Brain on Fire: Anti-NMDA Receptors Encephalitis
ASMA AIT SAID.
The
Central Nervous System(CNS) is the ultimate priority of the immune system when
the human body is being invaded by any given pathogen.The blood-brain barrier is an actual
shield preventing any potentially harmful microorganism from attending the CNS ensuring
thus the safety of neurones and their functions.However, many types of
microorganisms, namely viruses (Herpes simplex virus for instance) are able to
cross this strong wall and reach the human brain resulting in an inflammation
of the brain parenchyma associated with neurological dysfunction causing viral,
bacterial or even fungi encephalitis. Nonetheless, Encephalitis can also be
induced by an auto-immune disorder and the most common one is called anti-NMDA
Receptors encephalitis which has been recently discovered.
This illness can be very dangerous
and life threatening. Hence, early diagnosis and treatment are fundamental. In
view of the possibility of misdiagnosing it as a primary psychiatric disorder
-namely schizophrenia- this article aims to highlight the principal mechanisms
of this auto-immune disease, the different phases through which patients go,
the key to a firm diagnosis and the proper treatment.
Introduction:
The etiology of encephalitis is primarily
suspected to be viral. However, viral-linked investigations frequently failed
to identify a specific pathogen. This has led health professionals to make
further research to discover other likely causes among which auto-immune
disorders were detected.
Anti-NMDA receptors encephalitis is
an autoimmune disorder in which the immune system produces anti-bodies against
specific receptors called NMDA (N-Methyl-D-Aspartate); generating an
inflammatory process in the brain parenchyma. These receptors are highly
expressed in the limbic
system (hippocampus, amygdala, hypothalamus, cingulate gyrus and limbic cortex) as well as other parts of the CNS.
They play a critical role in synaptic transmission and plasticity contributing
to the control of thoughts, attitude, emotions and movements. The antibodies
addressed against them engender continued deterioration of these functions.
This disease can arise in children
as well as young adults. Both male and female with a higher female prevalence.
Symptoms
include prominent psychiatric signs along with a highly characteristic set of neurological
deficits, cognitive and behavioural manifestations.
Since the emergence of anti-NMDA-R
encephalitis in 2007, neurologists and other specialists recognize it to be a
considerable differential diagnosis for viral encephalitis, on the one hand
(especially herpetic encephalitis) and for psychotic conditions in their early
phase on the other hand; especially schizophrenia which is marked by similar
symptoms to those of the early stage of anti-NMDAR encephalitis.
What are NMDA receptors? (4,5,10)
NMDAR, along with AMPA and Kainate
receptors, are a sub-type of ionotropic Glutamate receptors, a category of ligand-gated
channels that bind the major excitatory transmitter in the brain and spinal
cord, in order to open: Amino acid L-Glutamate.
NMDA receptors are made of two
sub-units: NR1 and NR2. Each binding a specific substance: the former binds to
Glutamate and the latter to Glycine. NR1 was proved to be the main target of
the produced anti-bodies (4).
These receptors are typically
clustered at post-synaptic sites in the membrane, taking a great part of
excitatory synapses of the mature nervous system.
NMDA receptors have many interesting
features. They are permeable to Ca2+ ions,as well as to Na+ and K+ ions. Their
opening depends on both membrane voltage as well as the nature of the neuro-transmitter.
The binding of glutamate to the NR2 subunit depends on the concentration of the
glycine in extra cellular space which is quite effective under normal conditions.
The ionic current is controlled by extra cellular Mg2+. In fact, at resting
membrane potentials, Mg2+ binds to a specific site of the ligand-binding
channels, inhibiting the ion current. When a depolarization of the
post-synaptic membrane occurs by the opening of AMPA channels for instance,
Mg2+ molecules are removed from their inhibitory sites, and allow Ca2+ and Na+ ions
to enter. When let it in normal amounts, Ca2+ ionsgenerate signalling pathways
that reinforce synaptic transmission. A process which is fundamental for
special types of memories.
What also grabs our attention
concerning these receptors, is the presence of a site in the pore of the
channel that could inhibit the NMDA receptor if bound to a hallucinogenic drug
phencylidinePCP (also known as angel dust). It owns its name to the
hallucinations induced by blocking the NMDA receptors.
We acknowledge therefore, that any
kind of disturbance of the natural mechanism of NMDA receptors would highly influence
the synaptic plasticity which plays a considerable role in the storage of
information and other higher brain functions.
When the antibodies addressed
against NMDAR bind to them, they leadto their internalization from the cell
surface and to a state of relative NMDA receptor hypofunction. Resulting in the
symptoms of the disease which were proved to be reversible with the removal of
the antibodies (4,5).
Phases of theillness in anti-NMDA receptor encephalitis:
Viral prodromal phase:
Most patients present in the first 5
days (no more than 2 weeks) non-specific cold or viral-like symptoms: fever, drowsiness, asthenia, headaches,
myalgias, upper respiratory symptoms, nausea and even diarrhea. Preceding the
beginning of psycho-behavioural changes.
Initial psychiatric symptoms:
Considering the common absence of
neurologic manifestations in this period, patients usually see a psychiatrist
first. For this reason, the diagnosis of anti NMDA encephalitis could be
confused at this stage with other mental illnesses such as schizophrenia. They
often experience various mental symptoms over which schizophrenia-like symptoms
govern; chiefly psychosis, which is characterized as a defective or lost
contact with reality, resulting in delusional ideas, suspiciousness,
hallucinations, disorganized speech, such as
switching topics erratically and loss of self-awareness. Moreover, patients
usually show emotional disturbances (anxiety, fear, loneliness, apathy…),
strange behaviours (such as smiling oddly at their own reflection in a mirror)
and agitation in addition to paranoia, mood changes and personality
transitions. They can easily and suddenly become cantankerous and aggressiveleading
to their withdrawalfrom society.
Furthermore, short-term amnesia, confusion and
cognitive impairment can be difficult to detect at the onset of the phase,
because of the prominence of the psychiatric signs and could even be
sub-syndromal.
Interestingly,
children show different symptoms: sleep dysfunction, irritability, behavioural
flare-ups, hyperactivity and hyper-sexuality seem to take the place of
psychotic symptoms.
This phase usually lasts from 1 to 3
weeks but could be protracted in some cases in a less severe manner.
Seizures can occur at this phase and
the patients fall into unresponsiveness driving them to the hospital.
Unresponsive phase:
Patients at this stage go through a
debilitated state. Akinetic, they undergo progressive decay in speech and
language such as a reduced fluency of speech (alogia), mimicking the examiner’s
movements or words (echolalia) and uttering; along with a catatonic behaviour
by being unresponsive to verbal commands and mutism despite their eyes being
open. Paradoxically, they can occasionally be passive to some
‘’suggestive’’orders of the examiner.
This phase is also accompanied by
Catalepsy-like symptoms (presenting muscle rigidity and fixity of posture
despite external stimuli) and athetoid dystonic postures. Brainstem reflexes are usually normal, but the visual
threat reflex is absent, as well as spontaneous eyes movements.
Hyperkinetic phase and neurologic complications:
Oro-facial dyskenias progressively develop after
the akinetic phase. The patient is caught licking or biting his/her lip, chewing,
clenching his/her teeth or grimacing. Jaw opening dystonia, intermittent ocular
movements and athetoid dystonic postures of the fingers are also noticed. Because
the speed, the distribution and the motor pattern of these dyskenesias
fluctuate from a moment to another, they can unlawfully lead us to think of a
psychogenic movement disorder. Seizures however reinforce the diagnosis of
anti-NMDAR encephalitis as they are present in 80% of cases. They are
especially prominent at this stage but could be very intense and frequent at
the onset of the illness; regardless of their unpredictable occurrence.
In thepediatric population, abnormal movements
appear early on in the progression ofdisease; unlike in adults where they come
into sight at the last phase.
Other important features to emphasize at this phase,
are signs of instability of the autonomic nervous system; including -among
others- : hyperthermia, diaphoresis, tachycardia or bradycardia and erratic
blood pressure. The patients can also experience severe central hypoventilation
giving rise to a potential coma.
Anti-NMDA receptors encephalitis and tumor:
A few years before this illness was attested
to be an auto-immune disorder, similar symptoms (psychiatric symptoms, memory
deficits, occurrence of seizures, decreased consciousness, sever oral facial
dyskinesia, autonomic instability and hypoventilation) were identified in young
women (4) who had an associatedtumor which was particularly benign
(astoundingly found to be an ovarian Teratoma). Later, biological experiences made
on lab rats identified not only the presence of neural tissue in the tumor; but
also, the NMDA Receptors (2) (3). Hence, many hypotheses suggested the
possibility of the antibodies being initially formed to attack these receptors
within the tumor itself and secondarily invaded the CNS to bind to the existing
NMDAR. The mechanism was consequently thought to be exclusively a
paraneoplastic disorder. However, today this condition is shown to appear independently
of a tumor.
The presence of the tumor is related
to age, gender and race. Women past eighteen years of age (and somewhat
predominantly black women) were found to be more frequently subjected to the
tumor in question. Tumor screening is hence imperative in every patient
diagnosed with Anti-NMDA receptors encephalitis. Especially that the removal of
the tumor along with the immunotherapy proved a better response to treatment
and less neurological recurrences and relapses.
These patients should benefit from a
regular examination even after tumor resection, given the possibility of its re-emergence.
Diagnosis of the disease:
After clinically
suspecting anti-NMDAR encephalitis, it is critical to expose the antibodies
addressed against these receptors in the serum and principally in the Cerebral
Spinal Fluid (CSF) of which the analysis usually reveals pleocytosis and elevated levels of proteins. The
finding of oligoclonal bands (which are usually present in 60% of cases) (7,8)
indicating the inflammation of the CNS, in multiples samples makes a firm
diagnosis of this illness.
Other
imaging techniques are also essential but not always contributing to the
diagnosis. As a matter of fact, 50% of the cases present a normal brain MRI. When
it is abnormal, MRI shows T2 or FLAIR hypersignals in cortical or subcortical
brain regions (7,8,9). EEG is commonly abnormal and exhibits slow and chaotic
activity in the delta/theta range, sometimes overlapped with electrographic
seizures (8).
Brain
biopsy does not provide a firm diagnosis. Studies have shown normal or
non-specific findings such as microglial activation.
Since the anti-NMDAR
encephalitis can be paraneoplastic especially in young women, a tumor, precisely
the ovarian teratoma, needs to be spotted if present by MRI, CT scan or
ultrasound.
Treatment and outcomes:
Although it’s a newly
discovered syndrome, experts have come up with clear guidelines for the treatment
of anti-NMDA encephalitis, which is still being under research. It mainly
focuses on immunotherapy and convenient medical or surgical treatment of the
tumor -if it exists- making the treatment act faster and more effectively. Corticosteroids and immunoglobulins are justified in
order to handle the immune response. It is recommended to give them intravenously
especially in agitated patients as well as those presenting autonomic
instability. Plasma exchange can also be effective, but not in the previous
cases. In patients without an associated tumor, second line immunotherapy is
required (rituximab or cyclophosphamide) (13).
The
treatment of this illness usually takes a long period for patients to fully
recover and gain their normal functions back. This could go on for months and
even years. Which requires continuous supervision and rehabilitation. After no
less than several years of perserverences, around 75% of the patients are
expecte to either fully recover or keep delicate cognitive and behavioural
squelae; while the remaining 25% stay severely disabled or possibly die(7, 8).
Conclusion:
Anti-NMDA-receptor encephalitis represents a newly discovered
disease among other immune-mediated disorders. It is implicated in the
modification of synaptic functions in the CNS, by decreasing the number of NMDA
receptors or inducing their hypofunction. This results in cognitive, behavioural
and psychotic manifestations that can drive to a misdiagnosis of this illness
especially in its mild form which is purely psychiatric in nature. This
requires the involvement of psychiatrists –among other specialists- especially
in the early phase of the disease, in order to prevent neurologic
decompensation. Future medical researchers are working on ways to improve the treatment and to guarantee
ideal medical care especially during the long phase of recovery.
It is also important to highlight recent hypotheses that
suggest the involvement of NMDA receptors modulation in schizophrenia. Their
hypofunction seems to worsen psychiatric symptoms in this disease or even induce
them in healthy patients. However, boosting their function shows a progress of
the clinical signs. This could lead to a promising improvement in the treatment
of Schoziphrenia.
Refrences :
Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor
encephalitis: case series and analysis of the effects of
antibodies. Lancet Neurol. 2008;7:1091–8. (7)
Dalmau J, Tuzun E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor
encephalitis associated with ovarian teratoma. Ann
Neurol. 2007;61:25–36. (8)
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR,
Balice-Gordon R. Clinical experience and laboratory investigations in patients
with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74.
(9)
Principales of Neural science Eric R.
Kandel; James H. Schwartz; Thomas M. Jessel; Steven A. Siegelbaum; A. J.
Hudspeth (10)
Inspired by the book: Brain on Fire: My Month of Madness
by Susannah Cahalan
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