COVID-19 and neuropsychiatric symptoms in teenagers

Investigators reported anti-SARS-CoV-2 autoantibodies in the cerebrospinal fluid of three teens who came to the emergency department with neuropsychiatric symptoms. The scientists believe that emergency department doctors should be open to the possibility that young people presenting for the first time with unexplained neuropsychiatric problems could have an autoantibody response to the COVID-19 infection, and should be evaluated accordingly. 

Scientists have identified anti-SARS-CoV-2 antibodies and anti-neuronal auto-antibodies in the cerebrospinal fluid (CSF) of two of three teenagers who presented to an emergency department with subacute neuropsychiatric problems, including paranoid delusions, suicidal ideation, anxiety, obsessive behavior, and cognitive slowing. 

While many teenagers present to the emergency department with neuropsychiatric symptoms, these three teens were the only ones who presented to the University of California, San Francisco (UCSF) with these symptoms in the setting of a recent COVID-19 infection and for whom a neurology consult was called. Two tested positive with direct detection tests, and one was seropositive (antibody testing) with a recent exposure. 

All three also had abnormal CSF with restricted oligoclonal bands, elevated protein, and/or an elevated immunoglobulin G (IgG) index. None of them met the criteria for multisystem inflammatory syndrome in children, which has been associated with some cases of COVID-19 in young patients. 

The findings, published online on October 25 in JAMA Neurology, suggest that the virus could be associated with central nervous system inflammation and leave some pediatric COVID-19 patients with new onset neuropsychiatric symptoms that do not respond to traditional psychiatric medications. 

One of the teenagers seemed to improve after immunotherapy, another had a modest response, while the third teens' symptoms improved after treatment with lorazepam and olanzapine without immunotherapy. 

The scientists believe that emergency department doctors should be open to the possibility that young people presenting for the first time with unexplained neuropsychiatric problems could have an auto-antibody response to the COVID-19 infection, and should be evaluated accordingly…

In the first case, UCSF pediatric resident Claire Johns, MD, had evaluated a teenager who presented with acute delusions and psychosis, and called on the neurology service to help assess the patient. The teenager had erratic and paranoid-like behavior, insomnia and social withdrawal. The teen had a history of marijuana use and unspecified anxiety and depression, was initially treated with psychiatric medications, but was discharged after 11 days. The teen was readmitted a day later with persistent delusions.

The teenager had tested positive for COVID-19 during the first hospitalization, although the teen had no respiratory symptoms. On readmission, a lumbar puncture showed elevated protein and elevated IgG index. An MRI of the brain showed non-specific T2/FLAIR white matter hyperintensities in the frontal lobes. The pediatric specialists ordered intravenous immunoglobulin (IVIg) and the teen quickly improved enough to be discharged from the hospital. The teen's blood and CSF were later sent for further analysis to Dr. Wilson and his colleagues who identified abnormal antibody production in the teen's CSF.

The second teen had a history of anxiety and motor tics and a “foggy brain,: according to the description in the paper. The teen's father had just been diagnosed with COVID-19, and a week later the teen developed fever and respiratory symptoms and improved without treatment. Over the next six weeks, the teen experienced a host of neuropsychiatric symptoms, including word-finding difficulty and problems concentrating, insomnia, mood swings, and it morphed into aggression and suicidal ideation. The teen was treated without success with psychiatric medications, and admitted to the hospital ten weeks after the neuropsychiatric symptoms began.

Back in the hospital, the patient tested positive for SARS-CoV2 antibodies. The teen's slowed thinking and memory problems improved after IV methylprednisolone, and was discharged on lithium and risperidone. Six days later, still in the throes of aggression and suicidal ideation, the teen was readmitted. Another lumbar puncture showed elevated CSF protein and IVIg was administered for three days. The patient was discharged with psychiatric medicines but six months later there was still lingering forgetfulness and attention problems. A third lumbar puncture at six months still showed elevated protein.

The third teenager was taken to the emergency department after four days of extremely erratic and odd repetitive behaviors, insomnia, and anorexia. There was no previous history of psychiatric symptoms. In the ED, a SARS-CoV-2 test came back positive. The teen had an elevated white blood cell count, creatine kinase, and C-reactive protein as well as ideomotor apraxia, a lack of motivation, disorganized behavior, and agitation. Psychiatric medications were administered for a few days and then stopped. The patient's symptoms improved during the weeklong hospitalization, and the teen was discharged without any psychiatric medications.“One important difference is that the teen who improved was treated soon after their symptoms started whereas the second patient's treatment was delayed by over two months,” said Dr. Johns. The third young person had mania and insomnia and tested positive for SARS-CoV2 but did not have evidence of auto-antibodies in the CSF…

“Merely identifying these autoantibodies and some of their antigens does not causally link them to these young peoples' symptoms,” added Dr. Bartley. “In some patients, the specific regions of the SARS-CoV-2 proteome targeted by the serum antibodies differed from the antigens in the CSF, suggesting that a compartmentalized immune response might be occurring in the CNS.”

https://journals.lww.com/neurotodayonline/Fulltext/2021/11040/COVID_19_and_Neuropsychiatric_Symptoms_in.2.aspx

Bartley CM, Johns C, Ngo TT, Dandekar R, Loudermilk RL, Alvarenga BD, Hawes IA, Zamecnik CR, Zorn KC, Alexander JR, Wapniarski AE, DeRisi JL, Francisco C, Nash KB, Wietstock SO, Pleasure SJ, Wilson MR. Anti-SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms. JAMA Neurol. 2021 Oct 25:e213821. doi: 10.1001/jamaneurol.2021.3821. Epub ahead of print. PMID: 34694339; PMCID: PMC8546622.

Abstract

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

Objective: 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, setting, and participants: This case series includes 3 patients with recent SARS-CoV-2 infection as confirmed by reverse transcriptase-polymerase chain reaction or IgG serology with recent exposure history who were hospitalized at the University of California, San Francisco Benioff Children's Hospital and for whom a neurology consultation was requested over a 5-month period in 2020. During this period, 18 total children were hospitalized and tested positive for acute SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction or rapid antigen test.

Main outcomes and measures: Detection and characterization of CSF anti-SARS-CoV-2 IgG and antineural antibodies.

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

Conclusions and relevance: Pediatric patients with COVID-19 and prominent subacute neuropsychiatric symptoms, ranging from severe anxiety to delusional psychosis, may have anti-SARS-CoV-2 and antineural antibodies in their CSF and may respond to immunotherapy.