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The N-methyl-D-aspartate receptors (NMDAR) are cation channels in the brain that play important roles in the transmission of nerve impulses and neuronal plasticity. These ligand-gated channels have two subunits, they bind glycine on one subunit, called the NR1 subunit, while the NR2 subunit, which can be A, B, C or D in type, binds glutamate. Different forms of NMDA receptors exist based upon the varying combinations of subunits.

This affects their activities and where they are found, as well as how they respond to intracellular messenger molecules. Both over- and under-activity of the NMDA receptors is associated with pathological manifestations, such as hyperexcitation and schizophrenia, respectively.

Anti-NMDAR encephalitis is a disorder caused by antibodies raised against the NR1-NR2 subunits. This leads to a neuropsychiatric condition, and was first diagnosed in four young women with ovarian teratomas. These women first came to attention with memory problems or acute psychotic conditions, but rapidly developed more neurological symptoms and had to be hospitalized for intensive care. They had what was eventually found to be an autoimmune encephalitis directed against antigens found most richly in the hippocampal region of the brain, which were identified as the NMDAR. It is the most common autoimmune encephalitic disorder following acute demyelinating encephalomyelitis (ADEM).

Surgery to remove the tumor coupled with immunotherapy often proved to be curative despite the stormy clinical course. The antibodies are usually directed against the NR1 rather than NR2 subunits and have potentially reversible effects on the receptors.

Clinical Features

Most patients with anti-NMDAR encephalitis were young women, with a median age of 23 years, though some patients have been young children or very elderly. Current overviews support the changed perception that anti-NMDAR encephalitis may affect both males and females at any age, with or without tumors.

The universal presentation is with psychosis or altered memory, often associated with seizures, catatonia, various levels of unconsciousness, dyskinesias or abnormal movement, autonomic variations such as in the heart beat or temperature, and hypoventilation. Almost 60% of them had a tumor, of which the most common was ovarian teratoma.

Management

Early and aggressive treatment with immunotherapy was associated with a better outcome. Plasma exchange to remove the antibodies led to a restoration of the numbers of cell surface NMDAR and clusters of NMDAR in the postsynaptic dendrites, which was low at first following the onset of the disorder. This seems to confirm the pathogenic nature of the antibodies, especially since the administration of NMDAR antagonists produces many of the same symptoms.

Prognosis

Three of every four patients may be expected to recover completely or almost completely. Patients who recover from this disorder characteristically fail to remember the illness, which is probably due to the failure of neuronal plasticity at the synapses by the antibody binding. Recovery is prolonged, and relapses are common, especially if the tumor is unidentified or recurs, though they may happen even in patients without tumors. This could be because the immune response within the brain is difficult to control by immunotherapy. In refractory patients, cyclophosphamide and rituximab in isolation or together proved effective.

In conclusion, anti-NMDAR encephalitis is an immune-mediated condition of the paraneoplastic type, which is diagnosed by serologic tests. It is treatable and carries a very good prognosis but requires intensive care during its course because of the severity to which the brain is involved.

Further Reading

• All Encephalitis Content
• What is Encephalitis?
• What can Aedes mosquitos transmit?
• Autoimmune Encephalitis Classification
• Autoimmune encephalitis

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.