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When the brain is under attack

A new disease at the crossroads of psychiatry and neurology could help in the understanding of psychosis

Josep Dalmau, a neurologist at the University of Pennsylvania, and his lab have conducted important research into anti-NMDA receptor encephalitis.FRANCISCO AVIA

Annalisa Meier dreamed about moving to Manhattan for college and voting in her first presidential election in 2008. But with freshman year about to begin, the assertive and lively 18-year-old’s behavior changed. She grew indecisive, withdrawn, and quick to anger.

Then, Meier had a seizure.

Susannah Cahalan was a young New York Post reporter when she started to forget assignments. She became fixated on the idea that her home was infested with bedbugs. Paranoid and irrational, she laughed and cried inappropriately, moods rocketing from euphoria to intense sadness.

She thought it must be stress, or the flu. One doctor told her she had mono. Her parents suspected she was on the verge of a nervous breakdown. Then she, too, had a seizure.


The women’s slow unraveling could have been the beginning of a psychotic break, followed by a lifetime of hospitalization and medication.

Instead, they were found to have a newly described disease called anti-NMDA receptor encephalitis, caused when the body’s immune system goes haywire and attacks a protein in the brain. The protein, the NMDA receptor, helps neurons communicate; it is the same receptor that’s blocked by PCP or ketamine — both drugs that can make a normal person act like someone with schizophrenia.

The disease typically strikes young women, but also can affect men and children. It can begin subtly, with a change in behavior, often after a headache or flu-like illness. Symptoms worsen to include agitation, paranoia, delusions, or hallucinations. Then seizures begin. Psychosis worsens. Blood pressure might plummet. Patients could ultimately grow sick enough to require a breathing tube. Some slip into a state of complete unresponsiveness. But with aggressive therapies to suppress the immune system, most awaken to return to normal lives.

Experts suggest that the disease and others like it — at the intersection of psychiatry and neurology — can broaden our understanding of the basis of psychosis and, perhaps, in some cases, its treatment.


“We are learning more even as we speak,” said Sander Markx, a psychiatrist at Columbia University who studies the genetics of psychiatric disorders, such as schizophrenia. The discovery of the disease “seems to be the beginning of a much larger story that is leading to a paradigm shift in neurology and psychiatry,” he said.

Some speculate anti-NMDA receptor encephalitis could be behind historical descriptions of what was believed to be demonic possession. Cahalan described her first seizure in a book about her experience, “Brain on Fire”: “My arms suddenly whipped straight out in front of me, like a mummy, as my eyes rolled back and my body stiffened. I was gasping for air. . . . Blood and foam began to spurt out of my mouth through clenched teeth.”

But the autoimmune disease wasn’t identified until Josep Dalmau, a neurologist at the University of Pennsylvania, was called to see a patient in the intensive care unit in 2002. The woman had come in months before, agitated and hallucinating. By the time Dalmau arrived, she couldn’t speak and could breathe only with the aid of a ventilator. She’d gone through “a million dollars’ worth of tests,” Dalmau recently recounted. All were negative.

Before coming to Pennsylvania, Dalmau had trained as a neuro-oncologist — a physician who specializes in the vast and mysterious brain manifestations of cancer. His colleagues suspected that this patient might have a tumor hiding somewhere, causing her strange symptoms. She did have a small growth on her ovary, called a teratoma, but it was the kind of finding “you wouldn’t normally pay too much attention to at that time and in a severely ill patient undergoing intensive care support,” Dalmau said.


He took samples of her blood and spinal fluid to his lab. The spinal fluid showed evidence of inflammation, but nothing specific. Her condition continued to worsen. With little left to lose, the physicians decided to give her medication to suppress her immune system; it was a Hail Mary. Remarkably, she recovered.

Before long, colleagues referred three more patients to Dalmau, each with teratomas, whose stories were eerily similar: young women with behavioral and personality changes that degenerated into severe neurological impairment. But with removal of the teratoma and immune-suppressing medication, three of the four women recovered. Armed with blood and spinal fluid samples of all four, Dalmau and his team began a hunt for the source.

In Dalmau’s lab, researchers exposed slices of rat brains to the patients’ spinal fluid. The rat brains lit up with evidence of an attack by immune-system cells called antibodies, which presumably were produced as part of the body’s response to the patients’ teratomas. Dalmau and his team hadn’t identified the specific antibody at fault, but given the risk that the curable disease could be misdiagnosed, Dalmau published his findings in 2005.

By 2007 he had described 12 patients, and the disease had a name: “anti-NMDA receptor encephalitis.”


For decades, physicians including Joseph Coyle, a psychiatry professor at Harvard’s McLean Hospital in Belmont, have hypothesized that poor functioning of the NMDA receptor plays a role in schizophrenia.

But the idea that the body itself might attack the NMDA receptor was new. Days after his second article was published, Dalmau’s inbox was flooded. Physicians from around the world had similar cases of patients both with and without ovarian teratomas, and they were eager for Dalmau’s lab to test their patients’ samples.

Cahalan would ultimately be one of those patients. But, as she describes in her book, it would take time. After the then 24-year-old suffered her first seizure, a neurologist suggested she was simply partying too hard and prescribed her an epilepsy medication. A psychiatrist gave her an antipsychotic used to treat bipolar disorder.

Her thoughts grew more jumbled. She seized again. She stopped sleeping, and believed her father had taken her prisoner. Finally, at her mother’s urging, she was admitted to a neurologic unit at a New York hospital.

When she arrived, Cahalan began to seize on the floor of the hospital lobby, and she remembers almost nothing of her time there. She wrote in her book: “The break between my consciousness and my physical body was now fully complete. In essence, I was gone. . . . This was the beginning of my lost month of madness.”

As she grew increasingly psychotic and her neurologic symptoms worsened, a new neurologist was called to consult on her case. Tests for anti-NMDA receptor encephalitis were sent to Dalmau’s lab; they returned positive. Cahalan started to receive “intravenous immunoglobulin,” a medication that fights the misdirected immune system, and her long recovery began.


Cahalan has since returned to work at the Post. With appropriate diagnosis and treatment, more than 80 percent of patients have a good outcome. Annalisa Meier, too, is doing well. After three months in the intensive care unit and many more at rehab, she is now a junior at Columbia University studying gender relations in Latin America. She voted in her first presidential election last year.

Cahalan wonders where she would be now had she gotten sick earlier.

“Just a couple of years mark the difference from me being treated for an autoimmune disorder versus a psychiatric one,” Cahalan said. “It just shows how far we must still have to go.”

Markx, the Columbia psychiatrist, met Dalmau a few years ago, after Markx had just cared for two patients with anti-NMDA receptor encephalitis. “This was eye-opening for me,” Markx said.

“What if people were walking around with a psychiatric diagnosis, treated with psychotropic medications, but who may in fact have a potentially curable auto-immune disease?” he said. That is, could patients who have been diagnosed with schizophrenia actually have anti-NMDA receptor encephalitis?

The question remains unanswered.

As Cahalan’s experience suggests, a patient early in the disease process might be hard to distinguish from someone with a first episode of schizophrenia, or other psychiatric disease.

Markx and Dalmau are planning to collaborate with German researchers to study patients who have either come to the hospital with a “first break” — an initial episode of psychotic symptoms — or who are showing early signs, such as social withdrawal or cognitive problems, that typically precede the onset of psychosis. Blood and spinal fluid samples from these patients will be tested for antibodies to the NMDA receptor, and other antibodies. The results might change psychiatry’s approach to patients with new-onset psychosis, Markx said.

“We may only find that a small number of people who initially present with predominantly psychiatric symptoms have an auto-immune condition, but even if it’s only a small fraction, having a potential cure that is as dramatic as Susannah’s story is something that’s worth finding out,” Markx said.

Dr. Daniela J. Lamas can be reached at DanielaLamasMD@gmail.com.