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 [5].

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 [10]. 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 [11].

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 [2]. 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 %) [3]. 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 [12]. 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 [13]. 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 [14]. Conversely, Brey and coworkers found the risk of stroke to be 1.5 times higher in males carrying aCL than those without [15]. 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 [16]. 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 [17]. 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 [18]. 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 [19]). 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 [20].

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 [21]. 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 [2].

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 [22]. 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 [23]. 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 [24].

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 [25]. The prevalence of multi-infarct dementia in patients with APS has been reported to be around 2.5 % [2]. 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 [12]. 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 [26]. 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 [25].

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 [27]. 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 [2]. 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 [16]. 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 [28].

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 [29]. 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 [30]. 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 [31].

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 [39]; 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 [40].

Myelopathy is a rare manifestation of APS, with a prevalence of less than 1 % [2]. 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 [41]. The correlation between aPL positivity and the occurrence of transverse myelitis holds significance even when considering SLE individuals only [17]. 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 % [2]. Similarly, in a more recent series of 538 patients with APS, epilepsy was reported in 8.6 % of subjects [44]. The prevalence of IgG aCL was even higher in patients with focal epilepsy than in those with generalized epilepsy (14 versus 8 %) [45]. 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 [46]. However, even newly diagnosed patients with epilepsy were found to present a higher positivity rate of aCL IgG compared to controls [40]. Another hypothesis envisages that disease itself, through the production of proinflammatory cytokines such as IL-6, might induce autoantibody production [42]. 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) [44]. Consistently, patients with SLE and aPL are more prone to develop convulsions than those who are aPL negative [47].

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 [47]. 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 [48], 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 [49].

Several anecdotal reports have highlighted the association of sensorineural hearing loss with aPL [25]. Series carried out in otologic centers showed that 27 % of patients with sudden deafness or progressive sensorineural hypoacusia had positive aCL [50]. 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 [25].

Ocular vaso-occlusive disease is frequently found in patients with APS, with amaurosis fugax being the most common manifestation [51]. Severe vaso-occlusive retinopathy leads to poor visual outcomes with visual loss in 80 % of cases with neovascularization occurring in 40 % of cases [52]. 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 [53].