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..