Anti-N-methyl-D-aspartate receptor (Anti-NMDAR) encephalitis, a disease in which the body attacks the brain, was first discovered in 2007, and has been characterized by many as the possible root of demonic possessions. Symptoms of the disease often begin as flu-like, including fever and fatigue, and quickly progress to a psychotic stage, which begins with feelings of disorientation and confusion. This progresses to visual and auditory hallucinations, paranoia, and ultimately catatonia. Over the span of just a few weeks, individuals can go from healthy, successful people who are living full and busy lives, to patients being restrained in hospital beds, under strict 24-hour surveillance. An article written by Peery et al. in 2007 states: “ “Demonic possession” throughout history is the earliest appellation given to what may have been anti-NMDAR encephalitis”. Whether or not you’re a scary movie-junkie, the unfortunate truth is that movies about demonic possession, such as ‘The Exorcist’ and ‘Paranormal Activity’, may reflect real-life medical conditions, such as anti-NMDAR encephalitis.

Anti-NMDAR encephalitis was first discovered after a group of twelve women presenting a severe neuropsychiatric syndrome were studied. Since the first patients were diagnosed in 2007, the number of documented cases has greatly increased, which has led to the assumption that the disease is not rare (Wandinger et al., 2011). A finding of over 400 patients in a three-year period by one group solidifies this assumption; however, since the disease is still not well-known, many patients may be misdiagnosed as having a seizure disorder or some other psychiatric illness (Peery et al., 2007). This means that the disease may me much more common than one would expect. Unfortunately, the longer the disease goes undiagnosed, the longer the encephalitis has to damage the brain, meaning early detection is key to a full recovery.

Susannah Cahalan, author of “Brain on Fire: My Month of Madness” which is a book she wrote about her first-hand experience with the disease, vividly describes the first seizure she had when her body was first attacked by the disease. She shot straight up in bed, eyes rolling into the back of her head, while she started vomiting up blood, and foaming at the mouth. This detailed description may remind you of a famous scene in ‘The Exorcist’ where the main character, Regan, who is possessed by the devil, begins violently projectile vomiting on a priest. Furthermore, like Regan, after Susannah is cured, she has no memory of the ordeal she had endured. In fact, she described waking up alone in a hospital room, strapped to her bed, and unable to move or speak, with her hospital records chronicling a month-long stay in the hospital, of which she has no memory.

Image via: susannahcahalan.com

Anti-NMDAR encephalitis is widely linked ovarian teratomas in females, and, not surprisingly, roughly 80% of patients with the disease are female. The disease has also been linked to other types of tumors, including brain tumors and testicular tumors. Seeing as anti-NMDAR encephalitis has been linked to various tumors, it is characterized as a paraneoplastic syndrome, meaning it has been caused by cancer. However, not all cases of anti-NMDAR encephalitis are accompanied by a tumor, which is actually unfortunate, because it seems that the disease is much easier to treat when it is caused by a tumor, because the tumor can easily be removed (Dalmau et al., 2007). In the Cahalan case, symptoms were not caused by a tumor, and because of this her road to recovery was quite slow.

While the link to tumors is clear, the major defining feature of the disease is the autoantibodies targeting NMDA-type glutamate receptors (Fig. 1). NMDA receptors are ligand-gated cation channels that play critical roles in synaptic transmission and plasticity. The receptor is built from two different subunits called NR1 and NR2, with the NR1 subunit binding glycine, and the NR2 subunit binding glutamate. With an autoimmune disease such as anti-NMDAR encephalitis, the patients own immune systems generates antibodies against cellular proteins, in this case the NR1 subunit of the receptor (Dalmau et al., 2008). The attack of the healthy NMDA-receptors by the antibodies will cause inflammation of the brain, which mainly affects the frontal and temporal lobes of the brain (Fig. 2). These lobes are involved in functions such as processing sensory input, emotion, comprehending language, and cognition. Given the functions of these regions of the brain, it is no surprise that patients suffering from anti-NMDAR encephalitis suffer from delusions, loss of speech, and memory deficits.

Figure 1: NR1 subunit of glutamate receptors (type NMDA) being attacked by antibodies. Figure 2: Image of a human brain, indicating the various lobes.

Diagnosis of the disease is widely based on brain imagine techniques, such as MRI or EEG. Doctors can be tipped off to the presence of the disease, via the detection of abnormalities in the cerebrospinal fluid, like an uncharacteristically high amount of white blood cells. This is, in conjunction with psychiatric symptoms, is what made the doctor who was in charge of the Cahalan case look into the possibility of anti-NMDAR encephalitis as the disease affecting Susannah. After the preliminary test results, the presence of NMDAR autoantibodies in Susannah’s cerebrospinal fluid showed that anti-NMDAR encephalitis was, in fact, the underlying cause of all the strange symptoms.

Treatment of the disease generally begins with immunotherapy, and then the detection and removal of the tumor, if one is present. Most patients receive corticosteroids, to control the swelling, and intravenous immunoglobulin, or plasma exchange. If no tumor is found in the patient, or if diagnosis is not rapid, additional immunotherapy is often necessary, with patients receiving additional treatments with intravenous immunoglobulin (Wandinger et al., 2011). Once diagnosed, roughly 75% of patients fully recover, or only suffer mild long-term complications; the other 25% of patients remain severely disabled from the disease, or die.

If we were paralleling this to other parts of the world, or earlier times when less was known about diseases affecting the mind, people with anti-NMDAR encephalitis may have easily been subjected to exorcisms, or various gruesome forms of “treatment”. Attempts to treat mental illness have been dated as far back as 5000 BC, which is evident due to the discovery or trephined skulls from ancient civilizations. Early civilizations believed that mental illness was due to phenomena such as demonic possession, and attempted to rid one’s head form the “evil spirit” that inhabited it, by chipping a hole, or trephine, into the skulls using various instruments, and allowing the spirit to be released (Porter, 2002).

The process of recovery is a multi-step process that basically occurs in the reverse order of how the symptoms first present themselves. The patients will gradually awaken from their coma, and their autonomic functions begin to stabilize, and muscular movements begin to be controlled. Typically, full recovery from the disease is slow, ranging from a few months to over a few years. In most cases, patients have to re-learn how to write, walk, and speak. In the Cahalan case, once Susannah started treatment, she slowly regained conscious thought, and within several weeks she was able to walk and speak. In her book, she writes about the frustration of knowing that she had not yet gotten back to her old self. She recalls speaking in short, simple sentences, and her movements were jerky and robotic. It wasn’t until almost six months after her treatment began that Susannah felt as if she was “normal” again. Relapse is possible, although uncommon, and the median time between initial presentation of the disease and relapse is roughly 18 months. Relapse occurs much less often in patients with early tumor treatment, and in patients that had no associated tumors (Wandinger et al., 2011).

To wrap everything up, as you can see, the frightening symptoms brought about by anti-NMDAR encephalitis have a similar onset and can be closely paralleled with symptoms portrayed in movies like “The Exorcist” and “Paranormal Activity”. Its scary to think of how many people throughout time have been subjected to things like exorcisms or, how many people might currently be locked up in mental health institutions across the world, with misdiagnoses of schizophrenia, or “undiagnosed psychosis”, when they may simply have been suffering from a treatable autoimmune disease. Thanks to a great team of doctors working on the Cahalan case, Susannah did make a full recovery, and was able to return to her full time job as an editor at the New York Post. Hopefully, doctors and psychiatrists now know enough about this disease to recognize it early on, and prevent any more unnecessary misdiagnoses!

[Featured image via: Shutterstock.com]

References

Dalmau J; Gleichman AJ; Hughes EG; Rossi JE; Peng X; Lai M; Dessain SK; Rosenfeld MR; Balice-Gordon R; Lynch DR. (2008). Anti-NMDA-receptor encephalitis: Case series and analysis of the effects of antibodies. The Lancet Neurology 7 (12): 1091–8. dii:10.1016/S1474-4422(08)70224-2

Dalmau J; Tüzün, E; Wu H; Masjuan J; Rossi JE.; Voloschin A; Baehring JM; Shimazaki H; Koide R; King D; Mason W; Sansing LH.; Dichter MA.; Rosenfeld MR; LR. (2007). Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Annals of Neurology 61 (1): 25–36. doi:10.1002/ana.21050



Peery HG; Day GS; Dunn S et al. (2012) Anti-NMDA receptor encephalitis: The disorder, the diagnosis and the immunobiology. Autoimmun Rev. 11 (12): 863–872. doi:10.1016/j.autrev.2012.03.001

Porter, Roy. Madness: A Brief History. New York City: Oxford University Press, 2002.

Wandinger KP; Saschenbrecker S; Stoecker W; Dalmau J. (2011) Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. J Neuroimmunol 231:86–91. doi:10.1016/j.jneuroim.2010.09.012