Antiphospholipid antibodies as biomarkers in psychiatry: review of psychiatric manifestations in antiphospholipid syndrome

REVIEW ARTICLE

Antiphospholipid antibodies as biomarkers in psychiatry: review of psychiatric manifestations in antiphospholipid syndrome

Sanil Rege1* and Charles Mackworth-Young2

1Psych Scene Pty Ltd., Beleura Private Hospital, Mornington, Australia and 2Department of Rheumatology, Charing Cross Hospital, London, UK

Abstract

Antiphospholipid syndrome (APS) has been implicated in a range of neuropsychiatric presentations. However, there is a paucity of systematic studies on APS in psychiatry. This paper reports the clinical manifestations of APS that are relevant to psychiatrists. The aspects of APS pathogenesis, diagnosis, and treatment presented in this paper are based on a literature review. Treatment-resistant and atypical psychiatric illnesses, severe cognitive dysfunction, migraines, transient ischaemic attacks, and thromboembolic episodes, along with characteristic skin manifestations are the common clinical features of this syndrome. Antiphospholipid antibodies (aPL) may have a causal role in the development of some neuropsychiatric conditions. The existing criteria of APS may not apply to psychiatric patients, which may result in the underdiagnosis of APS in psychiatry. There is no evidence-based guidance available for the treatment of APS in patients with psychiatric symptoms. The treatment of APS with antithrombotic agents in case reports has been reported to yield dramatic improvements in complex and treatment-resistant cases. The possibility of a causal role of aPL in high-morbidity conditions, such as psychosis, depression, and dementia, requires the psychiatrist to be vigilant to the occurrence of this syndrome. There is an urgent need to conduct studies that elucidate the role of aPL in psychiatric presentations, identify patient characteristics, and consider whether new criteria with greater applicability in psychiatry are needed.

Keywords: beta 2 GPI; lupus anticoagulant; anticardiolipin antibodies; psychosis; cognitive dysfunction; depression; thrombosis

Received: 13 July 2014; Revised: 23 October 2014; Accepted: 24 November 2014; Published: 2 February 2015

Translational Developmental Psychiatry 2015. © 2015 Sanil Rege and Charles Mackworth-Young. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Citation: Translational Developmental Psychiatry 2015, 3: 25452 - http://dx.doi.org/10.3402/tdp.v3.25452

 

Antiphospholipid syndrome (APS), which is also known as sticky blood or Hughes syndrome, was first fully described 30 years ago as a syndrome that involves arterial and venous thrombosis with prominent cerebral involvement. The main reported features of this syndrome include migraines, chorea, epilepsy, and cerebrovascular accidents (1). Initially, the syndrome was considered to be a distinct entity, called anticardiolipin syndrome in 1985, and it was later renamed antiphospholipid antibody syndrome (2). APS is an autoimmune disease in which autoantibody production results in a hypercoagulable state that causes recurrent arterial and venous thrombosis and/or recurrent foetal loss.

The history of APS can be regarded as starting in 1952, when the finding of a chronic biological false-positive serological test for syphilis was fully delineated (3). Shortly afterwards, it was shown that the majority of women with this abnormality subsequently developed systemic lupus erythematosus (SLE) (4). It was already known that the bovine heart extract used for this complement fixation test contained a phospholipid, namely cardiolipin (CL) (5). Parallel to this finding was the description of an in vitro clotting disturbance in patients with SLE. This disturbance causes a prolongation of the partial thromboplastin time and was labelled the ‘lupus anticoagulant’ (LA) (6).

However, this term is misleading because the disorder is characterised in vivo by increased thrombosis. LA activity was described in patients with thrombosis (7) and foetal loss (8) and is associated with a chronic biological false-positive serological test for syphilis. Although it was soon shown that LA activity could be absorbed by CL (9), it was not until the development of a sensitive assay for anticardiolipin antibodies (aCL) that APS could be fully described (1).

This syndrome can affect all organ systems; therefore, it can present to any specialty. It is under-recognised and underdiagnosed in all specialties (10). It can have devastating consequences if left untreated due to uncontrolled thrombosis, and it can lead to permanent disability, severe maternal morbidity, and even death (10). The main criteria for the disorder are described in Table 1 (11).


Table 1. Research criteria for defining antiphospholipid syndrome
Clinical criteria
  1. Vascular thrombosis
    One or more clinical episodes of arterial, venous, or small-vessel thrombosis.
  2. Pregnancy morbidity
    (a) One or more unexplained deaths of a morphologically normal foetus at or beyond the 10th week of gestation.
    (b) One or more pre-term births of a morphologically normal neonate before the 34th week of gestation because of the following:
    (i) eclampsia or severe pre-eclampsia or (ii) recognised features of placental insufficiency.
    (c) Three or more unexplained consecutive spontaneous miscarriages before the 10th week of gestation, with the exclusion of maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes.
Laboratory criteria
  1. The presence of lupus anticoagulant (LA) in the plasma on two or more occasions at least 12 weeks apart.
  2. The presence of the anticardiolipin (aCL) antibody of immunoglobulin (Ig)G and/or IgM isotype in the serum or plasma in medium or high titre (i.e. >40 GPL units or MPL units, or >the 99th percentile) on two or more occasions at least 12 weeks apart.
  3. The presence of the anti-b2-glycoprotein I antibody of IgG and/or IgM isotype in the serum or plasma (in titres>the 99th percentile) on two or more occasions at least 12 weeks apart.
Antiphospholipid antibody syndrome (APS) is present if at least one of the above-mentioned clinical criteria and one of the above-mentioned laboratory criteria are met.
GPL units, IgG antiphospholipid units; MPL units, IgM antiphospholipid units.
Adapted from Miyakis et al. (11).

In psychiatry, APS has not been systematically investigated despite its association with a range of neuropsychiatric manifestations. Psychiatric illness may be the initial manifestation of the syndrome, requiring psychiatrists to be vigilant for the occurrence of the syndrome due to its potential preventive and therapeutic implications (12).

Phospholipids, antiphospholipid antibodies, and the brain

Phospholipids are the major component of cell membranes. These molecules constitute approximately 60% of the dry weight of the brain and play an important role in neurodevelopment (13, 14). Alteration of the lipid environment in the phospholipid bilayer has functional consequences for the activity of the receptors and other proteins that are embedded in the membrane phospholipids (15) and has been proposed to contribute to the deterioration of central nervous system (CNS) function with increasing age (16). Phospholipids also facilitate signal transduction responses to neurotransmitters, such as serotonin, dopamine, glutamate, and acetylcholine that play a key role in the pathophysiology of psychiatric disorders. Autoimmune reactions against key brain phospholipid antigens can result in both a structural breakdown and functional interference, thus leading to the pathogenesis of psychiatric syndromes. The breakdown of phospholipids has been proposed to play a role in the pathogenesis of the development of schizophrenia, bipolar disorder, and depression (17, 18). Imaging studies have shown abnormalities in phospholipid metabolism in the brains of people with schizophrenia, particularly in the frontal and temporal lobes (19).

Antiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies that are directed against anionic phospholipids or protein phospholipid complexes, which also play an important role in the coagulation process (20). ‘Antiphospholipid antibodies’ is a generic term for antibodies that are directed against antigenic targets such as beta 2-glycoprotein I (β2 GPI) and prothrombin, which are considered to be the main antigenic targets (21). Other antigenic targets include CL, phosphatidylserine (PS), tissue plasminogen activator (tPA), plasmin, annexin A2, and thrombin. It is believed that most aPL associated with clinical features of APS recognise the phospholipid-associated protein β2 GPI (20).

In clinical practice, antibodies are usually detected by the presence of one or more of the following: LA, antibodies against β2 GPI, and aCL (IgG and IgM). aPL are present in the normal population at a rate of 1–5% (10). The main tests used for the detection of the LA phenomenon are kaolin clotting time, dilute Russell viper venom test, silica clotting time, and activated partial thromboplastin time (22). Consensus suggests that reactivity with the LA assay is mainly mediated by the antibodies that are directed against prothrombin and β2 GPI, but the aCL positivity associated with clinical features is caused by β2 GPI-dependent aPL (23). There is significant batch-to-batch variability among the tests and a lack of standardisation of assays; therefore, good communication between the laboratory personnel and the clinician is important when making the diagnosis of APS (24). LA, aCL, and β2 GPI testing is required to make an accurate diagnosis of APS (25).

The pathogenesis of aPL is multifactorial and has not been clearly elucidated. A two-hit hypothesis has been proposed (Fig. 1) (26, 27). APS is thought to be triggered by infections and other entities through a process called molecular mimicry between human β2 GPI and molecules that are similar to β2 GPI (e.g. in invading bacteria), which results in the production of anti-β2 GPI antibodies (28). According to the two-hit hypothesis, the first hit disrupts the vascular endothelium and the second hit potentiates thrombus formation (29). The precise trigger is unknown, but it may be related to a complex interaction between genes, hormones, and the environment. Females are most likely to develop APS, which may be related to the immunogenic potential of oestrogen. Oestrogen is thought to induce a genetic programme that alters the survival and activation of B cells in a B cell-autonomous manner, which consequently skews the naive immune system towards autoreactivity (30).

Fig 1

Fig. 1. Infections trigger the development of aPL through a process called molecular mimicry due to cross reactivity between the bacterial antigens and antigenic epitopes of the β2 GPI protein. The β2 GPI protein is a glycoprotein that binds to phospholipids. This binding of aPL to the β2 GPI protein creates a prothrombotic state that is not sufficient to cause thrombosis by itself; a second hit, such as trauma or infection, is required. This second hit results in cell injury and a conformational change in the β2 GPI protein that results in the exposure of phospholipid antigens that would normally be present on the inside of the cell. This exposure allows the already circulating aPL to bind to the exposed epitopes, resulting in a cascade of aPL pathogenic mechanism activation (20, 23, 26).

There is good evidence from animal models that aPL can cause features of systemic APS. In a mouse model of thrombosis, which involves a controlled pinch injury to a femoral vein, infusion of aPL increases the size of the clot (31). Passive transfer of murine or human aPL into pregnant mice results in an increased rate of foetal resorption, which is the murine equivalent of miscarriage in humans (32, 33).

There are many mechanisms by which these effects may occur [reviewed in (29)]. It is likely that the main pathogenic process associated with thrombosis involves activation of endothelial cells, monocytes, and platelets, which results in a more prothrombotic phenotype. This activation most likely occurs through the binding of aPL to cell surface molecules, notably β2 GPI, which causes upregulation of adhesion molecules, tissue factor, complement proteins, and components of the coagulation pathway (23). Patients with APS have also been shown to have antibodies for a wide range of coagulation-related proteins, including those involved in the clotting and fibrinolytic pathways, and there may be direct functional effects on such proteins (34). Some of these mechanisms, particularly endothelial and complement activation, may lead to placental insufficiency and account for foetal loss (35). Oxidative stress and mitochondrial dysfunction are also known to play important roles in APS. Alterations in the redox balance result in a conformational change in β2 GPI, which exposes the cryptic immunogenic epitope located on domain I to antibodies. The antibody complexes (anti-β2 GPI) in turn interact with several receptors (e.g. TLR, annexin A2, and APOER2) and activate a downstream cascade that ultimately leads to a prothrombotic cellular phenotype in a β2 GPI-dependent manner.

The pathogenesis of neuropsychiatric APS is less clearly understood. Thromboembolic phenomena are not sufficient to explain the pathogenesis of neuropsychiatric manifestations in APS. Animal studies offer us a glimpse into the possible pathogenic mechanisms of aPL in the genesis of neuropsychiatric symptoms. Mice immunised with aPL showed a range of abnormalities, such as hyperactivity, increased explorative behaviour, depression-like behaviour, and cognitive deficits, such as impaired short-term memory (36). These behavioural changes were linked to a range of mechanisms such as increased 5HT 1A b in the cortical and hippocampal regions, decreased NMDA receptor binding densities (36), structural change in the hippocampal neurons (37), and changes in the brain proinflammatory and anti-inflammatory cytokines (38). According to Chapman et al., aPL can produce direct neuronal injury by affecting the synaptoneurosomes (39). Liou et al. showed that aCL interacts with the neuronal GABA ionotropic receptors (40).

Katzav et al. reported observing antibody-specific behavioural effects in mice injected with aPL; these mice showed hyperactivity, whilst those injected with anti-ribosomal P (a postulated antibody in neuropsychiatric lupus) exhibited depression-like behaviour (41). Furthermore, mice immunised with β2 GPI were found to have IgG antibodies accumulating in the hippocampal neurons (42), indicating the ability of these antibodies to not only pass the BBB to directly affect the hippocampal neurons but also possibly initiate a downstream cascade of neuroinflammation by involving other immune cells of the brain such as astrocytes. Examination of the brain tissue of the immunised mice revealed thrombotic occlusion of capillaries with mild inflammation (43). β2 GPI is the key pathogenic target in APS. This molecule is not present in brain tissue but is expressed by astrocytes, neuronal cells, and endothelial cells, and thus these cells can be pathogenic targets in an autoimmune reaction. One of the most promising auto-antigens is HRGP (histidine-rich glycoprotein), which shares homology with β2 GPI and is found in human brain tissue (44).

A detailed description of the pathogenesis is outside the scope of this article, and readers are referred to the comprehensive review by Rand (20) and Arnson et al. (44). In summary, aPL are thought to act in the following three ways: by disrupting the haemostatic reactions that occur on cell membranes; by stimulating certain cells, for example, platelets and monocytes, which alters the expression and secretion of various molecules and leads to procoagulant activity; and by direct and indirect neural involvement (Fig. 1).

The genetic predisposition for APS is partially explained by markers called human leukocyte antigens (HLAs). Intriguingly, the HLA region has been implicated in psychiatric disorders and other autoimmune disorders, which highlights the possibility that there may be common etiological mechanisms between these disorders (4547).

Neuropsychiatric manifestations of APS

APS can be primary or secondary. Secondary APS occurs most often in individuals with SLE. SLE affects approximately 20 in every 100,000 women, and approximately 30% of these women develop secondary APS. The prevalence of primary antiphospholipid syndrome (PAPS) is 0.5% in the general population. APS occurs primarily in women of fertile age, and the mean age at diagnosis is 34 years (48).

The features of APS include stroke, migraines, recurrent miscarriages, memory dysfunction, seizures, chorea, labile hypertension, dementia, multiple sclerosis-like syndromes, Guillain-Barre syndrome, sensorineural hearing loss, valvular heart disease, and renal and endocrinal disorders. Its high concentration of phospholipids makes the brain a likely target in APS. This article reviews the presentations of APS in psychiatry, including clues from multisystem involvement that can help psychiatrists detect the condition. This article is also relevant to other specialties with respect to the detection of psychiatric manifestations in patients with APS.

Psychosis

Kurtz described the first case report of the association of aPL with psychosis in a 50-year-old woman who presented with a schizophrenia-like syndrome as the primary manifestation of APS. He concluded that APS may present as psychosis many years before the occurrence of somatic symptoms (49).

More recently, additional case reports have shown an association between psychosis and both primary and secondary APS. Siu et al. reported a case of first-episode psychosis in a Chinese woman during the second trimester of pregnancy. In this case, the atypical presentation and fluctuating mental state with visual hallucinations suggested an organic condition, and investigations revealed SLE with aPL antibodies. The authors suggested that psychosis can be the initial presentation of APS and that psychiatrists should consider SLE in the differential diagnosis of psychosis occurring during pregnancy (50). Fernandez Ga de las Herras et al. reported the case of a 49-year-old woman who demonstrated a partial response to antipsychotics and had a previous history of deep vein thrombosis (DVT) and multiple white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) that responded to immunomodulation (51). The authors postulated that the syndrome may be underdiagnosed in psychiatry and highlighted the importance of considering the presence of medical conditions in patients with a first episode of psychosis. In another case, a 28-year-old woman with episodic psychosis and catatonia was discovered to have APS after she developed popliteal vein thrombosis and a mild purpuric rash. Following anticoagulation, treatment with haloperidol and venlafaxine, and immunosuppression (azathioprine, prednisolone), she became asymptomatic. Although the classification criteria for SLE were not met, the authors postulated that the inflammatory disorder (as indicated by elevated erythrocyte sedimentation rate and C-reactive protein) may have indicated an early stage of this disease (52). Catatonia is now considered to be a manifestation of SLE, and its pathogenesis in this instance may be related to the affinity of aPL antibodies for the basal ganglia (53). Pego-Reigosa studied 11 patients with lupus psychosis, and aPL were observed in 10% of the cases (54). In another case, a 24-year-old woman presented with acute psychotic symptoms and fever, and the serological work-up revealed aPL positivity, low protein S with elevated d-dimer, and brain hypoperfusion. Early immunomodulation treatment led to complete remission of the psychotic symptoms, preservation of cognitive function, and prevention of APS progression (55).

APS is an important differential diagnosis of psychosis in children. A 9-year-old girl who developed psychotic illness without thrombotic manifestations was found to have a persistent presence of aCL with negative ANA. Marked improvement occurred after combined treatment with antidepressants, antipsychotics, small-dose aspirin (100 mg a day), and hydroxychloroquine (100 mg a day). The patient developed right axillary vein thrombosis 5 months after aspirin was stopped by her family (56). The above cases raise the question of whether testing for aPL should be incorporated into the differential diagnosis of first-episode psychosis, especially in the treatment-resistant cases, for the following two main reasons: the possibility that non-psychotropics may be required for complete remission and the implication for the prevention of future thromboembolic episodes and multisystem involvement related to APS. The above cases highlight the importance of collaboration between psychiatrists and other specialties in the management of psychiatric disorders. Although a causal role of aPL in psychosis cannot be established based on the above case reports, the response of the patients to immunomodulation and anticoagulation suggests an association of the immune system with the presentations, along with the possibility of hypercoagulability.

One of the strongest indicators of a primary causal role of aPL is derived from a study by Schwartz et al. (57) The authors studied 34 unmedicated patients without known autoimmune disorders who were admitted with acute psychosis. aCL and LA were determined before and after neuroleptic treatment to evaluate the presence of antibodies relative to the treatment condition. The authors found that 32% of untreated patients had low to moderate titres of aCL, which indicates their possible causal role in psychosis. In 1999, Schwartz et al. reported that they observed aPL in 52% of patients with schizophrenia (n=50) who were undergoing long-term neuroleptic treatment. The authors posited that neuroleptics may increase phospholipid expression and activation on the cell membrane, which induces aCL binding to CL epitopes without involving β2 GPI (58). Firer et al. (59) and Chengappa et al. (60) reported increased aCL in medicated and unmedicated patients with schizophrenia and their relatives. aCL may also be responsible for the increased cardiovascular morbidity and mortality in individuals with schizophrenia (61). Psychosis has been conceptualised to be caused by a plasminogen activator imbalance based on a study of five psychotic patients with thrombotic episodes who achieved remission of their psychotic symptoms while on chronic warfarin therapy and were free of psychotropic medication from 2 to 11 years. The patients had at least one thrombophilic disorder, including APS (62).

Dystonia, dyskinetic movements, and secondary parkinsonism are recognised side effects of antipsychotic treatment but can also occur in neuroleptic-naive schizophrenia patients (63). Many cases of movement disorders previously thought to be idiopathic or degenerative are now considered to be autoimmune in origin due to the identification of multiple synaptic antibodies, many of which are implicated in the pathogenesis of psychiatric disorders, including schizophrenia (64). Movement disorders are a recognised manifestation of APS. For example, choreic movements have been linked to the isolated presence of aPL or to primary or secondary APS. A neurotoxic effect of aPL on the basal ganglia has been postulated (65).

An intriguing possibility is that the association of dystonia, parkinsonism, and dyskinetic movements with the use of antipsychotics in some subsets of patients may be due to a protopathic bias (confounding by indication) (66, 67), with aPL as the primary aetiological mechanism and antipsychotics as confounders by indication. Thus, antipsychotics may not be the true causal mechanism, but they may exacerbate the subclinical hypodopaminergic state in the basal ganglia, which is caused by the action of aPL antibodies on the basal ganglia. A similar analogy exists in cases that were previously reported as chorea gravidarum and oestrogen-containing oral contraceptive-related chorea, which were later attributed to aPL with or without SLE (68, 69). The role of aPL in antipsychotic-related movement disorders is a matter for further research.

aPL are also implicated in cases of venous thromboembolism associated with the use of antipsychotics (70). The increased risk has been postulated to be the result of drug-induced sedation, obesity, hyperleptinaemia, aPL, and increased activity of the coagulation system (71). Among the existing antipsychotics, phenothiazines are causally associated with APS (50). Clozapine, which is used in treatment-resistant schizophrenia, is positively correlated with aCL antibodies in individuals with schizophrenia in a dose-dependent manner (72), and this finding may explain the association of venous thromboembolism in patients treated with clozapine.

Affective disorders

Maes et al. investigated the presence of aPL antibodies in depressed patients and compared this presence with that in controls. The authors found that depressed subjects exhibited significantly higher aPL antibody titres compared with normal controls (73). A case control study in 30 patients with PAPS showed that they had higher Fibromyalgia Impact Questionnaire scores, higher Becks Depression Inventory (BDI) scores, and more depression diagnoses according to the BDI scores (74). Spyropolou et al. reported a case of a 34-year-old pregnant woman with acute depressive syndrome as the initial manifestation of APS, followed by foetal demise. The patient exhibited multiple high-density foci in her subcortical white matter in the frontal lobes on brain MRI (75). The association of WMHs with late-life depression has given rise to the vascular hypothesis of depression (76). A form of subcortical ischaemic depression has recently been proposed (77). It will be interesting to determine whether aPL are responsible for this form of depression. Similar findings have been reported in bipolar disorder with a high prevalence of WMHs, which holds true even for adolescents with bipolar disorder (78, 79). Depression is common in patients with SLE, with a prevalence of 69–74% (80). The pathogenesis of depression in SLE is multifactorial, and aPL may be implicated in some cases. Migraines, which are a prominent feature of APS and SLE, may also play a causal role in the development of depression through direct biological mechanisms (8183).

The link between depression, stroke, and cardiovascular disease could be explained in at least some patients by the presence of aPL antibodies. In psychiatry, this link has also been attributed to elevated homocysteine levels (84). Interestingly, homocysteine levels have been observed to be elevated in some patients with aPL antibodies and may be responsible for their thrombotic manifestations (8587). One pathogenic mechanism in APS is the presence of antibodies in response to oxidised low-density lipoprotein. These antibodies are associated with atherosclerosis and inflammatory cytokines (88), which increase the risk of both vascular depression and heart disease.

Mania has also been reported in patients with APS, although less frequently. Raza et al. reported a case of mania in a patient who was found to have APS, which was detected due to bilateral pulmonary emboli that developed 5 months after the initial episode of mania. After the acute manic phase, the persistence of cognitive dysfunction and somnolence in the absence of mood symptoms was initially attributed to olanzapine. The initiation of warfarin for the treatment of pulmonary emboli improved the patient’s cognitive function. A family history of thromboembolic deaths was noteworthy (89).

Gorman and Cummings described a series of seven patients who presented with neurobehavioural findings (including irritability, mood lability, suicidal ideation, slowed thinking, akathisia, and movement disturbances) and were observed to have elevated titres of aPL and/or APS (90). Aggressive behaviour has also been described in patients with aPL (39).

Cognitive dysfunction and dementia

Some of the most common complaints in patients with APS are poor memory, difficulty concentrating, and difficulty maintaining attention for long periods of time, which indicates a possible pre-clinical phase of neurological involvement. The cognitive symptoms are one of the most sensitive markers of the syndrome (91, 92). In vivo experiments in mice have shown that the injection of purified IgG from patients with APS into the cerebral ventricles of mice resulted in impairment of learning and memory (93). aPL antibodies may play a primary role in the pathogenesis of cognitive impairment, and neuropsychological testing is useful for detecting early neuropsychiatric involvement (9496). Other studies in primary APS or asymptomatic aPL antibody-positive patients have shown that cognitive deficits may be present independent of any history of known CNS involvement, as well as that the cognitive dysfunction may be subclinical and apparent only with neuropsychological testing in some cases (97, 98). LA positivity is associated with a pattern of deficits compatible with subcortical involvement, possibly on the basis of ongoing LA-related microthrombotic events or vasculopathy (99). The importance of cognitive impairment cannot be underestimated because it is a common feature of depression, schizophrenia, and bipolar disorder and is one of the strongest predictors of poor social functioning in psychiatric patients, which leads to significant burden on patients, families, and society. Livedo reticularis, a characteristic skin sign, and the presence of white matter lesions on brain MRI are associated with an increased risk for cognitive dysfunction in patients with APS (100). There have been anecdotal reports of improvement in cognitive function after commencement of anticoagulation therapy for other reasons, and this finding provides support for the cerebral thrombosis/ischaemia model of cognitive dysfunction (101).

APS can be considered as a vascular cognitive disorder, which encompasses vascular cognitive impairment and vascular dementia (102). Strokes and transient ischaemic attacks (TIAs) are considered to be the second most common clinical manifestation of PAPS after venous thrombosis, with approximately one in five (20%) strokes in individuals under the age of 45 years being associated with APS (103). According to Levine et al. the cerebral ischaemia is characterised by early onset, female gender, high risk of recurrence, and prognostic correlation with IgG aCL (104). Episodes of ischaemia can be transient or permanent. Recurrent episodes can lead to multifocal disease that can cause multi-infarct dementia.

Asherson et al. were the first to report the association of multi-infarct dementia with APS (105). In a 10-year follow-up study of 66 patients with primary APS, Erkan et al. (106) found that three patients (<30 years old) with PAPS developed dementia independent of the presence of cerebrovascular accidents. In a recent study of 30 patients with APS who were followed between 1983 and 2003, silent brain infarcts were present in 14 (47%) of the patients, and dementia was the presenting manifestation of APS in 11 (37%) of the patients. Cortical infarcts were found in 19 (63%) of the patients; subcortical infarcts were found in 9 (30%) of the patients; basal ganglia infarcts were found in 7 (23%) of the patients; and signs of cerebral atrophy were found in 11 (37%) of the patients (107). There is a significant correlation between cognitive deficits and white matter lesions (100). Therefore, cerebral CT or MRI evaluation is commonly recommended in patients with APS. Conversely, ruling out APS should be recommended in the clinical approach to dementia, especially in young patients. Kao et al. (108) studied 22 patients with primary APS who had only mild neuropsychiatric manifestations (headache, depression, personality disorders, memory loss, and cognitive function deficits) and normal brain MRI results. The authors found that 16 (73%) of the patients had abnormal single photon emission computed tomography (SPECT) findings, mainly diffuse hypoperfusion lesions in the cerebral cortex, which indicated that SPECT may be more sensitive in detecting abnormalities. This finding has already been established in neuropsychiatric SLE (109, 110). Positron emission tomography scans showed a considerable diffuse impairment of cortical glucose metabolism combined with reduced cerebral perfusion in the arterial border zones. These findings indicate that PAPS-associated vascular dementia is accompanied by cortical neuronal loss, which is presumably caused by small-vessel disease with immune-mediated intravascular thrombosis (110).

Juby et al. (111) reported a significant association between multi-infarct dementia and aCL. A recent animal study revealed a significant interaction between the amyloid precursor protein (APP) genotype and the induction of APS in females (112). ApoE receptors are essential for neurodevelopment and the regulation of APP metabolism, which has been implicated in the pathogenesis of Alzheimer’s disease (AD) (113). The ApoE 2 receptor is a target for β2 GPI, and this binding has been demonstrated in endothelial cells and platelets. Thus, there may be a common aetiological mechanism for both APS and AD.

Most of the studies on the evaluation of cognitive dysfunction in APS have been carried out in the fields of rheumatology and neurology. Considering the prevalence of cognitive dysfunction and dementia in psychiatry, it is surprising that the association of cognitive dysfunction with aPL antibodies has not been investigated in systematic research.

Migraine

Migraine is one of the most commonly observed symptoms in patients with APS; however, studies have reported contradictory results regarding the association between migraine and APS (92). In psychiatric practice, migraine is not a clinical feature that is commonly asked during history-taking, despite being closely associated with major depressive disorder, bipolar disorder, panic disorder, and social phobia, resulting in poorer clinical outcomes (114116). Migraines are also associated with increased suicide attempts in young adults (117).

The importance of migraine is highlighted by its association with dementia, stroke, and psychiatric disorders. Subjects with migraine are at a greater risk of having white matter abnormalities on magnetic resonance images than those without migraines. This increased risk is present even in younger individuals who do not have risk factors for co-occurring cerebrovascular disease (118). Many patients with APS who present with thrombosis, TIAs, or stroke before the age of 40 years state a history of severe headaches that are often migrainous and date back to childhood. There is often a familial history of migraines, and the combination of migraines, APS, and stroke are being reported in a number of large family cohorts (81, 92, 119). The postulated mechanisms of these vascular events include the activation and aggregation of platelets and the expression of proteins such as endothelin-1 or tissue factor, which is the major initiator of the coagulation cascade in vivo, on endothelial cells (120).

Migraines in patients with APS are considered to be a harbinger of stroke (121), which in turn is associated with depression and dementia. Thus, aPL may act as a modifiable causal agent that links several neurological and psychiatric syndromes. APS-related migraines, strokes, and dementia have similarities with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is an autosomal-dominant disorder, the clinical features of which include migraines with aura and subcortical TIAs, strokes, or mood disorders that occur in individuals between 35 and 55 years of age. This disorder has been genetically mapped to the NOTCH 3 gene on chromosome 19, and it often progresses to subcortical dementia. This disorder is often suggested by the following: 1 or more recurrent subcortical ischaemic strokes (especially before the age of 60 years and in the absence of vascular risk factors); migraine; early cognitive decline or subcortical dementia; bilateral, multifocal, T2/FLAIR hyperintensities in the deep white matter and periventricular white matter with lesions; and an autosomal-dominant family history of migraines, early-onset stroke, or dementia. In certain individuals or families, migraines may be the only clinical manifestation (122). It is unclear whether aPL play a role in the pathogenesis of this disorder, but this is a possibility. Pantoni reported three cases of CADASIL with aPL (123). Some cases of APS have also been reported to be autosomal-dominant (124), and the question arises as to whether CADASIL and some cases of APS represent the same disorder with differing nomenclature by two different specialties.

Epilepsy

A complex relationship exists between epilepsy and psychiatric disorders, and a discussion of this relationship is outside the scope of this article. The association of aPL with epilepsy, which was first reported in 1985 (125), may be of significant importance in the investigation of seizures in general. Temporal lobe epilepsy, which is the most relevant disorder to psychiatrists because it can mimic psychiatric disorders, has also been described in patients with APS (81).

Epilepsy is more common in APS secondary to SLE than in PAPS (126). In patients with lupus who present with seizures, the most likely underlying pathology is APS. Patients of all ages are affected, and all forms of epilepsy are observed, including the subclinical abnormal electroencephalography forms (127). The most likely mechanism is interference with the GABA pathway.

The risk of seizures is linked to vascular disease, valvulopathy, Sneddon’s syndrome, livedo reticularis, and smoking (128).

Sneddon’s syndrome and livedo reticularis

A characteristic skin sign in many patients with APS is livedo reticularis. This symptom may be the presenting sign of APS in 17.5–40% of patients, and it may be observed in up to 70% of patients with SLE and APS (129). Another syndrome associated with livedo reticularis is Sneddon’s syndrome, which is characterised by livedo reticularis and cerebrovascular accidents. There is a significant overlap between APS, SLE, and Sneddon’s syndrome. Recognising livedo reticularis is important because it is independently associated with cerebral and ocular ischaemic arterial events, cognitive deficits, seizures, heart valve abnormalities, hypertension, and Raynaud’s phenomenon; therefore, its presence should alert the psychiatrist to the possibility of APS, irrespective of the presence or absence of antibodies. This finding has prompted some of the authors to suggest that livedo reticularis may be a clinical marker of sero-negative APS (130, 131).

Treatment

A discussion on the detailed treatment of APS is outside the scope of this article, and we refer readers to the article by Cohen et al. (10) and Comarmond and Cacoub (132).

Treatment options for APS include aspirin and hydroxychloroquine, anticoagulants (heparin and warfarin), and immunomodulation. Unfortunately, most of the patients who are encountered in clinical practice do not correspond directly to those enrolled in clinical trials that fulfil the classical criteria (133); therefore, close collaboration with a haematologist or rheumatologist is required. This need for close collaboration may be even more relevant in psychiatric practice because psychiatric manifestations are not included in the criteria and may pose management problems in the absence of close collaboration with other specialties. Moreover, aPL titres are often found to show low or moderately positive levels (52, 58), which makes this syndrome a diagnostic dilemma in psychiatry. The St. Thomas ‘alternative criteria’ for APS may be a useful clinical tool for psychiatrists. These criteria include cognitive impairment, affective disorders, headaches, and livedo reticularis, with improvement after aspirin treatment being an additional diagnostic indicator (134). Although guidelines for thrombotic manifestations are well documented in the literature, treatment for non-thrombotic manifestations, which include psychiatric disorders, epilepsy, and headaches, is less clear, and most of the literature consists of anecdotal reports. Nevertheless, warfarin treatment that was started in these patients for other thrombotic disorders resulted in the resolution of non-thrombotic manifestations. Therefore, it is important for psychiatrists to recognise this condition and promptly refer patients due to the devastating implications of this disorder for physical and psychological health.

Implications for psychiatry

Valid aetiological markers are often elusive to psychiatrists, whose treatment plans are often based on empirical models. The finding of possible aetiological markers, such as aPL, in psychosis, affective disorders, and dementia is of great importance. The question of whether aPL play a causal role or are an epiphenomenon remains open to debate, and more research will be required to elucidate their connection. Nonetheless, the complete remission of cases with psychosis with warfarin treatment (62), improvement in the word-finding score from 15 to 95% after 3 weeks of subcutaneous heparin (135), and other cases described earlier in the article suggest that aPL may play a role in the pathogenesis of some neuropsychiatric presentations. Similarly, cases of previously diagnosed multiple sclerosis have shown sustained improvement with anticoagulation therapy (135). The rapid response to heparin in patients with APS with headache and memory dysfunction has led to the proposal that heparin should be used as a therapeutic trial in certain cases (101, 136). There have been no such controlled trials in psychiatry, and there are consequently no treatment guidelines; however, treatment with anticoagulants and immunomodulation has shown promising results in previous case reports and needs more research. According to the International Consensus Statement regarding an update of the classification criteria for definite APS, there is insufficient evidence to include cognitive dysfunction, headache, migraine, or epilepsy in the revised APS classification criteria. The existing criteria may not apply to psychiatric patients because the manifestations of APS extend beyond those described in the criteria and include symptoms that can cause considerable morbidity in patients. Therefore, studies that are performed in psychiatric patients may reveal new findings and may add to the existing research.

Autoimmune conditions, such as APS, may be missed because many of the clues in the diagnosis of multisystem disorders, such as APS and SLE, can be identified through longitudinal history-taking that begins from childhood and requires probing for clinical features such as migraines, TIAs, and recurrent miscarriages. Thus, it is important for the psychiatrist to maintain a high level of suspicion. APS highlights the importance of medical evaluation in psychiatric patients. Table 2 lists the signs and symptoms that should raise the psychiatrist’s suspicion for APS.


Table 2. When to suspect antiphospholipid syndrome in psychiatry
Atypical psychiatric presentation
Treatment-resistant psychiatric illness
Cognitive dysfunction and dementia
Abnormal involuntary movements with or without the use of antipsychotics
Migraines
History of DVT in patients <50 years of age
History of pulmonary embolism with or without the use of antipsychotics
Stroke or TIA in patients <50 years of age
Livedo reticularis
Recurrent early miscarriages
Raynaud’s phenomenon
Diagnosis of SLE
Unexplained white matter hyperintensities (WMHs) on MRI in patients <50 years of age

aPL antibodies are implicated in the development of psychiatric illness, metabolic syndrome, autoimmune diseases, APS, and atherosclerosis through common aetiological mechanisms. Leboyer et al. proposed that mental illnesses, such as bipolar disorder, may actually be multisystem disorders that are underpinned by inflammatory or immune mechanisms, with the psychiatric disorder being an early manifestation of the systemic disease (137). More research may elucidate a possible relationship between psychiatric disease, obesity, metabolic syndrome, autoimmune diseases, APS, and atherosclerosis, and it may explain the high morbidity and early mortality in psychiatric patients (138, 139). aPL antibodies have also been implicated in disorders such as autism and Tourette’s syndrome (140, 141). Importantly, there is a need to more clearly identify the subsets of patients with aPL antibodies and describe the clinical features that are associated with the particular antibodies associated with psychiatric disorders.

The identification of aPL in psychiatry has a number of therapeutic implications. Since the discovery of psychotropics, neurotransmitter dysregulation has been the main research model. The immune hypothesis has made a significant impact on neuropsychiatry following the discovery of antineuronal antibodies and more research on the neuropsychiatric manifestations of SLE. The possibility that hypercoagulability and/or autoimmune reactions against phospholipids play a role in some psychiatric disorders opens new avenues for research in the treatment of psychiatric disorders, especially dementia, which is considered irreversible in most cases. Promising treatments based on the phospholipid hypothesis have included the use of eicosapentaenoic acid, which reduced the positive and negative symptoms of schizophrenia in a double-blind pilot trial (142). Omega-3 fatty acids have also been used successfully in the prophylaxis of recurrent miscarriages in patients with APS (143). The therapeutic effect of omega-3 fatty acids may be due to the rebalancing of the eicosanoid dysregulation that is induced by aPL. High levels of platelet aggregator and vasoconstrictor TXA2 are found in patients with aPL. Aspirin, which acts as an antiplatelet agent at lower doses, is useful in preventing the thrombotic manifestations of aPL by reducing the formation of thromboxane, which is a powerful vasoconstrictor (144). Although it is not currently possible to recommend anticoagulation as a treatment for psychiatric illness, other benign therapies may be useful. Aspirin, omega-3, and statins (145) are three evidence-based treatments that have shown benefit in both psychiatric disorders and thrombotic illnesses and may be beneficial in psychiatric disorders associated with aPL. The use of hydroxychloroquine is another relatively benign treatment that is known to reduce the binding of antiphospholipid β2 GPI complexes to phospholipid membranes (146). However, trials of hydroxychloroquine in schizophrenia and Alzheimer’s dementia have not shown any benefit (147, 148). More research is required to determine whether hydroxychloroquine would be beneficial in certain psychiatric patients with aPL. Lithium, carbamazepine, and valproate, which are used in bipolar disorder, are also known to reduce the turnover of Arachidonic acid (AA) which reduces the proinflammatory state that is induced by AA release during phospholipid breakdown (149) and may be beneficial for patients with psychiatric presentations of APS.

Approximately one in five cases of stroke and DVT are associated with APS (135). If this 1:5 ratio were to hold true in psychiatric disorders, it would offer significant hope for many patients in addition to the significant reduction of health costs. There is an urgent need for large-scale studies in psychiatric patients to identify various antibody profiles, including aPL antibodies, and if determining if these antibodies play a causative role in the development of psychiatric syndromes. A survey of patients’ experiences with APS diagnosis in the United Kingdom revealed that there was a long lag time before the diagnosis of APS was made and a lack of awareness among specialists and general practitioners that resulted in increased costs to the NHS and emotional and financial costs to the patients (150). The operational boundaries that separate the clinical disciplines of psychiatry, neurology, and immunology are becoming increasingly blurred, requiring new holistic approaches in the study of neuropsychiatric disorders (151). Syphilis was considered to be the great imitator for several years because it presented with a range of neuropsychiatric manifestations. SLE took over as the great imitator with the reduction in the incidence of syphilis, and it appears that APS may be the new great imitator (152). It is hoped that this article has provided a glimpse of this mimicry in psychiatry; however, a concerted effort will be required by multiple specialties to identify its true nature.

Conflict of interest and funding

This research received no specific funding support from any funding agency in the public, commercial, or not-for-profit sectors.

References

  1. Hughes GR. The Prosser-White oration 1983. Connective tissue disease and the skin. Clin Exp Dermatol 1984; 9: 535. Publisher Full Text
  2. Harris EN, Hughes GR, Gharavi AE. Antiphospholipid antibodies: an elderly statesman Dons new garments. J Rheumatol Suppl 1987; 14(Suppl 13): 208–13.
  3. Moore JE, Mohr CF. Biologically false positive serologic tests for syphilis: type, incidence, and cause. J Am Med Assoc 1952; 150: 467–73. Publisher Full Text
  4. Moore JE, Lutz WB. The natural history of systemic lupus erythematosus: an approach to its study through chronic biologic false positive reactors. J Chron Dis 1955; 1: 297–316. Publisher Full Text
  5. Pangborn MC. A new serologically active phospholipid from beef heart. Proc Soc Exp Biol Med 1941; 48: 484–6. Publisher Full Text
  6. Conley CL. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest 1952; 31: 621–2.
  7. Bowie EW. Thrombosis in systemic lupus erythematosus despite circulating anticoagulants. J Lab Clin Med 1963; 62: 416–30.
  8. Nilsson IM, Åstedt B, Hedner U, Berezin D. Intrauterine death and circulating anticoagulant (‘antithromboplastin’). Acta Medica Scandinavica 1975; 197: 153–9. Publisher Full Text
  9. Laurell AB, Nilsson IM. Hypergammaglobulinemia, circulating anticoagulant, and biologic false positive Wassermann reaction: a study in two cases. J Lab Clin Med 1957; 49: 694–707.
  10. Cohen D, Berger SP, Steup-Beekman GM, Bloemenkamp KW, Bajema IM. Diagnosis and management of the antiphospholipid syndrome. BMJ 2010; 340: c2541. Publisher Full Text
  11. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306. Publisher Full Text
  12. Manna R, Ricci V, Curigliano V, Pomponi M, Adamo F, Costa A, et al. Psychiatric manifestations as a primary symptom in antiphospholipid syndrome. Int J Immunopathol Pharmacol 2006; 19: 915–7.
  13. Martinez M, Mougan I. Fatty acid composition of human brain phospholipids during normal development. J Neurochem 1998; 71: 2528–33. Publisher Full Text
  14. Bennett CN, Horrobin DF. Gene targets related to phospholipid and fatty acid metabolism in schizophrenia and other psychiatric disorders: an update. Prostaglandins Leukot Essent Fatty Acids 2000; 63: 47–59. Publisher Full Text
  15. Fenton WS, Hibbeln J, Knable M. Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia. Biol Psychiatry 2000; 47: 8–21. Publisher Full Text
  16. Söderberg M, Edlund C, Kristensson K, Dallner G. Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease. Lipids 1991; 26: 421–5. Publisher Full Text
  17. Horrobin DF, Bennett CN. Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate genes. Prostaglandins Leukot Essent Fatty Acids 1999; 60: 217–34. Publisher Full Text
  18. Ross BM, Hudson C, Erlich J, Warsh JJ, Kish SJ. Increased phospholipid breakdown in schizophrenia. Evidence for the involvement of a calcium-independent phospholipase A2. Arch Gen Psychiatry 1997; 54: 487–94. Publisher Full Text
  19. Keshavan MS, Stanley JA, Pettegrew JW. Magnetic resonance spectroscopy in schizophrenia: methodological issues and findings – part II. Biol Psychiatry 2000; 48: 369–80. Publisher Full Text
  20. Rand JH. Molecular pathogenesis of the antiphospholipid syndrome. Circ Res 2002; 90: 29–37. Publisher Full Text
  21. Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629–32.
  22. Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost 1995; 74: 1185–90.
  23. Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011; 7: 330–9. Publisher Full Text
  24. Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009; 7: 1737–40. Publisher Full Text
  25. Gardiner C, Hills J, Machin SJ, Cohen H. Diagnosis of antiphospholipid syndrome in routine clinical practice. Lupus 2013; 22: 18–25. Publisher Full Text
  26. Tripodi A, de Groot PG, Pengo V. Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment. J Intern Med 2011; 270: 110–22. Publisher Full Text
  27. Girón-González JA, del Río EG, Rodríguez C, Rodríguez-Martorell J, Serrano A. Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: prospective analysis of 404 individuals. J Rheumatol 2004; 31: 1560–7.
  28. Blank M, Krause I, Fridkin M, Keller N, Kopolovic J, Goldberg I, et al. Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest 2002; 109: 797–804. Publisher Full Text
  29. Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. New Engl J Med 2013; 368: 1033–44. Publisher Full Text
  30. Nalbandian G, Kovats S. Understanding sex biases in immunity: effects of estrogen on the differentiation and function of antigen-presenting cells. Immunol Res 2005; 31: 91–106. Publisher Full Text
  31. Pierangeli SS, Harris EN. Antiphospholipid antibodies in an in vivo thrombosis model in mice. Lupus 1994; 3: 247–51. Publisher Full Text
  32. Branch DW, Scott JR, Kochenour NK, Hershgold E. Obstetric complications associated with the lupus anticoagulant. New Engl J Med 1985; 313: 1322–6. Publisher Full Text
  33. Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci U S A 1991; 88: 3069–73. Publisher Full Text
  34. Mackworth-Young CG. Antiphospholipid syndrome: multiple mechanisms. Clin Exp Immunol 2004; 136: 393–401. Publisher Full Text
  35. Girardi G, Salmon JE. Antiphospholipid antibody-induced pregnancy loss and thrombosis. In: MA Khamashta (ed.), Hughes syndrome: antiphospholipid syndrome, p. 395–402. London: Springer; 2006.
  36. Frauenknecht K, Katzav A, Grimm C, Chapman J, Sommer CJ. Altered receptor binding densities in experimental antiphospholipid syndrome despite only moderately enhanced autoantibody levels and absence of behavioral features. Immunobiology 2014; 219: 341–9. Publisher Full Text
  37. Frauenknecht K, Katzav A, Weiss Lavi R, Sabag A, Otten S, Chapman J, et al. Mice with experimental antiphospholipid syndrome display hippocampal dysfunction and a reduction of dendritic complexity in hippocampal CA1 neurons. Neuropathol Appl Neurobiol 2014. doi: 10.1111/nan.12180.
  38. Menachem A, Chapman J, Katzav A. Significant changes in the levels of secreted cytokines were observed in the brains of experimental antiphospholipid syndrome mice. Autoimmune Dis 2012; 2012: 404815.
  39. Chapman J, Rand JH, Brey RL, Levine SR, Blatt I, Khamashta MA, et al. Non-stroke neurological syndromes associated with antiphospholipid antibodies: evaluation of clinical and experimental studies. Lupus 2003; 12: 514–7. Publisher Full Text
  40. 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: 1119–25. Publisher Full Text
  41. Katzav A, Ben-Ziv T, Blank M, Pick CG, Shoenfeld Y, Chapman J. Antibody-specific behavioral effects: intracerebroventricular injection of antiphospholipid antibodies induces hyperactive behavior while anti-ribosomal-P antibodies induces depression and smell deficits in mice. J Neuroimmunol 2014; 272: 10–5. Publisher Full Text
  42. Katzav A, Menachem A, Maggio N, Pollak L, Pick CG, Chapman J. IgG accumulates in inhibitory hippocampal neurons of experimental antiphospholipid syndrome. J Autoimmun 2014; 55: 86–93. doi: 10.1016/j.jaut.2014.07.006.
  43. Ziporen L, Polak-Charcon S, Korczyn DA, Goldberg I, Afek A, Kopolovic J, et al. Neurological dysfunction associated with antiphospholipid syndrome: histopathological brain findings of thrombotic changes in a mouse model. Clin Dev Immunol 2004; 11: 67–75. Publisher Full Text
  44. Arnson Y, Shoenfeld Y, Alon E, Amital H. The antiphospholipid syndrome as a neurological disease. Semin Arthritis Rheu 2010; 40: 97–108. Publisher Full Text
  45. Harley JB. The genetic etiology of systemic lupus erythematosus: a short dispatch from the combat zone. Genes Immun 2002; 3 (Suppl 1): S1–4. Publisher Full Text
  46. Jonsen A, Bengtsson AA, Sturfelt G, Truedsson L. Analysis of HLA DR, HLA DQ, C4A, FcgammaRIIa, FcgammaRIIIa, MBL, and IL-1Ra allelic variants in Caucasian systemic lupus erythematosus patients suggests an effect of the combined FcgammaRIIa R/R and IL-1Ra 2/2 genotypes on disease susceptibility. Arthritis Res Ther 2004; 6: 557–62. Publisher Full Text
  47. International Schizophrenia Consortium, Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–52.
  48. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46: 1019–27. Publisher Full Text
  49. Kurtz G, Muller N. The antiphospholipid syndrome and psychosis. Am J Psychiatry 1994; 151: 1841–2. Publisher Full Text
  50. Siu BW, Chow HM, Kwok SS, Li OL, Koo ML, Poon PW. Systemic lupus erythematosus as a cause of first-episode psychosis in the second trimester of pregnancy. East Asian Arch Psychiatry 2010; 20: 145–50.
  51. Fernandez Ga de las Heras V, Gorriti MA, García-Vicuña R, Santos Ruiz JL. Psychosis leading to the diagnosis of unrecognized systemic lupus erythematosus: a case report. Rheum Int 2007; 27: 883–5. Publisher Full Text
  52. Cardinal RN, Shah DN, Edwards CJ, Hughes GR, Fernández-Egea E. Psychosis and catatonia as a first presentation of antiphospholipid syndrome. Br J Psychiatry 2009; 195: 272. Publisher Full Text
  53. Pustilnik S, Trutia A. Catatonia as the presenting symptom in systemic lupus erythematosus. J Psychiatr Pract 2011; 17: 217–21. Publisher Full Text
  54. Pego-Reigosa JM, Isenberg DA. Psychosis due to systemic lupus erythematosus: characteristics and long-term outcome of this rare manifestation of the disease. Rheumatology 2008; 47: 1498–502. Publisher Full Text
  55. Lai JY, Wu PC, Chen HC, Lee MB. Early neuropsychiatric involvement in antiphospholipid syndrome. Gen Hosp Psychiatry 2012; 34: 579.e1–3. Publisher Full Text
  56. Shalaby M, Alhumayed S, Alshehri A. Paediatric case report: primary antiphospholipid syndrome presented with non-thrombotic neurological picture psychosis; treat by antidepressants alone? Int J Rheum Dis 2009; 12: 170–3. Publisher Full Text
  57. Schwartz M, Rochas M, Weller B, Sheinkman A, Tal I, Golan D, et al. High association of anticardiolipin antibodies with psychosis. J Clin Psychiatry 1998; 59: 20–3. Publisher Full Text
  58. Schwartz M, Rochas M, Toubi E, Sharf B. The presence of lupus anticoagulant and anticardiolipin antibodies in patients undergoing long-term neuroleptic treatment. J Psychiatry Neurosci 1999; 24: 351–2.
  59. Firer M, Sirota P, Schild K, Elizur A, Slor H. Anticardiolipin antibodies are elevated in drug-free, multiply affected families with schizophrenia. J Clin Immunol 1994; 14: 73–8. Publisher Full Text
  60. Chengappa KN, Carpenter AB, Keshavan MS, Yang ZW, Kelly RH, Rabin BS, et al. Elevated IGG and IGM anticardiolipin antibodies in a subgroup of medicated and unmedicated schizophrenic patients. Biol Psychiatry 1991; 30: 731–5. Publisher Full Text
  61. Leuci E, Manenti L, Maggini C. Anti-phospholipid antibodies, neuroleptic treatment and cardiovascular morbidity. Br J Psychiatry 2007; 190: 81. Publisher Full Text
  62. Hoirisch-Clapauch S, Nardi A. Psychiatric remission with warfarin: should psychosis be addressed as plasminogen activator imbalance? Med Hypotheses 2013; 80: 137–41. Publisher Full Text
  63. Geisler S, Sheitman B, Kane JM, Geisler S, Sheitman B, Woerner M, et al. Prevalence and clinical correlates of extrapyramidal signs and spontaneous dyskinesia in never-medicated schizophrenic patients. Am J Psychiatry 1995; 152: 1724–9. Publisher Full Text
  64. Panzer J, Dalmau J. Movement disorders in paraneoplastic and autoimmune disease. Curr Opin Lipidol 2011; 24: 346–53.
  65. Peluso S, Antenora A, De Rosa A, Roca A, Maddaluno G, Brescia Morra V, et al. Antiphospholipid-related chorea. Front Neurol 2012; 3: 150. Publisher Full Text
  66. Shapiro S. Confounding by indication? Epidemiology 1997; 8: 110.
  67. Horwitz RI, Feinstein AR. The problem of ‘protopathic bias’ in case-control studies. Am J Med 1980; 68: 255–8. Publisher Full Text
  68. Martino D, Chew NK, Mir P, Edwards MJ, Quinn NP, Bhatia KP. Atypical movement disorders in antiphospholipid syndrome. Mov Disord 2006; 21: 944–9. Publisher Full Text
  69. Janavs JL, Aminoff MJ. Dystonia and chorea in acquired systemic disorders. J Neurol Neurosurg Psychiatry 1998; 65: 436–45. Publisher Full Text
  70. Borras L, Eytan A, de Timary P, Constant EL, Huguelet P, Hermans C. Pulmonary thromboembolism associated with olanzapine and risperidone. J Emerg Med 2008; 35: 159–61. Publisher Full Text
  71. Hagg S, Spigset O. Antipsychotic-induced venous thromboembolism: a review of the evidence. CNS Drugs 2002; 16: 765–76. Publisher Full Text
  72. Shen H, Li R, Xiao H, Zhou Q, Cui Q, Chen J. Higher serum clozapine level is associated with increased antiphospholipid antibodies in schizophrenia patients. J Psychiatr Res 2009; 43: 615–9. Publisher Full Text
  73. Maes M, Meltzer H, Jacobs J, Suy E, Calabrese J, Minner B, et al. Autoimmunity in depression: increased antiphospholipid autoantibodies. Acta Psychiatr Scand 1993; 87: 160–6. Publisher Full Text
  74. Costa SP, Lage LV, da Mota LM, de Carvalho JF. Fibromyalgia in primary antiphospholipid (Hughes) syndrome. Lupus 2011; 20: 1182–6. Publisher Full Text
  75. Spyropoulou AC, Tsartsara EI, Angelopoulou A, Zervas IM. Psychiatric manifestations preceding fetal death in antiphospholipid syndrome. Gen Hosp Psychiatry 2010; 32: 225–7. Publisher Full Text
  76. Herrmann LL, Le Masurier M, Ebmeier KP. White matter hyperintensities in late life depression: a systematic review. J Neurol Neurosurg Psychiatry 2008; 79: 619–24. Publisher Full Text
  77. Krishnan KR, Taylor WD, McQuoid DR, MacFall JR, Payne ME, Provenzale JM, et al. Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression. Biol Psychiatry 2004; 55: 390–7. Publisher Full Text
  78. Pillai JJ, Friedman L, Stuve TA, Trinidad S, Jesberger JA, Lewin JS, et al. Increased presence of white matter hyperintensities in adolescent patients with bipolar disorder. Psychiatry Res 2002; 114: 51–6. Publisher Full Text
  79. Ahn KH, Lyoo IK, Lee HK, Song IC, Oh JS, Hwang J, et al. White matter hyperintensities in subjects with bipolar disorder. Psychiatry Clin Neurosci 2004; 58: 516–21. Publisher Full Text
  80. Popescu A, Kao A. Neuropsychiatric systemic lupus erythematosus. Curr Neuropharmacol 2011; 9: 449–57. Publisher Full Text
  81. Strikingly APS. Antiphospholipid syndrome, migraine and stroke. Lupus 2010; 19: 555–6. Publisher Full Text
  82. Buse DC, Silberstein SD, Manack AN, Papapetropoulos S, Lipton RB. Psychiatric comorbidities of episodic and chronic migraine. J Neurol 2013; 260: 1960–9. Publisher Full Text
  83. Omdal R, Waterloo K, Koldingsnes W, Husby G, Mellgren SI. Somatic and psychological features of headache in systemic lupus erythematosus. J Rheumatol 2001; 28: 772–9.
  84. Folstein M, Liu T, Peter I, Buell J, Arsenault L, Scott T, et al. The homocysteine hypothesis of depression. Am J Psychiatry 2007; 164: 861–7. Publisher Full Text
  85. Avivi I, Lanir N, Hoffman R, Brenner B. Hyperhomocysteinemia is common in patients with antiphospholipid syndrome and may contribute to expression of major thrombotic events. Blood Coag Fibrinolysis 2002; 13: 169–72. Publisher Full Text
  86. Carvalho JFD, Caleiro MTC, Bonfá E. Hyperhomocysteinemia and primary antiphospholipid syndrome. Rev Bras Reumatol 2009; 49: 337–45.
  87. Martínez-Berriotxoa A, Ruiz-Irastorza G, Egurbide MV, Rueda M, Aguirre C. Homocysteine, antiphospholipid antibodies and risk of thrombosis in patients with systemic lupus erythematosus. Lupus 2004; 13: 927–33. Publisher Full Text
  88. Hulthe J, Fagerberg B. Circulating oxidized LDL is associated with subclinical atherosclerosis development and inflammatory cytokines (AIR Study). Arterioscler Thromb Vasc Biol 2002; 22: 1162–7. Publisher Full Text
  89. Raza H, Epstein SA, Rosenstein DL. Mania: psychiatric manifestations of the antiphospholipid syndrome. Psychosomatics 2008; 49: 438. Publisher Full Text
  90. Gorman DG, Cummings JL. Neurobehavioral presentations of the antiphospholipid antibody syndrome. J Neuropsychiatry Clin Neurosci 1993; 5: 37–42. Publisher Full Text
  91. Jacobson MW, Rapport LJ, Keenan PA, Coleman RD, Tietjen GE. Neuropsychological deficits associated with antiphospholipid antibodies. J Clin Exp Neuropsychol 1999; 21: 251–64. Publisher Full Text
  92. Sanna G, Bertolaccini ML, Cuadrado MJ, Khamashta MA, Hughes GR. Central nervous system involvement in the antiphospholipid (Hughes) syndrome. Rheumatology 2003; 42: 200–13. Publisher Full Text
  93. 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: 436–42. Publisher Full Text
  94. Hanly JG, Walsh NM, Fisk JD, Eastwood B, Hong C, Sherwood G, et al. Cognitive impairment and autoantibodies in systemic lupus erythematosus. Rheumatology 1993; 32: 291–6. Publisher Full Text
  95. Hanly JG, Hong C, Smith S, Fisk JD. A prospective analysis of cognitive function and anticardiolipin antibodies in systemic lupus erythematosus. Arthritis Rheum 2001; 42: 728–34. Publisher Full Text
  96. Muscal E, Brey R. Neurological manifestations of systemic lupus erythematosus in children and adults. Neurol Clin 2010; 28: 61–73. Publisher Full Text
  97. Erkan D, Kozora E, Lockshin MD. Cognitive dysfunction and white matter abnormalities in antiphospholipid syndrome. Pathophysiology 2011; 18: 93–102. Publisher Full Text
  98. Austin S, Cohen H. Antiphospholipid syndrome. Medicine 2010; 38: 101–4. Publisher Full Text
  99. Denburg SD, Carbotte RM, Ginsberg JS, Denburg JA. The relationship of antiphospholipid antibodies to cognitive function in patients with systemic lupus erythematosus. J Int Neuropsychol Soc 1997; 3: 377–86.
  100. Tektonidou MG, Varsou N, Kotoulas G, Antoniou A, Moutsopoulos HM. Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic resonance imaging findings. Arch Intern Med 2006; 166: 2278–84. Publisher Full Text
  101. Hughes GR, Cuadrado MJ, Khamashta MA, Sanna G. Headache and memory loss: rapid response to heparin in the antiphospholipid syndrome. Lupus 2001; 10: 778. Publisher Full Text
  102. Roman GC, Sachdev P, Royall DR, Bullock RA, Orgogozo JM, López-Pousa S, et al. Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci 2004; 226: 81–7. Publisher Full Text
  103. Rodrigues CE, Carvalho JF, Shoenfeld Y. Neurological manifestations of antiphospholipid syndrome. Eur J Clin Invest 2010; 40: 350–9. Publisher Full Text
  104. Levine SR, Brey RL, Sawaya KL, Salowich-Palm L, Kokkinos J, Kostrzema B, et al. Recurrent stroke and thrombo-occlusive events in the antiphospholipid syndrome. Ann Neurol 2004; 38: 119–24. Publisher Full Text
  105. Asherson RA, Mercey D, Phillips G, Sheehan N, Gharavi AE, Harris EN, et al. Recurrent stroke and multi-infarct dementia in systemic lupus erythematosus: association with antiphospholipid antibodies. Ann Rheum Dis 1987; 46: 605–11. Publisher Full Text
  106. Erkan D, Yazici Y, Sobel R, Lockshin MD. Primary antiphospholipid syndrome: functional outcome after 10 years. J Rheumatol 2000; 27: 2817–21.
  107. Gomez-Puerta JA, Cervera R, Calvo LM, Gómez-Ansón B, Espinosa G, Claver G, et al. Dementia associated with the antiphospholipid syndrome: clinical and radiological characteristics of 30 patients. Rheumatology 2005; 44: 95–9. Publisher Full Text
  108. Kao CH, Lan JL, Hsieh JF, Ho YJ, ChangLai SP, Lee JK, et al. Evaluation of regional cerebral blood flow with 99mTc-HMPAO in primary antiphospholipid antibody syndrome. J Nucl Med 1999; 40: 1446–50.
  109. Sibbitt WL, Sibbitt RR, Brooks WM. Neuroimaging in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 1999; 42: 2026–38. Publisher Full Text
  110. Hilker R, Thiel A, Geisen C, Rudolf J. Cerebral blood flow and glucose metabolism in multi-infarct-dementia related to primary antiphospholipid antibody syndrome. Lupus 2000; 9: 311–6. Publisher Full Text
  111. Juby A, Davis P, Genge T, McElhaney J. Anticardiolipin antibodies in two elderly subpopulations. Lupus 1995; 4: 482–5. Publisher Full Text
  112. Katzav A, Faust-Socher A, Kvapil F, Michaelson DM, Blank M, Pick CG, et al. Antiphospholipid syndrome induction exacerbates a transgenic Alzheimer disease model on a female background. Neurobiol Aging 2011; 32: 272–9.
  113. Herz J. ApoE receptors in the nervous system. Curr Opin Lipidol 2009; 20: 190. Publisher Full Text
  114. Merikangas KR, Merikangas JR, Angst J. Headache syndromes and psychiatric disorders: association and familial transmission. J Psychiatr Res 1993; 27: 197–210. Publisher Full Text
  115. Merikangas KR, Stevens DE. Comorbidity of migraine and psychiatric disorders. Neurol Clin 1997; 15: 115–23. Publisher Full Text
  116. Jette N, Patten S, Williams J, Becker W, Wiebe S. Comorbidity of migraine and psychiatric disorders – a national population-based study. Headache 2008; 48: 501–16. Publisher Full Text
  117. Breslau N, Davis GC, Andreski P. Migraine, psychiatric disorders, and suicide attempts: an epidemiologic study of young adults. Psychiatry Res 1991; 37: 11–23. Publisher Full Text
  118. Swartz RH, Kern RZ. Migraine is associated with magnetic resonance imaging white matter abnormalities: a meta-analysis. Arch Neurol 2004; 61: 1366. Publisher Full Text
  119. Hughes GR. Hughes syndrome (the antiphospholipid syndrome): ten clinical lessons. Autoimmun Rev 2008; 7: 262–6. Publisher Full Text
  120. Cuadrado MJ, Khamashta MA, Hughes GRV. Migraine and stroke in young women. Q J Med 2000; 93: 317–8. Publisher Full Text
  121. Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 2005; 330: 63. Publisher Full Text
  122. Gladstone JP, Dodick DW. Migraine and cerebral white matter lesions: when to suspect cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neurologist 2005; 11: 19–29. Publisher Full Text
  123. Pantoni L, Sarti C, Pescini F, Bianchi S, Bartolini L, Nencini P, et al. Thrombophilic risk factors and unusual clinical features in three Italian CADASIL patients. Eur J Neurol 2004; 11: 782–7. Publisher Full Text
  124. Goel N, Ortel TL, Bali D, Anderson JP, Gourley IS, Smith H, et al. Familial antiphospholipid antibody syndrome: criteria for disease and evidence for autosomal dominant inheritance. Arthritis Rheum 2001; 42: 318–27. Publisher Full Text
  125. Mackworth-Young CG, Hughes GR. Epilepsy: an early symptom of systemic lupus erythematosus. J Neurol Neurosurg Psychiatry 1985; 48: 185. Publisher Full Text
  126. Shoenfeld Y, Lev S, Blatt I, Blank M, Font J, von Landenberg P, et al. Features associated with epilepsy in the antiphospholipid syndrome. J Rheumatol 2004; 31: 1344–8.
  127. Hughes GRV. Migraine, memory loss, and ‘multiple sclerosis’. Neurological features of the antiphospholipid (Hughes’) syndrome. Postgrad Med J 2003; 79: 81–3. Publisher Full Text
  128. de Carvalho JF, Pasoto SG, Appenzeller S. Seizures in primary antiphospholipid syndrome: the relevance of smoking to stroke. Clin Dev Immunol 2012; 2012: 981519.
  129. Uthman IW, Khamashta MA. Livedo racemosa: a striking dermatological sign for the antiphospholipid syndrome. J Rheumatol 2006; 33: 2379–82.
  130. Frances C, Niang S, Laffitte E, Pelletier FI, Costedoat N, Piette JC. Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases. Arthritis Rheum 2005; 52: 1785–93. Publisher Full Text
  131. Hughes G, Khamashta M. Seronegative antiphospholipid syndrome. Ann Rheum Dis 2003; 62: 1127. Publisher Full Text
  132. Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev 2013; 12: 752–7. Publisher Full Text
  133. Garcia D, Munther K, Crowther M. How we diagnose and treat thrombotic manifestations of the antiphospholipid syndrome: a case-based review. Blood 2007; 110: 3122–7. Publisher Full Text
  134. Rosenthal E, Foster R, Sangle S, D’Cruz D. Patients know it: Hughes syndrome is unique. J Rheumatol 2006; 33: 1919–20.
  135. Hughes GR. Put Hughes syndrome on your radar. Rheumatologist 2007; 1: 20–1.
  136. Hughes GRV. Heparin, antiphospholipid antibodies and the brain. Lupus 2012; 2012: 1039–40. Publisher Full Text
  137. Leboyer M, Soreca I, Scott J, Frye M, Henry C, Tamouza R, et al. Can bipolar disorder be viewed as a multi-system inflammatory disease? J Affect Dis 2012; 141: 1–10. Publisher Full Text
  138. Palomo I, Alarcon M, Moore-Carrasco R, Argilés JM. Hemostasis alterations in metabolic syndrome (review). Int J Mol Med 2006; 18: 969–74.
  139. Arteaga RB, Chirinos JA, Soriano AO, Jy W, Horstman L, Jimenez JJ, et al. Endothelial microparticles and platelet and leukocyte activation in patients with the metabolic syndrome. Am J Cardiol 2006; 98: 70–4. Publisher Full Text
  140. Sokol DK, Chen LS, Wagenknecht DR, McIntyre JA. Anti-phospholipid antibodies in cerebrospinal fluid but not serum from a boy with psychosis. Pediatr Neurol 2008; 39: 293–4. Publisher Full Text
  141. Singer HS, Krumholz A, Giuliano J, Kiessling LS. Antiphospholipid antibodies: an epiphenomenon in Tourette syndrome. Mov Disord 1997; 12: 738–42. Publisher Full Text
  142. Peet M, Brind J, Ramchand CN, Shah S, Vankar GK. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res 2001; 49: 243–51. Publisher Full Text
  143. Rossi E, Costa M. Fish oil derivatives as a prophylaxis of recurrent miscarriage associated with antiphospholipid antibodies (APL): a pilot study. Lupus 1993; 2: 319–23. Publisher Full Text
  144. Årfors L, Vesterqvist O, Johnsson H, Gréen K. Increased thromboxane formation in patients with antiphospholipid syndrome. Eur J Clin Invest 1990; 20: 607–12.
  145. Jajoria P, Murthy V, Papalardo E, Romay-Penabad Z, Gleason C, Pierangeli SS. Statins for the treatment of antiphospholipid syndrome? Ann N Y Acad Sci 2009; 1173: 736–45. Publisher Full Text
  146. Rand JH, Wu XX, Quinn AS, Chen PP, Hathcock JJ, Taatjes DJ. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody–β2-glycoprotein I complexes to phospholipid bilayers. Blood 2008; 112: 1687–95. Publisher Full Text
  147. Van Gool WA, Weinstein HC, Scheltens PK, Walstra GJ. Effect of hydroxychloroquine on progression of dementia in early Alzheimer’s disease: an 18-month randomised, double-blind, placebo-controlled study. Lancet 2001; 358: 455–60. Publisher Full Text
  148. Desta M, Tadesse A, Gebre N, Barci BM, Torrey EF, Knable MB. Controlled trial of hydroxychloroquine in schizophrenia. J Clin Psychopharmacol 2002; 22: 507–10. Publisher Full Text
  149. Tassoni D, Kaur G, Weisinger RS, Sinclair AJ. The role of eicosanoids in the brain. Asia Pacific J Clin Nutr 2008; 17: 220–8.
  150. Donnan PT, McDonald MJ. Patients’ experiences of a diagnosis of Hughes’ syndrome. Clin Rheumatol 2009; 28: 1091–100. Publisher Full Text
  151. Mayberg H. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull 2003; 65: 193–207. Publisher Full Text
  152. LeFanu J. Doctor’s diary: is Hughes syndrome the new syphilis? Telegraph 2012. Available from: http://www.telegraph.co.uk/health/9292522/Doctors-Diary-Is-Hughes-syndrome-the-new-syphilis.html [cited 14 January 2015].

*Sanil Rege
Psych Scene Pty Ltd.
Beleura Private Hospital
Mornington, Australia
Email: sanil.rege@ymail.com

TDP Translational Developmental Psychiatry 2001-7022 Co-Action Publishing 25452 10.3402/tdp.v3.25452 REVIEW ARTICLE Antiphospholipid antibodies as biomarkers in psychiatry: review of psychiatric manifestations in antiphospholipid syndrome Rege Sanil 1 * Mackworth-Young Charles 2 Psych Scene Pty Ltd., Beleura Private Hospital, Mornington, Australia Department of Rheumatology, Charing Cross Hospital, London, UK Sanil Rege, Psych Scene Pty Ltd., Beleura Private Hospital, Mornington, Australia. Email: sanil.rege@ymail.com 02 02 2015 2015 3 10.3402/tdp.v3.25452 13 07 2014 23 10 2014 24 11 2014 © 2015 Sanil Rege and Charles Mackworth-Young 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Antiphospholipid syndrome (APS) has been implicated in a range of neuropsychiatric presentations. However, there is a paucity of systematic studies on APS in psychiatry. This paper reports the clinical manifestations of APS that are relevant to psychiatrists. The aspects of APS pathogenesis, diagnosis, and treatment presented in this paper are based on a literature review. Treatment-resistant and atypical psychiatric illnesses, severe cognitive dysfunction, migraines, transient ischaemic attacks, and thromboembolic episodes, along with characteristic skin manifestations are the common clinical features of this syndrome. Antiphospholipid antibodies (aPL) may have a causal role in the development of some neuropsychiatric conditions. The existing criteria of APS may not apply to psychiatric patients, which may result in the underdiagnosis of APS in psychiatry. There is no evidence-based guidance available for the treatment of APS in patients with psychiatric symptoms. The treatment of APS with antithrombotic agents in case reports has been reported to yield dramatic improvements in complex and treatment-resistant cases. The possibility of a causal role of aPL in high-morbidity conditions, such as psychosis, depression, and dementia, requires the psychiatrist to be vigilant to the occurrence of this syndrome. There is an urgent need to conduct studies that elucidate the role of aPL in psychiatric presentations, identify patient characteristics, and consider whether new criteria with greater applicability in psychiatry are needed.

beta 2 GPI lupus anticoagulant anticardiolipin antibodies psychosis cognitive dysfunction depression thrombosis

Antiphospholipid syndrome (APS), which is also known as sticky blood or Hughes syndrome, was first fully described 30 years ago as a syndrome that involves arterial and venous thrombosis with prominent cerebral involvement. The main reported features of this syndrome include migraines, chorea, epilepsy, and cerebrovascular accidents (1). Initially, the syndrome was considered to be a distinct entity, called anticardiolipin syndrome in 1985, and it was later renamed antiphospholipid antibody syndrome (2). APS is an autoimmune disease in which autoantibody production results in a hypercoagulable state that causes recurrent arterial and venous thrombosis and/or recurrent foetal loss.

The history of APS can be regarded as starting in 1952, when the finding of a chronic biological false-positive serological test for syphilis was fully delineated (3). Shortly afterwards, it was shown that the majority of women with this abnormality subsequently developed systemic lupus erythematosus (SLE) (4). It was already known that the bovine heart extract used for this complement fixation test contained a phospholipid, namely cardiolipin (CL) (5). Parallel to this finding was the description of an in vitro clotting disturbance in patients with SLE. This disturbance causes a prolongation of the partial thromboplastin time and was labelled the ‘lupus anticoagulant’ (LA) (6).

However, this term is misleading because the disorder is characterised in vivo by increased thrombosis. LA activity was described in patients with thrombosis (7) and foetal loss (8) and is associated with a chronic biological false-positive serological test for syphilis. Although it was soon shown that LA activity could be absorbed by CL (9), it was not until the development of a sensitive assay for anticardiolipin antibodies (aCL) that APS could be fully described (1).

This syndrome can affect all organ systems; therefore, it can present to any specialty. It is under-recognised and underdiagnosed in all specialties (10). It can have devastating consequences if left untreated due to uncontrolled thrombosis, and it can lead to permanent disability, severe maternal morbidity, and even death (10). The main criteria for the disorder are described in Table 1, (11).

Research criteria for defining antiphospholipid syndrome


Clinical criteria
1. Vascular thrombosis
 One or more clinical episodes of arterial, venous, or small-vessel thrombosis.
2. Pregnancy morbidity
 (a) One or more unexplained deaths of a morphologically normal foetus at or beyond the 10th week of gestation.
(b) One or more pre-term births of a morphologically normal neonate before the 34th week of gestation because of the following: (i) eclampsia or severe pre-eclampsia or (ii) recognised features of placental insufficiency.
(c) Three or more unexplained consecutive spontaneous miscarriages before the 10th week of gestation, with the exclusion of maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes.
Laboratory criteria
1. The presence of lupus anticoagulant (LA) in the plasma on two or more occasions at least 12 weeks apart.
2. The presence of the anticardiolipin (aCL) antibody of immunoglobulin (Ig)G and/or IgM isotype in the serum or plasma in medium or high titre (i.e. >40 GPL units or MPL units, or >the 99th percentile) on two or more occasions at least 12 weeks apart.
3. The presence of the anti-b2-glycoprotein I antibody of IgG and/or IgM isotype in the serum or plasma (in titres>the 99th percentile) on two or more occasions at least 12 weeks apart.
Antiphospholipid antibody syndrome (APS) is present if at least one of the above-mentioned clinical criteria and one of the above-mentioned laboratory criteria are met.
GPL units, IgG antiphospholipid units; MPL units, IgM antiphospholipid units.

Adapted from Miyakis et al. (11).

In psychiatry, APS has not been systematically investigated despite its association with a range of neuropsychiatric manifestations. Psychiatric illness may be the initial manifestation of the syndrome, requiring psychiatrists to be vigilant for the occurrence of the syndrome due to its potential preventive and therapeutic implications (12).

Phospholipids, antiphospholipid antibodies, and the brain

Phospholipids are the major component of cell membranes. These molecules constitute approximately 60% of the dry weight of the brain and play an important role in neurodevelopment (13, 14). Alteration of the lipid environment in the phospholipid bilayer has functional consequences for the activity of the receptors and other proteins that are embedded in the membrane phospholipids (15) and has been proposed to contribute to the deterioration of central nervous system (CNS) function with increasing age (16). Phospholipids also facilitate signal transduction responses to neurotransmitters, such as serotonin, dopamine, glutamate, and acetylcholine that play a key role in the pathophysiology of psychiatric disorders. Autoimmune reactions against key brain phospholipid antigens can result in both a structural breakdown and functional interference, thus leading to the pathogenesis of psychiatric syndromes. The breakdown of phospholipids has been proposed to play a role in the pathogenesis of the development of schizophrenia, bipolar disorder, and depression (17, 18). Imaging studies have shown abnormalities in phospholipid metabolism in the brains of people with schizophrenia, particularly in the frontal and temporal lobes (19).

Antiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies that are directed against anionic phospholipids or protein phospholipid complexes, which also play an important role in the coagulation process (20). ‘Antiphospholipid antibodies’ is a generic term for antibodies that are directed against antigenic targets such as beta 2-glycoprotein I (β2 GPI) and prothrombin, which are considered to be the main antigenic targets (21). Other antigenic targets include CL, phosphatidylserine (PS), tissue plasminogen activator (tPA), plasmin, annexin A2, and thrombin. It is believed that most aPL associated with clinical features of APS recognise the phospholipid-associated protein β2 GPI (20).

In clinical practice, antibodies are usually detected by the presence of one or more of the following: LA, antibodies against β2 GPI, and aCL (IgG and IgM). aPL are present in the normal population at a rate of 1–5% (10). The main tests used for the detection of the LA phenomenon are kaolin clotting time, dilute Russell viper venom test, silica clotting time, and activated partial thromboplastin time (22). Consensus suggests that reactivity with the LA assay is mainly mediated by the antibodies that are directed against prothrombin and β2 GPI, but the aCL positivity associated with clinical features is caused by β2 GPI-dependent aPL (23). There is significant batch-to-batch variability among the tests and a lack of standardisation of assays; therefore, good communication between the laboratory personnel and the clinician is important when making the diagnosis of APS (24). LA, aCL, and β2 GPI testing is required to make an accurate diagnosis of APS (25).

The pathogenesis of aPL is multifactorial and has not been clearly elucidated. A two-hit hypothesis has been proposed (Fig. 1) (26, 27). APS is thought to be triggered by infections and other entities through a process called molecular mimicry between human β2 GPI and molecules that are similar to β2 GPI (e.g. in invading bacteria), which results in the production of anti-β2 GPI antibodies (28). According to the two-hit hypothesis, the first hit disrupts the vascular endothelium and the second hit potentiates thrombus formation (29). The precise trigger is unknown, but it may be related to a complex interaction between genes, hormones, and the environment. Females are most likely to develop APS, which may be related to the immunogenic potential of oestrogen. Oestrogen is thought to induce a genetic programme that alters the survival and activation of B cells in a B cell-autonomous manner, which consequently skews the naive immune system towards autoreactivity (30).

Infections trigger the development of aPL through a process called molecular mimicry due to cross reactivity between the bacterial antigens and antigenic epitopes of the β2 GPI protein. The β2 GPI protein is a glycoprotein that binds to phospholipids. This binding of aPL to the β2 GPI protein creates a prothrombotic state that is not sufficient to cause thrombosis by itself; a second hit, such as trauma or infection, is required. This second hit results in cell injury and a conformational change in the β2 GPI protein that results in the exposure of phospholipid antigens that would normally be present on the inside of the cell. This exposure allows the already circulating aPL to bind to the exposed epitopes, resulting in a cascade of aPL pathogenic mechanism activation (20, 23) (26).

There is good evidence from animal models that aPL can cause features of systemic APS. In a mouse model of thrombosis, which involves a controlled pinch injury to a femoral vein, infusion of aPL increases the size of the clot (31). Passive transfer of murine or human aPL into pregnant mice results in an increased rate of foetal resorption, which is the murine equivalent of miscarriage in humans (32, 33).

There are many mechanisms by which these effects may occur [reviewed in (29)]. It is likely that the main pathogenic process associated with thrombosis involves activation of endothelial cells, monocytes, and platelets, which results in a more prothrombotic phenotype. This activation most likely occurs through the binding of aPL to cell surface molecules, notably β2 GPI, which causes upregulation of adhesion molecules, tissue factor, complement proteins, and components of the coagulation pathway (23). Patients with APS have also been shown to have antibodies for a wide range of coagulation-related proteins, including those involved in the clotting and fibrinolytic pathways, and there may be direct functional effects on such proteins (34). Some of these mechanisms, particularly endothelial and complement activation, may lead to placental insufficiency and account for foetal loss (35). Oxidative stress and mitochondrial dysfunction are also known to play important roles in APS. Alterations in the redox balance result in a conformational change in β2 GPI, which exposes the cryptic immunogenic epitope located on domain I to antibodies. The antibody complexes (anti-β2 GPI) in turn interact with several receptors (e.g. TLR, annexin A2, and APOER2) and activate a downstream cascade that ultimately leads to a prothrombotic cellular phenotype in a β2 GPI-dependent manner.

The pathogenesis of neuropsychiatric APS is less clearly understood. Thromboembolic phenomena are not sufficient to explain the pathogenesis of neuropsychiatric manifestations in APS. Animal studies offer us a glimpse into the possible pathogenic mechanisms of aPL in the genesis of neuropsychiatric symptoms. Mice immunised with aPL showed a range of abnormalities, such as hyperactivity, increased explorative behaviour, depression-like behaviour, and cognitive deficits, such as impaired short-term memory (36). These behavioural changes were linked to a range of mechanisms such as increased 5HT 1A b in the cortical and hippocampal regions, decreased NMDA receptor binding densities (36), structural change in the hippocampal neurons (37), and changes in the brain proinflammatory and anti-inflammatory cytokines (38). According to Chapman et al., aPL can produce direct neuronal injury by affecting the synaptoneurosomes (39). Liou et al. showed that aCL interacts with the neuronal GABA ionotropic receptors (40).

Katzav et al. reported observing antibody-specific behavioural effects in mice injected with aPL; these mice showed hyperactivity, whilst those injected with anti-ribosomal P (a postulated antibody in neuropsychiatric lupus) exhibited depression-like behaviour (41). Furthermore, mice immunised with β2 GPI were found to have IgG antibodies accumulating in the hippocampal neurons (42), indicating the ability of these antibodies to not only pass the BBB to directly affect the hippocampal neurons but also possibly initiate a downstream cascade of neuroinflammation by involving other immune cells of the brain such as astrocytes. Examination of the brain tissue of the immunised mice revealed thrombotic occlusion of capillaries with mild inflammation (43). β2 GPI is the key pathogenic target in APS. This molecule is not present in brain tissue but is expressed by astrocytes, neuronal cells, and endothelial cells, and thus these cells can be pathogenic targets in an autoimmune reaction. One of the most promising auto-antigens is HRGP (histidine-rich glycoprotein), which shares homology with β2 GPI and is found in human brain tissue (44).

A detailed description of the pathogenesis is outside the scope of this article, and readers are referred to the comprehensive review by Rand (20) and Arnson et al. (44). In summary, aPL are thought to act in the following three ways: by disrupting the haemostatic reactions that occur on cell membranes; by stimulating certain cells, for example, platelets and monocytes, which alters the expression and secretion of various molecules and leads to procoagulant activity; and by direct and indirect neural involvement (Fig. 1).

The genetic predisposition for APS is partially explained by markers called human leukocyte antigens (HLAs). Intriguingly, the HLA region has been implicated in psychiatric disorders and other autoimmune disorders, which highlights the possibility that there may be common etiological mechanisms between these disorders ( 45–(47) ).

Neuropsychiatric manifestations of APS

APS can be primary or secondary. Secondary APS occurs most often in individuals with SLE. SLE affects approximately 20 in every 100,000 women, and approximately 30% of these women develop secondary APS. The prevalence of primary antiphospholipid syndrome (PAPS) is 0.5% in the general population. APS occurs primarily in women of fertile age, and the mean age at diagnosis is 34 years (48).

The features of APS include stroke, migraines, recurrent miscarriages, memory dysfunction, seizures, chorea, labile hypertension, dementia, multiple sclerosis-like syndromes, Guillain-Barre syndrome, sensorineural hearing loss, valvular heart disease, and renal and endocrinal disorders. Its high concentration of phospholipids makes the brain a likely target in APS. This article reviews the presentations of APS in psychiatry, including clues from multisystem involvement that can help psychiatrists detect the condition. This article is also relevant to other specialties with respect to the detection of psychiatric manifestations in patients with APS.

Psychosis

Kurtz described the first case report of the association of aPL with psychosis in a 50-year-old woman who presented with a schizophrenia-like syndrome as the primary manifestation of APS. He concluded that APS may present as psychosis many years before the occurrence of somatic symptoms (49).

More recently, additional case reports have shown an association between psychosis and both primary and secondary APS. Siu et al. reported a case of first-episode psychosis in a Chinese woman during the second trimester of pregnancy. In this case, the atypical presentation and fluctuating mental state with visual hallucinations suggested an organic condition, and investigations revealed SLE with aPL antibodies. The authors suggested that psychosis can be the initial presentation of APS and that psychiatrists should consider SLE in the differential diagnosis of psychosis occurring during pregnancy (50). Fernandez Ga de las Herras et al. reported the case of a 49-year-old woman who demonstrated a partial response to antipsychotics and had a previous history of deep vein thrombosis (DVT) and multiple white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) that responded to immunomodulation (51). The authors postulated that the syndrome may be underdiagnosed in psychiatry and highlighted the importance of considering the presence of medical conditions in patients with a first episode of psychosis. In another case, a 28-year-old woman with episodic psychosis and catatonia was discovered to have APS after she developed popliteal vein thrombosis and a mild purpuric rash. Following anticoagulation, treatment with haloperidol and venlafaxine, and immunosuppression (azathioprine, prednisolone), she became asymptomatic. Although the classification criteria for SLE were not met, the authors postulated that the inflammatory disorder (as indicated by elevated erythrocyte sedimentation rate and C-reactive protein) may have indicated an early stage of this disease (52). Catatonia is now considered to be a manifestation of SLE, and its pathogenesis in this instance may be related to the affinity of aPL antibodies for the basal ganglia (53). Pego-Reigosa studied 11 patients with lupus psychosis, and aPL were observed in 10% of the cases (54). In another case, a 24-year-old woman presented with acute psychotic symptoms and fever, and the serological work-up revealed aPL positivity, low protein S with elevated d-dimer, and brain hypoperfusion. Early immunomodulation treatment led to complete remission of the psychotic symptoms, preservation of cognitive function, and prevention of APS progression (55).

APS is an important differential diagnosis of psychosis in children. A 9-year-old girl who developed psychotic illness without thrombotic manifestations was found to have a persistent presence of aCL with negative ANA. Marked improvement occurred after combined treatment with antidepressants, antipsychotics, small-dose aspirin (100 mg a day), and hydroxychloroquine (100 mg a day). The patient developed right axillary vein thrombosis 5 months after aspirin was stopped by her family (56). The above cases raise the question of whether testing for aPL should be incorporated into the differential diagnosis of first-episode psychosis, especially in the treatment-resistant cases, for the following two main reasons: the possibility that non-psychotropics may be required for complete remission and the implication for the prevention of future thromboembolic episodes and multisystem involvement related to APS. The above cases highlight the importance of collaboration between psychiatrists and other specialties in the management of psychiatric disorders. Although a causal role of aPL in psychosis cannot be established based on the above case reports, the response of the patients to immunomodulation and anticoagulation suggests an association of the immune system with the presentations, along with the possibility of hypercoagulability.

One of the strongest indicators of a primary causal role of aPL is derived from a study by Schwartz et al. (57) The authors studied 34 unmedicated patients without known autoimmune disorders who were admitted with acute psychosis. aCL and LA were determined before and after neuroleptic treatment to evaluate the presence of antibodies relative to the treatment condition. The authors found that 32% of untreated patients had low to moderate titres of aCL, which indicates their possible causal role in psychosis. In 1999, Schwartz et al. reported that they observed aPL in 52% of patients with schizophrenia (n=50) who were undergoing long-term neuroleptic treatment. The authors posited that neuroleptics may increase phospholipid expression and activation on the cell membrane, which induces aCL binding to CL epitopes without involving β2 GPI (58). Firer et al. (59) and Chengappa et al. (60) reported increased aCL in medicated and unmedicated patients with schizophrenia and their relatives. aCL may also be responsible for the increased cardiovascular morbidity and mortality in individuals with schizophrenia (61). Psychosis has been conceptualised to be caused by a plasminogen activator imbalance based on a study of five psychotic patients with thrombotic episodes who achieved remission of their psychotic symptoms while on chronic warfarin therapy and were free of psychotropic medication from 2 to 11 years. The patients had at least one thrombophilic disorder, including APS (62).

Dystonia, dyskinetic movements, and secondary parkinsonism are recognised side effects of antipsychotic treatment but can also occur in neuroleptic-naive schizophrenia patients (63). Many cases of movement disorders previously thought to be idiopathic or degenerative are now considered to be autoimmune in origin due to the identification of multiple synaptic antibodies, many of which are implicated in the pathogenesis of psychiatric disorders, including schizophrenia (64). Movement disorders are a recognised manifestation of APS. For example, choreic movements have been linked to the isolated presence of aPL or to primary or secondary APS. A neurotoxic effect of aPL on the basal ganglia has been postulated (65).

An intriguing possibility is that the association of dystonia, parkinsonism, and dyskinetic movements with the use of antipsychotics in some subsets of patients may be due to a protopathic bias (confounding by indication) (66, 67), with aPL as the primary aetiological mechanism and antipsychotics as confounders by indication. Thus, antipsychotics may not be the true causal mechanism, but they may exacerbate the subclinical hypodopaminergic state in the basal ganglia, which is caused by the action of aPL antibodies on the basal ganglia. A similar analogy exists in cases that were previously reported as chorea gravidarum and oestrogen-containing oral contraceptive-related chorea, which were later attributed to aPL with or without SLE (68, 69). The role of aPL in antipsychotic-related movement disorders is a matter for further research.

aPL are also implicated in cases of venous thromboembolism associated with the use of antipsychotics (70). The increased risk has been postulated to be the result of drug-induced sedation, obesity, hyperleptinaemia, aPL, and increased activity of the coagulation system (71). Among the existing antipsychotics, phenothiazines are causally associated with APS (50). Clozapine, which is used in treatment-resistant schizophrenia, is positively correlated with aCL antibodies in individuals with schizophrenia in a dose-dependent manner (72), and this finding may explain the association of venous thromboembolism in patients treated with clozapine.

Affective disorders

Maes et al. investigated the presence of aPL antibodies in depressed patients and compared this presence with that in controls. The authors found that depressed subjects exhibited significantly higher aPL antibody titres compared with normal controls (73). A case control study in 30 patients with PAPS showed that they had higher Fibromyalgia Impact Questionnaire scores, higher Becks Depression Inventory (BDI) scores, and more depression diagnoses according to the BDI scores (74). Spyropolou et al. reported a case of a 34-year-old pregnant woman with acute depressive syndrome as the initial manifestation of APS, followed by foetal demise. The patient exhibited multiple high-density foci in her subcortical white matter in the frontal lobes on brain MRI (75). The association of WMHs with late-life depression has given rise to the vascular hypothesis of depression (76). A form of subcortical ischaemic depression has recently been proposed (77). It will be interesting to determine whether aPL are responsible for this form of depression. Similar findings have been reported in bipolar disorder with a high prevalence of WMHs, which holds true even for adolescents with bipolar disorder (78, 79). Depression is common in patients with SLE, with a prevalence of 69–74% (80). The pathogenesis of depression in SLE is multifactorial, and aPL may be implicated in some cases. Migraines, which are a prominent feature of APS and SLE, may also play a causal role in the development of depression through direct biological mechanisms ( 81–(83) ).

The link between depression, stroke, and cardiovascular disease could be explained in at least some patients by the presence of aPL antibodies. In psychiatry, this link has also been attributed to elevated homocysteine levels (84). Interestingly, homocysteine levels have been observed to be elevated in some patients with aPL antibodies and may be responsible for their thrombotic manifestations ( 85–(87) ). One pathogenic mechanism in APS is the presence of antibodies in response to oxidised low-density lipoprotein. These antibodies are associated with atherosclerosis and inflammatory cytokines (88), which increase the risk of both vascular depression and heart disease.

Mania has also been reported in patients with APS, although less frequently. Raza et al. reported a case of mania in a patient who was found to have APS, which was detected due to bilateral pulmonary emboli that developed 5 months after the initial episode of mania. After the acute manic phase, the persistence of cognitive dysfunction and somnolence in the absence of mood symptoms was initially attributed to olanzapine. The initiation of warfarin for the treatment of pulmonary emboli improved the patient's cognitive function. A family history of thromboembolic deaths was noteworthy (89).

Gorman and Cummings described a series of seven patients who presented with neurobehavioural findings (including irritability, mood lability, suicidal ideation, slowed thinking, akathisia, and movement disturbances) and were observed to have elevated titres of aPL and/or APS (90). Aggressive behaviour has also been described in patients with aPL (39).

Cognitive dysfunction and dementia

Some of the most common complaints in patients with APS are poor memory, difficulty concentrating, and difficulty maintaining attention for long periods of time, which indicates a possible pre-clinical phase of neurological involvement. The cognitive symptoms are one of the most sensitive markers of the syndrome (91, 92). In vivo experiments in mice have shown that the injection of purified IgG from patients with APS into the cerebral ventricles of mice resulted in impairment of learning and memory (93). aPL antibodies may play a primary role in the pathogenesis of cognitive impairment, and neuropsychological testing is useful for detecting early neuropsychiatric involvement ( 94–(96) ). Other studies in primary APS or asymptomatic aPL antibody-positive patients have shown that cognitive deficits may be present independent of any history of known CNS involvement, as well as that the cognitive dysfunction may be subclinical and apparent only with neuropsychological testing in some cases (97, 98). LA positivity is associated with a pattern of deficits compatible with subcortical involvement, possibly on the basis of ongoing LA-related microthrombotic events or vasculopathy (99). The importance of cognitive impairment cannot be underestimated because it is a common feature of depression, schizophrenia, and bipolar disorder and is one of the strongest predictors of poor social functioning in psychiatric patients, which leads to significant burden on patients, families, and society. Livedo reticularis, a characteristic skin sign, and the presence of white matter lesions on brain MRI are associated with an increased risk for cognitive dysfunction in patients with APS (100). There have been anecdotal reports of improvement in cognitive function after commencement of anticoagulation therapy for other reasons, and this finding provides support for the cerebral thrombosis/ischaemia model of cognitive dysfunction (101).

APS can be considered as a vascular cognitive disorder, which encompasses vascular cognitive impairment and vascular dementia (102). Strokes and transient ischaemic attacks (TIAs) are considered to be the second most common clinical manifestation of PAPS after venous thrombosis, with approximately one in five (20%) strokes in individuals under the age of 45 years being associated with APS (103). According to Levine et al. the cerebral ischaemia is characterised by early onset, female gender, high risk of recurrence, and prognostic correlation with IgG aCL (104). Episodes of ischaemia can be transient or permanent. Recurrent episodes can lead to multifocal disease that can cause multi-infarct dementia.

Asherson et al. were the first to report the association of multi-infarct dementia with APS (105). In a 10-year follow-up study of 66 patients with primary APS, Erkan et al. (106) found that three patients (<30 years old) with PAPS developed dementia independent of the presence of cerebrovascular accidents. In a recent study of 30 patients with APS who were followed between 1983 and 2003, silent brain infarcts were present in 14 (47%) of the patients, and dementia was the presenting manifestation of APS in 11 (37%) of the patients. Cortical infarcts were found in 19 (63%) of the patients; subcortical infarcts were found in 9 (30%) of the patients; basal ganglia infarcts were found in 7 (23%) of the patients; and signs of cerebral atrophy were found in 11 (37%) of the patients (107). There is a significant correlation between cognitive deficits and white matter lesions (100). Therefore, cerebral CT or MRI evaluation is commonly recommended in patients with APS. Conversely, ruling out APS should be recommended in the clinical approach to dementia, especially in young patients. Kao et al. (108) studied 22 patients with primary APS who had only mild neuropsychiatric manifestations (headache, depression, personality disorders, memory loss, and cognitive function deficits) and normal brain MRI results. The authors found that 16 (73%) of the patients had abnormal single photon emission computed tomography (SPECT) findings, mainly diffuse hypoperfusion lesions in the cerebral cortex, which indicated that SPECT may be more sensitive in detecting abnormalities. This finding has already been established in neuropsychiatric SLE (109, 110). Positron emission tomography scans showed a considerable diffuse impairment of cortical glucose metabolism combined with reduced cerebral perfusion in the arterial border zones. These findings indicate that PAPS-associated vascular dementia is accompanied by cortical neuronal loss, which is presumably caused by small-vessel disease with immune-mediated intravascular thrombosis (110).

Juby et al. (111) reported a significant association between multi-infarct dementia and aCL. A recent animal study revealed a significant interaction between the amyloid precursor protein (APP) genotype and the induction of APS in females (112). ApoE receptors are essential for neurodevelopment and the regulation of APP metabolism, which has been implicated in the pathogenesis of Alzheimer's disease (AD) (113). The ApoE 2 receptor is a target for β2 GPI, and this binding has been demonstrated in endothelial cells and platelets. Thus, there may be a common aetiological mechanism for both APS and AD.

Most of the studies on the evaluation of cognitive dysfunction in APS have been carried out in the fields of rheumatology and neurology. Considering the prevalence of cognitive dysfunction and dementia in psychiatry, it is surprising that the association of cognitive dysfunction with aPL antibodies has not been investigated in systematic research.

Migraine

Migraine is one of the most commonly observed symptoms in patients with APS; however, studies have reported contradictory results regarding the association between migraine and APS (92). In psychiatric practice, migraine is not a clinical feature that is commonly asked during history-taking, despite being closely associated with major depressive disorder, bipolar disorder, panic disorder, and social phobia, resulting in poorer clinical outcomes ( 114–(116) ). Migraines are also associated with increased suicide attempts in young adults (117).

The importance of migraine is highlighted by its association with dementia, stroke, and psychiatric disorders. Subjects with migraine are at a greater risk of having white matter abnormalities on magnetic resonance images than those without migraines. This increased risk is present even in younger individuals who do not have risk factors for co-occurring cerebrovascular disease (118). Many patients with APS who present with thrombosis, TIAs, or stroke before the age of 40 years state a history of severe headaches that are often migrainous and date back to childhood. There is often a familial history of migraines, and the combination of migraines, APS, and stroke are being reported in a number of large family cohorts (81, 92) (119). The postulated mechanisms of these vascular events include the activation and aggregation of platelets and the expression of proteins such as endothelin-1 or tissue factor, which is the major initiator of the coagulation cascade in vivo, on endothelial cells (120).

Migraines in patients with APS are considered to be a harbinger of stroke (121), which in turn is associated with depression and dementia. Thus, aPL may act as a modifiable causal agent that links several neurological and psychiatric syndromes. APS-related migraines, strokes, and dementia have similarities with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is an autosomal-dominant disorder, the clinical features of which include migraines with aura and subcortical TIAs, strokes, or mood disorders that occur in individuals between 35 and 55 years of age. This disorder has been genetically mapped to the NOTCH 3 gene on chromosome 19, and it often progresses to subcortical dementia. This disorder is often suggested by the following: 1 or more recurrent subcortical ischaemic strokes (especially before the age of 60 years and in the absence of vascular risk factors); migraine; early cognitive decline or subcortical dementia; bilateral, multifocal, T2/FLAIR hyperintensities in the deep white matter and periventricular white matter with lesions; and an autosomal-dominant family history of migraines, early-onset stroke, or dementia. In certain individuals or families, migraines may be the only clinical manifestation (122). It is unclear whether aPL play a role in the pathogenesis of this disorder, but this is a possibility. Pantoni reported three cases of CADASIL with aPL (123). Some cases of APS have also been reported to be autosomal-dominant (124), and the question arises as to whether CADASIL and some cases of APS represent the same disorder with differing nomenclature by two different specialties.

Epilepsy

A complex relationship exists between epilepsy and psychiatric disorders, and a discussion of this relationship is outside the scope of this article. The association of aPL with epilepsy, which was first reported in 1985 (125), may be of significant importance in the investigation of seizures in general. Temporal lobe epilepsy, which is the most relevant disorder to psychiatrists because it can mimic psychiatric disorders, has also been described in patients with APS (81).

Epilepsy is more common in APS secondary to SLE than in PAPS (126). In patients with lupus who present with seizures, the most likely underlying pathology is APS. Patients of all ages are affected, and all forms of epilepsy are observed, including the subclinical abnormal electroencephalography forms (127). The most likely mechanism is interference with the GABA pathway.

The risk of seizures is linked to vascular disease, valvulopathy, Sneddon's syndrome, livedo reticularis, and smoking (128).

Sneddon's syndrome and livedo reticularis

A characteristic skin sign in many patients with APS is livedo reticularis. This symptom may be the presenting sign of APS in 17.5–40% of patients, and it may be observed in up to 70% of patients with SLE and APS (129). Another syndrome associated with livedo reticularis is Sneddon's syndrome, which is characterised by livedo reticularis and cerebrovascular accidents. There is a significant overlap between APS, SLE, and Sneddon's syndrome. Recognising livedo reticularis is important because it is independently associated with cerebral and ocular ischaemic arterial events, cognitive deficits, seizures, heart valve abnormalities, hypertension, and Raynaud's phenomenon; therefore, its presence should alert the psychiatrist to the possibility of APS, irrespective of the presence or absence of antibodies. This finding has prompted some of the authors to suggest that livedo reticularis may be a clinical marker of sero-negative APS (130, 131).

Treatment

A discussion on the detailed treatment of APS is outside the scope of this article, and we refer readers to the article by Cohen et al. (10) and Comarmond and Cacoub (132).

Treatment options for APS include aspirin and hydroxychloroquine, anticoagulants (heparin and warfarin), and immunomodulation. Unfortunately, most of the patients who are encountered in clinical practice do not correspond directly to those enrolled in clinical trials that fulfil the classical criteria (133); therefore, close collaboration with a haematologist or rheumatologist is required. This need for close collaboration may be even more relevant in psychiatric practice because psychiatric manifestations are not included in the criteria and may pose management problems in the absence of close collaboration with other specialties. Moreover, aPL titres are often found to show low or moderately positive levels (52, 58), which makes this syndrome a diagnostic dilemma in psychiatry. The St. Thomas ‘alternative criteria’ for APS may be a useful clinical tool for psychiatrists. These criteria include cognitive impairment, affective disorders, headaches, and livedo reticularis, with improvement after aspirin treatment being an additional diagnostic indicator (134). Although guidelines for thrombotic manifestations are well documented in the literature, treatment for non-thrombotic manifestations, which include psychiatric disorders, epilepsy, and headaches, is less clear, and most of the literature consists of anecdotal reports. Nevertheless, warfarin treatment that was started in these patients for other thrombotic disorders resulted in the resolution of non-thrombotic manifestations. Therefore, it is important for psychiatrists to recognise this condition and promptly refer patients due to the devastating implications of this disorder for physical and psychological health.

Implications for psychiatry

Valid aetiological markers are often elusive to psychiatrists, whose treatment plans are often based on empirical models. The finding of possible aetiological markers, such as aPL, in psychosis, affective disorders, and dementia is of great importance. The question of whether aPL play a causal role or are an epiphenomenon remains open to debate, and more research will be required to elucidate their connection. Nonetheless, the complete remission of cases with psychosis with warfarin treatment (62), improvement in the word-finding score from 15 to 95% after 3 weeks of subcutaneous heparin (135), and other cases described earlier in the article suggest that aPL may play a role in the pathogenesis of some neuropsychiatric presentations. Similarly, cases of previously diagnosed multiple sclerosis have shown sustained improvement with anticoagulation therapy (135). The rapid response to heparin in patients with APS with headache and memory dysfunction has led to the proposal that heparin should be used as a therapeutic trial in certain cases (101, 136). There have been no such controlled trials in psychiatry, and there are consequently no treatment guidelines; however, treatment with anticoagulants and immunomodulation has shown promising results in previous case reports and needs more research. According to the International Consensus Statement regarding an update of the classification criteria for definite APS, there is insufficient evidence to include cognitive dysfunction, headache, migraine, or epilepsy in the revised APS classification criteria. The existing criteria may not apply to psychiatric patients because the manifestations of APS extend beyond those described in the criteria and include symptoms that can cause considerable morbidity in patients. Therefore, studies that are performed in psychiatric patients may reveal new findings and may add to the existing research.

Autoimmune conditions, such as APS, may be missed because many of the clues in the diagnosis of multisystem disorders, such as APS and SLE, can be identified through longitudinal history-taking that begins from childhood and requires probing for clinical features such as migraines, TIAs, and recurrent miscarriages. Thus, it is important for the psychiatrist to maintain a high level of suspicion. APS highlights the importance of medical evaluation in psychiatric patients. Table 2 lists the signs and symptoms that should raise the psychiatrist's suspicion for APS.

When to suspect antiphospholipid syndrome in psychiatry


Atypical psychiatric presentation
Treatment-resistant psychiatric illness
Cognitive dysfunction and dementia
Abnormal involuntary movements with or without the use of antipsychotics
Migraines
History of DVT in patients <50 years of age
History of pulmonary embolism with or without the use of antipsychotics
Stroke or TIA in patients <50 years of age
Livedo reticularis
Recurrent early miscarriages
Raynaud's phenomenon
Diagnosis of SLE
Unexplained white matter hyperintensities (WMHs) on MRI in patients <50 years of age

aPL antibodies are implicated in the development of psychiatric illness, metabolic syndrome, autoimmune diseases, APS, and atherosclerosis through common aetiological mechanisms. Leboyer et al. proposed that mental illnesses, such as bipolar disorder, may actually be multisystem disorders that are underpinned by inflammatory or immune mechanisms, with the psychiatric disorder being an early manifestation of the systemic disease (137). More research may elucidate a possible relationship between psychiatric disease, obesity, metabolic syndrome, autoimmune diseases, APS, and atherosclerosis, and it may explain the high morbidity and early mortality in psychiatric patients 138, (139). aPL antibodies have also been implicated in disorders such as autism and Tourette's syndrome (140, 141). Importantly, there is a need to more clearly identify the subsets of patients with aPL antibodies and describe the clinical features that are associated with the particular antibodies associated with psychiatric disorders.

The identification of aPL in psychiatry has a number of therapeutic implications. Since the discovery of psychotropics, neurotransmitter dysregulation has been the main research model. The immune hypothesis has made a significant impact on neuropsychiatry following the discovery of antineuronal antibodies and more research on the neuropsychiatric manifestations of SLE. The possibility that hypercoagulability and/or autoimmune reactions against phospholipids play a role in some psychiatric disorders opens new avenues for research in the treatment of psychiatric disorders, especially dementia, which is considered irreversible in most cases. Promising treatments based on the phospholipid hypothesis have included the use of eicosapentaenoic acid, which reduced the positive and negative symptoms of schizophrenia in a double-blind pilot trial (142). Omega-3 fatty acids have also been used successfully in the prophylaxis of recurrent miscarriages in patients with APS (143). The therapeutic effect of omega-3 fatty acids may be due to the rebalancing of the eicosanoid dysregulation that is induced by aPL. High levels of platelet aggregator and vasoconstrictor TXA2 are found in patients with aPL. Aspirin, which acts as an antiplatelet agent at lower doses, is useful in preventing the thrombotic manifestations of aPL by reducing the formation of thromboxane, which is a powerful vasoconstrictor (144). Although it is not currently possible to recommend anticoagulation as a treatment for psychiatric illness, other benign therapies may be useful. Aspirin, omega-3, and statins (145) are three evidence-based treatments that have shown benefit in both psychiatric disorders and thrombotic illnesses and may be beneficial in psychiatric disorders associated with aPL. The use of hydroxychloroquine is another relatively benign treatment that is known to reduce the binding of antiphospholipid β2 GPI complexes to phospholipid membranes (146). However, trials of hydroxychloroquine in schizophrenia and Alzheimer's dementia have not shown any benefit (147, 148). More research is required to determine whether hydroxychloroquine would be beneficial in certain psychiatric patients with aPL. Lithium, carbamazepine, and valproate, which are used in bipolar disorder, are also known to reduce the turnover of Arachidonic acid (AA) which reduces the proinflammatory state that is induced by AA release during phospholipid breakdown (149) and may be beneficial for patients with psychiatric presentations of APS.

Approximately one in five cases of stroke and DVT are associated with APS (135). If this 1:5 ratio were to hold true in psychiatric disorders, it would offer significant hope for many patients in addition to the significant reduction of health costs. There is an urgent need for large-scale studies in psychiatric patients to identify various antibody profiles, including aPL antibodies, and if determining if these antibodies play a causative role in the development of psychiatric syndromes. A survey of patients’ experiences with APS diagnosis in the United Kingdom revealed that there was a long lag time before the diagnosis of APS was made and a lack of awareness among specialists and general practitioners that resulted in increased costs to the NHS and emotional and financial costs to the patients (150). The operational boundaries that separate the clinical disciplines of psychiatry, neurology, and immunology are becoming increasingly blurred, requiring new holistic approaches in the study of neuropsychiatric disorders (151). Syphilis was considered to be the great imitator for several years because it presented with a range of neuropsychiatric manifestations. SLE took over as the great imitator with the reduction in the incidence of syphilis, and it appears that APS may be the new great imitator (152). It is hoped that this article has provided a glimpse of this mimicry in psychiatry; however, a concerted effort will be required by multiple specialties to identify its true nature.

Conflict of interest and funding

This research received no specific funding support from any funding agency in the public, commercial, or not-for-profit sectors.

References Hughes GR. The Prosser-White oration 1983. Connective tissue disease and the skin Clin Exp Dermatol 1984 9 535 Harris EN Hughes GR Gharavi AE. Antiphospholipid antibodies: an elderly statesman Dons new garments J Rheumatol Suppl 1987 14(Suppl 13) 208 13 Moore JE Mohr CF. Biologically false positive serologic tests for syphilis: type, incidence, and cause J Am Med Assoc 1952 150 467 73 Moore JE Lutz WB. The natural history of systemic lupus erythematosus: an approach to its study through chronic biologic false positive reactors J Chron Dis 1955 1 297 316 Pangborn MC. A new serologically active phospholipid from beef heart Proc Soc Exp Biol Med 1941 48 484 6 Conley CL. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus J Clin Invest 1952 31 621 2 Bowie EW. Thrombosis in systemic lupus erythematosus despite circulating anticoagulants J Lab Clin Med 1963 62 416 30 Nilsson IM Åstedt B Hedner U Berezin D. Intrauterine death and circulating anticoagulant (‘antithromboplastin’) Acta Medica Scandinavica 1975 197 153 9 Laurell AB Nilsson IM. Hypergammaglobulinemia, circulating anticoagulant, and biologic false positive Wassermann reaction: a study in two cases J Lab Clin Med 1957 49 694 707 Cohen D Berger SP Steup-Beekman GM Bloemenkamp KW Bajema IM. Diagnosis and management of the antiphospholipid syndrome BMJ 2010 340 c2541 Miyakis S Lockshin MD Atsumi T Branch DW Brey RL Cervera R International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS) J Thromb Haemost 2006 4 295 306 Manna R Ricci V Curigliano V Pomponi M Adamo F Costa A Psychiatric manifestations as a primary symptom in antiphospholipid syndrome Int J Immunopathol Pharmacol 2006 19 915 7 Martinez M Mougan I. Fatty acid composition of human brain phospholipids during normal development J Neurochem 1998 71 2528 33 Bennett CN Horrobin DF. Gene targets related to phospholipid and fatty acid metabolism in schizophrenia and other psychiatric disorders: an update Prostaglandins Leukot Essent Fatty Acids 2000 63 47 59 Fenton WS Hibbeln J Knable M. Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia Biol Psychiatry 2000 47 8 21 Söderberg M Edlund C Kristensson K Dallner G. Fatty acid composition of brain phospholipids in aging and in Alzheimer's disease Lipids 1991 26 421 5 Horrobin DF Bennett CN. Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate genes Prostaglandins Leukot Essent Fatty Acids 1999 60 217 34 Ross BM Hudson C Erlich J Warsh JJ Kish SJ. Increased phospholipid breakdown in schizophrenia. Evidence for the involvement of a calcium-independent phospholipase A2 Arch Gen Psychiatry 1997 54 487 94 Keshavan MS Stanley JA Pettegrew JW. Magnetic resonance spectroscopy in schizophrenia: methodological issues and findings – part II Biol Psychiatry 2000 48 369 80 Rand JH. Molecular pathogenesis of the antiphospholipid syndrome Circ Res 2002 90 29 37 Bevers EM Galli M Barbui T Comfurius P Zwaal RF. Lupus anticoagulant IgG's (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin Thromb Haemost 1991 66 629 32 Brandt JT Triplett DA Alving B Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH Thromb Haemost 1995 74 1185 90 Meroni PL Borghi MO Raschi E Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies Nat Rev Rheumatol 2011 7 330 9 Pengo V Tripodi A Reber G Rand JH Ortel TL Galli M Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis J Thromb Haemost 2009 7 1737 40 Gardiner C Hills J Machin SJ Cohen H. Diagnosis of antiphospholipid syndrome in routine clinical practice Lupus 2013 22 18 25 Tripodi A de Groot PG Pengo V. Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment J Intern Med 2011 270 110 22 Girón-González JA del Río EG Rodríguez C Rodríguez-Martorell J Serrano A. Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: prospective analysis of 404 individuals J Rheumatol 2004 31 1560 7 Blank M Krause I Fridkin M Keller N Kopolovic J Goldberg I Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome J Clin Invest 2002 109 797 804 Giannakopoulos B Krilis SA. The pathogenesis of the antiphospholipid syndrome New Engl J Med 2013 368 1033 44 Nalbandian G Kovats S. Understanding sex biases in immunity: effects of estrogen on the differentiation and function of antigen-presenting cells Immunol Res 2005 31 91 106 Pierangeli SS Harris EN. Antiphospholipid antibodies in an in vivo thrombosis model in mice Lupus 1994 3 247 51 Branch DW Scott JR Kochenour NK Hershgold E. Obstetric complications associated with the lupus anticoagulant New Engl J Med 1985 313 1322 6 Blank M Cohen J Toder V Shoenfeld Y. Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies Proc Natl Acad Sci U S A 1991 88 3069 73 Mackworth-Young CG. Antiphospholipid syndrome: multiple mechanisms Clin Exp Immunol 2004 136 393 401 Girardi G Salmon JE. Khamashta MA Antiphospholipid antibody-induced pregnancy loss and thrombosisHughes syndrome: antiphospholipid syndrome 2006 London Springer 395 402 Frauenknecht K Katzav A Grimm C Chapman J Sommer CJ. Altered receptor binding densities in experimental antiphospholipid syndrome despite only moderately enhanced autoantibody levels and absence of behavioral features Immunobiology 2014 219 341 9 Frauenknecht K Katzav A Weiss Lavi R Sabag A Otten S Chapman J Mice with experimental antiphospholipid syndrome display hippocampal dysfunction and a reduction of dendritic complexity in hippocampal CA1 neurons Neuropathol Appl Neurobiol 2014 Menachem A Chapman J Katzav A. Significant changes in the levels of secreted cytokines were observed in the brains of experimental antiphospholipid syndrome mice Autoimmune Dis 2012 2012 404815 Chapman J Rand JH Brey RL Levine SR Blatt I Khamashta MA Non-stroke neurological syndromes associated with antiphospholipid antibodies: evaluation of clinical and experimental studies Lupus 2003 12 514 7 Liou HH Wang CR Chou HC Arvanov VL Chen RC Chang YC Anticardiolipin antisera from lupus patients with seizures reduce a GABA receptor-mediated chloride current in snail neurons Life Sci 1994 54 1119 25 Katzav A Ben-Ziv T Blank M Pick CG Shoenfeld Y Chapman J. Antibody-specific behavioral effects: intracerebroventricular injection of antiphospholipid antibodies induces hyperactive behavior while anti-ribosomal-P antibodies induces depression and smell deficits in mice J Neuroimmunol 2014 272 10 5 Katzav A Menachem A Maggio N Pollak L Pick CG Chapman J IgG accumulates in inhibitory hippocampal neurons of experimental antiphospholipid syndrome J Autoimmun 2014; 55: 86–93 Ziporen L Polak-Charcon S Korczyn DA Goldberg I Afek A Kopolovic J Neurological dysfunction associated with antiphospholipid syndrome: histopathological brain findings of thrombotic changes in a mouse model Clin Dev Immunol 2004 11 67 75 Arnson Y Shoenfeld Y Alon E Amital H. The antiphospholipid syndrome as a neurological disease Semin Arthritis Rheu 2010 40 97 108 Harley JB. The genetic etiology of systemic lupus erythematosus: a short dispatch from the combat zone Genes Immun 2002 3 (Suppl 1) S1 4 Jonsen A Bengtsson AA Sturfelt G Truedsson L. Analysis of HLA DR, HLA DQ, C4A, FcgammaRIIa, FcgammaRIIIa, MBL, and IL-1Ra allelic variants in Caucasian systemic lupus erythematosus patients suggests an effect of the combined FcgammaRIIa R/R and IL-1Ra 2/2 genotypes on disease susceptibility Arthritis Res Ther 2004 6 557 62 International Schizophrenia Consortium Purcell SM Wray NR Stone JL Visscher PM O'Donovan MC Common polygenic variation contributes to risk of schizophrenia and bipolar disorder Nature 2009 748 52 Cervera R Piette JC Font J Khamashta MA Shoenfeld Y Camps MT Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients Arthritis Rheum 2002 46 1019 27 Kurtz G Muller N. The antiphospholipid syndrome and psychosis Am J Psychiatry 1994 151 1841 2 Siu BW Chow HM Kwok SS Li OL Koo ML Poon PW. Systemic lupus erythematosus as a cause of first-episode psychosis in the second trimester of pregnancy East Asian Arch Psychiatry 2010 20 145 50 Fernandez Ga de las Heras V Gorriti MA García-Vicuña R Santos Ruiz JL. Psychosis leading to the diagnosis of unrecognized systemic lupus erythematosus: a case report Rheum Int 2007 27 883 5 Cardinal RN Shah DN Edwards CJ Hughes GR Fernández-Egea E. Psychosis and catatonia as a first presentation of antiphospholipid syndrome Br J Psychiatry 2009 195 272 Pustilnik S Trutia A. Catatonia as the presenting symptom in systemic lupus erythematosus J Psychiatr Pract 2011 17 217 21 Pego-Reigosa JM Isenberg DA. Psychosis due to systemic lupus erythematosus: characteristics and long-term outcome of this rare manifestation of the disease Rheumatology 2008 47 1498 502 Lai JY Wu PC Chen HC Lee MB. Early neuropsychiatric involvement in antiphospholipid syndrome Gen Hosp Psychiatry 2012 34 579.e1–3 Shalaby M Alhumayed S Alshehri A. Paediatric case report: primary antiphospholipid syndrome presented with non-thrombotic neurological picture psychosis; treat by antidepressants alone? Int J Rheum Dis 2009 12 170 3 Schwartz M Rochas M Weller B Sheinkman A Tal I Golan D High association of anticardiolipin antibodies with psychosis J Clin Psychiatry 1998 59 20 3 Schwartz M Rochas M Toubi E Sharf B. The presence of lupus anticoagulant and anticardiolipin antibodies in patients undergoing long-term neuroleptic treatment J Psychiatry Neurosci 1999 24 351 2 Firer M Sirota P Schild K Elizur A Slor H. Anticardiolipin antibodies are elevated in drug-free, multiply affected families with schizophrenia J Clin Immunol 1994 14 73 8 Chengappa KN Carpenter AB Keshavan MS Yang ZW Kelly RH Rabin BS Elevated IGG and IGM anticardiolipin antibodies in a subgroup of medicated and unmedicated schizophrenic patients Biol Psychiatry 1991 30 731 5 Leuci E Manenti L Maggini C. Anti-phospholipid antibodies, neuroleptic treatment and cardiovascular morbidity Br J Psychiatry 2007 190 81 Hoirisch-Clapauch S Nardi A. Psychiatric remission with warfarin: should psychosis be addressed as plasminogen activator imbalance? Med Hypotheses 2013 80 137 41 Geisler S Sheitman B Kane JM Geisler S Sheitman B Woerner M Prevalence and clinical correlates of extrapyramidal signs and spontaneous dyskinesia in never-medicated schizophrenic patients Am J Psychiatry 1995 152 1724 9 Panzer J Dalmau J. Movement disorders in paraneoplastic and autoimmune disease Curr Opin Lipidol 2011 24 346 53 Peluso S Antenora A De Rosa A Roca A Maddaluno G Brescia Morra V Antiphospholipid-related chorea Front Neurol 2012 3 150 Shapiro S. Confounding by indication? Epidemiology 1997 8 110 Horwitz RI Feinstein AR. The problem of ‘protopathic bias’ in case-control studies Am J Med 1980 68 255 8 Martino D Chew NK Mir P Edwards MJ Quinn NP Bhatia KP. Atypical movement disorders in antiphospholipid syndrome Mov Disord 2006 21 944 9 Janavs JL Aminoff MJ. Dystonia and chorea in acquired systemic disorders J Neurol Neurosurg Psychiatry 1998 65 436 45 Borras L Eytan A de Timary P Constant EL Huguelet P Hermans C. Pulmonary thromboembolism associated with olanzapine and risperidone J Emerg Med 2008 35 159 61 Hagg S Spigset O. Antipsychotic-induced venous thromboembolism: a review of the evidence CNS Drugs 2002 16 765 76 Shen H Li R Xiao H Zhou Q Cui Q Chen J. Higher serum clozapine level is associated with increased antiphospholipid antibodies in schizophrenia patients J Psychiatr Res 2009 43 615 9 Maes M Meltzer H Jacobs J Suy E Calabrese J Minner B Autoimmunity in depression: increased antiphospholipid autoantibodies Acta Psychiatr Scand 1993 87 160 6 Costa SP Lage LV da Mota LM de Carvalho JF. Fibromyalgia in primary antiphospholipid (Hughes) syndrome Lupus 2011 20 1182 6 Spyropoulou AC Tsartsara EI Angelopoulou A Zervas IM. Psychiatric manifestations preceding fetal death in antiphospholipid syndrome Gen Hosp Psychiatry 2010 32 225 7 Herrmann LL Le Masurier M Ebmeier KP. White matter hyperintensities in late life depression: a systematic review J Neurol Neurosurg Psychiatry 2008 79 619 24 Krishnan KR Taylor WD McQuoid DR MacFall JR Payne ME Provenzale JM Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression Biol Psychiatry 2004 55 390 7 Pillai JJ Friedman L Stuve TA Trinidad S Jesberger JA Lewin JS Increased presence of white matter hyperintensities in adolescent patients with bipolar disorder Psychiatry Res 2002 114 51 6 Ahn KH Lyoo IK Lee HK Song IC Oh JS Hwang J White matter hyperintensities in subjects with bipolar disorder Psychiatry Clin Neurosci 2004 58 516 21 Popescu A Kao A. Neuropsychiatric systemic lupus erythematosus Curr Neuropharmacol 2011 9 449 57 Strikingly APS. Antiphospholipid syndrome, migraine and stroke Lupus 2010 19 555 6 Buse DC Silberstein SD Manack AN Papapetropoulos S Lipton RB. Psychiatric comorbidities of episodic and chronic migraine J Neurol 2013 260 1960 9 Omdal R Waterloo K Koldingsnes W Husby G Mellgren SI. Somatic and psychological features of headache in systemic lupus erythematosus J Rheumatol 2001 28 772 9 Folstein M Liu T Peter I Buell J Arsenault L Scott T The homocysteine hypothesis of depression Am J Psychiatry 2007 164 861 7 Avivi I Lanir N Hoffman R Brenner B. Hyperhomocysteinemia is common in patients with antiphospholipid syndrome and may contribute to expression of major thrombotic events Blood Coag Fibrinolysis 2002 13 169 72 Carvalho JFD Caleiro MTC Bonfá E. Hyperhomocysteinemia and primary antiphospholipid syndrome Rev Bras Reumatol 2009 49 337 45 Martínez-Berriotxoa A Ruiz-Irastorza G Egurbide MV Rueda M Aguirre C. Homocysteine, antiphospholipid antibodies and risk of thrombosis in patients with systemic lupus erythematosus Lupus 2004 13 927 33 Hulthe J Fagerberg B. Circulating oxidized LDL is associated with subclinical atherosclerosis development and inflammatory cytokines (AIR Study) Arterioscler Thromb Vasc Biol 2002 22 1162 7 Raza H Epstein SA Rosenstein DL. Mania: psychiatric manifestations of the antiphospholipid syndrome Psychosomatics 2008 49 438 Gorman DG Cummings JL. Neurobehavioral presentations of the antiphospholipid antibody syndrome J Neuropsychiatry Clin Neurosci 1993 5 37 42 Jacobson MW Rapport LJ Keenan PA Coleman RD Tietjen GE. Neuropsychological deficits associated with antiphospholipid antibodies J Clin Exp Neuropsychol 1999 21 251 64 Sanna G Bertolaccini ML Cuadrado MJ Khamashta MA Hughes GR. Central nervous system involvement in the antiphospholipid (Hughes) syndrome Rheumatology 2003 42 200 13 Shoenfeld Y Nahum A Korczyn AD Dano M Rabinowitz R Beilin O Neuronal-binding antibodies from patients with antiphospholipid syndrome induce cognitive deficits following intrathecal passive transfer Lupus 2003 12 436 42 Hanly JG Walsh NM Fisk JD Eastwood B Hong C Sherwood G Cognitive impairment and autoantibodies in systemic lupus erythematosus Rheumatology 1993 32 291 6 Hanly JG Hong C Smith S Fisk JD. A prospective analysis of cognitive function and anticardiolipin antibodies in systemic lupus erythematosus Arthritis Rheum 2001 42 728 34 Muscal E Brey R. Neurological manifestations of systemic lupus erythematosus in children and adults Neurol Clin 2010 28 61 73 Erkan D Kozora E Lockshin MD. Cognitive dysfunction and white matter abnormalities in antiphospholipid syndrome Pathophysiology 2011 18 93 102 Austin S Cohen H. Antiphospholipid syndrome Medicine 2010 38 101 4 Denburg SD Carbotte RM Ginsberg JS Denburg JA. The relationship of antiphospholipid antibodies to cognitive function in patients with systemic lupus erythematosus J Int Neuropsychol Soc 1997 3 377 86 Tektonidou MG Varsou N Kotoulas G Antoniou A Moutsopoulos HM. Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic resonance imaging findings Arch Intern Med 2006 166 2278 84 Hughes GR Cuadrado MJ Khamashta MA Sanna G. Headache and memory loss: rapid response to heparin in the antiphospholipid syndrome Lupus 2001 10 778 Roman GC Sachdev P Royall DR Bullock RA Orgogozo JM López-Pousa S Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia J Neurol Sci 2004 226 81 7 Rodrigues CE Carvalho JF Shoenfeld Y. Neurological manifestations of antiphospholipid syndrome Eur J Clin Invest 2010 40 350 9 Levine SR Brey RL Sawaya KL Salowich-Palm L Kokkinos J Kostrzema B Recurrent stroke and thrombo-occlusive events in the antiphospholipid syndrome Ann Neurol 2004 38 119 24 Asherson RA Mercey D Phillips G Sheehan N Gharavi AE Harris EN Recurrent stroke and multi-infarct dementia in systemic lupus erythematosus: association with antiphospholipid antibodies Ann Rheum Dis 1987 46 605 11 Erkan D Yazici Y Sobel R Lockshin MD. Primary antiphospholipid syndrome: functional outcome after 10 years J Rheumatol 2000 27 2817 21 Gomez-Puerta JA Cervera R Calvo LM Gómez-Ansón B Espinosa G Claver G Dementia associated with the antiphospholipid syndrome: clinical and radiological characteristics of 30 patients Rheumatology 2005 44 95 9 Kao CH Lan JL Hsieh JF Ho YJ ChangLai SP Lee JK Evaluation of regional cerebral blood flow with 99mTc-HMPAO in primary antiphospholipid antibody syndrome J Nucl Med 1999 40 1446 50 Sibbitt WL Sibbitt RR Brooks WM. Neuroimaging in neuropsychiatric systemic lupus erythematosus Arthritis Rheum 1999 42 2026 38 Hilker R Thiel A Geisen C Rudolf J. Cerebral blood flow and glucose metabolism in multi-infarct-dementia related to primary antiphospholipid antibody syndrome Lupus 2000 9 311 6 Juby A Davis P Genge T McElhaney J. Anticardiolipin antibodies in two elderly subpopulations Lupus 1995 4 482 5 Katzav A Faust-Socher A Kvapil F Michaelson DM Blank M Pick CG Antiphospholipid syndrome induction exacerbates a transgenic Alzheimer disease model on a female background. Neurobiol Aging 2011 32 272 9 Herz J. ApoE receptors in the nervous system Curr Opin Lipidol 2009 20 190 Merikangas KR Merikangas JR Angst J. Headache syndromes and psychiatric disorders: association and familial transmission J Psychiatr Res 1993 27 197 210 Merikangas KR Stevens DE. Comorbidity of migraine and psychiatric disorders Neurol Clin 1997 15 115 23 Jette N Patten S Williams J Becker W Wiebe S. Comorbidity of migraine and psychiatric disorders – a national population-based study Headache 2008 48 501 16 Breslau N Davis GC Andreski P. Migraine, psychiatric disorders, and suicide attempts: an epidemiologic study of young adults Psychiatry Res 1991 37 11 23 Swartz RH Kern RZ. Migraine is associated with magnetic resonance imaging white matter abnormalities: a meta-analysis Arch Neurol 2004 61 1366 Hughes GR. Hughes syndrome (the antiphospholipid syndrome): ten clinical lessons Autoimmun Rev 2008 7 262 6 Cuadrado MJ Khamashta MA Hughes GRV. Migraine and stroke in young women Q J Med 2000 93 317 8 Etminan M Takkouche B Isorna FC Samii A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies BMJ 2005 330 63 Gladstone JP Dodick DW. Migraine and cerebral white matter lesions: when to suspect cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Neurologist 2005 11 19 29 Pantoni L Sarti C Pescini F Bianchi S Bartolini L Nencini P Thrombophilic risk factors and unusual clinical features in three Italian CADASIL patients Eur J Neurol 2004 11 782 7 Goel N Ortel TL Bali D Anderson JP Gourley IS Smith H Familial antiphospholipid antibody syndrome: criteria for disease and evidence for autosomal dominant inheritance Arthritis Rheum 2001 42 318 27 Mackworth-Young CG Hughes GR. Epilepsy: an early symptom of systemic lupus erythematosus J Neurol Neurosurg Psychiatry 1985 48 185 Shoenfeld Y Lev S Blatt I Blank M Font J von Landenberg P Features associated with epilepsy in the antiphospholipid syndrome J Rheumatol 2004 31 1344 8 Hughes GRV. Migraine, memory loss, and ‘multiple sclerosis’. Neurological features of the antiphospholipid (Hughes’) syndrome Postgrad Med J 2003 79 81 3 de Carvalho JF Pasoto SG Appenzeller S. Seizures in primary antiphospholipid syndrome: the relevance of smoking to stroke Clin Dev Immunol 2012 2012 981519 Uthman IW Khamashta MA. Livedo racemosa: a striking dermatological sign for the antiphospholipid syndrome J Rheumatol 2006 33 2379 82 Frances C Niang S Laffitte E Pelletier FI Costedoat N Piette JC. Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases Arthritis Rheum 2005 52 1785 93 Hughes G Khamashta M. Seronegative antiphospholipid syndrome Ann Rheum Dis 2003 62 1127 Comarmond C Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies Autoimmun Rev 2013 12 752 7 Garcia D Munther K Crowther M. How we diagnose and treat thrombotic manifestations of the antiphospholipid syndrome: a case-based review Blood 2007 110 3122 7 Rosenthal E Foster R Sangle S D'Cruz D. Patients know it: Hughes syndrome is unique J Rheumatol 2006 33 1919 20 Hughes GR Put Hughes syndrome on your radar Rheumatologist 2007; 1: 20–1 Hughes GRV. Heparin, antiphospholipid antibodies and the brain Lupus 2012 2012 1039 40 Leboyer M Soreca I Scott J Frye M Henry C Tamouza R Can bipolar disorder be viewed as a multi-system inflammatory disease? J Affect Dis 2012 141 1 10 Palomo I Alarcon M Moore-Carrasco R Argilés JM. Hemostasis alterations in metabolic syndrome (review) Int J Mol Med 2006 18 969 74 Arteaga RB Chirinos JA Soriano AO Jy W Horstman L Jimenez JJ Endothelial microparticles and platelet and leukocyte activation in patients with the metabolic syndrome Am J Cardiol 2006 98 70 4 Sokol DK Chen LS Wagenknecht DR McIntyre JA. Anti-phospholipid antibodies in cerebrospinal fluid but not serum from a boy with psychosis Pediatr Neurol 2008 39 293 4 Singer HS Krumholz A Giuliano J Kiessling LS. Antiphospholipid antibodies: an epiphenomenon in Tourette syndrome Mov Disord 1997 12 738 42 Peet M Brind J Ramchand CN Shah S Vankar GK. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia Schizophr Res 2001 49 243 51 Rossi E Costa M. Fish oil derivatives as a prophylaxis of recurrent miscarriage associated with antiphospholipid antibodies (APL): a pilot study Lupus 1993 2 319 23 Årfors L Vesterqvist O Johnsson H Gréen K. Increased thromboxane formation in patients with antiphospholipid syndrome Eur J Clin Invest 1990 20 607 12 Jajoria P Murthy V Papalardo E Romay-Penabad Z Gleason C Pierangeli SS. Statins for the treatment of antiphospholipid syndrome? Ann N Y Acad Sci 2009 1173 736 45 Rand JH Wu XX Quinn AS Chen PP Hathcock JJ Taatjes DJ. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody–β2-glycoprotein I complexes to phospholipid bilayers Blood 2008 112 1687 95 Van Gool WA Weinstein HC Scheltens PK Walstra GJ. Effect of hydroxychloroquine on progression of dementia in early Alzheimer's disease: an 18-month randomised, double-blind, placebo-controlled study Lancet 2001 358 455 60 Desta M Tadesse A Gebre N Barci BM Torrey EF Knable MB. Controlled trial of hydroxychloroquine in schizophrenia J Clin Psychopharmacol 2002 22 507 10 Tassoni D Kaur G Weisinger RS Sinclair AJ. The role of eicosanoids in the brain Asia Pacific J Clin Nutr 2008 17 220 8 Donnan PT McDonald MJ. Patients’ experiences of a diagnosis of Hughes’ syndrome Clin Rheumatol 2009 28 1091 100 Mayberg H. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment Br Med Bull 2003 65 193 207 LeFanuJDoctor's diary: is Hughes syndrome the new syphilis? Telegraph 2012Available from: http://www.telegraph.co.uk/health/9292522/Doctors-Diary-Is-Hughes-syndrome-the-new-syphilis.html [cited 14 January 2015]
About The Authors

Sanil Rege
Psych Scene Pty Ltd Positive Psychology Wellness Centre
Australia

Charles Mackworth-Young
Consultant Physician, Department of Rheumatology, Charing Cross Hospital, Fulham Place Road, London W6 8RF.
United Kingdom

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