A Look Into the "Brain on Fire" Disease
You may have seen the movie “Brain on Fire” on Netflix or read the novel “Brain on Fire: My Month of Madness” written by Susanah Cahalan. Both the novel and film tell Cahalan’s story of suffering from the strange disorder: Anti-NMDA Receptor Encephalitis. Her story of battling this disorder is truly remarkable and inspiring. Anti-NMDA Receptor Encephalitis is an autoimmune disease caused by the body synthesizing antibodies which attack N-methyl-D-aspartate receptors (NMDAR’s) in the brain. What triggers this autoimmune response is still uncertain, as this disease was only discovered in 2007 by Dr. Joseph Dalmau.
Dr. Dalmau noticed that the majority of encephalitic patients were female and diagnosed with a tumor, particularly, an ovarian teratoma. Ovarian teratomas express NMDAR’s, which the body treats as foreign bodies and subsequently, creates antibodies of type IgG to attack them. These antibodies will eventually spread to the brain, where individuals will progressively suffer from worsening symptoms. Patients may often experience psychosis and schizophrenia-like symptoms, such as delusions and hallucinations. Patients may also experience behavioral shifts, including being more anxious or aggressive. If left untreated, patients will later suffer from seizures and catatonia. Anti-NMDAR Encephalitis can be fatal if treatment, such as immunosuppressive therapy or tumor removal, is not administered in time. Fortunately, patients may recover from this disease, but the percent of cognitive restoration depends on how swiftly the treatment is given. The sooner patients are treated, the more their cognition will be restored.
What causes the severity of these symptoms? NMDAR’s are crucial for learning and memory; they play a key role in synaptic plasticity which is a process that determines how neurons communicate according to learning and experiences. NMDA hypofunction (a decrease in NMDA activity) can prove to be very harmful to one’s cognition and behavior. In fact, the many theories that explain the causes of schizophrenia revolve around NMDA hypofunction and explain why encephalitic patients commonly experience hallucinations and delusions.
What makes this disease reversible? Dr. Dalmau published a paper in 2008, in which he observed the antibodies’ reversible effect in the hippocampus of rats. The hippocampus is a region of the brain responsible for memory consolidation, and is especially rich in NMDAR’s. Rat neurons were infused with patient’s antibodies, which caused clusters of NMDAR’s to decrease. After stopping this infusion for several days, Dr. Dalmau noticed that NMDAR clusters were increasing back to baseline. This explains the cognitive restoration of patients after being given treatment, but the exact mechanism for this reversibility is still unknown.
Because the early symptoms pertain to changes in behavior and one’s mental state, patients will often seek help from psychiatrists. In addition, since Anti-NMDAR Encephalitis is a widely unknown and underdiagnosed disorder, psychiatrists will misdiagnose encephalitic patients with schizophrenia and will refer them to psychiatric institutions. Once admitted to these institutions, patients will have progressed to the late stage of symptoms, such as catatonia, and will be closer to death. Spoiler alert: this is similar to what Cahalan experienced and reflects the core of her message, which is to raise awareness of this disorder so that less individuals are misdiagnosed.
The most interesting aspect of this disease is that it can easily be diagnosed, yet many patients in the past were left to die in psychiatric institutions without access to treatment. Examining the cerebrospinal fluid (CSF) of patients and determining if there is an abnormally low amount of NMDARs is typically how this disease is diagnosed. Dr. Najjar, the doctor who diagnosed Cahalan, noticed that Cahalan was unable to draw a clock - her drawing depicted a clock with all the numbers to the right side. This was because the NMDA receptors in the right hemisphere of her brain were being internalized by antibodies, meaning that Cahalan was unable to process images from her left visual field. The simple task of drawing a clock saved Cahalan’s life, as her medical team was finally able to eliminate a diagnosis of schizophrenia.
If you have only watched the film “Brain on Fire”, I would strongly suggest also reading the novel written by Cahalan. The novel is very detailed and difficult to put down. With Cahalan’s story, it can only be hoped that more information and awareness will be spread about this fatal disease.
References:
https://www.med.upenn.edu/autoimmuneneurology/nmdar-encephalitis.html
Newcomer JW, Farber NB, Olney JW. NMDA receptor function, memory, and brain aging. Dialogues Clin Neurosci. 2000 Sep;2(3):219-32.
Kayser MS, Dalmau J. Anti-NMDA receptor encephalitis, autoimmunity, and psychosis. Schizophr Res. 2016 Sep;176(1):36-40.
Florance NR, Davis RL, Lam C, Szperka C, Zhou L, Ahmad S, Campen CJ, Moss H, Peter N, Gleichman AJ, Glaser CA, Lynch DR, Rosenfeld MR, Dalmau J. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009 Jul;66(1):11-8.
