Article In Brief

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.

We don't know if this could be a more general phenomenon, said the senior study author Michael R. Wilson, MD, FAAN, associate professor and Debbie and Andy Rachleff Distinguished Chair in neurology at the UCSF Weill Institute for Neurosciences. Scientists at UCSF are now analyzing CSF from more young people.

Together with Samuel J. Pleasure, MD, PhD, the Glenn W. Johnson, Jr. Memorial Endowed Chair in Neurology at UCSF, Dr. Wilson, and first co-author Christopher Bartley, MD, PhD, have been using multiple technologiesgenomics, immune system sequencing techniques, and phage displayto characterize the immune system's response to pathogens and to screen for antibodies in the CSF of COVID-19 patients with neurologic symptoms.

For this latest study, the scientists conducted a detailed analysis of CSF and blood from three teenagers presenting to UCSF Benioff Children's Hospital with neurological or psychiatric symptoms during a five-month period in 2020.

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.

You get to one underlying question: SARS-CoV-2 is infecting millions and millions of people, and a great majority don't get critically ill. The ones who do tend to be older and/or have co-morbidities. What we don't know is if there are underlying issues that put certain people at risk for neuropsychiatric problems or long COVID, said Dr. Pleasure.

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.

But we won't build more confidence about a potential link until we've been able to assess additional patients to determine whether these autoantibodies consistently track with particular clinical phenotypes. Ultimately, these autoantibodies may be reflective of a broader immune dysregulation that is related to their symptoms, but it's too early to tell. These teenagers were treated as psychiatric patients and COVID was found incidentally. We should definitely have this on our radar. Some of these patients may have subtle evidence of neuroinflammation and warrant a different treatment approach.

The scientists published previous studies in 2020 that led up to this latest work. In a paper Cell Reports Medicine done in close collaboration with Shelli Farhadian, MD, PhD, and Serena Spudich, MD, at Yale University, they identified early evidence for CSF anti-neural autoantibodies using mouse brain tissue to look for immunofluorescence. They identified some of the antibody targets using a combination of immunoprecipitation-mass spectrometry with rodent brain lysates and phage display. Then, they validated their finding in tissue culture cells engineered to express these antigens. Ultimately, five of the seven adults had evidence for CSF autoantibodies.

The immune response was so jazzed up, said Dr. Pleasure. It is not at all clear yet whether these antibodies, some of which appear to be cross-reactive between SARS-CoV-2 and neural antigens, are responsible for any of the neuropsychiatric symptoms.

The UCSF team now has samples from more than 50 COVID-19 patients who have unexplained neuropsychiatric symptoms. UCSF scientists are also studying patients with long-haul COVID, and Dr. Bartley said that they want to run the same types of experiments to see if they can identify auto-antibodies that may correlate with their enduring symptoms.

This is an important study that links infectious SARS-CoV-2 with neurological and neuropsychiatric complications in young people, said Carlos A. Pardo, MD, professor of neurology and pathology at Johns Hopkins Medicine and division of neuroimmunology and neuroinfectious disorders. The finding of auto-antibodies in spinal fluid is fascinating. It implicates the immunological responses in the brain, or unmasks the immunological responses against the brain.

We need to better characterize the mechanism of how the antibody triggers acute and long-term neuropsychiatric problems, added Dr. Pardo, who also studies CSF in patients with difficult neurological complications, including COVID-19. His laboratory recently published a study in The Journal of Neurological Sciences showing that almost 77 percent of patients with COVID-19 neurological complications had anti-SARS-CoV2 antibodies in their CSF.

The new study in JAMA Neurology opens the door to see how COVID triggers neurological and neuropsychiatric symptoms, he added. We are still a bit far away from recommending immune-based treatments.

There is currently great interest among neurologists regarding the potential for COVID infections to stir up an autoinflammatory process and induce autoimmunity resulting in a targeted immune attack against proteins in the brain, said Sean J. Pittock, MD, director of Mayo Clinic's center for multiple sclerosis and autoimmune neurology and of Mayo's neuroimmunology laboratory. Patients with COVID infections may develop encephalopathies but the immunopathological mechanisms underlying these remain unclear.

In this study, the UCSF scientists used their human phage display immunoprecipitation sequencing (testing for antibodies targeting the entire human proteome) and identified a multitude of autoantigens. The heterogenous autoantigen signature identified between patients indicates complexity and makes conclusions difficult, Dr. Pittock said. The identification of two potential novel targets in Case 1 is of interest but again the clinical implications remain unclear.

Many patients without autoimmune disease harbor autoantibodies (organ and non-organ specific).The two protein targets reported in this paper are intracellular proteins, thus it is unlikely that antibodies targeting such proteins are pathogenic, he added. Antibodies targeting intracellular proteins can indicate a pathogenic T cell response, however, if this were the case one would expect a more persistent and less responsive disorder than transient, as in these patients.

Overall, these findings are interesting and raise lots of questions which should stimulate more research in this area, Dr. Pittock said. Future studies investigating larger numbers of patients with COVID-associated encephalopathies will hopefully define the antibody, chemokine and cytokine signatures of this and other viral encephalopathies. This will further our understanding of these conditions and potentially identify therapeutic targets allowing repurposing of biologics for therapy.

He also said that although not applicable in this study, we must be careful in drawing too many conclusions: young patients develop primary psychiatric illness frequently, and when this diagnosis is combined with high levels of concomitant infection, there may or may not be a causal relationship.

The findings are pointing us in an intriguing direction, added Sarosh Irani, MD, associate professor at University of Oxford and head of the Oxford Autoimmune Neurology Group. These young people had atypical forms of encephalitis. The patients were identified retrospectively and it's not known if their neuropsychiatric symptoms would have occurred anyway or were due to COVID. Nevertheless, this is a very interesting preliminary finding and now needs validation in a larger consecutive cohort, ideally the pre-and post-COVID era.

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COVID-19 and Neuropsychiatric Symptoms in Teenagers : Neurology Today - LWW Journals