Neurological Manifestations Of Antiphospholipid Syndrome Research Articles

Neurologic Manifestations of the Antiphospholipid Syndrome - an Update.

Purpose of ReviewIn recent years, the spectrum of neurological manifestations of antiphospholipid syndrome (APS) has been growing. We provide a critical review of the literature with special emphasis on presentation, proposed mechanisms of disease, and treatment of neurological involvement in APS.Recent FindingsAlthough stroke is the most common cause of neurological manifestations in patients with APS, other neurological disorders have been increasingly associated with the disease, including cognitive dysfunction, headache, and epilepsy. Direct oral anticoagulants have failed to show non-inferiority compared to vitamin K antagonists for the prevention of major thrombotic events. Antiphospholipid antibodies are often found in patients with acute COVID-19 but clear evidence supporting an association between these antibodies and the risk of thrombotic events, including stroke and cerebral venous thrombosis, is still lacking.SummaryAPS patients may present with several distinct neurological manifestations. New criteria will facilitate the classification of patients presenting with increasingly recognized non-criteria neurological manifestations.

Antiphospholipid Syndrome and the Neurologist: From Pathogenesis to Therapy.

Antiphospholipid syndrome (APS) is an autoimmune antibody-mediated condition characterized by thrombotic events and/or pregnancy morbidity in association with persistent positivity to antiphospholipid antibodies (aPL). The nervous system is frequently affected, as intracranial vessels are the most frequent site of arterial pathology. Over the course of years, many other neurological conditions not included in the diagnostic criteria, have been associated with APS. The pathogenic mechanisms behind the syndrome are complex and not fully elucidated. aPL enhance thrombosis, interfering with different pathways. Nevertheless, ischemic injury is not always sufficient to explain clinical features of the syndrome and immune-mediated damage has been advocated. This may be particularly relevant in the context of neurological complications. The reason why only a subgroup of patients develop non-criteria nervous system disorders and what determines the clinical phenotype are questions that remain open. The double nature, thrombotic and immunologic, of APS is also reflected by therapeutic strategies. In this review we summarize known neurological manifestations of APS, revisiting pathogenesis and current treatment options.

Neurologic manifestations of antiphospholipid syndrome.

Neurological involvement in antiphospholipid antibody syndrome (APS) is common, and its occurrence increases morbidity and mortality. Patients may present variable neurological involvement, such as cerebrovascular disease, cognitive dysfunction, headache, seizures, movement disorders, multiple sclerosis-like syndrome, transverse myelitis and ocular symptoms. Most neurological manifestations are associated with thrombosis of the microcirculation or of large vessels; nonetheless, there is compelling evidence suggesting that, in some cases, symptoms are secondary to an immune-mediated pathogenesis, with direct binding of aPL on neurons and glia. Herein we describe clinical characteristics and management of neurological APS manifestations.

'Non-Criteria' Neurologic Manifestations of Antiphospholipid Syndrome: A Hidden Kingdom to be Discovered.

Neurological manifestations or disorders associated with the central nervous system are among the most common and important clinical characteristics of antiphospholipid syndrome (APS). Although in the most recently updated (2006) APS classification criteria, the neurological manifestations encompass only transient ischemic attack and stroke, diverse 'non-criteria' neurological disorders or manifestations (i.e., headache, migraine, bipolar disorder, transverse myelitis, dementia, chorea, epileptic seizures, multiple sclerosis, psychosis, cognitive impairment, Tourette's syndrome, parkinsonism, dystonia, transient global amnesia, obsessive compulsive disorder and leukoencephalopathy) have been observed in APS patients. To date, the underlying mechanisms responsible for these abnormal neurological manifestations in APS remain unclear. In vivo experiments and human observational studies indicate the involvement of thrombotic events and/or high titers of antiphospholipid antibodies in the neuro-pathogenic cascade of APS. Although different types of neurologic manifestations in APS patients have successfully been treated with therapies involving anti-thrombotic regimens (i.e., anticoagulants and/or platelet antiaggregants), antineuralgic drugs (i.e., antidepressants, antipsychotics and antiepileptics) and immunosuppressive drugs alone or in combination, evidence-based guidelines for the management of the neurologic manifestations of APS remain unavailable. Therefore, further experimental, clinical and retrospective studies with larger patient cohorts are warranted to elucidate the pathogenic linkage between APS and the central nervous system in addition to randomized controlled trials to facilitate the discovery of appropriate medications for the 'non-criteria' neurologic manifestations of APS.

Hughes syndrome and epilepsy: when to test for antiphospholipid antibodies?

Epilepsy and seizures are reported among the neurological manifestations of antiphospholipid syndrome (APS) at a prevalence rate of approximately 8%, which is nearly 10 times the prevalence of epilepsy in the general population. The association of seizures with antiphospholipid antibodies (aPL) is even more significant in the presence of systemic lupus erythematosus (SLE). In this review, we discuss the epidemiological, pathophysiological, laboratory, clinical, and radiological aspects of this association, and derive suggestions on when to consider testing for aPL in epileptic patients and how to manage seizures secondary to APS based on literature data. Epilepsy due to APS should be considered in young patients presenting with seizures of unknown origin. Temporal lobe epilepsy seems to be particularly prevalent in APS patients. The pathogenesis is complex and may not only involve micro-thrombosis, but also a possible immune-mediated neuronal damage. Patients with seizures and positive aPL tend to develop thrombocytopenia and livedo racemosa more frequently compared with those without aPL. Magnetic resonance imaging (MRI) remains the imaging modality of choice in these patients. The presence of SLE and the presence of neurological symptoms significantly correlate with the presence of white matter changes on MRI. In contrast, the correlation between aPL positivity and the presence of white matter changes is very weak. Furthermore, MRI can be normal in more than 30-40% of neuropsychiatric lupus patients with or without aPL. aPL testing is recommended in young patients presenting with atypical seizures and multiple hyper-intensity lesions on brain MRI in the absence of other possible conditions. New MRI techniques can better understand the pathology of brain damage in neuro-APS. The therapeutic management of epileptic APS patients relies on anti-epileptic treatment and anticoagulant agents when there is evidence of a thrombotic event. In the absence of consensual recommendations, the decision of lifelong anticoagulation is discussed on a case-by-case basis. The anti-thrombotic benefit of hydroxychloroquine and statins is supported by several studies.

Sclérose en plaques associée à un syndrome des antiphospholipides : difficultés diagnostiques et thérapeutiques

Strokes are the main neurological manifestation of antiphospholipid syndrome. Other clinical presentations are possible and may mimic classic symptoms of multiple sclerosis (MS). A 46-year-old woman, with a history of two miscarriages, presented four subacute neurological episodes (optic neuritis, right facial paralysis, paraparesis of the thigh, and right brachial monoparesis). Using McDonald criteria, the diagnosis of multiple sclerosis was retained. Because of the occurrence of thrombocytopenia during a final relapse, we reconsidered the diagnosis of MS. Search for antiphospholipid antibodies was positive. All clinical manifestations and complementary tests were compatible with the diagnosis of antiphospholipid syndrome associated with multiple sclerosis. Given the great similarity of clinical, radiological and biological findings in the two diseases, non-thrombotic neurological manifestations of antiphospholipid syndrome can be difficult to distinguish from MS associated with antiphospholipid syndrome.

Neurological and psychiatric manifestations of systemic lupus erythematosus and antiphospholipid syndrome

Neurological or psychiatric symptoms are present in 60% of the cases with systemic lupus erythematosus. Direct lesions of nervous system are associated with the presence of antibodies, vasculitis, thrombosis and impairments mediated by cytokines. Damages caused by injuries of other organs or those due to therapy are known as indirect causes. In the complex pathogenesis the primary cause is neuronal dysfunction mediated by autoantibodies, vasculopathia and coagulopathia. Until now, more than 20 antibodies have been identified in association with damages of the nervous system. These antibodies may impair neurons or astrocytes and may promote thrombotic processes in vessels of the brain. Activation of endothelial cells and disturbance of blood-brain barrier are also pathogenic factors. In patients with systemic lupus erythematosus the most frequent psychiatric manifestations are organic psychosyndrome, particularly deterioration of cognitive functions, and depression, while the most common neurological syndromes are epilepsy and ischemic stroke. In the pathogenesis of antiphospholipid syndrome β2-glycoprotein I plays the most important role; binding to its antibody the complex may interact with cells and modify haemostatic actions. The most frequent neurological manifestations of antiphospholipid syndrome are headache and ischemic stroke.

Antiphospholipid syndrome and the brain in pediatric and adult patients

The most common neurological manifestations of antiphospholipid syndrome (APS) in all age-groups include stroke and transient ischemic attacks due to arterial thromboses and cerebral ischemia. Antiphospholipid antibodies may cause additional non-criteria neurological impairments through vascular, neuroinflammatory and direct neuronal effects. Anti-aggregant or anticoagulant therapies are indicated for APS-related ischemic strokes. Treatment regimens for asymptomatic antibody-positive patients and those with refractory or recurrent disease remain controversial. There is scant literature on the epidemiology and therapy of neurological APS manifestations in pediatric patients. Assessments of modifiable cardiovascular and inherited thrombophilia risk factors are essential in patients with APS. There may be a role for novel neuroimaging modalities in quantifying APS-related microstructural brain damage. The clinical utility of statins, antimalarials, angiotensin-converting enzyme inhibitors, and thrombin inhibitors warrant further research.

Neurological manifestations of antiphospholipid syndrome

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. We review the latest data about neurologic disorders and APS. 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. This review summarizes the latest data regarding the clinical aspects, radiological and therapeutic of major neurologic manifestations associated with antiphospholipid antibodies.

Neurological manifestations of the antiphospholipid syndrome: risk assessments and evidence-based medicine

The antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterised by autoantibody production and vascular thrombosis or pregnancy morbidity. Autoantibodies generated against phospholipid and phospholipid-binding proteins often impair phospholipid-dependent clotting assays (lupus anticoagulants). These autoantibodies activate endothelial cells, platelets and biochemical cascades and can exist in autoimmune disorders such as lupus. Consistently positive antibodies may worsen the severity of thrombo-occlusive disease. The most common neurological manifestations of APS include stroke and transient ischaemic attacks due to arterial thromboses. Antiphospholipid antibodies may cause additional neurological impairments through both vascular and immune mechanisms. Antiaggregant or anticoagulant therapies are indicated for APS-related ischaemic strokes. Treatment regimens for asymptomatic antibody-positive patients and those with refractory disease remain controversial. There is scant literature on neurological APS manifestations in paediatric patients. Assessment of traditional cardiovascular and inherited thrombophilia risk factors is essential in patients with APS. Modifiable risk factors and valvular heart disease may worsen thrombotic and cerebrovascular outcomes. Alternative therapies such as statins, anti-malarials, angiotensin-converting enzyme inhibitors and thrombin inhibitors warrant further research.

Neurological dysfunction associated with antiphospholipid syndrome: histopathological brain findings of thrombotic changes in a mouse model.

The aim of this work was to study the pathological processes underlying neurological dysfunctions displayed by BALB/C mice induced with experimental antiphospholipid syndrome (APS), as we have previously reported. Experimental APS was induced in female BALB/C mice by immunization with a pathogenic monoclonal anticardiolipin (aCL) antibody, H-3 (n=10), or an irrelevant immunoglobulin in controls (n=10). Mice immunized with H-3 developed clinical and neurological manifestations of APS, including: embryo resorption, thrombocytopenia neurological defects and behavioral disturbances. In mouse sera, the titer of various autoantibodies were elevated, including: anti-phospholipids (aPLs), anti-2 glycoprotein-I (β2GPI), anti-endothelial cell antibodies (AECA) and low titer of anti-dsDNA antibodies. Five months after APS induction, mice were sacrificed and brain tissue specimens were processed for hematoxylin and eosin (H&E), immunofluorescence staining and transmission electron microscopy (TEM). H&E staining of cortical tissue derived from all APS mice revealed mild inflammation, localized mainly in the meninges. Prominent IgG deposits in the large vessel walls and perivascular IgG leakage were observed by immunofluorescence. No large thrombi were observed in large vessels. However, EM evaluation of cerebral tissue revealed pathological changes in the microvessels. Thrombotic occlusion of capillaries in combination with mild inflammation was the main finding and may underlie the neurological defects displayed by mice with APS.

Management of the neurological manifestations of APS—what do the trials tell us?

Purpose: To systematically review evidence from clinical trials about the management of neurological manifestations of Antiphospholipid Syndrome (APS). Methods: Articles reporting case-control, cohort and prospective studies and treatment trials of primary or secondary stroke prevention in patients with aPL were identified in an OVID literature search from 1966 to 2004, using the keywords: APS, aPL and cerebrovascular disease. Articles were evaluated according to the standard system for assessing medical evidence to answer the following questions: (1) What is the role of aPL and recurrent stroke risk in both primary and secondary APS populations? (2) What is the evidence to support specific treatment strategies for secondary prevention of aPL-associated stroke? (3) What is the evidence to support specific treatment strategies for primary prevention of aPL-associated stroke? Conclusions: (1) aPL are a risk factor for incident stroke (Grade A, established as useful for the given condition in the specified population). (2) The evidence to support the role of aPL in recurrent stroke is conflicting and, therefore, inconclusive. (3) Warfarin at moderate-intensity doses is equally effective in preventing a recurrent thrombotic event as warfarin at high-intensity doses in patients with APS (Grade A evidence, established as useful for the given condition in the specified population). (4) Warfarin, at moderate-intensity doses is as effective as aspirin (at a dose of 325 mg/day) in preventing recurrent thrombotic events in patients who are aPL-positive at the time of an initial stroke (Grade B evidence, probably useful for the given condition in the given population). (5) Currently there are no data to support the use of any prophylactic therapy in patients with aPL and no clinical manifestations for the purposes of preventing an incident stroke.

Transverse Myelitis in a Patient with Primary Antiphospholipid Syndrome

The neurological manifestations of antiphospholipid syndrome (APS) are diverse. Transverse myelitis (TM) is an uncommon, but well-known neurological complication of systemic lupus erythematosus (SLE). On the other hand, the reported cases associated with primary APS are extremely rare. To our knowledge, this is the first report of TM in a patient with primary APS in Korea. A 32-year-old male patient was admitted with the sudden onset of numbness, a tingling sensation, and weakness in both lower extremities. He had a 19 months history of external iliac and femoral arterial thromboses prior to admission. The laboratory results indicated the presence of anticardiolipin antibodies of the IgG class and lupus anticoagulant. No other autoantibodies were detected and there were no apparent clinical manifestations of SLE or multiple sclerosis. A T2-weighted magnetic resonance (MR) image showed swelling and increased intensity of the cervical and thoracic spinal cord between C6 and T7 with slight enhancement by contrast medium. After steroid pulse therapy, the patient's symptoms were gradually relieved and the abnormal findings on MR imaging disappeared.