'Rogue' antibodies found in brains of teens with delusions and paranoia after COVID-19

Two teenagers developed severe mental symptoms, including paranoia and delusions. They were suffering from mild COVID-19 infection. Scientists now believe they have identified the trigger: It could be that the teens were mistakenly infected with rogue antibodies, not the coronavirus.
Researchers discovered these rogue antibodies after two teenagers were examined at the University of California San Francisco (UCSF), Benioff Childrens Hospital. They had contracted COVID-19 in 2020. The new report published in JAMA Neurology Monday, Oct. 25, reports that the researchers found the cases. The antibodies were found in patients' cerebrospinal Fluid (CSF), which is a clear fluid that flows in and around hollow spaces in the brain and spinal cord.

Researchers wrote that although such antibodies could attack brain tissue, it is too early to conclude that they directly caused the troublesome symptoms seen in teens. This is because many of the antibodies identified appear to target structures on the inside of cells rather than the outside. Dr. Samuel Pleasure (a doctor-scientist and professor at UCSF) explained this to Live Science via email.

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He said that the COVID antibodies, which are antibodies that target the body and not the virus, "are likely to be indicative of an out-of-control autoimmune response that may be driving the symptoms without the antibodies necessarily causing them directly." He said that future studies are needed to confirm this hypothesis and to determine if any other undiscovered autoantibodies target cells' surface structures and cause damage.

Dr. Grace Gombolay is a pediatric neurologist at Children's Healthcare of Atlanta. She was also an assistant professor at Emory University School of Medicine and wasn't part of the new study. The results of the study show that COVID-19 can trigger brain-targeting antibodies. She also suggested that in some cases, treatment that "calms down" the immune system might help to resolve the psychiatric symptoms associated with COVID-19.

The treatment used to reset the immune system in autoimmune or inflammatory disorders was administered intravenously to both teens. After that, the teens experienced a complete recovery. Gombolay said that it is possible that the patients could have "improved themselves" without any treatment.

Although a possible mechanism has been identified, there are many questions.

Gombolay stated that other viruses, such as the herpes simplex virus, can cause antibodies to attack brain cells and trigger inflammation, which can lead to neurological symptoms. It is possible to speculate that a similar association could be observed in COVID-19.

The study authors had previously published evidence of neural antibodies in COVID-19 adults before they began their research on teens. The May 18th Cell Reports Medicine report stated that these adults suffered seizures, loss in smell, and difficult-to-treat headaches. Most of them were also hospitalized for COVID-19 symptoms.

Pleasure stated that the teens had very minimal symptoms of respiratory disease. Pleasure stated that this suggests that mild respiratory COVID-19 may be a trigger for such symptoms.

In 2020, 18 children or teens were admitted to UCSF Benioff Children's Hospital. They had COVID-19 confirmed. The patients were tested with either a rapid antigen test (PCR) or a rapid antigen test. The study authors selected three teenagers from this group to focus on the new case study. They underwent neurological evaluations.

One patient suffered from unspecified anxiety and depression. They developed paranoia and delusions after contracting COVID-19. Unspecified anxiety and motor symptoms were a common problem in the second patient. They experienced mood swings, suicidal thoughts, aggressive behavior, and rapid mood changes. The patients also had difficulty with homework completion, impaired concentration, and "foggy brain". After exhibiting repeated behaviors, disordered eating and agitation for several days, the third patient had no psychiatric history.

Each teen was subject to a spinal tap. This involves a drawing of CSF from the lower back. The CSF from all three patients showed elevated levels of antibodies. However, only patients 1 and 2 had antibodies against SARSCoV-2, which is the virus that causes COVID-19. The study authors suggested that the virus could have infiltrated the brains and spinal chords of the teens. Pleasure stated that although it seems like there has been a temporary viral invasion, there is still uncertainty.

The same patients also had neural autoantibodies in their CSF. In mice, this team discovered that the antibodies latch onto multiple areas of the brain including the brain stem, cerebellum, cortex, and the olfactory bulbs, which are involved in smell perception.

Lab-dish experiments were then used to determine which targets the neural antibodies seized onto. Researchers identified a variety of targets but narrowed in on one: transcription factor 4. According to a report published in the journal Translational Psychiatry in 2021, mutations in TCF4's gene can lead to a rare neurological disorder, Pitt-Hopkins syndrome. Some studies suggest that dysfunctional TCF4 could be responsible for schizophrenia.

These results suggest that autoantibodies may contribute to an immune system that produces psychiatric symptoms in COVID-19 patients. However, this small study can't prove that antibodies directly cause disease. These symptoms may also be caused by other immune-related factors than antibodies.

Although these autoantibodies are clinically most relevant as indicators of immune dysregulation, we have not found any evidence that they cause patients' symptoms. "There is certainly more work to do in this area," Dr. Christopher Bartley (co-first author), an adjunct instructor in psychiatry, at the UCSF Weill Institute for Neurosciences said in a statement.

Gombolay stated that future studies will be more useful if CSF from children with COVID-19 without neuropsychiatric symptoms is compared to those who do. However, it is difficult to obtain CSF from these patients as CSF must be taken by a spinal tap. A spinal tap is usually not done if a patient is suffering from neurological symptoms.

Pleasure stated that the team is currently collaborating with other groups who study long COVID and are collecting CSF samples of patients with and without neuropsychiatric symptoms. It is not unusual for adults to consent to a spinal tap to be done for research purposes, provided that they have received institutional review and informed consent. The team will use these samples and some animal models to identify the autoimmune mechanisms that cause these neuropsychiatric symptoms. They will also look into how autoantibodies can be used in this process.

Original publication on Live Science