A Case of Mistaken Identity: Antiphospholipid Syndrome with Predominant Neuropsychiatric Features

Despite the known association between autoimmune and psychiatric conditions, pertinent evaluations are often overlooked in clinical practice. The author of this report describes the successful identi ﬁ cation and treatment of a patient whose myriad neuropsychiatric symptoms were ultimately attributable to antiphospholipid syndrome. The importance of comprehensive and persistent workups is emphasized, particularly in the context of individuals with pre-existing in ﬂ ammatory diseases and/or cerebrovascular anomalies.


Introduction
The Antiphospholipid Syndrome (APS) is an autoimmune, multi-systemic condition fi rst described by Hughes et al in 1983 [1]. Classically, the diagnosis has required a history of recurrent gestational losses, venous and/or arterial thromboses, and low platelets, combined with the detection of anti-phospholipid antibodies [namely, anti-cardiolipin, lupus anticoagulant, anti-B2 glycoprotein] on 2 or more occasions, at least 12 weeks apart. Although APS can exist as a stand-alone disease, it is not uncommonly detected in conjunction with other medical conditions, such as systemic lupus erythematosus, temporal arteritis, and Raynaud's phenomenon. It has also been associated with infections (including COVID19), medications (i.e., chlorpromazine), and malignancies [2][3][4][5].
The involvement of the Central Nervous System in APS has been a common fi nding. Seizures, headaches, episodes of Transient Global Amnesia (TGA), TIAs, and/or strokes have been attributed to the prothrombotic effects of antiphospholipid antibodies via their interactions with endothelial cells.
Additional lines of research have implicated antibody-mediated disruption of brain function via direct binding to neurons and glia, alterations in the permeability of the blood-brain barrier, and/or activation of infl ammatory cytokines [3,6].
Non-vascular (non thrombotic) manifestations of APS have increasingly been documented in case reports and observational studies. Here, researchers have found associations between elevated titers of antiphospholipid antibodies and the emergence of dementia, cognitive dysfunction (i.e., poor concentration), mania, depression, movement disorders (chorea, parkinsonism), and psychosis.
Treatments include anti-thrombolytics for patients with histories of arterial and/or venous thrombosis, or immunomodulating medications (such as steroids or antimalarials) for non-vascular presentations. In some cases, the neuropsychiatric features of APS have been found to improve with the early use of these non-psychopharmacologic therapies.

Case presentation
Ms. X was a 66 year old female whose medical history included hypertension, hyperlipidemia, herpes zoster, joint pain, Giant cell arteritis, Raynaud's phenomenon, and myositis (statin induced). Psychiatric history was notable for ten years of exposure to an antidepressant medication (paroxetine) for symptoms of depression. The patient was a former smoker of cigarettes, abstinent for more than 20 years. Alcohol use consisted of two glasses of wine with evening meals. Home-grown cannabis (edibles) had been consumed intermittently over the preceding year as a treatment for joint or muscle pain. A past sensitivity to prednisone --involving changes in concentration and memory --had been identifi ed during an episode of temporal arteritis. Ms. X was transferred to the hospital's behavioral health unit for further treatment of confusion and disorganization.  Figure 2]. During this second admission, the author directly managed treatments and oversaw an extensive medical workup. MRI of the brain revealed small vessel ischemic changes bilaterally in the frontal and parietal white matter. An MRA of the cerebral vasculature was notable for left vertebral artery atresia. Autoimmune workup revealed +anti ds DNA Ab (61.1), + lupus AC, + ACL antibodies (IgM 33.7), positive P-ANCA and MPO antibodies, and low C4 (6 mg/dL). An autoimmune encephalopathy panel was negative, apart from GAD65 Ab (2.47). Anti TPO and anti-thyroglobulin antibodies were negative. Cancer markers (CA 19-9, CA 125, and AFP) paraneoplastic antibodies (anti-Yo, anti-Ri, anti-Hu), FTA-Ab, SSA/SSB Ab, RA factor, C-ANCA, ribosomal P Ab, ANA, and CRP were negative. B12 and cortisol levels were within normal limits. Consultations from hospital specialists in neurology and rheumatology were diagnostically inconclusive.  [7][8][9]. While she had a history of sensitivity to prednisone, exogenous steroids had never before impaired daily functioning. Furthermore, the time course and persistence of symptoms suggested another cause.
The appearance of facial lesions, accompanied by burning and itching in a dermatomal pattern, were consistent with an outbreak of varicella zoster provoked by steroid immunosuppression. The negative IgM antibody result was likely a "false" negative [10]. Importantly, VZV encephalitis was ruled out by a negative spinal fl uid exam.
The patient's pattern of alcohol consumption (two glasses of wine nightly) and intermittent cannabis may have contributed to initial mood and/or cognitive changes. However, following the onset of catatonia in the critical summer of the eye surgery, Ms. X adopted complete abstinence from both substances. Even in the aftermath of these behavioral adjustments, her neuropsychiatric diffi culties continued.
Serial radiographic studies were obtained. The fi rst MRI of the brain (August 2014) was interpreted as showing non-acute, "likely embolic" foci in the parieto-occipital and cerebellar cortices. These were not visualized on repeat scans. It is possible that these initial abnormalities, in addition to the fi ndings of small vessel ischemia, were refl ective of CNS vasculitis associated with APS rather than strokes [11]. MRA fi ndings of anomalies in the cerebral vasculature (left vertebral artery atresia in the fi rst exam; absence of the anterior and posterior communicating arteries in the second) were dismissed by neurology consultants as non-contributory.
Despite the consistent detection of elevated anti ds DNA antibody levels and several occasions of low complement (C4), ANA titers were variable. That fi nding, combined with a lack of qualifying medical problems (no history of anemia, malar or discoid rash, renal disorder, oral ulcers, photosensitivity, or serositis) precluded the diagnosis of systemic lupus erythematosus [12]. Other autoimmune tests, repeated at intervals, were positive for lupus AC, anti-cardiolipin, and beta 2 glycoprotein antibodies. Consequently, the applicable diagnosis was antiphospholipid syndrome.
Due to the fact that Ms. X lacked a medical history of pregnancy morbidity, arterial or venous thrombosis, thrombocytopenia, migraine headaches, or seizures, her presentation of antiphospholipid syndrome was purely psychiatric at its onset. Perhaps because of this factor, multiple clinicians in various settings, including inpatient hospitalists, failed to consider an autoimmune etiology of symptoms.

Clinical implications
The resolution of Ms. X's catatonia, manic features, and cognitive defi cits depended upon the careful identifi cation of antiphospholipid syndrome, and a synergistic treatment plan consisting of both rheumatologic medication

Discussion
The present case involved a perplexing set of neuropsychiatric features in a 66 year old female. Between (hydroxychloroquine) and psychotropic drugs (valproic acid, clonazepam, doxepin). Had the diagnosis of a primary psychiatric condition --such as schizophrenia or bipolar disorder --been casually accepted, the relevant treatment of the underlying autoimmune disease would have been overlooked. In that scenario, and just as problematically, an aggressive titration of antipsychotic, antiepileptic, or antidepressant medications could have contributed to cerebrovascular or thrombotic events in a patient already at high risk for the same [13][14][15][16][17][18][19][20][21][22][23].
In summary, it is important for clinicians to consider autoimmune pathologies in psychiatric presentations. This

Informed consent
Written informed consent was obtained from the patient for anonymized information to be published in this article.