Anti-NMDA receptor encephalitis

Anti-NMDA (N-methyl D-aspartate) receptor encephalitis is an acute form of encephalitis which is potentially lethal but has high probability for recovery. It is caused by an autoimmune reaction primarily against the NR1 subunit of the glutamate/glycine NMDA receptor.^[1] Different descriptions and syndromal designations for this disease existed in medical literature prior to 2007 but it was then that the disease was officially categorized and named by Dalmau and colleagues.^[2] The condition is associated with tumours, mostly teratomas of the ovaries, and is thus considered a paraneoplastic syndrome. However, there are a substantial number of cases with no detectable cancerous tissue.

Incidence and epidemiology

The overall incidence of the condition is unknown but estimates suggest that it accounts for only 1% of all encephalitides that are initially thought to be of unknown aetiology.^[3] More recent figures produced by the California Encephalitis Project showed that the disease had a higher incidence than its individual viral counterparts in patients <30 years.^[4] According to a review of 100 cases in The Lancet, 91 of the 100 patients were women, the mean age of all patients was 23 years (5-76 range) and of the 98 patients that underwent an oncological screening, 58 had a tumour - predominantly an ovarian teratoma. A larger and more recent review of 577 patients (501 of which were able to be assessed) showed that 394 patients (79%) had a good outcome by 24 months.^[5] 30 patients (6%) died and the rest were left with mild to severe deficits. This study also confirmed that patients with the condition are more likely to be of Asian or African origin.

Signs and symptoms

The disease seems to follow a fairly predictable progression of symptoms, although the exact order and presence of symptoms varies from patient to patient.^[6] 

1. A prodromal phase of nonspecific viral-like symptoms (fever, headache etc).  
2. Psychiatric disturbances with schizophrenic-like manifestations (hallucinations, visions, suicidal ideation). This is usually the phase that patients are admitted to hospital.
3. Memory impairment – in particular anterograde amnesia.
4. Dyskinesias (especially orofacial) and seizures (often tonic clonic but not associated with epileptiform activity as assessed by electroencephalography).
5. Loss of responsiveness, low Glasgow Coma Scale (GCS).
6. Hypoventilation/central respiratory depression.
7. Autonomic instability (e.g. variations in blood pressure and salivation rates). 

The aforementioned review of 100 patients showed that all patients presented with psychiatric symptoms or memory problems; 76 of them suffered from seizures, 88 developed unresponsiveness (decreased consciousness), 86 - dyskinesias, 69 - autonomic instability, and 66 - hypoventilation.

Pathophysiology

The presence of antibodies in the cerebrospinal fluid (CSF)

The condition is mediated by autoantibodies that target NMDA receptors in the brain. These are produced by cross reactivity with NMDA receptors in the teratoma; these tumours contain many different 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 that lack any form of neoplasm. Whilst the exact pathophysiology of the disease is still debated, empirical evaluation of the origin of anti-NMDA antibodies in the CSF leads to the consideration of two possible mechanisms.

1. Passive access involves the diffusion of antibodies from the blood across a pathologically disrupted blood-brain barrier (BBB).^[7] 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.^[8] 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 CSF.
2. Intrathecal production (production of antibodies in the intrathecal space) may also be 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 CSF. Furthermore cyclophosphamide and rituximab,^[9] drugs used to eliminate dysfunctional immune cells, have been shown to be successful second line treatments in patients where first line immunotherapy has failed.^[10] These destroy excess antibody producing cells in the thecal space, thus alleviating the symptoms.

A more sophisticated analysis of the processes involved in antibody presence in the CSF hint at a combination of these two mechanisms in tandem.

The binding of antibodies to NMDA receptors

Once the antibodies have entered the CSF, they bind to the NR1 subunit of the NMDA receptor. There are 3 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 depended on antibodies cross linking.^[11]
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^[12] and can insert into neurones as a molecular barrel, allowing water to enter. The cell subsequently lyses. Notably, this mechanism is unlikely as it causes cell to die, which is inconsistent with current evidence.

Management and prognosis

If patients 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. Likewise early diagnosis and therefore treatment has recently been shown to significantly improve patient outcome. Given that the majority of patients are initially seen by psychiatrists (not neurologists) due to the development of psychiatric symptoms, it is critical that all physicians (especially psychiatrists) consider anti-NMDA receptor encephalitis as a cause for acute psychosis in adolescents with no past neuropsychiatric history.

• After tumour removal, first line immunotherapy should be attempted. This involves steroids to suppress the immune system, intravenous immunoglobulins and plasmapheresis to physically remove autoantibodies. The study of 577 patients showed that over 4 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 been proven to be useful when other therapies have failed.
• Recently alemtuzumab was shown to enhance outcome, presumably due to its effect on memory B cells and T cells.^[13]

In the media

New York Post reporter Susannah Cahalan wrote a book called Brain on Fire: My Month of Madness about her experience with the disease.^[14]

See also

Anti-glutamate receptor antibodies

References

External links

• "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)