April Braker, a 30-year-old registered nurse, was four classes away from completing her master's degree and on her way to becoming a nurse practitioner. It was May 2018 and she had just started a new job at Rush University Medical Center's emergency department in Chicago when she started feeling odd. "I had just finished orientation at Rush," she recalled. "I started having weird symptoms -- headaches at first, then headaches with fever. I thought I had meningitis." She went to a community hospital for testing, then went home. When her symptoms persisted, she went to another hospital. "I called a stroke alert on myself, and one of my good friends responded," she recalled. "I managed to get admitted to the neurology floor. Within a week, I rapidly declined. I lost my ability to breathe. I spontaneously went into a comatose state." Diagnosing what caused Braker's coma took a while. Figuring out how to bring her out of it took much longer. Concerned that Braker had no diagnosis, a clinical friend found a paper about anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis, an immune-mediated disease that can strike young women. When Braker's cerebrospinal fluid tested positive for NMDA receptor antibodies, she was transferred to Stephen VanHaerents, MD, an epileptologist and specialist in autoimmune encephalitis at Northwestern Medicine in Chicago. Anti-NMDA receptor encephalitis can be tricky to diagnose, VanHaerents explained. "It's essentially a condition in which the immune system attacks the brain." First described in 2007, anti-NMDA receptor encephalitis is rare -- its incidence is estimated to be 1.5 per million people per year -- and is 4 times more prevalent in women than men. Patients develop a constellation of symptoms that vary depending on the stage of the disease. "The presentation can be different from patient to patient, but commonly include psychiatric symptoms and neurocognitive deficits," VanHaerents said. In the weeks before Braker became comatose, for example, her family reported she was uncharacteristically agitated, forgetful, even paranoid. Known triggers of NMDA receptor autoimmunity include tumors -- usually ovarian -- and herpes simplex encephalitis. About 80% of patients improve with immunotherapy and, if necessary, tumor removal. Braker was not one of those patients. "She was comatose when she came to Northwestern," VanHaerents said. "We put her on EEG and saw she had several seizures." VanHaerents also observed that Braker had a very specific EEG pattern for anti-NMDA encephalitis known as extreme delta brush. "We stabilized her, treated the seizures, and began immunotherapy," VanHaerents recalled. "We also looked for any potential neoplasm, which we found." Braker turned out to have a right ovarian teratoma, which was removed. She underwent multiple sessions of steroids, plasmapheresis, and intravenous immunoglobulins -- all with no response. No anti-NMDA receptor encephalitis treatments have been approved by the FDA, but clinicians tend to follow general guidelines, VanHaerents noted. When first-line immunotherapy didn't work, he turned to two second-line treatments, the anti-cancer agents rituximab (Rituxan) and cyclophosphamide, to try to wake Braker. "There's a big risk with patients like this," he noted. "The longer they stay in a coma, the more we worry about problems that could come up in the ICU. They could develop infections, especially if you're suppressing their immune system." But even with rituximab, cyclophosphamide, and additional plasmapheresis, Braker remained comatose. VanHaerents kept searching for an answer, calling colleagues around the country. He found case reports demonstrating how bortezomib (Velcade), a drug approved for multiple myeloma, had been used to treat several refractory cases of anti-NMDA receptor encephalitis. "Bortezomib is a proteasome inhibitor; it predisposes both short- and long-term plasma cells to apoptotic death," VanHaerents explained. At least two case series had been published about severe encephalitis patients who had been treated with the drug in Germany, including one in JAMA Neurology and one in Neurology. Then VanHaerents heard about another case at a large academic U.S. hospital. They told him their patient started to wake up after bortezomib therapy. "Their 'n of 1' was good," he said. "I had to convince our pharmacy and our critical care team that I wanted to try this medication based on these cases," he recalled. "They agreed. And so we did." And it worked. Braker received her first dose of bortezomib on August 9, 2018. A few weeks after starting bortezomib and 5 months after she first became comatose -- she began to wake up. "She was sort of there, but not really there," VanHaerents said. "She was very agitated, very combative." On Sept. 18, VanHaerents tested Braker's spinal fluid for NMDA receptor antibodies and "there wasn't even a detectable titer at that point," he said. "The bortezomib really got rid of it." By mid October, Braker could breathe on her own, but her recovery was still in its early stages. "She still was incredibly agitated and shockingly strong for someone who had been in a coma," VanHaerents said. "She pulled out her tubes and had to be restrained several times." In some patients who experience severe catatonia with anti-NMDA receptor encephalitis, electroconvulsive therapy (ECT) can help, VanHaerents noted. Working with Northwestern psychiatrist Lisa Rosenthal, MD, Braker started having "an amazing response" to ECT, he said. "She became more comfortable and began smiling. These were things she wasn't doing before because she was so agitated." After her second ECT session, she began to speak and follow simple commands. She continued ECT 3 days a week for a total of 10 sessions; her cognitive status waxed and waned, but she showed progressive improvement. "I think bortezomib woke her up and got her brain working," VanHaerents said. "But ECT really sped up her recovery." She started eating and drinking and with therapy, she regained much of her previous function. By April 2019 -- almost a year since she first sought treatment for her symptoms -- her IQ was in a normal range. "She's obviously very intelligent and is working very hard to get back to 100% but even at the level she's at now, she's functioning very well," VanHaerents said. Braker's case illustrates how treating anti-NMDA receptor encephalitis depends on many disciplines, he added. "This disease requires a lot of collaboration," he said. "Most patients start out in a psychiatric facility because they appear mentally ill. And once they're diagnosed correctly, it requires a huge team effort to figure out how to best care for them." Not every patient with anti-NMDA receptor encephalitis ends up in a coma and for those who do, bortezomib and ECT do not always work. But for April Braker, these treatments helped her reclaim her medical career. Last summer, Braker audited the last class she had taken before she became ill. "I wasn't ready to go back to graduate school full force, but I joined the class discussions, took the exams, and ended up doing well," she said. She officially re-enrolled in school this past September and plans to finish her master's degree in May. "It felt natural to get back to school," she said. "I'm not completely myself; I'd say I'm at 95%. But I'm pretty sure that eventually, I'll be better." Source
