Anti-phospholipid syndrome (APS) is an autoimmune disease characterized by recurrent arterial and/or venous thrombosis and/or pregnancy morbidity in the presence of persistently positive circulating anti-phospholipid antibodies (aPLa): anti-cardiolipin (aCL), anti-β2-glycoprotein I (A β2GPI) antibodies, and the lupus anti-coagulant (LAC).

There are many studies which demonstrate the association of APS with injury of the central nervous system (CNS) in a manner of thrombotic neurological events and nonthrombotic symptoms. The most common neurological manifestations are stroke and migraine with a prevalence of approximately 20% of patients, but other symptoms such as chorea, seizures, dementia, transverse myelitis, encephalopathy, pseudotumor cerebri, cerebral venous thrombosis, mononeuritis multiplex, cerebellar ataxia, hemiballismus, Guillan-Barré syndrome, or amaurosis fugax were also described [1–3].

The etiology of schizophrenia is unknown. Autoimmune mechanism may take place. One such mechanism may be molecular mimicry of early infection by microorganisms possessing antigens that are so similar to tissue in the CNS that resulting antibodies act against the brain [4]. According to a 30-year population-based register study, any history of hospitalization with infection increased the risk of schizophrenia by 60%. In addition, a prior autoimmune disease increased the risk by 29% [5].

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Obstetric complications have been implicated in schizophrenia, and some have speculated that infection in the mother produces antibodies that are transmitted to the fetus, producing autoantibodies that disrupt neural development and raise the risk for schizophrenia [6], eventually, some autoimmune diseases have high prevalence in schizophrenia [7].

Comparisons of schizophrenia patients and healthy subjects have revealed differences in immunologic parameters [8]. There has been repeated evidence of a genetic locus for schizophrenia in the area of the human leukocyte antigens (HLA) [9, 10]. The expression of various cytokines and Toll-like receptors is altered in patients with schizophrenia [10, 11], and there is an increase in the prevalence of certain autoantibodies, namely aCL and anti-N-methyl-d-aspartate (NMDA) receptor, in those patients [12]. The evidence of immune imbalance in schizophrenia patients support the mild encephalitis hypothesis that claims that low-level neuroinflammation represents the core pathogenic mechanism in a schizophrenia subgroup that has an overlap with other psychiatric disorders. This mild encephalitis may be triggered by infections, autoimmunity, toxicity, or trauma [13]. The hypothesis is further supported by case reports of anti-NMDA receptor autoantibodies (mainly as a paraneoplastic syndrome) causing the receptor internalization and hypofunction resulting in psychosis that is improved when the level of these antibodies is lowered by immunomodulation [14–18].

Psychiatric manifestations, such as psychosis, depression, and anxiety have been described in association with aPLa and APS. Some of these manifestations also appeared in animal models [19]. APLa were found in the serum and cerebrospinal fluid (CSF) of psychotic patients in a pattern suggesting autonomous CNS production of at least some of them [20]. Part of these associations was attributed to aPLa induced by neuroleptic medications used in these conditions [21], in some cases even in a dose-dependent manner [22]. However, statistically significant high incidence of aPLa was also detected in untreated psychotic patients and their healthy relatives [23, 24] and no difference was found between aPLa levels of treated and unmedicated schizophrenia patients [25]. In addition, some of these antibodies were found to be reduced to a normal level by neuroleptic treatment [26]. Moreover, there are several case reports of psychosis, schizophrenia, and schizophrenia-like symptoms as presenting signs of APS with or without association to systemic lupus erythematosus (SLE). In some of these cases, it has been months or years between the primary diagnosis of the psychotic disorder and the subsequent physical manifestations that led to the diagnosis of APS [27, 28]. In others, some signs of autoimmune disease appeared before the psychotic symptoms [29].

In our center, there are about 150 patients with APS in follow-up. Five patients were afflicted with both APS and schizophrenia. They were diagnosed for each disease separately and at a different stage in their life.

The interweaving of both diseases in a single individual warranted our attention especially since there is growing interest and research in the subject.

Herein, we present those five case reports (Table 1) along with a complete review of the literature in this subject.

Table 1 Characteristics of five patients with APS and schizophrenia
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Case reports

Case 1

The first patient is a 62-year-old man, married with five children, known to the psychiatric authorities for 47 years. During his military service, he was electrocuted and ever since had paranoid ideation. During his service, he was hospitalized in a psychiatric ward, treated with electroconvulsive therapy, and later—dismissed from service. At the time of his initial hospitalization, he was diagnosed with schizophrenia, paranoid type. Nine years prior (May 2001), he was hospitalized in Sheba Medical Center due to pain in his left groin and lower abdomen. The pain increased with walking or moving, was accompanied with high fever, chills, and left-flank pain. A computed tomography (CT) was preformed which demonstrated inferior vena cava (IVC) and renal vein thrombosis. As he recalled a strong family history of thrombosis (uncle) and heart attacks (brother and father), a coagulation profile was taken and he was placed under warfarin treatment. A month later, he returned with a cerebrovascular accident (CVA) with mild left hemiparesis. His LAC levels were 1.5–1.7 (normal range, 0–1.25) and aCL IgM antibodies level was above 80 IU/ml (normal range, 0–7 IU/ml) on at least two occasions at least 3 months apart. Accordingly, he was diagnosed with APS.

A CT-angio was also preformed. It showed the patient had an anatomic variant: a double inferior vena cava and an interruption of the IVC. In comparison with former CTs, the left IVC was small and a thrombus was demonstrated at the common and external iliac vein up to the level of L5. A thrombus was also demonstrated at the left renal vein. As his recent CVA was non-hemorrhagic and INR levels were significantly lower than expected—under warfarin treatment, the warfarin treatment was resumed.

A month and a half later, the patient returned to the emergency room with deep vein thrombosis (DVT) of the left ileofemoral vein—while on warfarin treatment. INR level at admission was 1.86. Eight months later, there was another admission due to recurrent DVT of the left ileofemoral vein. He admitted to low compliance. His INR levels were 1.08.

Several months later, he was hospitalized again because of dyspnea and suspected pulmonary embolism (PE). However, his INR levels were appropriate (2.4) and the ventilation/perfusion scan that was performed showed low probability for PE. That was his last admission to date.

During this span of time the patient was readmitted several times to the psychiatric ward due to exacerbation of his psychotic symptoms. Each time some change was made in his medications and he was released to his home. His current neuroleptic treatment comprised atypical anti-psychotics.

Case 2

The second patient is a 39-year-old woman who was born in Israel. This patient was diagnosed with schizophrenia, paranoid type, at the age of 22. She had multiple psychiatric problems including bulimia nervosa, a binge eating disorder, and mild mental retardation (IQ = 67). There was also an event of attempted suicide. The patient was treated with several anti-psychotic medications including: risperidal and olanzepine. When she was 25, this patient had a DVT in the left popliteal vein. Because of her mental state and low compliance, she was treated only with aspirin. No hypercoagulability studies were conducted at that point. While on anti-psychotic medication, the patient developed thrombocytopenia of 57,000. Her psychiatrist contemplated ITP and she was treated with prednisone. As the levels of her thrombocytes repeatedly fluctuated, the possibility of splenectomy was considered.

The patient was admitted to the internal medicine department with 30,000 thrombocytes. The referring physician thought that her thrombocytopenia might be due to the anti-psychotic medication she was taking (olanzapine + clonazepam). During her hospitalization, levels of anti-nuclear factor (ANF), LAC, and aCL were taken. The results came back positive: ANF was 1/40 in a fine speckled pattern, LAC level was 2.4 (normal range, 0–1.25), aCL IgG level was 60 IU/ml (normal range, 0–10 IU/ml), and aCL IgM level was 30 IU/ml (normal range, 0–7 IU/ml). Homocysteine levels were normal, and all other coagulation factors were within normal limits. As there were no clinical signs or symptoms of systemic lupus erythematosus, the patient was diagnosed with APS and started on hydroxychloroquine at 200 mg twice daily.

Since then, the patient was hospitalized several more times due to exacerbation of her psychotic symptoms. There were not, to date, other admissions due to manifestations of APS.

Case 3

The third patent was a 50-year-old woman, married with two children. This patient was diagnosed with major depressive disorder with psychotic features at the age of 18, after suffering the loss of her baby. Subsequently, she was diagnosed as having schizoaffective disorder with depression. She was also diagnosed with SLE at the age of 20. The disease manifested itself with polyarthritis, fever, mouth ulcers, and lupus nephritis. She also had a history of two spontaneous miscarriages. During 1999, after her third miscarriage, she was diagnosed with APS as she suffered from weakness, anemia, and thrombocytopenia and a coagulation panel was taken. Her IgM aCL was 9.4 (normal range, 0–7 IU/ml) while her lgG levels were within normal limits. LAC was strongly positive. Levels of A β2GPI were 4.9 (normal range, 0–5 IU/ml). She was started on hydroxychloroquine. On July 2000, during the resection of a myoma, she was diagnosed with poorly differentiated ovarian cancer. She underwent a hysterectomy and oophorectomy. She was initially treated with taxol and carboplatinum. The reaction to the treatment was good, and the biochemical markers decreased. However, 3–4 months later, they started to rise. Treatment was changed to melphalan—to no avail. An abdominal CT in January 2002 demonstrated enlarged lymph nodes in the retroperitoneum and pelvis along the large blood vessels. In the pelvis, the CT showed a space occupying a lesion with soft tissue density, 15 cm in diameter, which inflicted pressure on the urinary bladder. Her deterioration was swift, and on March 2002, she died.

Case 4

The fourth patient was a 57-year-old woman born in Turkey. She was diagnosed with schizophrenia, paranoid type, at the age of 25. She was hospitalized once and has been in the care of psychiatric authorities as an outpatient for most of her life. Her permanent psychiatric treatment was haloperidol.

Her first admission to Sheba Medical Center was due to PE in 1998. She was initially started on heparin and later on warfarin. Coagulation factors were taken. These showed her to be ANF positive and aCL positive of the IgM type. Anti-ds-DNA was 14%. There was a later admission due to SLE exacerbation. The patient’s lupus was manifested with arthritis, nephritis, interstitial lung disease, hemolytic anemia, and thrombocytopenia. The patient’s compliance to warfarin or heparin treatment was low. She was later admitted with massive PE and subsequently died.

Case 5

The fifth patient is a 41-year-old woman with a history of smoking and drug use. She was diagnosed with schizophrenia, paranoid type, when she was 27 and was treated with various neuroleptic drugs including clozapine, clonazepam, penfluridol, zuclopenthixol, promethazine, biperiden, and fluphenazine.

At the age of 34, she was first diagnosed with DVT in the right leg and PE. During the hospitalization, her laboratory results included ferritin at 334, ANF titer at 1/40, and aCL IgM at 15 (normal range, 0–7 IU/ml), IgG at 7 (normal range, 0–10 IU/ml), and she began warfarin treatment.

Three years later, she suffered from another event of DVT, this time in the left leg. She also had a deep ulcer in the left lateral malleolus.

In the subsequent 3 years, she had multiple events of DVT/PE including axillary, jugular, and iliac veins. She also continued suffering from ulcers in her feet with vasculitis and necrosis consistent with APS. Additionally, she had thrombocytopenia and anemia with positive Coombs test (IgG C3d) and low ferritin. She also had anti-endomysial antibodies but refused to undergo endoscopy or commit to a gluten-free diet.

Her serologic studies include positive SS-A, anti-double-stranded DNA (dsDNA) which became positive a year ago, weak positive A β2GPI IgG antibody (20–30 IU/ml; normal range, 0–5 IU/ml), aCL in the range of 20–50 IU/ml, and strong positive LAC.

Discussion

Schizophrenia patients or their relatives have been reported to have either higher or lower than expected prevalence of some autoimmune disorders, including rheumatoid arthritis [30], type 1 diabetes [31], thyroid disorders [32], and celiac disease [33]. In a big Danish survey of 29 autoimmune diseases (APS was not included) in patients with schizophrenia, 5 autoimmune disorders appeared more frequently in patients with schizophrenia prior to schizophrenia onset as well as in the patients’ parents: thyrotoxicosis, intestinal malabsorption, acquired hemolytic anemia, interstitial cystitis, and Sjögren’s syndrome [7]. In a similar study, based on Taiwan’s National Health Insurance Research Database, it was found that patients with schizophrenia were more likely to have Graves’ disease, psoriasis, pernicious anemia, celiac disease, and hypersensitivity vasculitis and less likely to have rheumatoid arthritis [34]. On the other hand, several autoimmune diseases, individually and in aggregate, have been identified as raising the risk for psychotic disorders. Possible explanations may be inflammation or brain-reacting autoantibodies associated with the autoimmune diseases [35].

The association between aPLa and schizophrenia was published in some case series, but this is the first case series study to check the existence of schizophrenia in patients with definite APS (primary or secondary). In our center, we found 5 patients with schizophrenia out of 150 patients with APS.

Several studies describe the association between schizophrenia or psychosis and aPLa or APS.

Initially, it was believed that the presence of aPLa in schizophrenic patients was the consequence of neuroleptic treatment and had no clinical relevance.

In 1988, Canoso et al. measured LAC and aCL antibodies in 96 chlorpromazine-treated schizophrenic patients. Fifty-four of them (56%) had IgM LAC. Thirty-one of those patients and five of LAC-negative patients had IgM aCL antibodies (37.5%). Twenty-six percent of the patients with both antibodies had high titers of IgM aCL antibodies. Three of the patients had single episodes of DVT or PE (one with LAC and no aCL antibodies and two with IgM aCL antibodies and no LAC). No correlation was found between presence of aPLa and thrombotic events [21].

In 1994, Metzer et al. studied the cases of 27 patients receiving long-term neuroleptic therapy. Although 26% of the patients showed lgG aCL antibodies, and 19% showed IgM aCL antibodies, none exhibited any manifestations of cerebrovascular disease since the initiation of treatment. No association was found between the elevated antibody levels while on anti-psychotic medication and thrombotic events as seen in APS [36].

Observational studies and case series indicate that the neuroleptic treatment itself is associated with an increased risk of thromboembolism. This risk is larger with low potency first-generation anti-psychotics but exists with the use of second-generation drugs as well; it correlates with the dose and is highest in the first 3 months of treatment. Several hypotheses have been proposed to explain this correlation; they include the increased levels of aPLa as well as sedation, body weight gain, enhanced platelet aggregation, hyperprolactinemia, hyperhomocysteinemia, and predisposing factors related to the mental illness [37, 38]. Ducloux et al. described a 25-year-old woman that had received chloropromazine for 3 years when she was admitted to the hospital with IVC thrombosis and PE. Subsequent tests revealed increased aCL antibodies which decreased to the normal range following the replacement of the treatment [39]. However, similar reports are rare in the literature.

This information advocates that schizophrenic patients under neuroleptic medication rarely develop APS although they may have positive aPLa tests.

Our interest lies particularly in those patients who have documented APS—with the accompanied manifestations, along with schizophrenia.

Many researchers pondered on the connection between schizophrenia and an immunological-based hypothesis for its development. Henneberg et al. found anti-brain antibodies in the sera of schizophrenic patients—but not in normal controls. He tested the sera of 50 patients suffering from an acute episode of schizophrenia and found that 70% of patients showed antibody binding to brain antigens. The binding was mediated by both lgG and IgM antibodies. The targets in the brain were mostly the amygdala, the frontal cortex, cingulated gyrus, and septal area [40]. A subsequent study, conducted by Margari et al., showed a significant association between schizophrenia and anti-brain autoantibodies against the neuroendothelium of blood vessels in the hypothalamus, hippocampus, and cerebellum [41].

Levy-Soussan et al. looked for the differences in the natural autoantibody patterns of patients with schizophrenia as opposed to normal individuals. They noticed that the isolated IgG fractions of schizophrenics had higher anti-DNA and anti-serotonin reactivities than those detected in the controls [42].

In 1994, Firer measured the incidence of aCL antibodies in patients with schizophrenia and their non-affected family members against a control group. This was done in order to shed light on the role of drug therapy versus family association on the prevalence of these antibodies in schizophrenia [24]. Firer examined the blood of 28 families: 103 schizophrenics and 65 first degree healthy relatives. The 103 patients were drug free for at least 3 months prior to entering the study. However, none of the people examined in this study had any symptoms consistent with APS. The blood that was taken was examined for aCL antibodies. The results showed that in the schizophrenic group, aCL antibodies of the IgG class were significantly more frequent than in the control group but not more common than in the healthy relatives that also showed high levels of those antibodies. IgM aCL antibodies were elevated significantly more in the schizophrenic group than in the other groups. Firer deduced that lgG aCL antibodies reflect an elevated specific immune response in some families of schizophrenics while IgM aCL antibodies are more closely related to actual disease development. Although none of the family members who were antibody positive exhibited any disease symptoms, either those of schizophrenia or APS, the duration of their follow-up was not long enough to merit any conclusions. Firer did postulate that the aCL antibodies could serve as an early marker for schizophrenia development.

In 1998, Schwartz et al. wanted to see whether there was a link between aCL antibodies and psychosis. They conducted their research on 34 unmedicated patients who were all suffering from an acute episode of psychosis. None suffered from APS or SLE. What they saw at the end of the follow-up period caught them by surprise, as they detected a high percentage of aPLa in the unmedicated patients. Twenty-four percent of the patients exhibited lgG aCL, and 9% exhibited LAC. The titers of IgM aCL were within normal limits. All in all, 32% of the unmedicated patients with a first-time psychotic episode had aPLa. Although none of the patients developed thrombotic events, Schwartz et al. could not exclude the possibility of their development—because no brain images of any kind were conducted as part of the study. Thus, there was no information regarding the microcirculation. Schwartz et al. postulate from their findings that aPLa might have a role in the development of the psychotic episode that is unrelated to the neuroleptic treatment [23].

These findings are similar to those found by Chengappa et al. already in 1991. He reported the presence of both lgG and IgM aCL antibodies in 16.7% of schizophrenic patients in their first episode of psychosis. As in previous studies, Chengappa found that the IgM aCL antibodies were more closely related to neuroleptic treatment while the lgG isotype was not [43].

Research regarding the association between schizophrenia and thromboembolism may shed light on a possible “missing link” between APS and schizophrenia. Hoirisch-Clapauch et al. presented a series of five psychotic patients with thrombotic episodes on chronic warfarin therapy that attained remission of psychotic symptoms and were free of psychotropic medications. All of the patients had at least one thrombophilia related to the inhibition of tissue plasminogen activators (tPA). Three of them had aPLa. Plasminogen activators participate both in blood clot dissolution and in tissue repair such as: remodeling of hippocampus after various insults, tolerance against excitotoxicity, synaptic remodeling, neuronal plasticity, and cognitive and emotional processing. Abnormalities in these processes have been implicated in schizophrenia genesis [44, 45]. The researchers continued and screened the serum of a group of schizophrenia patients and controls for the presence of conditions affecting tPA activity. They found an association between schizophrenia (especially acute episode) and several conditions affecting tPA including the following: hyperinsulinemia, hypertriglyceridemia, hyperhomocysteinemia, free-protein S deficiency, and aPLa that were detected in 30% of the patients and none of the controls [45]. Active or chronic schizophrenia was associated with more coexisting conditions affecting tPA activity than schizophrenia in remission. This observation led to the postulation that multiple conditions affecting tPA activity could contribute to the full expression of schizophrenia phenotype [46].

Several case reports were published in recent years presenting patients with both schizophrenia or psychotic symptoms and serologic and clinical manifestations of APS (Table 2).

Table 2 Characteristics of patients with APS and schizophrenia in case reports in the literature
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Kurtz and Müller described a 50-year-old woman diagnosed with schizophrenia, paranoid type, at the age of 29. Later she presented with amaurosis fugax and elevated erythrocyte sedmentation rate (ESR), and 10 years afterwards, she suffered from polyneuropathy, arthralgia, and myalgia. After one more year, seizures, livedo reticularis, and skin ulcer appeared. In her blood tests, she had ANF titer of 1:10.24, IgG aCL antibodies were 33 U/ml (normal <10) and IgM aCL antibodies were 17 U/ml (normal <6). Cranial CT showed infarction and areas of calcification. Immunosuppressive treatment led to improvement over several weeks [27].

Cardinal et al. reported a 28-year-old woman who presented with rapid onset of psychosis that responded to neuroleptic and anxiolytic treatment. A year later, she returned with catatonic psychosis that responded to haloperidol. In the same year, she suffered from a spontaneous popliteal vein thrombosis and a mild purpuric rash. She had elevated ESR and C-reactive protein (CRP) and positive aCL antibodies. Later, ANF became weakly positive. LAC and A β2GPI were normal as well as a head magnetic resonance imaging (MRI). Anti-coagulation and immunosuppression led to symptomatic resolution [28].

Fernández et al. presented a 49-year-old woman who was admitted with delusions, anxiety, and low mood which responded to atypical neuroleptics. Two years before that event, the women were admitted because of pneumonia with a subsequent pericardial effusion and a DVT in her left leg. Routine tests showed recurrent lymphopenia, ANF at 1:1280, and anti-dsDNA antibodies at 1:160. The brain MRI showed multiple hyperintensities, suggesting ischemic or vasculitic lesions. Two subsequent tests for aCL antibodies were positive. A diagnosis of SLE and secondary APS was made and anti-coagulation along with immunosuppressive therapy begun with favorable clinical and MRI response [29].

del Rio-Casanova et al. described a 23-year-old woman with a family history of mental illness admitted to the psychiatric ward twice with symptoms including delusions, psychosis, and uncoordinated movements that were attributed to a conversion disorder. She was initially treated with risperidal and later on with other neuroleptics. During the treatment, she developed movement disorders including chorea, hemiballismus, and dysarthria. The disorders were initially believed to be neuroleptic related, but they passed without a change in the treatment. Subsequently, MRI showed hypointense areas in the brain and the blood tests were positive for LAC and aCL IgM and IgG antibodies. With clopidogrel and chloroquine treatment, she had a remission without neuroleptics [47].

Braz Ade et al. presented a 37-year-old female with a diagnosis of schizophrenia 13 years prior to the current admission. She was hospitalized with arthralgia which progressed to arthritis and skin lesions that were macular in the beginning but quickly developed into ulcerations and extensive necrosis. On physical examination a malar rash was discovered. Blood tests revealed hemolytic anemia, leukopenia, and elevated ESR. Urinalysis showed microhematuria and proteinuria. Additional blood work showed decreased C3, positive anti-ds-DNA antibodies, and positive LAC and aPLa. The patient was diagnosed with SLE and secondary APS. She was treated with immunosuppression, anti-coagulation, and anti-psychotics with some improvement [48].

Lai et al. reported a 23-year-old female hospitalized twice with delusions and low-grade fever without other signs of infection. A review of her medical file revealed a 2-year history of palpitation, headache, dizziness, acute urticaria, and angioedema. She was then referred to a rheumatologist. All the immunological studies were normal except for mildly elevated IgG aCL antibodies, low protein S, and elevated D-dimer, suggesting occult thrombosis. Brain scan implied that vasculopathy or thrombosis occurred. APS was suspected and treatment with prednisone, aspirin, and hydroxychloroquine resulted in remission without the need for neuroleptics [49].

Three of the patients described in Hoirisch-Clapauch et al. series were diagnosed with schizophrenia and APS [44]. The first is a 50-year-old female with a history of recurrent miscarriages and popliteal vein thrombosis that was admitted due to delusions and paranoid hallucinations. She was diagnosed with APS due to high IgM aCL antibodies in recurrent tests. The second is a 38-year-old woman diagnosed with bipolar disorder with delusions 3 years after developing DVT during pregnancy. Five years after that, she was diagnosed with APS due to positive LAC that was discovered during preoperative examination. The third patient is a 29-year-old woman that was diagnosed with puerperal psychosis with catatonic symptoms. A year afterwards, she developed ileofemoral vein thrombosis and was diagnosed with APS due to persistent positive LAC.

Manna et al. described a 62-year-old woman admitted to the hospital with loss of memory, hallucinations, and delusions that were treated with risperdal with improvement. Her medical history revealed recurrent transient ischemic attacks (TIA) and brain imaging implied the presence of ischemia. ESR was elevated and LAC was positive, IgG aCL antibodies were elevated (45 IU/ml), A β2GPI antibodies were high, and anti-DNA and perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) were positive. The patient was diagnosed with APS and treated with anti-coagulation and hydroxychloroquine with improvement [50].

Taipa et al. presented a 68-year-old patient with a history of a miscarriage, recurrent erythema nodosum, acute myocardial infarction (AMI), and positive aCL and A β2GPI antibodies for the past 7 years. She was admitted due to mood and behavioral changes in the previous 3 months with hallucinations and delirium that culminated with seizures on the day before the admission. Her work up revealed normal CSF and serology, ischemic areas in the brain consistent with small vessel disease, and epileptic activity in the EEG. Immunologic tests showed positive rheumatic factor, ANF (1:160 titer), and antibodies to prothrombin and phosphatidylserine; aPLa and other autoantibodies were negative. She was diagnosed with primary APS and treated with anti-coagulants, anti-convulsive medications, and anti-psychotics with improvement. During follow-up, aCL antibodies were positive (21.6 MPL/mL) [51].

Several pediatric case reports regarding APS and schizophrenia were also described.

Shabana et al. presented a 9-year-old girl with recurrent attacks of delirium and drooling, depressive illness, hallucinations, abnormal behavior, drowsiness, confusion, and increased hours of sleep. Six months prior to her hospitalization, she had three generalized seizures and since then was suffering from recurrent diffuse abdominal pain. After her admission, she developed vasculitic lesions on her left foot. Her neurological exam, family history, and neuroimaging were normal. Her ESR was elevated, ANF was weakly positive, LAC was positive, A β2GPI was high, and IgG aCL antibodies were high. Following these findings, she was treated as APS patient with aspirin and hydroxychloroquine. Later, after stopping the aspirin treatment she developed DVT in the right axillary vein [52].

Sokol et al. described a 12-year-old boy with mental retardation and Asperger’s disorder after premature birth and intraventricular hemorrhage. He presented with acute psychosis. Brain imaging showed gliosis consistent with intraventricular hemorrhage. CSF was normal apart from a significant increase in IgG aCL antibodies despite normal levels in the blood tests [53]. This finding, along with Sokol’s finding that aPLa in the serum and CSF of the same patient had different specificities [20], suggests an autonomic CNS production of these antibodies.

Though our review of the literature awarded us with some input as to the current information at hand on the subject, we found no certain direct links between APS and the development of schizophrenia. Due to compounding evidence, we believe that more research, with a larger pool of patients, should be done on the subject. Much more light must be shed on this issue so that we could see whether a true link exists between APS and schizophrenia.