Neuropsychiatric Symptoms in COVID-19 Adolescents: Central Nervous System Autoimmunity and Viral Infection

More than 100 million people have been infected with SARS-CoV-2, including nearly 2 million children in the US.  Although respiratory illness in pediatric COVID-19 is generally mild, neurological sequelae are increasingly recognized. parainfectious and postinfectious.

These include encephalitis, seizures, aseptic meningitis and confusion, which are found in approximately 20% of cases of multisystem inflammatory syndrome in children. In particular, rates of new and recurrent psychiatric illnesses increase significantly in adults after SARS-CoV-2 infection compared to influenza and other respiratory infections.

SARS-CoV-2 RNA is rarely detected in the cerebrospinal fluid (CSF) of patients with COVID-19, but intrathecal antibodies against SARS-CoV-2 have been reported,  suggesting possible neuroinvasion. Although some neurologically impaired adults with COVID-19 have intrathecal antineural autoantibodies,  to  our knowledge  , no intrathecal anti-SARS-CoV-2 antibodies or antineural antibodies have been reported in pediatric patients with COVID-19 and neuropsychiatric presentations.

Importance   

Neuropsychiatric manifestations of COVID-19 have been reported in the pediatric population.

Aim   

To determine whether anti-SARS-CoV-2 and autoreactive antibodies are present in the cerebrospinal fluid (CSF) of pediatric patients with COVID-19 and subacute neuropsychiatric dysfunction.

Design, environment and participants  

This case series includes 3 patients with recent SARS-CoV-2 infection confirmed by reverse transcription-polymerase chain reaction or IgG serology with a history of recent exposure who were hospitalized at the University of Benioff Children’s Hospital. California in San Francisco. and for whom a neurology consultation was requested during a 5-month period in 2020.

During this period, 18 children in total were hospitalized and tested positive for acute SARS-CoV-2 infection by reverse transcriptase polymerase chain reaction or rapid antigen testing.

Main results and measures   

Detection and characterization of anti-SARS-CoV-2 IgG and antineural antibodies in CSF.

Results   

Of 3 adolescent patients included, 2 patients had intrathecal anti-SARS-CoV-2 antibodies. CSF IgG from these 2 patients also indicated antineural autoantibodies on anatomical immunostaining. Autoantibodies targeting transcription factor 4 (TCF4) were also validated in 1 patient who appeared to have a robust response to immunotherapy.

Discussion

We profiled intrathecal antibodies in 3 adolescent patients with subacute neuropsychiatric symptoms after SARS-CoV-2 infection, none of whom met the 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. 

In investigational 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. 

Similarly, patients 1 and 2 enriched for a diverse set of candidate autoantigens by human phage immunoprecipitation sequencing, whereas patient 3 did not appreciably immunostain or enrich for candidates by human phage immunoprecipitation sequencing.

The results for these patients were different. 

Patient 1 did not respond to psychiatric medications and his symptoms subsided after immunotherapy. 

Patient 2 experienced a modest response to immunotherapy, but 6 months later, the patient continued to have mood disturbances and cognitive symptoms. 

Patient 3’s symptoms resolved after 4 days of treatment with lorazepam and olanzapine without immunotherapy.

Overall, these findings indicate that severe neuropsychiatric symptoms can occur in the context of pediatric COVID-19, including patients lacking many of the cardinal systemic features. Like the adult COVID-19 population, CSF measures of inflammation may be subtle or absent. 

However, 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. 

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. 

These data highlight the possibility of SARS-CoV-2 neuroinvasion and/or CNS autoimmunity in pediatric patients with COVID-19 and neuropsychiatric symptoms.