key: cord-0916723-wk4wfuqb
authors: McAlpine, Lindsay S.; Lifland, Brooke; Check, Joseph R.; Angarita, Gustavo A.; Ngo, Thomas T.; Pleasure, Samuel J.; Wilson, Michael R.; Spudich, Serena S.; Farhadian, Shelli F.; Bartley, Christopher M.
title: Remission of subacute psychosis in a COVID-19 patient with an anti-neuronal autoantibody after treatment with intravenous immunoglobulin
date: 2021-04-12
journal: Biol Psychiatry
DOI: 10.1016/j.biopsych.2021.03.033
sha: b8fc09a830054d59ec8ca5542d29486829a90e68
doc_id: 916723
cord_uid: wk4wfuqb

nan

To the Editor: 1 COVID-19 patients are at increased risk for developing new or recurrent psychosis.(1) 2 Viral infections-including SARS-CoV-2 (2-4)-can cause psychosis in the context of 3 autoimmune encephalitis. (5) However, some individuals with para-infectious psychosis do not 4 meet criteria for autoimmune encephalitis, yet respond to immunotherapy. (6, 7) We present a 5 case of COVID-19-associated subacute psychosis that did not meet criteria for autoimmune 6

encephalitis, yet remitted after treatment with intravenous immunoglobulin (IVIg). We 7 subsequently identified a novel IgG class anti-neuronal autoantibody in the patient's 8 cerebrospinal fluid (CSF). 9

10

A 30-year-old man without medical, psychiatric, or substance use history developed 12 fever and malaise. The following day, he developed a delusion that the "rapture" was 13 imminent. On day 2, a nasopharyngeal swab was positive for SARS-CoV-2 by RT-PCR. He began 14 a 14-day isolation but maintained daily contact with family. He did not have anosmia, ageusia, 15 or respiratory symptoms, nor did he receive treatment for COVID-19. He initially suffered from 16 hypersomnia and slept 22 hours per day. He then developed insomnia, sleeping only 3-4 hours 17 per day. During this time, he began pacing and rambling about "lights." He worried that he was 18 dying and said that he had been speaking to deceased relatives and God. 19 20 On day 22, he kicked through a door and pushed his mother, prompting an emergency 21 department (ED) evaluation. In the ED, he endorsed speaking with the dead, falsely claimed to 22 J o u r n a l P r e -p r o o f be a veteran, and worried about being experimented on with "radiation." He did not have 23 suicidal ideation, homicidal ideation, or hallucinations. Non-contrast head computed 24 tomography was normal, and urine toxicology was negative. He was started on haloperidol 5 25 mg by mouth twice daily with significant improvement of his agitation and delusions. After 48 26 hours he was discharged to outpatient follow-up. Outpatient magnetic resonance imaging 27 (MRI) of the brain with and without gadolinium was unremarkable. 28 29 After discharge, his restlessness, insomnia, and cognitive slowing recurred, as did his 30 fears that he would be experimented on "like a guinea pig." On day 34, he punched through a 31 wall and was hospitalized to be evaluated for autoimmune encephalitis. A detailed neurological 32 exam was unremarkable. He had a flat affect, slowed speech, and akathisia, which resolved 33 after decreasing haloperidol and starting benztropine and lorazepam. A 12-hour video 34 electroencephalogram was normal. Blood studies were notable for an elevated ferritin and D-35 dimer, suggesting systemic inflammation (Table 1) . CSF studies, including a clinical autoimmune 36 encephalitis autoantibody panel, were only notable for an elevated IgG of 4.8 mg/dL (ref. 1.0-37 3.0 mg/dL) with a normal IgG index (see Table 1 ). 38 39 Lacking focal neurologic symptoms, seizures, MRI abnormalities, or CSF pleocytosis, his 40 presentation did not meet consensus criteria for autoimmune encephalitis. (7) Nevertheless, his 41 subacute psychosis, cognitive slowing, and recent SARS-CoV-2 infection raised concern for 42 autoimmune-mediated psychosis. Therefore, starting on day 35, he received a total of 2 43 grams/kilogram of IVIg over 3 days. His cognitive slowing and psychotic symptoms remitted 44 J o u r n a l P r e -p r o o f after the first day of treatment. His sleep cycle normalized, and he was discharged without 45 scheduled antipsychotics. He returned to work immediately after discharge and remained 46 symptom-free three months later. 47

Because his robust response to IVIg indicated an underlying autoimmune process, we 49 tested his CSF for anti-neural autoantibodies using anatomic mouse brain tissue staining (8) were immunostained (figure 1c). In the dentate gyrus, linearly organized puncta resembling 61 axonal transport vesicles and oblong neurons were apparent in the hilus (Figure 1d ). In the 62 thalamus, linear and less organized punctate staining was observed (Figure 1e ). In the 63 cerebellum, Purkinje cell bodies were modestly stained, while the overlying molecular layer was 64 densely stained with variably size puncta (Figure 1f ). 65

We identified a candidate novel neuronal autoantibody in the CSF of a COVID-19 patient 68 with antipsychotic-refractory subacute psychosis, whose symptoms rapidly and completely 69 remitted after treatment with IVIg. This autoantibody primarily localized to layer II/III callosal 70 cortical neurons, which have been implicated in schizophrenia. can prompt earlier immunotherapy and potentially improve outcomes. Only by relying on 90 ancillary criteria were we able to justify immunotherapy for our patient, suggesting that re-91 evaluating the criteria for autoimmune psychosis may improve its sensitivity. (27) 

Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA

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Presenting as Acute Psychosis

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Letter to the Editor: comment on

Indirect Immunofluorescence for Detecting Anti-Neuronal Autoimmunity in CSF after COVID-19 -Possibilities and Pitfalls

Figure 1. Characterization of anti-neuronal antibody staining. Mice were perfused with 4%

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

Relatively uniform punctate staining along the ventricular wall (filled arrowheads) and overlying corpus callosum

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

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

Thalamic axon-like (filled arrowhead) and scattered (unfilled arrowhead) punctate immunostaining. bv = blood vessel

Immunostaining of cerebellar Purkinje cell bodies (filled arrowheads) and neuropil of the molecular layer (m). gc = granule cell layer, pc = Purkinje cell layer