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Sudden, rapidly progressing neuropsychiatric symptoms ranging from severe anxiety to delusional psychosis caused three teenage patients with recent COVID-19 to be hospitalized, researchers reported.

Of the three pediatric patients, two had anti-SARS-CoV-2 antibodies and antineural autoantibodies in their cerebrospinal fluid (CSF), wrote Samuel Pleasure, MD, PhD, of the University of California San Francisco (UCSF), and co-authors in a brief report.

"What was perhaps unexpected here is that the two teens in this paper did not have severe respiratory COVID, but still had prominent evidence for autoimmunity in their CSF findings," Pleasure told 名媛直播.

The two patients whose CSF tested positive for SARS-CoV-2 antibodies and antineural antibodies were treated with immunotherapy: response was robust in one patient and modest in another. In the third patient, psychiatric symptoms remitted without immunotherapy.

"This is an important study that shows that in some patients, new-onset psychiatric illness in the context of COVID may be immune-mediated," noted Avindra Nath, MD, of the NIH's National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, who wasn't involved with the research.

"These patients responded to immunotherapy," Nath told 名媛直播. "They also showed evidence of synthesis of antibodies in the CNS [central nervous system]. This implies there are B cells being trapped in the CNS, which are recognizing CNS antigens or viral antigens. Whether these antibodies are pathogenic is not entirely clear."

SARS-CoV-2 RNA is rarely detected in the CSF of COVID-19 patients, but have been reported. "Our in adults showed that patients hospitalized due to respiratory complications with COVID who have neurologic complaints have a high frequency of autoantibodies and SARS-CoV-2-directed antibodies in their CSF," Pleasure said.

The pediatric study looked at three patients with confirmed COVID-19 who were hospitalized for subacute, functionally impairing behavioral changes at UCSF Benioff Children's Hospital over a 5-month period in 2020.

In all three cases, neuropsychiatric symptoms had sudden onset and rapid progression. None of the patients met criteria for multisystem inflammatory syndrome in children; all three had abnormal CSF. The two patients treated with immunotherapy also had histories of unspecified depression or anxiety.

The first patient was unresponsive to psychiatric medications, but had more organized thoughts, decreased paranoia, and improved insight 5 days after initiating immunotherapy. Treatment was IV immunoglobulin (IVIG) 2 g/kg over 3 days, followed by IV methylprednisolone 1 g for 3 days and a prednisone taper. Brain MRI showed nonspecific white matter hyperintensities in the frontal lobes. CSF revealed elevated protein levels, an elevated immunoglobulin G index, and autoantibodies targeting TCF4, a gene associated with psychiatric disorders.

The second patient developed multiple worsening psychiatric symptoms leading to hospital admission 10 weeks after fever and respiratory symptoms, which resolved without treatment. After a course of IV methylprednisolone, working memory and bradyphrenia improved and the patient was discharged. Six days later, the patient was readmitted and received an empirical trial of IVIG 2 g/kg over 3 days. MRI findings were normal, but repeated lumbar puncture showed persistently elevated CSF protein levels. Six months later, the patient was improved from initial presentation, but continued to have forgetfulness and attention difficulties.

The third patient's symptoms remitted after 4 days of treatment with lorazepam (Ativan) and olanzapine (Zyprexa) without immunotherapy. This patient had three unique oligoclonal bands in CSF. Autoantibody tests were negative and MRI was normal.

This study was an uncontrolled convenience sample with a small sample size, Pleasure and co-authors acknowledged. The first two patients had pre-existing psychiatric symptoms and may have improved without immunotherapy, they added. It's unknown whether patients predisposed to neuropsychiatric illnesses are more likely to develop worsened symptoms after COVID or whether COVID infection can act as an independent trigger, Pleasure noted.

In an earlier , UCSF and Yale University researchers reported a response to immunotherapy in an adult COVID-19 patient presenting with subacute psychosis. The 30-year-old man, who had no psychiatric or substance use history, did not achieve lasting remission with antipsychotic medications and was treated with IVIG for possible autoimmune-mediated psychosis. His symptoms improved after the first day of treatment and he eventually was discharged without antipsychotic medications.

"Clinicians taking care of patients with new onset of neuropsychiatric symptoms without a clear etiology should give some thought to whether the patient may have had COVID-19 infection in some temporal proximity to the new symptoms," Pleasure observed.

"Since the COVID-19 pandemic is affecting so many people over a fairly short time interval, we would expect some proportion of new-onset neuropsychiatric conditions to be post- or para-infectious," he added. "Identifying these patients may help decide which, if any, would benefit by immunomodulatory therapies."

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