Neurological manifestations of antiphospholipid syndrome

Transcription

1 DOI: /j x REVIEW Neurological manifestations of antiphospholipid syndrome Carlos E. M. Rodrigues *, Jozélio F. Carvalho * and Yehuda Shoenfeld,1 * University of São Paulo, São Paulo, Brazil, Tel-Aviv University, Tel-Hashomer, Israel ABSTRACT Background Neurologic disorders are among the most common and important clinical manifestations associated with the antiphospholipid syndrome (APS). It is characterized by diverse neurological manifestations. These include stroke, transient ischaemic attack, Sneddon s syndrome, convulsions epilepsy, dementia, cognitive deficits, headaches migraine, chorea, multiple sclerosis-like, transverse myelitis, ocular symptoms and Guillain Barré syndrome. Material and methods We review the latest data about neurologic disorders and APS. Results In patients under 45 years of age, 20% of strokes are potentially associated with APS. Our study group recently reported a correlation between primary APS and peripheral neuropathy. Only one study investigated the occurrence of peripheral neuropathy in patients diagnosed with PAPS through electrophysiological study and showed alterations in 35% of patients. The mechanism of nervous system involvement in APS is considered to be primarily thrombotic. However, other mechanisms have been described, such as antiphospholipid antibodies that bind to the neural tissue, deregulating their functions and having an immediate pathogenic effect. Conclusions This review summarizes the latest data regarding the clinical aspects, radiological and therapeutic of major neurologic manifestations associated with antiphospholipid antibodies. Keywords Antiphospholipid antibodies, antiphospholipid syndrome, neurological manifestations. Eur J Clin Invest 2010; 40 (4): Introduction Antiphospholipid syndrome (APS) is an autoimmune disease, characterized by recurrent thrombotic events, miscarriages and thrombocytopenia, and is associated with the presence of antiphospholipid antibodies (apl), which include anticardiolipin, lupus anticoagulant and anti-beta 2-glycoprotein I (b2gpi). In apparently healthy individuals, the prevalence of apl positivity ranges from 1% to 5% and increases with age, especially in older individuals with chronic diseases [1]. The mean age at the onset of the clinical manifestations of the disease is 31 years [2]. Cervera et al. [2] found the most common presentations to be as follows: deep venous thrombosis (38Æ9%), thrombocytopenia (29Æ6%), stroke (19Æ8%), pulmonary embolism (14Æ1%), superficial thrombophlebitis (11Æ7%), transient ischaemic attack (TIA, 11Æ1%), haemolytic anaemia (9Æ7%), epilepsy (7%) and obstetric morbidity. 1 Yehuda Shoenfeld is the incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University. Neurological system involvement in APS is responsible for high morbidity and mortality, stroke and transient ischaemic attack being the most common manifestations [3]. The importance of neurological manifestations was indeed predicted in the original description of the syndrome, by Hughes [4]. In early 1980, his group also reported a correlation between apl positivity and a spectrum of neuropsychiatric manifestations, including cerebral ischaemia, dementia, migraine, convulsions, chorea, transverse myelitis and Guillain-Barré syndrome [5 8], as shown in Table 1. Many other neuropsychiatric manifestations, including chronic headache, cognitive dysfunction, psychosis, depression and multiple sclerosis-like illness, have also been reported to correlate with apl positivity [9 14]. Our study group recently reported a correlation between primary APS and multiple mononeuropathy [15]. In APS, this association is infrequent, and, to our knowledge, there have been no case reports of primary APS with multiple mononeuropathy. Patients presenting with ischaemic neurological disease should be approached with a high degree of clinical suspicion 350 European Journal of Clinical Investigation Vol 40

2 APS AND NEUROLOGICAL MANIFESTATIONS Table 1 Neurological manifestations of antiphospholipid syndrome Neurological manifestations Prevalence Comments Stroke 19Æ8% [2] In patients 45 years of age, 20% of strokes are potentially associated with APS [12] Sneddon s syndrome The clinical course of Sneddon s syndrome is generally worse, and patients with Sneddon s syndrome present greater cognitive deterioration [17] Myelopathy < 1% [2] There is a strong correlation between transverse myelitis and apl in SLE [9] Convulsions 7% [2] It is possible that many cases of convulsions in apl-positive patients are caused by ischaemic events [55] Chorea 1Æ3% [2] It is a well-known phenomenon in patients with SLE and is strongly correlated with apl positivity [16] Headache and migraine 20Æ2% [2] Headache in APS is often untreatable, not responding to narcotics or analgesics and persisting for years before APS is diagnosed [9] Ocular syndromes 15 88% [9] Venous stasis retinopathy and neuro-ophthalmologic symptoms have been described in association with apl positivity [77] Multiple sclerosis multiple sclerosis-like expression There are no definite diagnostic tests for multiple sclerosis and APS [10] Dementia 2Æ5% [2] Factors associated with cognitive deterioration: persistently positive apl levels; prednisone use; diabetes; high scores for depression; and low level of education [83] Guillain-Barré syndrome Probably produced as a result of damage to myelin [86] Peripheral neuropathy Rare Peripheral nervous system involvement is rare in APS [87], being most commonly found in SLE and in vasculitis of small and medium-sized vessels APS, antiphospholipid syndrome; apl, antiphospholipid antibodies; SLE, systemic lupus erythematosus. for apl positivity. Screening for apl should be performed in patients with serological or clinical manifestations of APS (such as recurrent miscarriages, venous thrombosis and livedo reticularis), in young stroke patients, in any patient with recurrent stroke and in patients experiencing thrombo-occlusive events of undetermined origin [16]. Pathogenesis The precise mechanism by which apl affect homeostasis and induce hypercoagulability remains unknown [17]. However, various hypotheses have been proposed: endothelial reduction in the synthesis of prostacyclin and in the activation of protein C via thrombomodulin thrombin; interaction with membrane phospholipids leading to the activation and release of platelets; interference with the activation of prekallikrein to kallikrein, which activates the fibrinolytic system; and reduction in the release of tissue plasminogen activator in endothelial cells [17]. The mechanism of nervous system involvement in APS is considered to be primarily thrombotic [9]. The apl activate endothelial cells, monocytes and platelets, inducing the prothrombotic state. The binding of apl to endothelial surfaces leads to the upregulation of adhesion molecules and to the release of proinflammatory cytokines. The apl potentiate platelet aggregation and increase vasoconstriction. There is evidence to suggest that the cerebral endothelium is activated by apl, thereby promoting procoagulant activity [18 21]. However, it is not clear how these antibodies trigger thrombosis [22]. There is also evidence that apl can bind to glial cells, myelin and neurons, deregulating their functions and having an immediate pathogenic effect [23 25]. In lupus patients with convulsions, apl impair the function of a gamma-aminobutyric acid receptor-mediated chloride channel in the myelin sheath [26] and that apl can decrease the seizure threshold through a direct and reversible mechanism. It has been suggested that apl play a direct role in the development of cognitive and behavioural European Journal of Clinical Investigation Vol

3 C. E. M. RODRIGUES ET AL. deficit in patients with APS [27]. It is possible that the prothrombotic state associated with apl positivity is responsible for changes in the cerebral microcirculation as the principal cause of certain types of neuropsychiatric manifestations observed in APS, including convulsions and cognitive dysfunction [9]. Antibodies to proteins that bind to phospholipids such as b2gpi are central to many pathogenic mechanisms in APS. Antibodies to b2gpi are generated during apoptotic cell clearance [28]. George et al. [29] investigated the immunolocalization of b2gpi in human atherosclerotic plaques and suggested that immunological factors contributed to thrombosis and apl-mediated atherosclerosis. In that study, b2gpi was found to reside in the subendothelial regions and to interact with CD4 T lymphocytes [28]. Therefore, the b2gpimediated immune response might play an important role in atherogenesis, potentially serving as a target of antigenspecific therapies. Clinical manifestations Cerebrovascular disease The most common and severe complication of APS is stroke, and APS patients present considerable stroke-related morbidity. It has been suggested that more than 20% of strokes in patients younger than 45 years are associated with APS [12]. Patients with stroke and apl positivity are younger and are more likely to be female than are apl-negative stroke patients [30,31]. Of the 1000 patients investigated in the Euro-Phospholipid Project Group study, 19Æ8% presented with stroke, 11Æ1% presented with TIA, and 5Æ5% presented with acute myocardial infarction (AMI) [2]. It has been shown that 50% of all patients with arterial thrombosis commonly present with TIA or stroke [2,32,33]. The clinical manifestations of TIA include amaurosis fugax, transient paresthesia, muscle weakness, vertigo and transient global ischaemia [34]. Arterial occlusion can be thrombotic or embolic. Arterial occlusive events are relatively common and are suggestive of APS when they occur in individuals with no identifiable risk factors (family history, smoking, hyperlipidemia, hypertension, diabetes mellitus, etc.). Embolisms, which typically originate from aortic or mitral valve vegetations composed of platelets and fibrins, can cause cerebrovascular ischaemic events [35]. The clinical manifestations depend on the location and caliber of the occluded artery. Multiple arterial occlusions often result from the involvement of small arteries. Small, recurrent strokes can contribute to the profile of multiple-infarct dementia [36]. The presence of anticardiolipin antibodies is considered to be a risk factor for stroke [36]. However, there is still controversy as to whether apl positivity at the time of the first-ever stroke increases the risk of recurrence in unselected populations [9]. The Antiphospholipid Antibodies and Stroke Study Group conducted a study to investigate stroke and apl [36]. The authors reported that the risk of cerebral infarction was 2Æ31 times higher in patients testing positive for circulating apl than in those testing negative [36]. However, the presence of apl in patients with ischaemic stroke does not predict an increased risk of subsequent vascular occlusive events over a 2-year period or the differential response to antiplatelet therapy [37]. In the Framingham study [38], high serum concentrations of anticardiolipin antibodies, regardless of other cardiovascular risk factors, were shown to be significantly predictive of the risk of future stroke and TIA in females but not in males. Pursuing the same line of research, Brey et al. [39] found the risk of stroke and AMI to be 1Æ5 times higher in males with b2gpidependant IgG anticardiolipin antibodies than in those without. Various studies have reported that the prevalence of cerebral ischaemia accompanied by apl positivity is particularly high in children, ranging from 16% to 76% [40 42]. Kenet et al. [43] recently studied the prevalence of risk factors for thrombophilia in 58 paediatric stroke patients, comparing them with 145 controls. The authors concluded that the prevalence of thrombophilia markers, especially factor V Leiden and apl, is higher in children who have suffered a stroke than in those who have not. Sneddon s syndrome Sneddon s syndrome is defined as the development of cerebrovascular disease (stroke and TIA) associated with livedo reticularis. Some authors have suggested that Sneddon s syndrome should be included in the neurological manifestations of APS [44 47]. More than 40% of the patients with Sneddon s syndrome have APS, which suggests that there is an association between these two conditions [48]. Although clinical and magnetic resonance imaging findings are similar in the two disease, the clinical course of Sneddon s syndrome is generally worse, and patients with Sneddon s syndrome present cognitive deterioration that is more pronounced, as well as a greater number of disabilities [16]. In addition, patients with Sneddon s syndrome more often present leukoaraiosis and small lacunar infarcts, whereas patients with APS can present main cerebral artery territory infarction, such as middle cerebral artery territory infarction [49]. Sneddon s syndrome is not a single entity. It is possible that some of the patients diagnosed with this syndrome will develop APS immediately or not long after diagnosis. The distinction is important because the treatment for APS (anticoagulant therapy) differs from the treatment for Sneddon s syndrome [9]. 352 ª 2010 The Authors. Journal Compilation ª 2010 Stichting European Society for Clinical Investigation Journal Foundation

4 APS AND NEUROLOGICAL MANIFESTATIONS Myelopathy Myelopathy is a rare manifestation of APS, the prevalence of which is estimated to be less than 1% [2,50]. The age at the onset of the disease varies widely, ranging from childhood to 80 years [16]. Transverse myelitis is an acute inflammatory process that affects a focal area of the spinal cord and is clinically characterized by the development of neuromotor dysfunction accompanied by dysfunction at the sensory level and autonomic nerve dysfunction (sphincter dysfunction). There is a strong correlation between apl positivity and the occurrence of transverse myelitis in individuals with systemic lupus erythematosus (SLE) [9]. D Cruz et al. [51] studied a sample of 15 patients and reported that transverse myelitis was the initial manifestation of SLE or of lupus-like disease. We find it interesting that 73% of those patients tested positive for apl, which provides further evidence of a strong correlation between transverse myelitis and apl positivity. Some studies have demonstrated that the pathogenesis involves a direct interaction between apl and spinal cord phospholipids [52,53] more than it does a thrombotic process leading to ischaemia, although no strong correlation has been established between these manifestations and APS. Kim et al. [50] described a patient with recurrent attacks of transverse myelitis. The authors suggested that such attacks constitute a rare neurological complication of primary APS and that apl play a critical role in the pathogenesis of transverse myelitis. Convulsions The occurrence of central nervous system (CNS) manifestations (especially thromboembolic events) in APS suggests that ischaemic injury to the brain parenchyma triggers the development of an epileptic focus [54]. However, known factors, such as thrombotic events, only partially explain the occurrence of epilepsy in APS, and other causes, such as direct neuralimmune interaction, have been postulated. Cervera et al. [2] reported that, in their cohort of 1000 patients with APS, the prevalence of convulsions was 7Æ0%. More recently, Shoenfeld et al. [13] studied a cohort of 538 patients with APS and found the prevalence of epilepsy to be 8Æ6%. The authors also found that epilepsy was more common in patients with secondary APS than in those with primary APS (epilepsy being present in 13Æ7% and 6Æ0% respectively P <0Æ05). Multivariate logistic regression revealed that thromboembolic events involving the CNS constituted the factor most strongly associated with epilepsy, the odds ratio being 4Æ05 (95% confidence interval: 1Æ2 4Æ7). The authors concluded that epilepsy was common in APS, and that many of the risks were apparently related to vascular disease as manifested by extensive CNS involvement, heart valve disease, livedo reticularis and SLE. Convulsions are a well-recognized symptom of cerebral ischaemia, and it is possible that many cases of convulsions in apl-positive patients are caused by ischaemic events [55]. In patients with SLE, the rate of convulsions is higher among those who are apl-positive [56]. Early laboratory studies suggested that epilepsy is associated with the presence of certain autoantibodies, some directed against neuronal structures [57], and this was subsequently evaluated in more recent studies. One of these studies showed that patients with refractory epilepsy may present with high levels of autoantibodies against glutamic acid decarboxylase [58,59]. Rasmussen s encephalitis is an example of autoimmune disorder of the CNS that might be associated with epilepsia partialis continua [54]. The serum of patients with Rasmussen s encephalitis contains antibodies to the GluR3 glutamate receptor, as well as to the GluRepsilon2 subunit [60]. These patients can also present activated T cells stimulated by Glu- Repsilon2 in the peripheral blood. Therefore, humoral and cellular immunity against GluRepsilon2 can contribute to the pathophysiology of Rasmussen s encephalitis. A recent study evaluated the presence of antimitochondrial antibodies in a large cohort of nearly 1000 patients with epilepsy [61]. Antimitochondrial antibodies are associated with long-standing disease and later age of onset. Antimitochondrial antibodies might be a sign of immunological activation related to longstanding disease, similarly to what has been reported to occur in the association between anticardiolipin antibodies and longstanding epilepsy [61]. Chorea and other movement disorders Chorea is a rare manifestation of APS, and its prevalence has been estimated to be 1Æ3% [2]. Chorea is a well-known phenomenon in patients with SLE and is strongly correlated with apl positivity [16]. Chorea has been described in association with primary APS in a number of patients, many of whom were children [16]. Cervera et al. [62] reviewed the clinical, radiological and immunological characteristics of 50 patients with chorea and APS, of whom 15% had SLE, 12% had lupus-like syndrome and 30% had primary APS. In addition, 66% of the patients had experienced only one episode of chorea. The chorea was bilateral in 55%, and imaging studies revealed cerebral infarction in 35%. Patients with APS can present nearly all of the known neurological manifestations, and such manifestations are often the most prominent clinical features. A study investigating a cohort of 350 patients with neurological symptoms reported that 15% of the patients had elevated apl levels; nonthrombotic manifestations such as epilepsy, transverse myelitis, multiple sclerosis, dementia, psychiatric disorders, migraine and movement disorders were observed in 40% [63]. The apl damage the white matter and structures of the basal ganglia, leading to movement disorders and multiple sclerosis-like manifestations in patients with APS [25,64,65]. European Journal of Clinical Investigation Vol

5 C. E. M. RODRIGUES ET AL. Although basal ganglia involvement is common in primary APS, dystonia is a quite rare clinical manifestation of APS. Late dystonia has been reported in children with primary APS and in those with secondary APS [65,66], and one case of focal dystonia of the hands and parkinsonism with lesions in the basal ganglia was reported by Milanov et al. [68]. Headache and migraine Chronic headache, including migraine, is a common finding in patients with APS [2]. Cervera et al. [2] investigated 1000 patients in the Euro-Phospholipid Project Group study and 202 (20Æ2%) presented with migraine. In 2003, Hughes, in a review article entitled Migraine, memory loss and multiple sclerosis, suggested that apl testing be included in the arsenal of tests for migraine and recurrent headache [12]. One of the arguments presented by the author was the remarkable clinical improvement after anticoagulant therapy in patients with APSrelated migraine. However, there is still controversy regarding the correlation between migraine and apl positivity [69 71]. There are widely varying results from different reports. Many authors have reported an association between migraine and LA or acl [72], while others found no association [70,73,74]. The controversy may be partially due to the inherent difficulty in distinguishing the transient, focal neurological events of migraine from TIA [75]. Headache in APS is often untreatable, not responding to narcotics or analgesics and persisting for years before APS is diagnosed [9]. A prospective study investigating children found no association between anticardiolipin antibodies and migraine [74]. Tietjen et al. [71] evaluated the frequency of anticardiolipin antibody positivity in patients with transient focal neurological events and migraine (with and without aura), as well as in a group of controls, and found that apl positivity was not associated with migraine or with transient focal neurological events. Sanna et al. [76] studied 323 patients with SLE and found that, although the prevalence of headache among those patients was similar to that reported for the general population, in patients with headache were more likely to be apl-positive than were patients without headache. However, no association was found between apl positivity and any particular type of headache, including migraine. Ocular syndromes Ophthalmologic manifestations are found in 15 88% of patients with APS [9]. Venous stasis retinopathy and neuro-ophthalmologic symptoms have been described in association with apl positivity. Amaurosis fugax is suggestive of cerebral ischaemia and is one of the most common ocular manifestations of APS [9]. The anterior chamber of the eye is rarely affected by apl. Mild ocular involvement, e.g. conjunctivitis, telangiectasia, keratitis and dry eye, has been described. Uveitis has also been described in isolated cases, as has (more rarely) scleritis. However, the hallmark of APS is retinal vessel occlusion, which can have serious consequences and seems to be more common in individuals with IgG anticardiolipin antibodies. The APS should be considered in all unexplained cases of retinal arterial and venous thromboses, as well as in cases of unusual ocular inflammations [77], particularly in young individuals. The most common APS associated ocular changes are occlusions of retinal arteries and veins in individuals below 50 years of age in absence of risk factors. In all above mentioned and particularly in cases of recurrent occlusion ophthalmologist must take APS into account underlying APS [78]. Results of all major studies point out the need of apl antibodies screening in patients with visual decline and different pathological conditions, including systematic diseases of the connective tissue and other autoimmune diseases [78]. Many patients presenting to an ophthalmologist with alterations secondary to APS also present other associated symptoms. Miserocchi et al. [79] found headache, memory loss and diplopia to be the most common such symptoms. Therefore, ophthalmologists should be alert to this type of complaint, which can provide a clue to the diagnosis of APS. Severe forms of lupus retinopathy are suggestive of an increased risk of CNS involvement. One severe form of retinal disease is characterized by disseminated vaso-occlusive lesions that often lead to central retinal artery occlusion or central retinal vein occlusion. This more aggressive form is associated with the presence of apl. Multiple sclerosis and multiple sclerosis-like expression Multiple sclerosis is a demyelinating inflammatory disease of the CNS. Clinical syndromes such as APS can mimic multiple sclerosis, principally when the clinical profile is associated with apl. The difficulty in establishing a correct diagnosis occurs in atypical cases in which imaging studies show normal results or cannot distinguish between the two entities and there is no clinical history of thrombosis or recurrent miscarriage. There are no definite diagnostic tests for multiple sclerosis and APS [9]. Analysis of the oligoclonal bands is not specific for multiple sclerosis, and positivity for apl is not specific for APS [9]. The prevalence of apl positivity in patients with multiple sclerosis, in the absence of clinical manifestations of autoimmune disease or APS, has been shown to range from 8% to 33%, although only a few studies have evaluated this aspect [79 82]. Cuadrado et al. [10] analysed the clinical, laboratory and imaging findings regarding multiple sclerosislike expression in patients with APS and concluded that 354 ª 2010 The Authors. Journal Compilation ª 2010 Stichting European Society for Clinical Investigation Journal Foundation

6 APS AND NEUROLOGICAL MANIFESTATIONS patients with multiple sclerosis alone had higher severity scores for lesions of the white matter, pons and cerebellum, whereas patients with APS alone had higher severity scores for lesions of the caudate nucleus and putamen. Many patients with APS have responded well to oral anticoagulant therapy. In patients with secondary APS, the results have been less than satisfactory [69]. In 2006, Paran et al. [83] showed that changes in the evoked potential were more prevalent in patients with multiple sclerosis than in those with APS. The authors studied 30 patients with APS and 33 patients with definite multiple sclerosis and neurological disabilities and found abnormal visual evoked potential test results in 58% of the patients with multiple sclerosis and in 10% of the patients with APS. Dementia Chronic and recurrent ischaemic events affecting small vessels predispose patients to early-onset, multi-infarct dementia [64]. Cervera et al. [2] reported that the prevalence of multi-infarct dementia in patients with APS was 2Æ5% [2]. The following factors are associated with cognitive deterioration: persistently positive apl levels, prednisone use, diabetes, high scores for depression and low level of education. The most common clinical manifestations in APS patients with dementia are memory loss, language impairment, impaired concentration, impaired judgment and shortened attention span. Memory loss is less severe in most patients, although sufficiently worrisome to raise the suspicion of Alzheimer s disease [84]. It is this aspect of the syndrome that often improves (as occurs with headache) when anticoagulant therapy is initiated [12]. In some patients, APS, if left untreated, progresses to widespread cerebral infarction, grossly abnormal magnetic resonance images and, ultimately, multi-infarct dementia [12]. Magnetic resonance imaging infarct features favouring vascular dementia include bilaterality, multiplicity (> 1 infarct), location in the dominant hemisphere and location in the frontal or medial limbic structures [85]. In 2005, Gomez-Puerta et al. [14] reviewed the characteristics of 30 patients with APS-associated dementia. The mean age of the patients was 49 ± 15 years. Of the 30 patients, 47% had primary APS, 30% had SLE and 23% had lupus-like syndrome. Of the 30 patients, 37% had suffered a stroke, 33% had Sneddon s syndrome and 27% had heart valve lesions. Although 63% of the patients had APS manifestations before the diagnosis of dementia, only 37% were receiving anticoagulant therapy. The authors recommended that, due to the possibility of APS, as well as to the possibility of antithrombotic treatment, apl testing be performed in young individuals with no apparent reason for dementia, thereby preventing the progression of the disease. Guillain-Barré syndrome Guillain-Barré syndrome is an acute demyelinating disorder of the peripheral nervous system. This demyelinating neuropathy, which is uncommon in patients with SLE, was associated with apl positivity in the original description of Hughes syndrome [5]. The affected nerves are basically the motor nerves, with little or no involvement of the sensory nerves. The clinical profile includes progressive muscle weakness, generally initiating in the lower limbs, and might progress to total limb paralysis and respiratory muscle involvement associated with dysautonomia symptoms (tachycardia, hypotension or hypertension, arrhythmia and sphincter dysfunction). Gilburd et al. [86] studied the serum of patients with Guillain-Barré syndrome in terms of its reactivity to various apl, which are recognized as important constituents of myelin and act as autoantigens in other autoimmune diseases. The authors demonstrated that some Guillain-Barré syndrome patients produce autoantibodies to various phospholipids and nuclear antigens. However, those autoantibodies are probably produced as a result of damage to the myelin rather than being the cause of the demyelination. Peripheral neuropathy Peripheral nervous system involvement is rare in APS [87], and distal, asymmetric, axonal polyneuropathy (mononeuritis multiplex) is extremely rare, being most commonly found in SLE and in certain types of vasculitis, such as polyarteritis nodosa and Churg-Strauss syndrome. The pathogenesis of peripheral neuropathy involves immune and vascular mechanisms [88]. The inflammation and lesion of nerves might be caused by autoantibodies or immune complex deposits, or might be directly caused by vasculitis or thrombosis of the vasa nervorum [89]. Erten et al. [87] described a case of ischaemic peripheral neuropathy with axonal degeneration, revealed through sural nerve biopsy, in a patient with catastrophic secondary APS. Jeruc et al. [91] reported the case of a 49-year-old patient, with no clinical or laboratory evidence of autoimmune disease or systemic vasculitis, who developed mononeuritis multiplex secondary to vasculitis with positivity for anticardiolipin antibodies. Sural nerve biopsy revealed active necrotizing arteritis with transmural inflammatory infiltrate and thrombosis. Our group [15] has recently described the case of a patient who presented clinically with livedo reticularis and cyanosis of the toes accompanied by recurrent ulcerative lesions and who subsequently developed lower limb paresthesia and muscle weakness. Electroneuromyography revealed mononeuritis multiplex, and sural nerve biopsy revealed thrombosis of the vasa nervorum, without histopathological evidence for vasculitis, associated with apl on more than one occasion, confirming the diagnosis of APS according to the criteria described by Sapporo [91]. Santos et al. [92] European Journal of Clinical Investigation Vol

7 C. E. M. RODRIGUES ET AL. investigated the occurrence of peripheral neuropathy in patients diagnosed with PAPS. Twenty-six consecutive PAPS (Sapporo s criteria) patients and 20 age- and gender-matched healthy controls were enrolled at two referral centers. Exclusion criteria were secondary causes of peripheral neuropathy. A complete clinical neurological exam followed by nerve conduction studies (NCSs) were performed. Paresthesias were reported in eight patients (31%). Objective mild distal weakness and abnormal symmetric deep tendon reflexes were observed in three (11Æ5%) patients. With regard to the electrophysiological evidence of peripheral neuropathy, nine (35Æ0%) patients had alterations: four (15Æ5%) had pure sensory or sensorimotor distal axonal neuropathy and one (4%) had sensorimotor demyelinating and axonal neuropathy involving upper and lower extremities, while four patients (15Æ5%) showed isolated carpal tunnel syndrome. Clinical and serological results were similar in all PAPS patients, regardless of the presence of electrophysiological alterations. In conclusion, peripheral neuropathy is a common asymptomatic abnormality in PAPS patients. The routine performance of NCS may be considered when evaluating such patients. Treatment The three standbys aspirin, heparin and warfarin remain the cornerstone of treatment (Table 2). In some cases (e.g. asthmatics) clopidogrel (Plavix) replaces aspirin [93]. When neurological events in APS are discussed, great controversy arises regarding the international normalized ratio (INR) required to prevent thrombosis and reduce the risk of bleeding. This controversy has yet to be completely resolved. Khamashta et al. [94] analysed patients with APS over a period of 10 years. Of those treated only with aspirin, more than half developed thrombosis. Likewise, of those treated with warfarin to a target INR of less than 3, half developed thrombosis. Only in those maintained at an INR of 3 or over was there a significant 10-year benefit. One point, however, is clear: the danger of thrombosis and stroke in these patients far outweighs the risks of anticoagulant-induced bleeding. The fear of cerebral haemorrhage has almost certainly resulted in the undertreatment of many patients with APS [12]. Antiplatelet therapy and anticoagulant therapy have both been used for the prevention of secondary stroke in patients with APS and in patients with cerebrovascular disease associated with apl [37,95,96]. Two retrospective studies have obtained data suggesting that treatment with high-intensity warfarin (versus low- or moderate-intensity warfarin or aspirin) is associated with better results in patients having experienced various types of thrombotic events [94,95]. It should be taken into account that patients in those studies were screened for apl only once and did not meet the current criteria for APS. Conventional immuno-suppressives have not proved successful in APS, but recently, anecdotal reports of success with the anti-cd 20 agent rituximab have appeared [93] especially in cases of thrombocytopenia related to APS and catastrophic APS. I.V.I.G. has proved very valuable in the acute management of APS, but is both cumbersome and in short supply [93]. An interesting approach is that of Miri Blank in Israel who have used affinity purified anti-acl in the mouse model of APS and improved pregnancy success rates by a staggering 200-fold [97]. Finally, certain questions remain to be fully answered: What is the true role of apl with antineuronal direct effects mediated by inflammatory cytokines and complement in nonthrombotic neurological events associated with APS, such as chorea and transverse myelitis? In APS patients presenting with neurological signs and symptoms, can immunosuppressants and anticytokine Table 2 Treatment of antiphospholipid syndrome (APS) Clinical events INR Treatment Venous event 2 3 Warfarin First arterial event (stroke) 2 3 Aspirin ou warfarin Recurrent event 3 4 Warfarin Thrombocytopenia Rituximab or intravenous immune globulin and prednisone Catastrophic APS Heparin, intravenous methylprednisolone pulse therapy and plasmapheresis or intravenous immune globulin or rituximab Chorea and transverse myelitis Intravenous methylprednisolone INR, International normalized ratio. 356 ª 2010 The Authors. Journal Compilation ª 2010 Stichting European Society for Clinical Investigation Journal Foundation

8 APS AND NEUROLOGICAL MANIFESTATIONS agents play a therapeutic role comparable to that of anticoagulants? Studies involving large patient samples are needed in order to answer these questions. Conclusion There is strong evidence of an association between apl positivity and neurological syndromes in APS. An important characteristic of Hughes syndrome is the clinical response to anticoagulants. Manifestations such as headache and memory loss often improve drastically with the administration of warfarin at appropriate doses [11], thereby changing the prognosis of the disease. Currently, APS is recognized as a severe but potentially treatable cause of neurological disease. Therefore, early diagnosis is vital in order to avoid sequelae and to reduce APS-related morbidity and mortality. Financial support Jozélio Freire Carvalho is the recipient of a grant from the Federico Foundation. Address Department of Rheumatology, School of Medicine, Hospital das Clínicas, University of São Paulo, São Paulo, Brazil (C. E. M. Rodrigues, J. F. Carvalho); Department of Internal Medicine B, Center for Autoimmune Diseases, Sheba Medical Center (Affiliated to Tel-Aviv University), Tel-Hashomer 52621, Israel (Y. Shoenfeld). Correspondence to: Yehuda Shoenfeld, Department of Internal Medicine B, Center for Autoimmune Diseases, Sheba Medical Center (Affiliated to Tel-Aviv University), Tel-Hashomer 52621, Israel. Tel.: ; fax: ; shoenfel@post.tau.ac.il Received 6 January 2010; accepted 12 January 2010 References 1 Petri M. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun 2000;15: Cervera R, Boffa M-C, Khamastha MA, Hughes GRU. The Euro-Phospholipid Project epidemiology of the antiphospholipid syndrome in Europe. Lupus 2009;18(Spec No): Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346: Hughes GRV. 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9 C. E. M. RODRIGUES ET AL Khalili A, Cooper RC. A study of immune responses to myelin and cardiolipin in patients with systemic lupus erythematosus (SLE). Clin Exp Immunol 1991;85: Katzav A, Chapman J, Shoenfeld Y. CNS dysfunction in the antiphospholipid syndrome. Lupus 2003;12: Liou HH, Wang CR, Chou HC, Arvanov VL, Chen RC, Chang YC et al. Anticardiolipin antisera from lupus patients with seizures reduce a GABA receptor-mediated chloride current in snail neurons. Life Sci 1994;54: Shoenfeld Y, Nahum A, Korczyn AD, Dano M, Rabinowitz R, Beilin O et al. Neuronal-binding antibodies from patients with antiphospholipid syndrome induce cognitive deficits following intrathecal passive transfer. Lupus 2003;12: Hanly JG. Antiphospholipid syndrome: an overview. CMAJ 2003;168: George J, Harats D, Gilburd B, Arnon A, Yair L, Jacob S et al. Immunolocalization of beta2-glycoprotein I(apolipoprotein H) to human atherosclerotic plaques: potential implications for lesion progression. 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