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identical to anti‑NMDAR encephalitis. A nationwide synaptic function may explain the clinical symptoms
survey conducted on AJFNHE showed that the of patients with this encephalopathy, who initially
annual incidence was 0.33/100,000 people in Japan. [5] present with behavioral or cognitive dysfunction with
One retrospective study in Thailand reported that or without seizure, followed by abnormal movements,
[11]
anti‑NMDAR encephalitis represented 5% of all cases dysautonomia, and coma with hypoventilation. A
[6]
of encephalitis. Increases in clinical awareness and recent study using an animal model of anti‑NMDAR
laboratory availability have led to a rise in the number encephalitis showed that continuous intraventricular
of diagnoses and case reports, suggesting that the infusion of anti‑NMDAR from the CSF of patients
incidence of the disease might be similar to Western with anti‑NMDAR encephalitis to mice produced
countries. progressive memory deficit, anhedonia, and
[12]
depressive‑like behavior. This correlated with the
IMMUNOPATHOGENESIS degree of hippocampal binding by anti‑NMDAR and
decreases in the density of total and synaptic NMDAR
A nt i‑N M DA R a nt ibody ca n be detected i n clusters as well as total NMDAR protein concentration.
cerebrospinal fluid (CSF) and/or serum. To be After discontinuation of the infusion, the symptoms
considered pathogenic, the autoantibody should bind improved over the course of a week. The reversal of
to an extracellular antigen (such as an ion channel or symptoms correlated with decreased hippocampal
neurotransmitter receptor) and cause a functional or bound antibody and restoration of NMDAR levels.
[12]
structural change. Anti‑NMDAR antibody has been The clinical symptoms of the frontostriatal syndrome
shown to bind the NR1 subunit of the NMDAR and (psychosis, catatonia, and dystonia) and semi‑rhythmic
reduce the density of NMDARs on the cell membrane. [7] movements may be mainly due to the inactivation
Because NMDARs are protected by the blood‑brain of GABAergic neurons as a result of the decreased
barrier (BBB), the antibody somehow enters privileged NMDAR function. This may be explained by the
sites via unknown mechanisms. Disruption of the BBB hypofunction of NMDARs, causing the alteration of
may be initiated by infection, followed by up‑regulation homeostatic synaptic plasticity to adjust the inhibitory
of the major histocompatibility complex or other tone in a compensatory direction by down‑regulation
inflammatory mediators that finally weaken the barrier of inhibitory synapses on excitatory neurons. [10]
(some patients develop flu‑like symptoms prior to This decreased function also affects dopaminergic,
the occurrence of clinical encephalopathy). In some noradrenergic, and cholinergic pathways, which may
patients, ovarian teratoma is detected at the time of the explain the autonomic dysfunction and effects on
development of encephalopathy. It has been postulated the ponto‑medullary respiratory network that lead to
that the immune response is initiated by this tumor, hypoventilation. [11]
[8]
which expresses NMDAR on its surface. The
mechanism underlying immune tolerance is disrupted, CLINICAL MANIFESTATIONS
potentially by the ectopic expression of NMDARs
by the tumor or another mechanism in combination Typical manifestations of anti‑NMDAR encephalitis
with leakage of the BBB, leading to an attack by the are described as classic symptoms of psychotic or
[9]
immune system on the NMDAR. It is likely that cognitive dysfunction, seizure, abnormal movement,
memory B cells activate T‑cells by crossing the BBB and autonomic dysfunction. The symptoms develop
and undergoing clonal expansion and differentiation in an acute‑to‑subacute onset that is usually preceded
[13]
into plasma cells that produce anti‑NMDAR. These by prodromal and followed by psychotic features.
autoantibodies bind to NMDARs expressed in various The spectrum of psychiatric features is varied, and
areas of the central nervous system and subsequently more than one feature can be detected individually.
cause receptor dysfunction. Short‑term memory problems are common, but they
may be under‑detected due to the overwhelming
The acute effect of anti‑NMDAR on the NMDAR psychotic features. The sequence of symptoms is as
[10]
has been investigated. One study has shown that follows: seizure, hyperkinetic movement disorders,
a decrease in the NMDAR density on the surface autonomic instability, and then unresponsiveness
of both excitatory and inhibitory hippocampal with hypoventilation. The seizure may develop early
neurons caused NMDAR hypofunction through in the course of the disease and usually decreases
immunoglobulin‑induced receptor internalization in frequency with disease progression. [13] After 2‑3
[10]
(crosslinking of the receptors). This internalization weeks, patients who have not been treated develop
of receptors resulted in a rapid and selective loss of an unresponsive phase. This clinical presentation
NMDARs from the neuronal membrane that was of the patient includes mutism, akinetic mutism,
titer‑dependent and could be reversed after removal and unresponsiveness to verbal commands with
of the antibodies. The degree of loss of NMDAR eye‑opening but the loss of eye contact similar to
[9]

80 Neuroimmunol Neuroinflammation | Volume 3 | March 28, 2016