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Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CaliforniaDepartment of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, California
Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CaliforniaDepartment of Neurology, University of California, San Francisco, San Francisco, California
Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CaliforniaDepartment of Neurology, University of California, San Francisco, San Francisco, California
Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CaliforniaDepartment of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CaliforniaHanna H. Gray Fellowship Program, Howard Hughes Medical Institute, Chevy Chase, Maryland
). 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 antineuronal autoantibody in the patient’s cerebrospinal fluid (CSF).
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 reverse transcriptase 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 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 evaluation. In the emergency department, 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. 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 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 (reference 1.0–3.0 mg/dL) with a normal IgG index (see Table 1).
Table 1Clinical Studies
Source
Test
Result (Reference)
Nasopharyngeal Swab
SARS-CoV-2 RNA PCR
Day 2: positive Day 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)
Negative for AMPA Ab, amphiphysin Ab, antiglial nuclear Ab, neuronal nuclear Ab (types 1, 2, and 3), CASPR2, CRMP-5, DPPX, GABAB 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 (>12 hours) awake and asleep inpatient video electroencephalogram.
Lacking focal neurologic symptoms, seizures, magnetic resonance imaging abnormalities, or CSF pleocytosis, his presentation did not meet consensus criteria for autoimmune encephalitis (
). 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 indicated an underlying autoimmune process, we tested his CSF for antineural autoantibodies using anatomic mouse brain tissue staining (
), 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 (
). 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 1Characterization of antineuronal antibody staining. Mice were perfused with 4% paraformaldehyde; 12-μm frozen sagittal brain sections were immunostained with cerebrospinal fluid at a 1:4 dilution and counterstained with an antihuman IgG secondary antibody (green) (Jackson #709-545-149 at 2 μg/mL). Nuclei were labeled with DAPI (blue). Scale bars = 10 μm. (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) Cerebrospinal fluid immunostains Satb2-expressing (red) neurons (filled arrowheads) but not surrounding Satb2-negative cells (unfilled arrowhead) (Abcam #ab51502 at 1 μg/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). (D) Hippocampal immunostaining of an axon-like process in the hilus (h) of the dentate gyrus (filled arrowheads) and a subset of hilar cell bodies (unfilled arrowheads). (E) Thalamic axon-like (filled arrowhead) and scattered (unfilled arrowhead) punctate immunostaining. (F) Immunostaining of cerebellar Purkinje cell bodies (filled arrowheads) and neuropil of the molecular layer (m). bv, blood vessel; gc, granule cell layer; ip, internal plexiform layer; mc, mitral cell layer; pc, Purkinje cell layer; v, ventricle.
In this case 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 (
). Although autoimmune encephalitis can be established on clinical grounds, the diagnosis requires neurologic, magnetic resonance imaging, and/or CSF abnormalities (
) proposed criteria for autoimmune psychosis. 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 probable autoimmune psychosis: infectious prodrome, rapid progression, and insufficient response to antipsychotics (
). Moreover, his mood dysregulation, cognitive slowing, and hypersomnia were evocative of the mixed symptomatology more typical of autoimmune encephalitis (
). 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 (
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.
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.
Acknowledgments and Disclosures
This work was supported by National Institute of Mental Health Grant Nos. R01MH122471 (to SJP, MRW), R01MH125396 (to SS), R21MH118109 (to SS), and R01AI157488 (to SFF); National Institute of Neurological Disorders and Stroke Grant No. R01NS118995-14S (to SJP); a Scientific Innovations Award from the Brain Research Foundation (to SJP); the National Institute of Allergy and Infectious Diseases Grant No. K23MH118999 (to SFF); the Hanna H. Gray Fellowship from the Howard Hughes Medical Institute (to CMB); the President’s Postdoctoral Fellowship Program from the University of California (to CMB); and the John A. Watson Scholar Program of the University of California, San Francisco (to CMB).
We thank Trung Huynh and Anne Wapniarski for laboratory assistance.
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 has received a research grant from Roche/Genentech. All other authors report no biomedical financial interests or potential conflicts of interest.
References
Taquet 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.
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.
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