Brain on Fire: My Month of Madness（抗NMDA受容体脳炎患者の記録）
当院では3例の患者を経験しているが、1999年の症例（前任者が担当）は残念なことに学会発表されていなかった。1997年に藤田保健衛生大学神経内科野倉先生が卵巣奇形腫に伴う脳炎の世界初症例をActa Neurologica Scandinavicaに発表していた。
Nokura K, Yamamoto H, Okawara Y, Koga H, Osawa H, Sakai K. Reversible limbic encephalitis caused by ovarian teratoma. Acta Neurol Scand. 1997 Jun;95(6):367-73.
Department of Neurology, School of Medicine, Fujita Health University, Aichi, Japan.
A 19-year-old woman developed memory loss followed by psychosis, coma, convulsion, and central hypoventilation requiring mechanical ventilation. MRI of the brain showed minimal changes, and SPECT imaging revealed a small region of increased uptake in the cortex. Intravenous acyclovir and high-dose corticosteroids were administered without any effect. An extensive work-up revealed an elevated serum alpha-fetoprotein (AFP) concentration and the presence of an ovarian tumor. Following resection of the tumor, an immature teratoma by pathology, the patient had significant recovery of her cognitive function with some psychotic sequela. Serum anti-neuronal antibody (anti-Hu) was negative both by immunohistochemistry and by Western blot analysis. A rare combination of paraneoplastic limbic encephalitis and brainstem encephalitis was the suspected diagnosis. Because the tumor contained a neuronal component, we propose an immunologic cross-reaction as the pathomechanism, but the lack of a specific antibody may suggest cell-mediated rather than globulin-mediated immunity
Brain on Fire: My Month of Madness [Excerpt]
In a new memoir a young journalist traces her recovery from an autoimmune disorder that masqueraded as psychosis
By Susannah Cahalan
In 2009 Susannah Cahalan was a healthy 24-year-old reporter at the New York Post, one of the country’s oldest newspapers, when she suddenly developed a range of worrying symptoms. Her left hand went numb, paranoid thoughts obsessed her mind, and migraines and stomachaches beset her body. Initially diagnosed with mononucleosis, Cahalan continued to grow worse, eventually suffering a series of near-fatal seizures, psychosis, and a gradual loss of brain function. She ended up at New York University’s Langone Medical Center, where a team of doctors, led by neurologist Souhel Najjar, diagnosed her with a disease that had been discovered only two years earlier: NMDA-receptor autoimmune encephalitis. In this excerpt Cahalan tells the story of how University of Pennsylvania neuro-oncologist Josep Dalmau first identified the disorder.
Excerpt from BRAIN ON FIRE, by Susannah Cahalan. Copyright © 2012 by Susannah Cahalan. Reprinted by permission of Simon & Schuster, Inc., N.Y.
Four years earlier, in 2005, Dr. Dalmau had been the senior author on a paper in the neuroscience journal Annals of Neurology that focused on four young women who had developed prominent psychiatric symptoms and encephalitis. All had white blood cells in their cerebrospinal fluid, confusion, memory problems, hallucinations, delusions, and difficulty breathing, and they all had tumors called teratomas in their ovaries. But the most remarkable finding was that all four patients had similar antibodies that appeared to be reacting against specific areas of the brain, mainly the hippocampus. Something about the combination of the tumor and the antibodies was making these women very sick.
Dr. Dalmau had noticed a pattern in these four women; now he had to learn more about the antibody itself. He and his research team began to work night and day on an elaborate immunohistrochemistry experiment involving frozen sections of rat brains, which had been sliced into paper-thin pieces and then exposed to the cerebrospinal fluid of those four sick women. The hope was that the antibodies from the cerebrospinal fluid would bind directly to some receptors in the rat brain and reveal a characteristic design. It took eight months of tinkering before a pattern finally emerged.
Dr. Dalmau had prepared the rat brain slides all the same, placing a small amount of cerebrospinal fluid from each of the four patients on each. Twenty-four hours later…[f]our beautiful images, like cave drawings or abstract seashell patterns, revealed the antibodies’ binding to the naked eye. “It was a moment of great excitement,” Dr. Dalmau later recalled. “Everything had been negative. Now we became totally positive that all four not only had the same illness, but the same antibody.”
He had clarified that the pattern of reactivity was more intense in the hippocampus of the rat brain, but this was only the beginning. A far more difficult question now arose: Which receptors were these antibodies targeting? Through a combination of trial and error, plus a few educated guesses about which receptors are most common in the hippocampus, Dr. Dalmau and his colleagues eventually identified the target. Using a kidney cell line bought from a commercial lab that came with no receptors on their surfaces at all, a kind of “blank slate,” his lab introduced DNA sequences that direct the cells to make certain types of receptors, allowing the lab to control which receptors were available for binding. Dalmau chose to have them express only NMDA receptors, after figuring out that those were the most likely to have been present in high volume in the hippocampus. Sure enough, the antibodies in the cerebrospinal fluid of the four patients bound to the cells. There was his answer: the culprits were NMDA-receptor-seeking antibodies.
NMDA (N-methyl-D-aspartate acid) receptors are vital to learning, memory, and behavior, and they are a main staple of our brain chemistry. If these are incapacitated, mind and body fail. NMDA receptors are located all over the brain, but the majority are concentrated on neurons in the hippocampus, the brain’s primary learning and memory center, and in the frontal lobes, the seat of higher functions and personality. These receptors receive instructions from chemicals called neurotransmitters. All neurotransmitters carry only one of two messages: they can either “excite” a cell, encouraging it to fire an electrical impulse, or “inhibit” a cell, which hinders it from firing. These simple conversations between neurons are at the root of everything we do, from sipping a glass of wine to writing a newspaper lead.
In those unfortunate patients with Dr. Dalmau’s anti-NMDA-receptor encephalitis, the antibodies, normally a force for good in the body, had become treasonous persona non grata in the brain. These receptor-seeking antibodies planted their death kiss on the surface of a neuron, handicapping the neuron’s receptors, making them unable to send and receive those important chemical signals. Though researchers are far from fully understanding how NMDA receptors (and their corresponding neurons) affect and alter behavior, it’s clear that when they are compromised the outcome can be disastrous, even deadly.
Still, a few experiments have offered up some clues as to their importance. Decrease NMDA receptors by, say, 40 percent, and you might get psychosis; decrease them by 70 percent, and you have catatonia. In “knockout mice” without NMDA receptors at all, even the most basic life functions are impossible: most die within ten hours of birth due to respiratory failure. Mice with a very small number of NMDA receptors don’t learn to suckle, and they simply starve to death within a day or so. Those mice with at least 5 percent of their NMDA receptors intact survive, but exhibit abnormal behavior and strange social and sexual interactions. Mice with half their receptors in working order also live, but they show memory deficits and abnormal social relationships.
As a result of this additional research, in 2007, Dr. Dalmau and his colleagues presented another paper, now introducing his new class of NMDA-receptor-seeking diseases to the world. This second article identified twelve women with the same profile of neurological symptoms, which could now be called a syndrome. They all had teratomas, and almost all of them were young women. Within a year after publication, one hundred more patients had been diagnosed; not all of them had ovarian teratomas and not all of them were young women (some were men and many were children), enabling Dr. Dalmau to do an even more thorough study on the newly discovered, but nameless, disease.
“Why not name it the Dalmau disease?” people often asked him. But he didn’t think “Dalmau disease” sounded right, and it was no longer customary to name a disease after its discoverer. “I didn’t think that would be wise. It’s not very humble.” He shrugged.
By the time I was a patient at NYU, Dr. Dalmau had fine-tuned his approach, designing two tests that could swiftly and accurately diagnose the disease. As soon as he received my samples, he could test the spinal fluid. If he found that I had anti-NMDA-receptor autoimmune encephalitis, it would make me the 217th person worldwide to be diagnosed since 2007. It just begged the question: If it took so long for one of the best hospitals in the world to get to this step, how many other people were going untreated, diagnosed with a mental illness or condemned to a life in a nursing home or a psychiatric ward?