David Lynch, M.D., Ph.D.

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Suppose you thought that you were losing your identity—changing almost overnight and doing things you could not explain? This inexplicable scenario helps launch Brain on Fire: My Month of Madness, in which Susannah Cahalan chronicles her experience with the rare disorder anti-NMDA-receptor encephalitis. The onset of this newly identified entity results from the production of antibodies against the N-methyl-D-aspartate (NMDA). The NMDA receptor regulates synaptic plasticity in the brain and is critical for learning and memory. The syndrome evolves over days to weeks and presents as a psychosis similar to that seen in schizophrenia. Cahalan, who suffered from seizures and other neurologic symptoms, creates a medical detective story from a patient’s perspective as she captivatingly describes her descent into madness. The result is entertaining reading that gets us to think about the biological origins of our own personalities.

Cahalan presents her experience as a remembrance three years after the onset of her disorder. At the book’s beginning, she is a young reporter struggling to find story ideas that will resonate with her editors at the New York Post. Over several weeks, she gradually finds her personality changing as she begins suffering from paranoia and hallucinations and withdraws from her friends and colleagues. She describes her thoughts (as she perceives them at the time) and confusion about the origin of her symptoms. Associated with her uncertainty is the realization that the medical community has no explanation for her rapid change.

Eventually, Cahalan develops the neurological features that lead to a correct diagnosis by a medical team at the NYU Langone Medical Center. After weeks of downward spiraling, the team puts all the facts together and arrives at the answer: anti-NMDA-receptor encephalitis, a multistage, autoimmune disease that varies wildly in its presentation. Cahalan slowly recovers after undergoing immunomodulatory therapies (steroids, IVIG treatment, and plasmapheresis) in the hospital for a month, plus six months of outpatient follow-up.

For a neuroscientific audience, Cahalan’s story stimulates readers to think about the essence of the brain and the personality on several levels. First is the way that she portrays the early events of her encephalitis. She is never sure whether her bizarre behavior is being driven by a disease or is the result of reactions to stress or other events. These reactions include irrational fears of jealously, emotional lability, and even illusions that she can sense other people’s thoughts. Almost all of her friends attribute these behaviors to the demands of her job or to psychological issues, but she later realizes that they are subtle early symptoms of anti-NMDA-receptor encephalitis. To a neuroscientist, Cahalan’s attempt to decipher her symptoms represents the core of the discussion about where the neurological features of disease end and those of psychiatry begin. It also shows the overlap between these disciplines. In addition, with treatment, the changes in Cahalan’s personality reverse not immediately but over long periods of time. This is consistent with the idea of a resilient, structural basis of memory and personality that is attacked by anti-NMDA-receptor encephalitis but is then slowly rebuilt. One issue, which Cahalan describes, is that anti-NMDA-receptor encephalitis is associated with a significant amnesia for the period of acute illness. Cahalan was able to trigger exquisite firsthand details about the experience by revisiting her family’s notes, diaries, and recollections, and she points out that it is difficult to tell where her personal memory ends and others’ memories begin. This paradox gives readers fascinating insight into the way that people constantly construct their own perceptions.

Brain on Fire is also very effective as an illustration of the diagnostic odyssey of an individual with an unknown disease. Cahalan’s signs seem so clear as she presents them three years later, now that the number of individuals reported with anti-NMDA-receptor encephalitis has risen from several hundred to many thousands and the disorder is no longer a research curiosity. Cahalan was diagnosed and treated only after weeks of progression, after finally being admitted to a specialized neurology service in a tertiary care center—and even at that center, the tale is presented as if only one specialist was familiar with the condition. Viewed from that perspective, Cahalan could be considered lucky even to have received the correct diagnosis. The author does not condemn physicians unaware of the diagnosis, as she recognizes the difficulty in staying abreast of new developments in medicine. The book is dedicated to undiagnosed patients, a group that goes far beyond anti-NMDA-receptor encephalitis. Even in the age of whole-genome sequencing, the medical community lacks much information about even common diseases, much less rare ones. Good news is that the NIH Undiagnosed Diseases Program is currently undergoing revision and expansion, in recognition of the number of disorders that remain unknown and might become recognizable.

In some ways, Cahalan oversimplifies the medical and scientific communities. For example, she essentially attributes her diagnosis and the original discovery of anti-NMDA-receptor encephalitis to single individuals. This presentation fails to recognize the manner in which medical care is delivered by interactive teams and the collaborative way that science moves forward. But the perspective presented provides insight on how people outside the medical and scientific communities view their work, and suggests that there is a need for broader education on the collaborative nature of the scientific and medical fields, particularly as the available time for such collaboration decreases.

Another misperception reflects the increasing incidence of anti-NMDA-receptor encephalitis. As Cahalan notes in her discussions with neurological experts, it is easy to speculate that this disorder might be responsible for many episodes of demonic possession or mental illness throughout history. However, this speculation does not match present medical observations, as untreated anti-NMDA-receptor encephalitis is an almost uniformly debilitating disease; scientists have identified few spontaneous survivors who did not have ICU-level care in the acute period. Thus, it seems unlikely that this specific disorder caused such reversible events throughout history, though an as-yet-unappreciated variant conceivably could have done so.

After reading Cahalan’s riveting account, neuroscientists may wonder about the specific molecules that influence memory and personality, while physicians may contemplate where the next new disease will arise.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704309/

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 on November 16, 2012

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.

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?