Cecilia Beatrice Chighizola1, 2 , Davide Sangalli3, Barbara Corrà3, Vincenzo Silani3 and Laura Adobbati3
Department of Clinical Sciences and Community Health, University of Milan, Via Festa del Perdono 7, Milan, 20122, Italy
Immunology Research Laboratory, IRCCS Istituto Auxologico Italiano, Via Zucchi 18, Cusano Milanino, Milan, 20095, Italy
Department of Neurology – Stroke Unit, IRCCS Istituto Auxologico Italiano, University of Milan, P. Brescia 20, Milan, 20149, Italy
Cecilia Beatrice Chighizola
Antiphospholipid syndrome (APS) is a systemic autoimmune disease; the revised Sapporo criteria for the diagnosis of APS require either pregnancy morbidity or at least one episode of vascular thrombosis in any tissue or organ (demonstrated by appropriate imaging studies or histopathology) as well as the occurrence of circulating antiphospholipid antibodies (aPL) on two or more occasions at least 12 weeks apart. Three laboratory tests are considered in the same APS diagnostic criteria, namely, antibodies against β2-glycoprotein I (anti-β2GPI antibodies) and cardiolipin (aCL), together with a functional assay, lupus anticoagulant (LA) . aPL-related vascular thrombosis might affect the venous and the arterial district of all anatomical sites, regardless of their size. In the Euro-Phospholipid Project Group study, which included 1,000 APS patients, stroke emerged as the most frequent vascular clinical manifestation at disease onset, being the most common presenting event after deep venous thrombosis . In the follow-up study conducted over a 10-year period, stroke and transient ischemic attack were the most common aPL-related clinical events . The importance of neurological manifestations in APS was first stressed in the early 1980s, when Graham Hughes reported the association of aPL with a spectrum of neuropsychiatric manifestations in the original description of the syndrome . Indeed, besides cerebrovascular events, a wide range of “non-criteria” neurological manifestations has been associated with aPL. Dementia, migraine, multiple sclerosis, myelopathy, and epilepsy are regarded as clinical features undoubtedly frequent but not specific for APS diagnosis (Table 8.1, ). Many of these manifestations can be hardly explained by mere pro-thrombotic mechanisms, suggesting that aPL may exert a direct effect on brain cells, disrupting their function.
Non-criteria neurological manifestations of APS and level of evidence of their association with aPL 
Level of evidence
Association between LA and dementia
Association between aPL and cognitive dysfunction
No association between migraine and aPL
No association between aPL and clinical outcome
Association between aPL and transverse myelitis in SLE
Association between aPL and epilepsy
Level I: Prospective study in a broad spectrum of the representative population or meta-analysis of randomized-controlled trials. Level II: Prospective study in a narrow spectrum of the representative population or well-designed cohort or case–control analytic study or retrospective study in a broad spectrum of the representative population. Level III: Retrospective study in a narrow spectrum of the representative population. Level IV: Study design where predictor is not applied in a blinded fashion or descriptive case series or expert opinion
As a whole, the neurological involvement is responsible for a consistent burden of morbidity and mortality in APS, making rather relevant to promptly formulate the correct diagnosis. Therefore, clinicians should be aware of the constellation of neurological manifestations associated with aPL, in order to best manage these conditions.
8.2 aPL-Mediated Mechanisms of Neurological Damage
It is still not clear why aPL display such a particular tropism for the cerebral circulation, even though the mechanism of nervous system involvement in APS is considered to be primarily thrombotic. aPL exert a thrombogenic effect by interfering with both soluble components and cells involved in the coagulation cascade. These autoantibodies have been found to bind to some members of the serine protease family, which enlists proteins involved in hemostasis (procoagulant factors as thrombin, prothrombin, factors VIIa, IXa, and Xa and anticoagulants as protein C) as well as in fibrinolysis (plasmin and tissue plasminogen activator). aPL induce a proinflammatory and procoagulant endothelial phenotype upregulating cellular adhesion molecules, promoting the synthesis of endothelial nitric oxide synthase and proinflammatory cytokines as interleukin (IL)-6 and tumor necrosis factor (TNF)-α. In both endothelial cells and monocytes, aPL significantly increase the expression of tissue factor, the major initiator of the clotting cascade. Further, they promote aggregation and activation of platelets. It should be noted that aPL are necessary but not sufficient to trigger thrombosis in vivo: according to the two-hit hypothesis, the antibodies (first hit) induce a thrombophilic condition but clotting takes place in the presence of another thrombophilic condition (second hit). This theory might explain why aPL-positive subjects develop thrombotic events only occasionally despite aPL persistency .
It has been hypothesized that aPL tropism for cerebral circulation might be attributed to the peculiar morphological and functional features of brain microvascular endothelium compared to other anatomical districts. Indeed, brain microvascular endothelial cells display tight junctions, lack of fenestrations, and low active fluid-phase transport. In addition, these cells produce a very high amount of energy, necessary to activate transport of nutrients via receptor-dependent mechanisms, with a higher electrical resistance compared to that of endothelial monolayers from other districts. Notably, the brain microvasculature has been shown not to express the anticoagulant thrombomodulin while it exposes consistent amounts of β2GPI, the main antigenic target of aPL [6, 7].
Further mechanisms other than vascular thrombosis have been advocated to explain such tropism. It has been postulated that impairment in the blood–brain barrier (BBB) facilitates the passage of pathogenic autoantibodies into the brain with detrimental consequences. Such disruption of the BBB might be ascribed to proinflammatory cytokines as IL-6, which are produced by the damaged endothelium in response to aPL. Once gained the access to the central nervous system (CNS), aPL have been demonstrated to bind to various cells: in animal models anti-β2GPI antibodies have been found to adhere to the surface of not only endothelial cells but also neurons and astrocytes. aPL binding to CNS target cells leads to deregulation of their functions, thus causing peculiar clinical manifestations. At this regard, aPL have been demonstrated to depolarize synaptic brain extracts and to interfere with glutamatergic pathways in cerebellar granule cells, leading to neurotoxicity [8, 9]. Besides aPL, other autoantibodies might be involved in the pathogenesis of CNS involvement. Most recently, antibodies against an extracellular epitope located in the N-terminal domain of the NR1 subunit of the N-methyl-D-aspartate receptor NR2 (anti-NR2) have been described in 33 % of 15 unselected patients with primary APS . Anti-NR2 antibodies can cause neuronal damage via an apoptotic pathway; in addition, it has been suggested that a decrease of NMDA receptors in inhibitory GABAergic neurons and glutamatergic synapses causes disinhibition of excitatory pathways and an increase in extracellular glutamate, resulting in a fronto-striatal syndrome and disinhibition of brainstem central pattern generators, thus causing complex elaborate movements and dyskinesias .
8.3 Cerebrovascular Manifestations
The association between cerebrovascular disease and aPL was already reported in the early description of the syndrome and later confirmed in many prospective studies. In the Euro-Phospholipid Project Group study, 19.8 % of patients presented with stroke and 11.1 % with transient ischemic attack . In the follow-up study, stroke was the most common APS clinical manifestations (5.3 % of the total cohort), followed by transient ischemic attacks (4.7 %) . Individuals with stroke and aPL positivity are significantly younger compared to aPL-negative subjects: aPL are believed to mediate approximately one third of strokes occurring in individuals before 45 years, with a serious social impact . In particular, the risk of cerebral infarction has been estimated to be 2.3 times higher in patients with positive aPL than in those testing negative . Patients with stroke and aPL are also more likely to be female: in the Framingham study, high serum aCL titers were identified as an independent predictor of the risk of future stroke in females but not in males . Conversely, Brey and coworkers found the risk of stroke to be 1.5 times higher in males carrying aCL than those without . In a case–control study focusing on risk factors for stroke in women in the general population younger than 50 years of age, 17 % of the patients with stroke were positive for LA, as compared with 0.7 % of controls. The risk was further increased by taking oral contraceptive pills or smoking . Even though aCL are a well-recognized risk factor for stroke, it is still debated whether aPL positivity at the time of the first event increases the risk of recurrence in unselected populations . Indeed, aPL positivity in patients with ischemic stroke was not predictive of an increased risk of subsequent vascular occlusive events over a 2-year period . However, it should be mentioned that studies not confirming the association between recurrent stroke and aPL used a very low cutoff to define aCL positivity (e.g., the APASS study considered aCL titers higher than 10 GPL ). Consistently, when stratifying patients upon aCL titers, it clearly emerges that those with higher titers (aCL >40 GPL) carry a higher risk of developing subsequent thrombo-occlusive events in the cerebral circulation [13, 19].
The clinical manifestations of stroke depend on the location and the caliber of the occluded vessel. The territory of the middle cerebral artery is more commonly affected. Transient episodes of cerebral ischemia can present with amaurosis fugax, transient paresthesia, muscle weakness, vertigo, and transient global ischemia .
The occlusion of cerebral vessels can occur on a thrombotic or embolic basis. Embolisms typically originate from aortic or mitral valve vegetations composed of platelets and fibrin, and particularly left-sided valvular vegetations provide a frequent finding in APS patients . Therefore, a complete evaluation of young patients with aPL and cerebral embolism should include transthoracic and transesophageal echocardiography to rule out valvular abnormalities. On the other hand, arterial thrombotic events are relatively common in the general population and are suggestive of APS when they occur in individuals with no identifiable risk factors. Indeed, family history, age, smoking, hyperlipidemia, hypertension, diabetes mellitus, and other vascular risk factors should be evaluated in patients with cerebrovascular disease and aPL: the presence of these frequent conditions does not exclude APS diagnosis but certainly makes it difficult to fully attribute a stroke to the pathogenic potential of aPL. Surely, the association between aPL and stroke holds a particular clinical significance in young patients presenting additional features of APS and/or with a diagnosis of systemic lupus erythematosus (SLE) or other systemic autoimmune diseases.
Stroke provides the most severe complication of APS, and patients present a considerable stroke-related morbidity burden. Indeed, aPL-related stroke carries a poor prognosis: in the European APS cohort, stroke accounted for 13 % of deaths, at a mean age of 42 years .
The association of cerebrovascular disease with livedo reticularis is named Sneddon’s syndrome. More than 40 % of the patients with Sneddon’s syndrome have APS, suggesting an association between these two conditions . Although clinical and magnetic resonance imaging findings are similar in the two diseases, the clinical course of Sneddon’s syndrome is more severe, and patients present a more pronounced cognitive deterioration and a greater number of disabilities . In addition, patients with Sneddon’s syndrome more often display leukoaraiosis and small lacunar infarcts, whereas patients with APS usually develop main cerebral artery territory infarction .
8.4 Cognitive Impairment and Dementia
aPL-related cognitive dysfunction varies from global dysfunction in the context of multi-infarct dementia to subtle cognitive deficits in otherwise asymptomatic patients with aPL.
Chronic and recurrent ischemic events, affecting small vessels, predispose patients to early-onset multi-infarct dementia . The prevalence of multi-infarct dementia in patients with APS has been reported to be around 2.5 % . aPL-associated dementia cannot be easily differentiated from other forms of dementia such as Alzheimer’s disease, senile dementia, and metabolic or toxic conditions involving the brain. The most common clinical manifestations enlist memory loss, language impairment, impaired concentration, impaired judgment, and shortened attention span. Memory loss is not severe in most patients and often improves once anticoagulant therapy is initiated . In a 2005 review of the characteristics of 30 patients with APS-associated dementia, the mean age of patients was 49 years; 47 % of cases had primary APS, 30 % had SLE, and 23 % had lupus-like syndrome . As a whole, aPL testing is surely recommended in young individuals with no apparent reason for dementia.
The application of formal neuropsychological assessment has allowed the recognition of subtle forms of cognitive dysfunction, indicating a probable preclinical phase of neurological involvement: these patients frequently complain of poor memory and difficulty in concentrating and in verbal fluency. The association between cognitive dysfunction and aPL has been confirmed in cross-sectional as well as prospective longitudinal studies .
The potential pathogenicity of aPL in inducing cognitive impairment has been clearly shown in vivo: passive immunization of mice with β2GPI leads to memory and learning deficits more evident 4–5 months after single immunization without signs of ischemic damage in tissue specimen. When mice received intraventricular injection of IgG aPL purified from patients’ serum, antibodies were found to bind to specific areas of the brain, as hippocampus, cortex, and choroid plexus . Depression and psychosis have been also associated with aPL, but some authors suggested they may emerge as a reaction to neuroleptic drugs. Moreover it is clearly difficult to determine whether psychiatric symptoms are due to a psychological reaction, to steroid therapy or to aPL itself.
Chronic headache, including migraine, is a common finding in patients with APS: in a large cohort of 1,000 aPL-positive patients, 20.2 % complained of migraine . Headache in APS can vary from classic intermittent migraine to almost continuous incapacitating headache. It can persist for years before APS is diagnosed. It is often untreatable, since it does not respond to narcotics or analgesics . Despite the high prevalence among aPL carriers, the association between migraine and aPL is still controversial. Few authors reported an association between migraine and LA or aCL, while other investigators observed no association. Similarly, in SLE cohort patients with aPL are more likely to develop headache than those aPL negative, even though no association between aPL positivity and particular type of headache could be detected. This heterogeneity across studies might be attributed to the high prevalence of chronic headache in the general population and in the different definitions of migraine used. Interestingly, there are some anecdotal reports of the beneficial effect of anticoagulation in APS patients with migraine .
8.6 Multiple Sclerosis-Like Disease
Multiple sclerosis is a demyelinating inflammatory disease of the CNS. Clinical syndromes resembling multiple sclerosis, mainly in its relapsing–remitting pattern, were first reported in APS patients back in 1994 . The diagnostic process is complicated by the fact that white-matter lesions are common findings in APS as well as in multiple sclerosis, in both cases usually small and located in periventricular and subcortical areas. The clinical significance of these lesions, which are hyperintense on T2-weighted MRI sequences, in APS is still matter of debate. These lesions are thought to be due to small vessel thrombi: the white matter of the brain is much more vulnerable than the gray matter to hypoxemia and ischemia because of widely spaced linear arterioles, few anastomoses, and sparse collateralization . In an analysis of the characteristics of patients with APS and multiple sclerosis-like disease, APS patients were reported to have lower severity scores for lesions of the white matter, pons, and cerebellum and higher severity scores for lesions of the caudate nucleus and putamen compared to subjects with a diagnosis of multiple sclerosis .
Another controversial aspect concerns the high prevalence of aPL among subjects diagnosed with multiple sclerosis. Indeed, the prevalence of aPL positivity in patients with multiple sclerosis, without clinical manifestations of autoimmune disease or APS, has been shown to range from 8 to 33 % [32–36]. The prevalence of anti-β2GPI IgG and IgM has been reported to be higher among patients compared to controls; it is not clear whether this association displays a clinical significance or it is a mere epiphenomenon [37, 38]. Patients with a diagnosis of multiple sclerosis and persistently elevated aCL levels were reported to display a slower rate of progression and some atypical clinical features such as headaches and absence of oligoclonal bands in the cerebrospinal fluid. It has been proposed that aPL might affect response to treatment ; some authors even proposed that aPL might be involved in the pathogenesis of the neurological symptoms of multiple sclerosis, even suggesting that management should include antiplatelet or anticoagulant agents .
Myelopathy is a rare manifestation of APS, with a prevalence of less than 1 % . The association with aPL seems to be rather strong for transverse myelitis, an acute inflammatory process affecting a focal area of the spinal cord. It is clinically characterized by the development of neuromotor, sensory, and autonomic dysfunction. Since the first report back in 1985, many subsequent studies have confirmed the association of aPL with transverse myelitis. The age at disease onset varies widely, ranging from childhood to 80 years . The correlation between aPL positivity and the occurrence of transverse myelitis holds significance even when considering SLE individuals only . It has been proposed that the pathogenesis might involve not only a thrombotic process leading to ischemia but also a direct interaction between aPL and spinal cord phospholipids [42, 43].
In a large European cohort of 1,000 APS patients, the prevalence of convulsions was 7.0 % . Similarly, in a more recent series of 538 patients with APS, epilepsy was reported in 8.6 % of subjects . The prevalence of IgG aCL was even higher in patients with focal epilepsy than in those with generalized epilepsy (14 versus 8 %) . It has been suggested that the increased prevalence of autoantibodies described in epileptic patients might be secondary to antiepileptic drugs. Consistently, patients with partial epilepsy and a disease duration longer than 30 years were three times more likely to have aCL than subjects with recent onset . However, even newly diagnosed patients with epilepsy were found to present a higher positivity rate of aCL IgG compared to controls . Another hypothesis envisages that disease itself, through the production of proinflammatory cytokines such as IL-6, might induce autoantibody production . As seizure and epilepsy are a relative common manifestation of SLE, it is not surprising that epilepsy is more common in patients with secondary APS than in those with primary APS (13.7 % versus 6 %, respectively) . Consistently, patients with SLE and aPL are more prone to develop convulsions than those who are aPL negative .
At multivariate logistic regression analysis, thromboembolic events involving the CNS emerged as the strongest predictor of epilepsy, with an odds ratio of 4. Indeed, convulsions are a well-recognized symptom of cerebral ischemia, and it is possible that many cases of convulsions in aPL-positive patients are caused by ischemic events triggering the development of an epileptic focus . However, since thrombotic events may explain the occurrence of epilepsy in APS only partially, other mechanisms of damage have been investigated. In lupus patients with convulsions, aPL have been shown to impair the function of a gamma-aminobutyric acid receptor-mediated chloride channel in the myelin sheath , suggesting aPL might decrease the seizure threshold through a direct and reversible mechanism. These findings are in line with the increasing evidence of the association of epilepsy with specific autoantibodies targeting neuronal structures, such as antibodies against glutamic acid decarboxylase and against glutamate receptor GluR3 in some types of autoimmune encephalitis .
8.9 Sensorineural Hearing Loss
Several anecdotal reports have highlighted the association of sensorineural hearing loss with aPL . Series carried out in otologic centers showed that 27 % of patients with sudden deafness or progressive sensorineural hypoacusia had positive aCL . The etiology of sensorineural hearing loss in aPL carriers might be on a vascular basis, as certified by the improvement observed in some patients on anticoagulation .
8.10 Ocular Syndromes
Ocular vaso-occlusive disease is frequently found in patients with APS, with amaurosis fugax being the most common manifestation . Severe vaso-occlusive retinopathy leads to poor visual outcomes with visual loss in 80 % of cases with neovascularization occurring in 40 % of cases . Optic neuropathy is less frequent in APS than in SLE and usually monolateral rather than bilateral. It has been proposed that the underlying mechanisms are different, implying a pro-thrombotic milieu involving the ciliary vasculature in APS and an inflammatory vasculitis in SLE .
Chorea has been described in 1.3 % of APS patients, being thus regarded as a rare manifestation of APS . Chorea is a well-known phenomenon in patients with SLE and is strongly correlated with aPL positivity. Chorea has been described in association with primary APS in a number of patients, many of whom were children . In a review of the clinical presentation of 50 APS patients presenting with chorea, 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 % of cases, and imaging studies revealed cerebral infarction in 35 % . Besides a vascular mechanism, aPL might cause chorea by binding phospholipids in the basal ganglia, leading to movement disorders .
8.12 Guillain–Barre’ Syndrome
Guillain–Barre’ syndrome is an acute demyelinating disorder of the peripheral nervous system. In the original description of the syndrome, Hughes reported the association of demyelinating polyradiculoneuropathy and APS . The motor nerves are affected, with little or no involvement of the sensory nerves. On the other hand, some Guillain–Barre’ syndrome patients produce autoantibodies to various phospholipids and nuclear antigens. However, nowadays such association is not considered solid: those autoantibodies are probably produced as a result of damage to the myelin rather than being the cause of the demyelination .
8.13 Peripheral Neuropathy
Peripheral nervous system involvement is rare in APS ; distal, asymmetric, axonal polyneuropathy (mononeuritis multiplex) is extremely rare. Peripheral neuropathy might provide a common asymptomatic abnormality in primary APS patients: in a study on 26 primary APS patients, 35 % presented abnormalities at nerve conduction studies, 15.5 % had pure sensory or sensorimotor distal axonal neuropathy, 4 % had sensorimotor demyelinating and axonal neuropathy involving upper and lower extremities, and 15.5 % showed isolated carpal tunnel syndrome . The pathogenesis of peripheral neuropathy involves both immune and vascular mechanisms. 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 .
The management of stroke in APS patients is still rather controversial; therapeutic options include moderate- or high-intensity anticoagulant regimens as well as antiplatelet agents.
To date, two randomized controlled studies addressed the management of non-cardioembolic stroke. In the earlier one, the 2004 APASS study, aspirin given at a dose of 325 mg daily was shown to be as effective as low-intensity anticoagulants in the secondary prevention of stroke among aPL-positive patients . The APASS study is flawed by some limitations: aPL positivity was not confirmed 12 weeks apart, and patients were recruited even when aCL positivity was detected at low titers; the median INR in the patients receiving warfarin was 1.9, a value whose efficacy is unproven also for the treatment of thromboembolism. These biases preclude results extrapolation to patients with definite APS. However, it is generally accepted to consider prescribing low-dose aspirin (LDASA) to stroke patients without SLE and a low-risk aPL profile. In 2009, Okuma first shed light on the combination of LDASA with moderate-intensity anticoagulation as a therapeutic option in stroke patients with definite APS . In this randomized controlled trial, a lower incidence of recurrent stroke was observed among patients treated with LDASA plus warfarin compared to those receiving LDASA alone, with a cumulative stroke-free survival of 74 % versus 25 %. However, this study is flawed by important limitations: firstly, the sample size was rather small, no details of the aPL profiles were provided, and limited information on the number and type of recurrent strokes in each group were available. Nevertheless, considering the high incidence of recurrent stroke in the monotherapy arm, this study suggests that LDASA alone might not be sufficient for secondary stroke prevention in patients with definite APS.
The optimum intensity of oral anticoagulation has been also a matter of debate, since a retrospective analysis suggested a beneficial effect of high-intensity anticoagulation. Therefore, two randomized trials by Crowther and Finazzi recruited APS patients with a history of thrombotic events in order to confirm these findings, even though arterial thrombosis were underrepresented compared to subjects experiencing venous thrombosis (24 % in the study by Crowther and 32 % in the trial promoted by Finazzi). These two studies didn’t support a superiority of high intensity (INR 3–4) as compared to moderate-intensity anticoagulation (INR 2–3) [59, 60]. Consequently, a 2006 systematic review including only these randomized controlled trials recommended moderate anticoagulation . Nevertheless a systematic review by Ruiz-Irastorza, who considered also observational studies, supported the utility of the high-intensity regimen . This review concluded that oral anticoagulation to a standard target INR range of 2.0 to 3.0 was not sufficient in preventing recurrences among patients presenting with arterial events, with most of the new thrombotic events occurring at an INR below 3.0. Given this conflicting picture, an international task force could not reach a consensus about the optimal management of arterial thrombosis. Eight out of the 13 members of the task force suggested treatment with warfarin with an INR over 3.0 for patients with definite APS; the combination of moderate anticoagulation and aspirin was also listed as an option, while ASA was reserved to stroke patients with a low-risk profile and reversible thrombotic risk factors . The guidelines issued in 2014 by the American Heart Association/American Stroke Association recommended antiplatelet therapy in patients with ischemic stroke or transient ischemic attack with aPL who don’t fulfill the criteria for APS, but anticoagulant therapy might be considered for patients meeting the criteria for APS, depending on the perception of risk for recurrent thrombotic events and bleeding .
While ischemic manifestations of APS always imply the initiation of either antiplatelet drugs or long-term anticoagulants, no standard treatment is available for nonvascular neurological manifestations of APS. First-line treatment of aPL-related neurological manifestations follows the recommendation for the same manifestations outside APS field. In case of failure, the usage of steroids and other immunosuppressive agents might be justified by the probable flogistic/autoimmune mechanisms underlying these symptoms. Intravenous immunoglobulins, plasmapheresis, and rituximab have been occasionally reported to be effective in cases unresponsive to conventional drugs .
Besides cerebral ischemic events, several heterogeneous neurological manifestations have been identified as part of the spectrum of APS. An increasing body of evidence from experimental APS models as well as from patients currently suggests an immune-mediated pathogenesis underlying non-thrombotic manifestations of APS such as movement disorders and neuropsychiatric symptoms.
In consideration of the available literature, aPL might be worth testing in patients with autoimmune diseases and neuropsychiatric manifestations, in young individuals experiencing ischemic cerebral events without an underlying known disease, and in those with transverse myelitis or atypical seizures. Young subjects with atypical multiple sclerosis clinical features and those with multiple hyperintense lesions on brain MRI T2-weighted sequences, without other known causes, should also be tested for aPL. These complex and multifaceted neurological presentations represent a challenge for clinicians, who need to promptly recognize and effectively treat them in early stages, in order to avoid diagnostic and therapeutic delay. In fact some of these manifestations often improve drastically with the administration of anticoagulants at appropriate doses.
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