Anti-NMDA receptor encephalitis

Anti-NMDA receptor encephalitis, also known as NMDA receptor antibody encephalitis, is an acute form of encephalitis that is potentially lethal but has a high probability for recovery with treatment. It is caused by an autoimmune reaction, primarily against the NR1 subunit of the NMDA receptor (N-methyl D-aspartate receptor).^[1]

The condition is associated with tumours, mostly teratomas of the ovaries, and thus can be considered a paraneoplastic syndrome. However, there are a substantial number of cases with no detectable tumour, and in fact it appears that most patients do not have a tumour.^[2]

The disease was officially categorized and named by Josep Dalmau and colleagues in 2007.^[3]

Signs and symptoms

Prior to the development of a symptom complex that is specific to anti-NMDA receptor encephalitis, people may experience prodromal symptoms, including headaches, flu-like illness, or symptoms similar to an upper respiratory infection. These symptoms may be present for weeks or months prior to disease onset.^[1] Beyond the prodromal symptoms, the disease progresses at varying rates, and patients may present with a variety of neurologic symptoms. During the initial stage of the disease, symptoms vary slightly between children and adults. However, behavior changes are a common first symptom within both groups. These changes often include agitation, paranoia, psychosis, and violent behaviors. Other common first manifestations include seizures and bizarre movements, mostly of the lips and mouth, but also including pedaling motions with the legs or hand movements resembling playing a piano. Some other symptoms typical during the disease onset include impaired cognition, memory deficits, and speech problems (including aphasia, Perseveration or mutism).^[4][5]

The symptoms usually appear psychiatric in nature, which may confound the differential diagnosis. In many cases, this leads to the illness going undiagnosed.^[6] As the disease progresses, the symptoms become medically urgent and often include autonomic dysfunction, hypoventilation, cerebellar ataxia, hemiparesis, loss of consciousness, or catatonia. During this acute phase, most patients require treatment in an intensive care unit to stabilize breathing, heart rate, and blood pressure. Loss of feeling in one side of the body can be a symptom.^[7] One distinguishing characteristic of anti-NMDA receptor encephalitis is the concurrent presence of many of the above listed symptoms. The majority of patients experience at least four symptoms, with many experiencing six or seven over the course of the disease.^[4][5]

Pathophysiology

Antibodies in serum and cerebrospinal fluid

The condition is mediated by autoantibodies that target NMDA receptors in the brain. These can be produced by cross reactivity with NMDA receptors in teratomas, which contain many cell types, including brain cells, and thus present a window in which a breakdown in immunological tolerance can occur. Other autoimmune mechanisms are suspected for patients who do not have tumours. Whilst the exact pathophysiology of the disease is still debated, empirical evaluation of the origin of anti-NMDA antibodies in serum and cerebrospinal fluid leads to the consideration of two possible mechanisms.

These mechanisms may be informed by some simple observations. Firstly, serum NMDA-receptor antibodies are consistently found at higher concentrations than cerebrospinal fluid antibodies, on average ten times higher.^[2][8] This strongly suggests the antibody production is systemic rather than in the brain or cerebrospinal fluid. When concentrations are normalised for total IgG, intrathecal synthesis is detected. This implies that there are more NMDA-receptor antibodies in the cerebrospinal fluid than would be predicted given the expected quantities of total IgG.

1. Passive access involves the diffusion of antibodies from the blood across a pathologically disrupted blood-brain barrier (BBB).^[9] This cellular filter, separating the central nervous system from the circulatory system, normally prevents larger molecules from entering the brain. A variety of reasons for such a collapse in integrity have been suggested, with the most likely answer being the effects of acute inflammation of the nervous system. Likewise, the involvement of corticotropin releasing hormone on mast cells in acute stress has been shown to facilitate BBB penetration.^[10] However, it is also possible that the autonomic dysfunction manifested in many patients during the later phases of the condition aids antibody entry. For example, an increase in blood pressure would force larger proteins, such as antibodies, to extravasate into the cerebrospinal fluid.
2. Intrathecal production (production of antibodies in the intrathecal space) is also a possible mechanism. Dalmau et al. demonstrated that 53 out of 58 patients with the condition had at least partially preserved BBBs, whilst having a high concentration of antibodies in the cerebrospinal fluid. Furthermore, cyclophosphamide and rituximab,^[11] drugs used to eliminate dysfunctional immune cells, have been shown to be successful second-line treatments in patients where first-line immunotherapy has failed.^[12] These destroy excess antibody-producing cells in the thecal sac, thus alleviating the symptoms.

A more sophisticated analysis of the processes involved in antibody presence in the cerebrospinal fluid hints at a combination of these two mechanisms in tandem.

Antibodies to NMDA receptors

Once the antibodies have entered the CSF, they bind to the NR1 subunit of the NMDA receptor. There are three possible methods in which neuronal damage occurs.

1. A reduction in the density of NMDA receptors on the post synaptic knob,due to receptor internalisation once the antibody has bound. This is dependent on antibodies cross linking.^[13]
2. The direct antagonism of the NMDA receptor by the antibody, similar to the action of typical pharmacological blockers of the receptor, such as phencyclidine and ketamine.
3. The recruitment of the complement cascade via the classical pathway (antibody-antigen interaction). Membrane attack complex (MAC) is one of the end products of this cascade^[14] and can insert into neurons as a molecular barrel, allowing water to enter. The cell subsequently lyses. Notably, this mechanism is unlikely as it causes the cell to die, which is inconsistent with current evidence.

Management

If people are found to have a tumour, the long-term prognosis is generally better and the chance of relapse is much lower. This is because the tumour can be removed surgically, thus eradicating the source of autoantibodies. In general, early diagnosis and aggressive treatment is believed to improve patient outcomes, but this remains impossible to know without data from randomized controlled trials.^[4] Given that the majority of patients are initially seen by psychiatrists, it is critical that all physicians (especially psychiatrists) consider anti-NMDA receptor encephalitis as a possible cause of acute psychosis in young patients with no past neuropsychiatric history.

• If a tumour is detected, its removal should occur in conjunction with first-line immunotherapy. This involves steroids to suppress the immune system, intravenous immunoglobulin, and plasmapheresis to physically remove autoantibodies. A study of 577 patients showed that over four weeks, about half the patients improved after receiving first-line immunotherapy.
• Second-line immunotherapy includes rituximab, a monoclonal antibody that targets the CD20 receptor on the surface of B cells, thus destroying the self-reactive B cells. Cyclophosphamide, an alkylating agent that cross-links DNA and is used to treat both cancer and autoimmune diseases, has sometimes proven useful when other therapies have failed.
• Other medications, such as alemtuzumab, remain experimental.^[15]

Prognosis

The recovery process from anti-NMDA encephalitis can take many months. The symptoms reappear in reverse order: The patient may begin to experience psychosis again, leading many people to falsely believe the patient is not recovering. As the recovery process continues on, the psychosis fades. Lastly, the person's social behavior and executive functions begin to improve.^[1]

Epidemiology

The overall incidence of the condition is unknown.^[16] According to the California Encephalitis Project, the disease has a higher incidence than its individual viral counterparts in patients younger than 30.^[17] The largest case series to date characterized 577 patients with anti-NMDA receptor encephalitis. The epidemiological data were limited, but this study provides the best approximation of disease distribution. It found that women are disproportionally affected, with 81% of cases reported in female patients. Disease onset is skewed toward children, with a median age of diagnosis of 21 years. Over a third of cases were children, while only 5% of cases were patients over the age of 45. This same review found that 394 out of 501 patients (79%) had a good outcome by 24 months.^[4] 30 patients (6%) died, and the rest were left with mild to severe deficits. The study also confirmed that patients with the condition are more likely to be of Asian or African origin.

Society and culture

See Anneliese Michel- died of malnutrition and dehydration following a year of exorcisms by the catholic church in Germany in the 1970's. She suffered seizures, psychosis and bizarre movements and behaviors indicative of a likely case of anti-nmda receptor encephalitis. The movies "The Exorcism of Emily Rose" and "Requiem" are based (in the case of the former, loosely) on her case.

New York Post reporter Susannah Cahalan wrote a book titled Brain on Fire: My Month of Madness about her experience with the disease.^[18]

Dallas Cowboys defensive lineman Amobi Okoye spent 17 months battling anti-NMDA receptor encephalitis. In addition to three months in a medically-induced coma, he experienced a 145-day memory gap and lost 78 pounds. He returned to practice on October 23, 2014.^[19]

The protagonist of the Hannibal TV series, Will Graham, is diagnosed with anti-NMDA receptor encephalitis after an MRI scan in the 10th episode (titled "Buffet Froid") of the first season.

Knut, a polar bear at the Berlin Zoological Garden that died on 19 March 2011, was diagnosed with anti-NMDA receptor encephalitis in August 2015. This was the first case discovered outside of a human host.^[20][21][22]

See also

• Anti-glutamate receptor antibodies

References

External links

• "My mysterious lost month of madness", article by Susannah Cahalan about her experience with the disease (New York Post, October 4, 2009)
• "Quick Diagnosis of Rare Disease Leads to Remarkable Recovery", article by Susan Conova (Columbia University Medical Center, September 1, 2010)
• Autoimmune Encephalitis Alliance - Resources for patients and doctors about anti-NMDA and other forms of autoimmune encephalitis
• The Anti-NMDA Receptor Encephalitis Foundation, Inc. The Anti-NMDA Receptor Encephalitis Foundation, Inc. - Canadian Charitable Foundation dedicated to providing information, support to caregivers and recovering patients, raising awareness both within the medical establishment and the lay public.