One of us (ER) recently had the pleasure of participating in two events with Susannah Cahalan, author of the intriguing book Brain on Fire: My Month of Madness. Susannah is a journalist, and her book, a New York Times best seller, describes her battle with a recently described illness that has psychiatric and neurologic manifestations. Symptoms may include hallucinations (hearing and seeing things that aren't real), delusions (fixed false beliefs inconsistent with one’s culture), and dissociative phenomena such as the feeling of being outside one’s body looking at oneself. Over time, Susannah developed marked language difficulties and a variety of movement abnormalities, including a syndrome known as catatonia (involving mutism, staring, and rigid posturing). Early in her disorder, she also had seizures, numbness, and other neurologic symptoms. 

Over the course of her illness, Susannah was hospitalized and evaluated by several physicians. Eventually, one remarkable doctor figured out that Susannah had a recently described disorder known as “anti-NMDA receptor encephalitis,” an autoimmune disease. (An autoimmune disease results from the body producing antibodies that attack substances normally found in the body; in this case, the antibody was directed against NMDA receptors, a type of glutamate receptor that plays a key role in brain function.) This diagnosis led to Susannah receiving immunologic treatments designed to combat the part of her immune system that was malfunctioning. Over several months, she improved to the point of full recovery.

In 2007, Josep Dalmau, a physician at the University of Pennsylvania, published an important paper describing and defining the illness that Susannah subsequently developed. Dalmau studied patients that demonstrated unusual, rapidly progressive, neuropsychiatric symptoms. He and his research team discovered that some of these patients were producing antibodies to a specific brain protein known as the NMDA receptor. What does this mean? Nerve cells communicate with each other by releasing chemical neurotransmitters that traverse the tiny gaps between these cells and activate specific proteins (receptors) located on the membranes of adjacent cells. One such neurotransmitter is known as glutamate. Glutamate is the major fast excitatory (stimulating) transmitter in the brain and can interact with a variety of different receptors, including a family of proteins known as NMDA receptors. Glutamate is involved in several crucial brain functions, including processes involved in learning, memory, and behavior. When a person produces antibodies to NMDA receptors, these antibodies block the ability of glutamate to activate the receptors, leading to marked changes in brain function and the clinical syndrome.

Interestingly, these same NMDA receptors are also blocked by certain hallucinogenic drugs. Two examples are angel dust (phencyclidine or PCP) and ketamine. These drugs are used by some people as recreational drugs because of the unusual mind-altering effects that they can cause. If a person takes angel dust, he or she may rapidly develop the same symptoms that Susannah experienced. When caused by PCP or ketamine, these symptoms usually subside rapidly (hours or days) as the drug is cleared from the body, allowing the NMDA receptors to resume normal functioning. Interestingly, alcohol also inhibits NMDA receptors, but it has other properties that prevent the psychotic actions associated with PCP. 

In anti-NMDA receptor encephalitis, the NMDA receptor is blocked for as long as the antibodies are present. Immunologic treatments that diminish the level of antibodies can lead to marked clinical improvement in about 75% of patients. Why a person’s body would produce antibodies against their own NMDA receptors is unknown. Some women with this disorder have been found to have a rare tumor known as an ovarian teratoma. Surgical removal of the tumor is necessary in order for the immunotherapies to work. In these cases, it is likely that the body produces the antibody in reaction to this particular type of tumor. Initially, it was thought that anti-NMDA receptor encephalitis occurred only in young woman with teratomas. However, it is now known that women without such a tumor may develop the disorder as can children and men. This means that there must be several mechanisms that trigger production of these antibodies.

It has been thought that anti-NMDA receptor encephalitis was rare. However, more is being learned about this and closely related disorders caused by autoantibodies to different substances, and such illnesses are now being found in some patients previously thought to have schizophrenia or other primary psychotic disorders. It is important to emphasize that most patients with psychotic illnesses such as schizophrenia do not have anti-NMDA receptor encephalitis. However, a recent paper suggests that anti-NMDA receptor antibodies may be present in some patients presently diagnosed with schizophrenia. If this proves to be true, it could have important implications for treatment.

As those of you who follow Demystifying Psychiatry know, we are proponents of the need for psychiatrists to be well versed in brain sciences. This type of expertise is in addition to, and not in place of, skills involving communication, diagnosis, and various kinds of treatments to help patients with severe behavioral disorders. Susannah Cahalan’s experience highlights the importance of psychiatrists keeping up-to-date with cutting-edge research in the field. The discovery of a molecular cause for neuropsychiatric disorders that can be successfully treated with immunotherapy is likely to lead psychiatrists, neurologists, and immunologists to work together to advance our understanding and subsequently develop better treatment of this and related disorders. 

This post was written by Eugene Rubin MD, PhD and Charles Zorumski MD.

About the Authors

Charles F. Zorumski, MD

Charles F. Zorumski, MD, is Samuel B. Guze Professor and Head of Psychiatry at Washington University in St. Louis - School of Medicine.

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