U of U Health researchers lead a $22-million nationwide clinical trial for rare brain disorder

University of Utah Health researchers are leading a five-year, $22-million nationwide clinical trial for NMDA receptor encephalitis––a type of autoimmune encephalitis that prompts the immune system to mistakenly attack the brain, causing confusion, memory loss, seizures, and symptoms similar to bipolar disorder and other psychiatric conditions.

The rare brain disorder, which became well-known through the best-selling book Brain on Fire by Susannah Cahalan, can also lead to a host of potentially life-threatening physical problems affecting the nervous system, heart, lungs, and kidneys.

The research, supported by the National Institute of Neurological Disorders and Stroke (NINDS), a branch of the National Institutes of Health (NIH), seeks to evaluate the safety of a new drug treatment, measure its effectiveness in improving quality of life, and identify clinical indicators called biomarkers that could help doctors predict how well patients will recover from NMDA receptor encephalitis.

“These are patients who are often previously healthy, young members of our community, who are stricken quite literally overnight, and who without good treatment and care for this condition can be left permanently disabled or, worse, can die,” says Stacey L. Clardy, M.D., Ph.D., the study’s principal investigator and a clinical researcher at U of U Health. Clardy also holds a joint appointment in the Division of Neuroimmunology at University of Utah’s Department of Neurology and at the George E. Wahlen Department of Veteran Affairs Medical Center. “If we diagnose and treat these patients promptly, however, we can get the majority of them back to a normal life.”

The researchers, located at 20 academic hospital sites nationwide (including U of U Health) that are part of the NeuroNEXT Clinical Trial Network, as well as two sites in Europe, are beginning to recruit newly diagnosed participants with anti-NMDAR for the clinical trial.

Encephalitis is an inflammation in the brain that can be caused by a virus or, as is the case in NMDAR encephalitis, by an autoimmune response that occurs when antibodies mistakenly attack cells in certain parts of the brain.

First identified in 2007, NMDAR encephalitis is one of the most common types of autoimmune encephalitis. It typically affects individuals, predominately women, aged 10 to 50. It disrupts the function of N-methyl-D-aspartate acid (NMDA) receptors in the brain. These receptors play a critical role in learning, memory, and behavior. If they are incapacitated, the mind and body can go haywire.

The condition can begin with less severe symptoms such as memory or mood problems but can rapidly intensify into aggressive behavior, delusional thoughts, seizures, speech disorders, and difficulty moving. The condition can also lead to abnormal heart rhythms, shortness of breath, and other physical problems.

The patients can go from zero to 60 very quickly, in terms of progression from healthy to quite ill. They can be fine one day and intubated—and in the intensive care unit—the next day.”

Stacey L. Clardy, M.D., Ph.D., study’s principal investigator

Even with prompt treatment, up to 50% of patients can suffer long-term consequences, especially cognitive and mood symptoms. Recovery is also often slow—over months to years—and patients require prolonged hospital stays. Compounding the situation, individuals with anti-NDMAR can initially be misdiagnosed with schizophrenia, bipolar disorder, or other psychiatric conditions, delaying treatment directed at the underlying autoimmune cause.

To date, the most effective treatments for anti-NDMAR encephalitis are a combination of medications that target the immune system in different ways, including corticosteroids, intravenous immune globulin (IVIg), and plasma exchange, followed by other longer-acting chemotherapies to suppress the activity of the antibodies attacking the brain. It remains unclear what the best combination of medications is to treat NMDAR encephalitis. The Food and Drug Administration (FDA) hasn’t yet approved any treatments for the condition.

That’s the aim of this clinical trial.

Clardy and colleagues will test whether an intravenous drug called inebilizumab is an effective treatment for NMDAR encephalitis. Inebiliumab is a monoclonal antibody that can neutralize the activity of B-cells, a type of white blood cell suspected of leading the assault on NDMA receptors in the brain. All participants will first be treated with steroids and then either IVIg or plasma exchange—the current standard of care—prior to starting the study. Over the course of the study, one group of participants will next be given inebilizumab, and another group will be given a placebo. All participants also receive IVIg at three weeks. For the weeks and months afterward, the progress of all participants will be assessed.

“Right now, we tend to throw the kitchen sink of available medications at these patients because they are so sick,” Clardy says. “This approach comes with risks—especially of serious infefctions. Hopefully, we can take a more rational, safe approach to treatment if inebilizumab proves to be effective. In the future, we would like to be able to provide these critically ill patients and their families with higher-quality data on which to base treatment decisions for NMDAR encephalitis.”