Anti-SARS-CoV-2 and Autoantibody Profiling of a COVID-19 Patient With Subacute Psychosis Who Remitted After Treatment With Intravenous Immunoglobulin.

Patients with COVID-19 are at increased risk for developing new or recurrent psychosis (1Taquet M. Luciano S. Geddes J.R. Harrison P.J. Bidirectional associations between COVID-19 and psychiatric disorder: Retrospective cohort studies of 62 354 COVID-19 cases in the USA.Lancet Psychiatry. 2021; 8: 130-140Abstract Full Text Full Text PDF PubMed Scopus (700) Google Scholar,2Taquet M. Sillett R. Zhu L. Mendel J. Camplisson I. Dercon Q. Harrison P.J. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: An analysis of 2-year retrospective cohort studies including 1 284 437 patients.Lancet Psychiatry. 2022; 9: 815-827Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Viral infections—including SARS-CoV-2 (3Panariello A. Bassetti R. Radice A. Rossotti R. Puoti M. Corradin M. et al.Anti-NMDA receptor encephalitis in a psychiatric Covid-19 patient: A case report.Brain Behav Immun. 2020; 87: 179-181Crossref PubMed Scopus (90) Google Scholar, 4Monti G. 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First-episode psychotic disorder improving after immunotherapy.Acta Neurol Belg. 2016; 116: 113-114Crossref PubMed Scopus (5) Google Scholar,8Graus F. Titulaer M.J. Balu R. Benseler S. Bien C.G. Cellucci T. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (2055) Google Scholar). We identified anti-SARS-CoV-2 and candidate autoantibodies in the serum and cerebrospinal fluid (CSF) of a case of COVID-19–associated subacute psychosis that did not meet criteria for autoimmune or infectious encephalitis yet remitted after treatment with intravenous immunoglobulin (IVIg). 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 real-time reverse transcription–polymerase chain reaction. 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/day. He then developed insomnia, sleeping only 3 to 4 hours/day. During this time, he paced, rambled, and believed that he was dying and communicating with deceased relatives and God. On day 22, he kicked through a door and pushed his mother, prompting an emergency department evaluation. In the emergency department, he falsely claimed to be a veteran, and worried about being experimented on with radiation. He did not have suicidal ideation, homicidal ideation, or hallucinations. Noncontrast 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 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 and 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. CSF studies, including a clinical autoimmune encephalitis autoantibody panel, were notable only for an elevated IgG of 4.8 mg/dL (reference 1.0–3.0 mg/dL) with a normal IgG index (see Table 1).Table 1Clinical StudiesSourceTestResult (Reference)Nasopharyngeal SwabSARS-CoV-2 RNA PCRDay 2: positiveDay 34: negativeUrine9-drug toxicology screenNegativeSerumBasic metabolic panelWithin acceptable limits:Sodium 146 mmol/L (136–144 mmol/L)Potassium 3.1 mmol/L (3.3–5.1 mmol/L)Prothrombin time11.5 seconds (9.6–12.3 seconds)International normalized ratio1.07Complete blood countDay 24 WBC: 6.9 × 1000/μL (4.0–10.0 × 1000/μL)Day 34 WBC: 5.4 × 1000/μL (4.0–10.0 × 1000/μL)MPV 11.6 fL (6.0–11.0 fL)Thyroid-stimulating hormone2.520 μIU/mL (0.270–4.200 μIU/mL)D-dimer1.89 mg/L (≤0.50 mg/L)Liver enzymesAST 156 U/L (<35 U/L)ALT 372 U/L (<59 U/L)C-reactive protein1.7 mg/L (<1.0 mg/L)Ferritin1124 ng/mL (30–400 mg/mL)Ammonia27 μmol/L (11–35 μmol/L)Albumin4.2 g/dL (3.6–4.9 g/dL)IgG1230 mg/dL (700–1600 mg/dL)CSFCell count0 nucleated cellsProtein41.2 mg/dL (15–45 mg/dL)Glucose60 mg/dL (40–70 mg/dL)CultureNo growthOligoclonal bandingNoneAlbumin25.8 mg/dL (10–30 mg/dL)IgG4.8 mg/dL (1.0–3.0 mg/dL)IgG index0.67 (<0.7)Autoimmune encephalopathy panelNegative 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)ImagingCT head without contrastNo acute intracranial findingsMRI brain with contrastNo acute intracranial abnormality or definitive structural abnormality identified; specifically, no imaging findings suggestive of encephalitis or acute demyelinationElectroencephalographyNormal prolonged (>12 hours) awake and asleep inpatient video EEGAb, antibody; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; MPV, mean platelet volume; MRI, magnetic resonance imaging; PCR, polymerase chain reaction. Open table in a new tab Ab, antibody; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; MPV, mean platelet volume; MRI, magnetic resonance imaging; PCR, polymerase chain reaction. Lacking focal neurologic symptoms, seizures, magnetic resonance imaging abnormalities, or CSF pleocytosis, his presentation did not meet consensus criteria for autoimmune encephalitis (8Graus F. Titulaer M.J. Balu R. Benseler S. Bien C.G. Cellucci T. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (2055) Google Scholar). 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 g/kg 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 3 months later. Because his robust response to IVIg suggested an underlying neuroinflammatory process, we tested for anti-SARS-CoV-2 and anti-neural autoantibodies. Using a Luminex SARS-CoV-2 antigen panel (9Zamecnik C.R. Rajan J.V. Yamauchi K.A. Mann S.A. Loudermilk R.P. Sowa G.M. et al.ReScan, a multiplex diagnostic pipeline, pans human sera for SARS-CoV-2 antigens.Cell Rep Med. 2020; 1100123Google Scholar,10Sabatino Jr., J.J. Mittl K. Rowles W.M. McPolin K. Rajan J.V. Laurie M.T. et al.Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function.JCI Insight. 2022; 7e156978Crossref PubMed Scopus (29) Google Scholar), we detected anti-spike, anti-receptor binding domain, and anti-nucleocapsid protein antibodies in his serum and CSF (Figure 1A) (9Zamecnik C.R. Rajan J.V. Yamauchi K.A. Mann S.A. Loudermilk R.P. Sowa G.M. et al.ReScan, a multiplex diagnostic pipeline, pans human sera for SARS-CoV-2 antigens.Cell Rep Med. 2020; 1100123Google Scholar,10Sabatino Jr., J.J. Mittl K. Rowles W.M. McPolin K. Rajan J.V. Laurie M.T. et al.Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function.JCI Insight. 2022; 7e156978Crossref PubMed Scopus (29) Google Scholar). We then screened for anti-neural autoantibodies using anatomic mouse brain tissue staining (11Ricken G. Schwaiger C. De Simoni D. Pichler V. Lang J. Glatter S. et al.Detection methods for autoantibodies in suspected autoimmune encephalitis.Front Neurol. 2018; 9: 841Crossref PubMed Scopus (45) Google Scholar), a validated and standard method performed by incubating rodent brain sections with CSF. At a 1:4 dilution, his CSF IgG produced prominent punctate immunostaining of the accessory olfactory bulb, cytoplasmic and neuropil staining in upper layers of the cortex and thalamus, and cytoplasmic staining of hilar and granule neurons in the hippocampus (Figure 1B). We next used whole human peptidome phage display immunoprecipitation sequencing (PhIP-Seq) (12O'Donovan B. Mandel-Brehm C. Vazquez S.E. Liu J. Parent A.V. Anderson M.S. et al.High-resolution epitope mapping of anti-Hu and anti-Yo autoimmunity by programmable phage display.Brain Commun. 2020; 2 (fcaa059)PubMed Google Scholar) to screen for candidate autoantigens. Similar to COVID-19 patients with neurological symptoms (13Song E. Bartley C.M. Chow R.D. Ngo T.T. Jiang R. Zamecnik C.R. et al.Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms.Cell Rep Med. 2021; 2100288Google Scholar), the patient’s CSF enriched a diverse set of candidate autoantigens (n = 27), including multiple peptides mapping to MCTP1, a protein implicated in neurotransmitter release (Figure 1C) (14Genç Ö. Dickman D.K. Ma W. Tong A. Fetter R.D. Davis G.W. MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity.Elife. 2017; 6e22904Crossref PubMed Scopus (25) Google Scholar,15Téllez-Arreola J.L. Silva M. Martínez-Torres A. MCTP-1 modulates neurotransmitter release in C. elegans.Mol Cell Neurosci. 2020; 107103528Crossref PubMed Scopus (2) Google Scholar). The top PhIP-Seq–enriched peptide is encoded by 11 MCTP1 isoforms—but not the canonical isoform MCTP1L (National Center for Biotechnology Information RefSeq [https://www.ncbi.nlm.nih.gov/refseq/]). Surprisingly, MCTP1 autoantibodies did not validate by overexpression cell-based assay or immunoprecipitation using a representative isoform (isoform 3). However, an expanded PhIP-Seq comparison revealed that the patient enriched MCTP1 significantly more than a combined 3408 healthy CSF and sera and 808 negative control samples (Figure 1D). Finally, we evaluated whether PhIP-Seq candidate antigen enrichment was due to sequence similarity with SARS-CoV-2. We mapped our patient’s anti-SARS-CoV-2 target epitopes by SARS-CoV-1/2 phage display (9Zamecnik C.R. Rajan J.V. Yamauchi K.A. Mann S.A. Loudermilk R.P. Sowa G.M. et al.ReScan, a multiplex diagnostic pipeline, pans human sera for SARS-CoV-2 antigens.Cell Rep Med. 2020; 1100123Google Scholar) and compared viral epitopes with PhIP-Seq–identified candidate autoantigens using National Center for Biotechnology Information BlastP (https://blast.ncbi.nlm.nih.gov/Blast.cgi). Among the top 10 CSF- and serum-enriched SARS-CoV-2 peptides, we identified 15 unique peptides, none of which aligned to PhIP-Seq candidate autoantigens (Figure 1E). In this correspondence, we have profiled the antibody response of a COVID-19 patient with antipsychotic-refractory subacute psychosis whose symptoms rapidly and completely remitted after treatment with IVIg. We identified and mapped the epitope specificity of anti-SARS-CoV-2 antibodies in the patient’s CSF and characterized autoantibodies by rodent brain tissue staining and PhIP-Seq. Although anti-neural autoantibodies have been described in neurologically impaired COVID-19 patients (16Song E. Bartley C.M. Chow R.D. Ngo T. Jiang R. Zamecnik C.R. et al.Exploratory neuroimmune profiling identifies CNS-specific alterations in COVID-19 patients with neurological involvement.bioRxiv. 2020; https://doi.org/10.1101/2020.2009.2011.293464Crossref Google Scholar, 17Franke C. Ferse C. Kreye J. Momsen Reincke S. Sanchez-Sendin E. 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Runge K. et al.Spectrum of novel anti-central nervous system autoantibodies in the cerebrospinal fluid of 119 patients with schizophreniform and affective disorders.Biol Psychiatry. 2022; 92: 261-274Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,30Ehrenreich H. Gastaldi V.D. Wilke J.B.H. Quo vaditis anti-brain autoantibodies: Causes, consequences, or epiphenomena?.Biol Psychiatry. 2022; 92: 254-255Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). By PhIP-Seq, our patient’s CSF and serum significantly enriched MCTP1. MCTP1 enrichment was not explained by sequence similarity with SARS-CoV-2 proteins, suggesting a distinct antibody response, rather than molecular mimicry. Although anti-MCTP1 autoantibodies did not validate by cell-based assay or immunoprecipitation, neither method is dispositive (11Ricken G. Schwaiger C. De Simoni D. Pichler V. Lang J. Glatter S. et al.Detection methods for autoantibodies in suspected autoimmune encephalitis.Front Neurol. 2018; 9: 841Crossref PubMed Scopus (45) Google Scholar), and only 1 of 11 candidate MCTP1 isoforms was tested. Given the patient’s extreme PhIP-Seq enrichment of MCTP1, it remains a candidate autoantigen. Importantly, early initiation of immunotherapy for autoimmune disorders of the central nervous system significantly improves outcomes (31Nosadini M. Mohammad S.S. Ramanathan S. Brilot F. Dale R.C. Immune therapy in autoimmune encephalitis: A systematic review.Expert Rev Neurother. 2015; 15: 1391-1419Crossref PubMed Scopus (148) Google Scholar). Although autoimmune encephalitis can be established on clinical grounds, the diagnosis requires neurologic, magnetic resonance imaging, and/or CSF abnormalities (8Graus F. Titulaer M.J. Balu R. Benseler S. Bien C.G. Cellucci T. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (2055) Google Scholar). To identify individuals with potentially immune-responsive acute psychosis without neurological impairment, Pollak et al. (32Pollak T.A. Lennox B.R. Müller S. Benros M.E. Prüss H. Tebartz van Elst L. et al.Autoimmune psychosis: An international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin.Lancet Psychiatry. 2020; 7: 93-108Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar) proposed criteria for autoimmune psychosis. While “possible” autoimmune psychosis relies solely on clinical factors, “probable” and “definite” autoimmune psychosis 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 (32Pollak T.A. Lennox B.R. Müller S. Benros M.E. Prüss H. Tebartz van Elst L. et al.Autoimmune psychosis: An international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin.Lancet Psychiatry. 2020; 7: 93-108Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). Moreover, his mood dysregulation, cognitive slowing, and hypersomnia were evocative of the mixed symptomatology more typical of autoimmune encephalitis (33Muñoz-Lopetegi A. Graus F. Dalmau J. Santamaria J. Sleep disorders in autoimmune encephalitis.Lancet Neurol. 2020; 19: 1010-1022Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,34Al-Diwani A. Handel A. Townsend L. Pollak T. Leite M.I. Harrison P.J. et al.The psychopathology of NMDAR-antibody encephalitis in adults: A systematic review and phenotypic analysis of individual patient data.Lancet Psychiatry. 2019; 6: 235-246Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Given his overall clinical picture, we administered IVIg with apparent clinical response. 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 (35Franke C. Prüss H. Letter to the Editor: Comment on Mulder J et al. (2021) Indirect Immunofluorescence for Detecting Anti-Neuronal Autoimmunity in CSF after COVID-19 - Possibilities and pitfalls.Brain Behav Immun. 2021; 94: 473-474Crossref PubMed Scopus (3) Google Scholar). 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. This work was supported by National Institute of Mental Health Grant Nos. R01MH122471 (to SJP, MRW), R01MH125396 (to SSS), K23MH118999 (to SFF), and R21MH118109 (to SS); National Institute of Neurological Disorders and Stroke Grant No. R01NS118995-14S (to SJP); the Brain Research Foundation (to SJP); the National Intitute of Allergy and Infectious Diseases Grant No. R01AI157488 (to SFF); the Hanna H. Gray Fellowship of the Howard Hughes Medical Institute (to CMB); the President’s Postdoctoral Fellowship Program of the University of California (to CMB); the John A. Watson Scholar Program of the University of California, San Francisco (to CMB); and the Deeda Blair Research Initiative for Disorders of the Brain of the Foundation for the National Institutes of Health (to CMB). Sequencing was performed at the University of California, San Francisco (UCSF) Center for Advanced Technology, supported by UCSF Sandler Program for Breakthrough Biomedical Research, Research Resource Program Institutional Matching Instrumentation Awards, and National Institutes of Health (NIH Office of the Director) Grant Nos. 1S10OD028511-01. We thank Trung Huynh and Anne Wapniarski for laboratory assistance. We thank Andrew Kung and Joseph Derisi for use of the PhIP-Seq database. During the course of treatment, we obtained surrogate consent to use surplus cerebrospinal fluid for research. After regaining capacity, the patient provided written informed consent for this case report. This work has not previously been published in any form. MRW received a research grant from Roche/Genentech. All other authors report no biomedical financial interests or potential conflicts of interest.