The study was based on case studies involving three pediatric patients with subacute neuropsychiatric impairment as well as investigations as to whether there was anti–SARS-CoV-2 or antineural antibodies present in the cerebrospinal fluid of them.
The study findings found that 2 had intrathecal anti–SARS-CoV-2 antibodies as well as intrathecal antineural antibodies. Anti–transcription factor 4 (TCF4) autoantibodies in one patient who responded to immunotherapy were validated.
The study findings were published in the peer reviewed journal: JAMA Neurology. https://jamanetwork.com/journals/jamaneurology/fullarticle/2785032
More than 100 million people have been infected with SARS-CoV-2, including nearly 2 million children in the US.1 Although respiratory disease in pediatric COVID-19 is generally mild, parainfectious and postinfectious neurologic sequelae are increasingly recognized.2,3
These include encephalitis, seizures, aseptic meningitis, and confusion – found in about 20% of cases of multisystem inflammatory syndrome in children.4 Notably, rates of new and recurrent psychiatric illness are significantly increased in adults after SARS-CoV-2 infection compared with influenza and other respiratory infections.5
Discussion
We profiled intrathecal antibodies in 3 teenaged patients with subacute neuropsychiatric symptoms after SARS-CoV-2 infection, none of whom met criteria for multisystem inflammatory syndrome in children. All 3 had abnormal CSF with restricted oligoclonal bands, elevated protein levels, and/or an elevated IgG index.
On research testing, patients 1 and 2 had intrathecal anti–SARS-CoV-2 IgG. CSF IgG from these 2 patients also immunostained mouse brain tissue, indicating the presence of antineural autoantibodies. Likewise, patients 1 and 2 enriched a diverse set of candidate autoantigens by human phage immunoprecipitation sequencing, while patient 3 neither appreciably immunostained nor enriched candidates by human phage immunoprecipitation sequencing.
The outcomes for these patients differed.
Patient 1 was unresponsive to psychiatric medications, and their symptoms remitted after immunotherapy.
Patient 2 experienced a modest response to immunotherapy, but 6 months later, the patient continued to have impaired mood and cognitive symptoms.
Patient 3’s symptoms remitted after 4 days of treatment with lorazepam and olanzapine without immunotherapy.
Overall, these findings indicate that severe neuropsychiatric symptoms can occur in the setting of pediatric COVID-19, including patients who lack many of the cardinal systemic features. Like the adult COVID-19 population, measures of CSF inflammation may be subtle or absent.
Nevertheless, we found that 2 patients had intrathecal SARS-CoV-2 and antineural antibodies. In one patient, CSF immunostaining overlapped with commercial KIF21A, an axonal kinesin implicated in congenital fibrosis of extraocular muscles and abnormal brain development.10
In that same patient, we validated autoantibodies against TCF4, a gene that has been associated with psychiatric disorders, including schizophrenia, and is responsible for the neurodevelopmental disorder Pitt-Hopkins syndrome.11
These data highlight the possibility of SARS-CoV-2 neuroinvasion and/or CNS autoimmunity in pediatric patients with COVID-19 and neuropsychiatric symptoms.
