis: a manifestation of systemic lupus erythematosus strongly associated with antiphospholipid antibodies. J Rheumatol 1990;17(1):34–37 Ruiz-Argüelles GJ, Guzmán-Ramos J, Flores-Flores J, Garay-Martínez J. Refractory hiccough heralding transverse myelitis in the primary antiphospholipid syndrome. Lupus 1998;7(1):49–50 Kovacs B, Lafferty TL, Brent LH, DeHoratius RJ. Transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and review of the literature. Ann Rheum Dis 2000;59(2):120–124 Karussis D, Leker RR, Ashkenazi A, Abramsky O. A subgroup of multiple sclerosis patients with anticardiolipin antibodies and unusual clinical manifestations: do they represent a new nosological entity? Ann Neurol 1998;44(4):629–634 Tourbah A, Clapin A, Gout O, et al. Systemic autoimmune features and multiple sclerosis: a 5-year follow-up study. Arch Neurol 1998;55(4):517–521 Szmyrka-Kaczmarek M, Pokryszko-Dragan A, Pawlik B, et al. Antinuclear and antiphospholipid antibodies in patients with multiple sclerosis. Lupus 2012;21(4):412–420 Ahbeddou N, Ait Ben Haddou E, Hammi S, et al. [Multiple sclerosis associated with antiphospholipid syndrome: diagnostic and therapeutic difficulties]. Rev Neurol (Paris) 2012;168(1):65–69 Stosic M, Ambrus J, Garg N, et al. MRI characteristics of patients with antiphospholipid syndrome and multiple sclerosis. J Neurol 2010;257(1):63–71 Liedorp M, Sanchez E, van Hoogstraten IM, et al. No evidence of misdiagnosis in patients with multiple sclerosis and repeated positive anticardiolipin antibody testing based on magnetic resonance imaging and long term follow-up. J Neurol Neurosurg Psychiatry 2007;78(10):1146–1148 Lim W, Crowther MA, Eikelboom JW. Management of antiphospholipid antibody syndrome: a systematic review. JAMA 2006; 295(9):1050–1057 Panichpisal K, Rozner E, Levine SR. The management of stroke in antiphospholipid syndrome. Curr Rheumatol Rep 2012;14(1): 99–106 Appenzeller S, Cendes F, Costallat LT. Acute psychosis in systemic lupus erythematosus. Rheumatol Int 2008;28(3):237–243 Schneider C, Adamcova M, Jick SS, et al. Antimalarial chemoprophylaxis and the risk of neuropsychiatric disorders. Travel Med Infect Dis 2013;11(2):71–80

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

942

Copyright of Seminars in Thrombosis & Hemostasis is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.