Anti-NMDAR encephalitis is a rare autoimmune disease that causes severe neurological and psychiatric symptoms. These symptoms can range from movement disorder and psychosis to paranoid delusions . Recovery can range from months to years, but has improved with the development of immunotherapies. Still, the cause is unknown . Furthermore, this disease may provide insight into the past and present treatment for women in healthcare. In the past, it may have been said to be linked to cases of hysteria and demonic possession. In the present, it is an example of women’s struggle to receive psychiatric treatment. Finally, anti-NMDAR encephalitis represents the relationship between medicine and the media .
In the past, hysteria has been a common but unfounded diagnosis for women experiencing psychological issues. Previous treatments include hysterectomies, oophorectomies, and clitoridectomies. Some modern scientists suggest that the newly discovered anti-NMDAR encephalitis was responsible for these cases. The symptoms and patient population are congruent with hysteria; this encapsulates severe psychological issues in young women.
More commonly found in women, anti-NMDAR encephalitis is linked to ovarian tumors whose removal can improve the condition . Procedures removing the reproductive organs and possibly their tumors have reportedly occurred throughout history. It was primarily to treat women’s psychiatric issues. The most common of these operations was created by the 19th-century surgeon Robert Battey. Battey developed what he referred to as the “normal ovariotomy” to treat menstrual disorders and other symptoms. This was later used to treat psychiatric and neurological disorders in women. These sterilizations were often done without the permission of the patients. Still, surgeons continued to conduct them because the patients’ issues appeared to subside .
More uncommonly, it has been proposed that cases of “demonic possession” were, in fact, caused by anti-NMDAR encephalitis. Because it causes random, abrupt movement, and delusions of reality, it may have appeared supernatural in the past. Once again, because this encephalitis is more common in women, it may have led to myths that women are more susceptible to the supernatural or witchcraft .
Anti-NMDAR is an autoimmune disease that creates antibodies against NMDA receptors . Autoimmune diseases are characterized by the immune system attacking the body . The specific part of the body being attacked is the NMDA (N-methyl-D-aspartate) receptors. These proteins affect learning, judgment, perception, human interaction, memory, and unconscious activities (i.e., breathing, swallowing) . Specifically, the antibodies disrupt synapse function on the NR1 subunit of the NMDA receptor . This results in brain swelling and signal disruption, referred to as encephalitis .
A definitive cause is currently unknown. However, some possible links have been noted. Anti-NMDAR encephalitis is more common in young females and Asians/Pacific Islanders . According to the Encephalitis Society, 40% of patients are under 18 years of age .
Approximately 55% of cases in adults are associated with a tumor, typically an ovarian teratoma . This is much less common in men: only 5% experience a tumor . It is also uncommon in young children . However, it is more common in women, especially women between the ages of 20 and 35 . If a tumor is not found, it may be too small to detect, have been destroyed by the immune system, or not have been present at all .
There is also the possibility that anti-NMDAR occurs after an infection, which may trigger the production of anti-NMDAR proteins and overstimulate NMDA receptors . One of the more common viruses is herpes simplex virus (HSV) and, as such, an infectious disease team may need to be consulted .
Diagnosis typically begins with clinical symptoms followed by laboratory testing. The substances used in testing are blood serum or cerebrospinal fluid (CSF), which are checked for antibodies .CSF may also have elevated white blood cell count . Spinal fluid testing is often more specific and more sensitive than blood serum testing . To avoid false-negatives and false-positives, it is suggested to test both the serum and CSF .
Additional testing includes tumor imaging and an MRI . About half of patients have a normal MRI, but abnormal cases may show a lesion on the brain. Patients can also have an electroencephalogram (EEG) conducted, which assesses background electrical activity in the brain to detect seizures. Ninety percent of patients have slowed background frequencies, and the majority experience an abnormal EEG at some point . It has been suggested that increased levels of inflammatory cytokines in CSF cell-free mitochondrial DNA may serve as a biomarker for anti-NMDA encephalitis. .
The majority of patients experience multiple, often severe symptoms . Usually, the clinical symptoms progress in four stages: prodromal, psychotic, unresponsive, and hyperkinetic. In the prodromal phase, patients experience more mild, possibly viral symptoms, including a low-grade fever, headache, upper respiratory tract symptoms, fatigue, nausea, vomiting, and diarrhea. This stage may last up to 21 days .
Several symptoms are also related to behavior, which can result in NMDAR encephalitis being misdiagnosed as a psychiatric disorder. This occurs in about half of all cases. Psychiatric symptoms present during the psychotic stage, which usually occurs two weeks after the prodromal phase . In a retrospective study conducted by West China Hospital and Xuanwu Hospital, approximately 95% of patients exhibited one or more psychiatric symptoms. The prevalence and severity of symptoms also increased with a greater concentration of antibodies. Some of the more common psychiatric symptoms found are personality changes, suicidal ideation, delusions, mania, psychosis, insomnia, and catatonia . Typically, these psychiatric symptoms present prior to neurological symptoms, which begin 10-20 days later. Patients seldom experience only one of the two .
Neurological symptoms include cognition issues, memory deficiencies, speech disorders, loss of consciousness, movement disorders, seizures, and dysfunction of unconscious activities . Its effect on unconscious activities can cause complications, including breathing impairment, which may require the use of a ventilator . This leads to the unresponsive stage, where patients are often mute, especially young children; movement is also impaired. The hyperkinetic phase leads to instability in unconscious functions, hypo- or hypertension, hypo- or hyperthermia, cardiac arrhythmia, and hypoventilation .
Symptoms can present differently in different age groups, especially with very young children. Younger children often have hyperactivity and irritability. They often lack the full psychosis associated with adult patients . Patients over the age of 44 experience more psychiatric symptoms and memory deficits . Because patients receive a myriad of symptoms instead of a single one that is associated with anti-NMDAr encephalitis, care providers must be familiar with it to identify it swiftly . Despite this, the disease is not well-known to emergency physicians, who may be dealing with the admission of patients experiencing severe symptoms like psychosis or seizure .
First-line treatment includes removal of the tumor (should a tumor be present), steroids, plasma exchange, and intravenous immunoglobulin. Second-line treatment includes immunosuppressant drugs CellCept, Rituximab, and Cytoxan . The majority of treatments are designed to weaken the immune system. This either removes anti-NMDAR antibodies or decreases their circulation. Prognosis is better when treatment is begun earlier. However, misdiagnoses as a psychiatric disorder may complicate this . Patients may need additional treatments to ameliorate symptoms. Physical and speech therapy is also needed to regain function .
Length of recovery can range from months to years . The majority of patients recover within two years. Recovery becomes more likely with early diagnosis and treatment. Typically, the most severe symptoms resolve first, followed by cognitive, behavioral, and memory problems . Patients generally recover in a hospital, where they receive long-term care .
Younger patients, patients who had a tumor removed, and patients who received immunotherapy typically have better outcomes. Antibody concentration is not an ideal prognostic tool as the patient will have anti-NMDAR antibodies for the rest of their lives, even when the disease has subsided. . Patients with no underlying tumor have higher relapse rates and prolonged recovery time .
Overall, anti-NMDAR encephalitis appears to result in a disruption of synaptic function, not a substantial loss of synapses. This may contribute to the reversibility of symptoms. However, 25% of patients can experience long-term deficits in memory, cognition, and motor skills. In rare cases, anti-NMDAR encephalitis can be lethal . Approximately 6% of patients with anti-NMDAR encephalitis die . This is more common in older patients and patients with greater antibody concentration .
Modern Social Implications
Anti-NMDAR was only identified in 2007 by Dr. Dalmau at the University of Pennsylvania. The original sample was a group of twelve women, aged 14-44, who had developed severe psychiatric syndromes and were positive for antibodies . Afterward, this new discovery prompted an introspection into the past of healthcare. This led to discussions about the treatment of women, who may have been labeled “insane” or “hysterical” when they were experiencing genuine medical disorders. More discussion also surrounded ethics, where women did not consent to sterilizations conducted as treatment.
Despite modern progress, there are still concerns about women’s issues. Reportedly, women have experienced issues with receiving treatment for psychiatric disorders. Because anti-NMDAR encephalitis occurs predominantly in women and has severe psychiatric symptoms, some physicians are concerned that patients are unable to receive treatment. Rapid diagnosis and treatment are especially important in recovery, but several patients are misdiagnosed with psychiatric disorders and then receive improper treatment .
In popular culture, the novel Brain on Fire: My Month of Madness details a woman’s struggle with anti-NMDAR encephalitis. In her memoir, journalist Susannah Cahalan describes her treatment or lack thereof. For a month, she was plagued with misdiagnoses, ranging from “parties too much” to bipolar disorder. At the time, only 10 percent of patients with anti-NMDAR encephalitis were correctly diagnosed. This best-selling novel and subsequent film led to anti-NMDAR encephalitis becoming one of the more famous encephalitides. Since Cahalan’s bout, diagnosis, and treatment options have improved .
Despite its rarity, anti-NMDAR encephalitis is a prime example of the interdisciplinary nature of science. It ranges from neurology, psychiatry, history, gender studies, and general society. Science is not isolated, nor is medicine. This is reflected in the link to womens’ issues, which continues to discuss the treatment of women in healthcare. Battey’s sterilizations have passed, but women still struggle to receive proper treatment, especially for psychiatric issues. Moreover, it is a case of how the media links science, medicine, and society to change all three disciplines. Scientists, physicians, and the layman should not underestimate this.
I am a student at a biotechnology high school. There, I pursue my endeavors in healthcare finance, with a neuroscience and writing interest as well.