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      Remission of subacute psychosis in a COVID-19 patient with an anti-neuronal autoantibody after treatment with intravenous immunoglobulin

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          Abstract

          To the Editor: COVID-19 patients are at increased risk for developing new or recurrent psychosis.(1) Viral infections—including SARS-CoV-2 (2, 3, 4)—can cause psychosis in the context of autoimmune encephalitis.(5) However, some individuals with para-infectious psychosis do not meet criteria for autoimmune encephalitis, yet respond to immunotherapy.(6, 7) We present a case of COVID-19-associated subacute psychosis that did not meet criteria for autoimmune encephalitis, yet remitted after treatment with intravenous immunoglobulin (IVIg). We subsequently identified a novel IgG class anti-neuronal autoantibody in the patient’s cerebrospinal fluid (CSF). Case: A 30-year-old man without medical, psychiatric, or substance use history developed fever and malaise. The following day, he developed a delusion that the “rapture” was imminent. On day 2, a nasopharyngeal swab was positive for SARS-CoV-2 by RT-PCR. He began a 14-day isolation but maintained daily contact with family. He did not have anosmia, ageusia, or respiratory symptoms, nor did he receive treatment for COVID-19. He initially suffered from hypersomnia and slept 22 hours per day. He then developed insomnia, sleeping only 3-4 hours per day. During this time, he began pacing and rambling about “lights.” He worried that he was dying and said that he had been speaking to deceased relatives and God. On day 22, he kicked through a door and pushed his mother, prompting an emergency department (ED) evaluation. In the ED, he endorsed speaking with the dead, falsely claimed to be a veteran, and worried about being experimented on with “radiation.” He did not have suicidal ideation, homicidal ideation, or hallucinations. Non-contrast head computed tomography was normal, and urine toxicology was negative. He was started on haloperidol 5 mg by mouth twice daily with significant improvement of his agitation and delusions. After 48 hours he was discharged to outpatient follow-up. Outpatient magnetic resonance imaging (MRI) of the brain with and without gadolinium was unremarkable. After discharge, his restlessness, insomnia, and cognitive slowing recurred, as did his fears that he would be experimented on “like a guinea pig.” On day 34, he punched through a wall and was hospitalized to be evaluated for autoimmune encephalitis. A detailed neurological exam was unremarkable. He had a flat affect, slowed speech, and akathisia, which resolved after decreasing haloperidol and starting benztropine and lorazepam. A 12-hour video electroencephalogram was normal. Blood studies were notable for an elevated ferritin and D-dimer, suggesting systemic inflammation (Table 1 ). CSF studies, including a clinical autoimmune encephalitis autoantibody panel, were only notable for an elevated IgG of 4.8 mg/dL (ref. 1.0—3.0 mg/dL) with a normal IgG index (see Table 1). Table 1 Clinical Studies. Source Test Result (reference) Nasopharyngeal Swab SARS-CoV-2 RNA PCR Day 2: PositiveDay 34: Negative Urine 9 drug toxicology screen Negative Serum Basic Metabolic Panel Within acceptable limits:Na 146 mmol/L (136-144 mmol/L)K 3.1 mmol/L (3.3-5.1 mmol/L) Prothrombin time 11.5 seconds (9.6-12.3 seconds) International normalized ratio (INR) 1.07 Complete blood count Day 24 WBC: 6.9 (4.0 – 10.0 x 1,000/μL)Day 34 WBC: 5.4 (4.0 – 10.0 x 1,000/μL)MPV 11.6 fL (6.0-11.0 fL) Thyroid Stimulating Hormone 2.520 uIU/mL (0.270-4.200 uIU/mL) D-dimer 1.89 mg/L (<= 0.50 mg/L) Liver enzymes AST 156 U/L (<35 U/L)ALT 372 U/L (<59 U/L) C-reactive protein 1.7 mg/L (<1.0 mg/L) Ferritin 1124 ng/mL (30-400 mg/mL) Ammonia 27 umol/L (11-35 umol/L) Albumin 4.2 g/dL (3.6-4.9 g/dL) IgG 1230 mg/dL (700-1600 mg/dL) CSF Cell Count 0 nucleated cells Protein 41.2 mg/dL (15-45 mg/dL) Glucose 60 mg/dL (40-70 mg/dL) Culture No growth Oligoclonal banding None Albumin 25.8 mg/dL (10-30 mg/dL) IgG 4.8 mg/dL (1.0-3.0 mg/dL) IgG Index 0.67 (<0.7) Autoimmune encephalopathy panel Negative for AMPA Ab, amphiphysin Ab, anti-glial nuclear Ab, neuronal nuclear Ab (types 1, 2, and 3), CASPR2, CRMP-5, DPPX, GABA-B receptor, GAD65, GFAP, IgLON5, LGI1-IgG, MGLUR1, NIF, NMDA receptor, Purkinje Cell Cytoplasmic Ab (types Tr, 1, and 2) Imaging CT Head without contrast No acute intracranial findings. MRI Brain with contrast No acute intracranial abnormality or definitive structural abnormality identified. Specifically, no imaging findings suggestive of encephalitis or acute demyelination. Electroencephalography Normal prolonged (>12h) awake and asleep inpatient video EEG Lacking focal neurologic symptoms, seizures, MRI abnormalities, or CSF pleocytosis, his presentation did not meet consensus criteria for autoimmune encephalitis.(7) Nevertheless, his subacute psychosis, cognitive slowing, and recent SARS-CoV-2 infection raised concern for autoimmune-mediated psychosis. Therefore, starting on day 35, he received a total of 2 grams/kilogram of IVIg over 3 days. His cognitive slowing and psychotic symptoms remitted after the first day of treatment. His sleep cycle normalized, and he was discharged without scheduled antipsychotics. He returned to work immediately after discharge and remained symptom-free three months later. Because his robust response to IVIg indicated an underlying autoimmune process, we tested his CSF for anti-neural autoantibodies using anatomic mouse brain tissue staining (8); a validated and standard method performed by incubating rodent brain sections with CSF and counterstaining with a human IgG-specific antibody. At a 1:4 dilution, his CSF produced a novel immunostaining pattern that we have not observed in over 500 screens of CSF from other patients with neuroinflammatory disorders. His IgG prominently immunostained Satb2-expressing upper layer (layer II/III) pyramidal neurons in the anteromedial cortex (Figure 1a ), a population of excitatory callosal projection neurons necessary for the integration of intercortical information.(9) We also observed relatively uniform puncta in the corpus callosum (Figure 1b), consistent with immunostaining of callosal projections. In the olfactory bulb, mitral cell bodies and the external plexiform neuropil were immunostained (figure 1c). In the dentate gyrus, linearly organized puncta resembling axonal transport vesicles and oblong neurons were apparent in the hilus (Figure 1d). In the thalamus, linear and less organized punctate staining was observed (Figure 1e). In the cerebellum, Purkinje cell bodies were modestly stained, while the overlying molecular layer was densely stained with variably size puncta (Figure 1f). Figure 1 Characterization of anti-neuronal antibody staining. Mice were perfused with 4% paraformaldehyde. 12μm frozen sagittal brain sections were immunostained with cerebrospinal fluid (CSF) at a 1:4 dilution and counterstained with an anti-human IgG secondary antibody (green) (Jackson #709-545-149 at 2μg/mL). Nuclei were labeled with DAPI (blue). In all panels, scale bars are 10μm. A. Cortical immunostaining of pyramidal neuron cell bodies and proximal processes in layer II of the anteromedial cortex. Staining of neuropil was also observed. Inset – CSF immunostains Satb2-expressing (red) neurons (filled arrowheads) but not surrounding Satb2-negative cells (unfilled arrowhead) (Abcam #ab51502 at 1μg/mL); B. Relatively uniform punctate staining along the ventricular wall (filled arrowheads) and overlying corpus callosum; C. Olfactory bulb immunostaining of mitral cell bodies (filled arrowheads) and neuropil of the external plexiform layer (ep). gc = granule cell layer, ip = internal plexiform layer, mc = mitral cell layer; D. Hippocampal immunostaining of an axon-like process in the hilus of the dentate gyrus (filled arrowheads) and a subset of hilar cell bodies (unfilled arrowheads). gc = granule cell layer, h = hilus. v = ventricle; E. Thalamic axon-like (filled arrowhead) and scattered (unfilled arrowhead) punctate immunostaining. bv = blood vessel; F. Immunostaining of cerebellar Purkinje cell bodies (filled arrowheads) and neuropil of the molecular layer (m). gc = granule cell layer, pc = Purkinje cell layer. Discussion: We identified a candidate novel neuronal autoantibody in the CSF of a COVID-19 patient with antipsychotic-refractory subacute psychosis, whose symptoms rapidly and completely remitted after treatment with IVIg. This autoantibody primarily localized to layer II/III callosal cortical neurons, which have been implicated in schizophrenia.(10) Although anti-neural autoantibodies are present in some neurologically impaired COVID-19 patients(11-13), autoantibody studies are rarely performed in cases of COVID-19-associated psychosis.(14, 15, 16, 17, 18, 19, 20, 21, 22) Importantly, early initiation of immunotherapy for autoimmune disorders of the central nervous system significantly improves outcomes. (23) Although autoimmune encephalitis can be established on clinical grounds, the diagnosis requires neurologic, MRI, and/or CSF abnormalities.(7) To identify individuals with potentially immune-responsive acute psychosis without neurological impairment, Pollak et. al. proposed criteria for autoimmune psychosis. (24) While “possible” autoimmune psychosis relies solely on clinical factors, “probable” and “definite” require abnormal imaging or laboratory studies. Our patient’s subacute psychosis and cognitive dysfunction qualified him for possible autoimmune psychosis. However, he had several “red flags” for autoimmune psychosis: infectious prodrome, rapid progression, and insufficient response to antipsychotics.(24) Moreover, his mood dysregulation, cognitive slowing, and hypersomnia were evocative of the mixed symptomatology more typical of autoimmune encephalitis.(25, 26) Given his overall clinical picture, we administered IVIg with apparent clinical response. Although our patient might have later developed autoimmune encephalitis, consideration of autoimmune psychosis can prompt earlier immunotherapy and potentially improve outcomes. Only by relying on ancillary criteria were we able to justify immunotherapy for our patient, suggesting that re-evaluating the criteria for autoimmune psychosis may improve its sensitivity.(27) Even so, this case should be interpreted with caution. Psychotic disorders are protean by nature, mixed symptomatology does occur, and most psychotic presentations are unlikely to be immune-mediated. However, given the scale of the COVID-19 pandemic, psychiatric practitioners should consider autoimmune psychosis in patients with COVID-19-associated psychosis. Uncited reference 11., 12., 13..

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          Most cited references28

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          A clinical approach to diagnosis of autoimmune encephalitis.

          Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.
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            Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA

            Background Adverse mental health consequences of COVID-19, including anxiety and depression, have been widely predicted but not yet accurately measured. There are a range of physical health risk factors for COVID-19, but it is not known if there are also psychiatric risk factors. In this electronic health record network cohort study using data from 69 million individuals, 62 354 of whom had a diagnosis of COVID-19, we assessed whether a diagnosis of COVID-19 (compared with other health events) was associated with increased rates of subsequent psychiatric diagnoses, and whether patients with a history of psychiatric illness are at a higher risk of being diagnosed with COVID-19. Methods We used the TriNetX Analytics Network, a global federated network that captures anonymised data from electronic health records in 54 health-care organisations in the USA, totalling 69·8 million patients. TriNetX included 62 354 patients diagnosed with COVID-19 between Jan 20, and Aug 1, 2020. We created cohorts of patients who had been diagnosed with COVID-19 or a range of other health events. We used propensity score matching to control for confounding by risk factors for COVID-19 and for severity of illness. We measured the incidence of and hazard ratios (HRs) for psychiatric disorders, dementia, and insomnia, during the first 14 to 90 days after a diagnosis of COVID-19. Findings In patients with no previous psychiatric history, a diagnosis of COVID-19 was associated with increased incidence of a first psychiatric diagnosis in the following 14 to 90 days compared with six other health events (HR 2·1, 95% CI 1·8–2·5 vs influenza; 1·7, 1·5–1·9 vs other respiratory tract infections; 1·6, 1·4–1·9 vs skin infection; 1·6, 1·3–1·9 vs cholelithiasis; 2·2, 1·9–2·6 vs urolithiasis, and 2·1, 1·9–2·5 vs fracture of a large bone; all p<0·0001). The HR was greatest for anxiety disorders, insomnia, and dementia. We observed similar findings, although with smaller HRs, when relapses and new diagnoses were measured. The incidence of any psychiatric diagnosis in the 14 to 90 days after COVID-19 diagnosis was 18·1% (95% CI 17·6–18·6), including 5·8% (5·2–6·4) that were a first diagnosis. The incidence of a first diagnosis of dementia in the 14 to 90 days after COVID-19 diagnosis was 1·6% (95% CI 1·2–2·1) in people older than 65 years. A psychiatric diagnosis in the previous year was associated with a higher incidence of COVID-19 diagnosis (relative risk 1·65, 95% CI 1·59–1·71; p<0·0001). This risk was independent of known physical health risk factors for COVID-19, but we cannot exclude possible residual confounding by socioeconomic factors. Interpretation Survivors of COVID-19 appear to be at increased risk of psychiatric sequelae, and a psychiatric diagnosis might be an independent risk factor for COVID-19. Although preliminary, our findings have implications for clinical services, and prospective cohort studies are warranted. Funding National Institute for Health Research.
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              Satb2 regulates callosal projection neuron identity in the developing cerebral cortex.

              Satb2 is a DNA-binding protein that regulates chromatin organization and gene expression. In the developing brain, Satb2 is expressed in cortical neurons that extend axons across the corpus callosum. To assess the role of Satb2 in neurons, we analyzed mice in which the Satb2 locus was disrupted by insertion of a LacZ gene. In mutant mice, beta-galactosidase-labeled axons are absent from the corpus callosum and instead descend along the corticospinal tract. Satb2 mutant neurons acquire expression of Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. Conversely, ectopic expression of Satb2 in neural stem cells markedly decreases Ctip2 expression. Finally, we find that Satb2 binds directly to regulatory regions of Ctip2 and induces changes in chromatin structure. These data suggest that Satb2 functions as a repressor of Ctip2 and regulatory determinant of corticocortical connections in the developing cerebral cortex.
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                Author and article information

                Journal
                Biol Psychiatry
                Biol Psychiatry
                Biological Psychiatry
                Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
                0006-3223
                1873-2402
                12 April 2021
                12 April 2021
                Affiliations
                [1 ]Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
                [2 ]Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
                [3 ]Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
                [4 ]Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA
                [5 ]Department of Neurology, University of California, San Francisco, CA, USA
                [6 ]Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
                [7 ]Hanna H. Gray Fellow, Howard Hughes Medical Institute, Chevy Chase, MD, USA
                Author notes
                [# ]Corresponding Author: Christopher M. Bartley 401 Parnassus Ave Suite LP-263 San Francisco, CA 94143 (415) 353 – 9111 ext. 50766
                [∗]

                Equal contributions

                Article
                S0006-3223(21)01215-4
                10.1016/j.biopsych.2021.03.033
                8041149
                34001372
                4c523b2f-89d8-4c97-a7e6-f3c1f8af441f
                © 2021 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 8 March 2021
                : 26 March 2021
                : 30 March 2021
                Categories
                Correspondence

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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