Anti-NMDA receptor antibody encephalitis, also termed NMDA receptor antibody 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 NMDA receptor.
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.
Movement disorder relapses after herpes simplex virus 1 encephalitis have been hypothesized
to be secondary to postviral autoimmunity.
Recently, a proportion of patients with HSV1 encephalitis were shown to produce autoantibodies
against N-methyl-D-aspartate receptor.
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 tumour and in fact
it is emerging that most cases do not have tumour.
This is an especially important point as the search for a tumour should not occupy attention
when immune treatments are being planned.
Incidence and epidemiology The overall incidence of the condition is
unknown . 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.
The largest cases series to date characterized 577 patients with anti-NMDA receptor encephalitis.
The epidemiologic data were limited but this study provides the best approximation of disease
distribution.
This case series found that women are disproportionally affected, with 81% of cases reported as female.
Disease onset is skewed towards 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 showed that 394 out of 501 patients had a good outcome by 24 months.
30 patients 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 Prior to the development of a symptom complex
that is specific to anti-NMDA receptor encephalitis, patients may experience prodromal symptoms.
These could include 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.
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 increased agitation, paranoia, psychosis, and violent behaviors.
Other common first manifestations include seizures and bizarre, often rhythmic, movements
mostly of the lips and mouth but also including pedaling motions with legs or hand movements
resembling playing a piano.
Some other symptoms typical during the disease onset include impaired cognition, memory deficits,
and speech problems.
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 care in an Intensive Care Unit to stabilize
breathing, heart rate, and blood pressure.
It is important to note one distinguishing characteristic of Anti-NMDA Receptor Encephalitis
is the concurrent presence of many of the above listed symptoms.
It is extremely unusual that patients have only one or two symptoms- the majority of
patients experience at least four symptoms with many experiencing six or seven over the
course of the disease.
Pathophysiology The presence of antibodies in the serum and
cerebrospinal fluid 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 serum and the CSF leads to the consideration
of two possible mechanisms.
These mechanisms may be informed by some simple observations.
Firstly, serum NMDAR-antibodies are consistently found at higher concentrations than CSF antibodies,
on average 10 fold higher.
This strongly suggests the antibody production is systemic rather than in the brain / CSF.
When concentrations are normalised for total IgG, 'intrathecal synthesis' is detected.
This implies that there is more NMDAR-antibody in the CSF than would be predicted given the
expected quantities of total IgG.
Passive access involves the diffusion of antibodies from the blood across a pathologically disrupted
blood-brain barrier.
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.
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.
Intrathecal production 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, drugs used to eliminate dysfunctional immune
cells, have been shown to be successful second line treatments in patients where first line
immunotherapy has failed.
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.
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.
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.
The recruitment of the complement cascade via the classical pathway.
Membrane attack complex is one of the end products of this cascade 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 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.
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.
Given that the majority of patients are initially seen by psychiatrists due to the development
of psychiatric symptoms, it is critical that all physicians consider anti-NMDA receptor
encephalitis as a cause for acute psychosis in adolescents 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 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.
Other medications, such as alemtuzumab remain experimental.
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.
Dallas Cowboys defensive lineman Amobi Okoye spent 17 months battling Anti-NMDA receptor
encephalitis.
In addition to 3 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.
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
"Quick Diagnosis of Rare Disease Leads to Remarkable Recovery", article by Susan Conova
Autoimmune Encephalitis Alliance - Resources for patients and doctors about Anti-NMDA and
other forms of autoimmune encephalitis