Clinical significance
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.
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.
( Paraneoplastic Anti–N-methyl-D-aspartate Receptor Encephalitis Associated with Ovarian Teratoma,2007 )
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. 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. 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.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.
( Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study,2013 )
Signs and sympotms
The disease seems to follow a fairly predictable progression of symptoms, although the exact order and presence of symptoms varies from patient to patient.
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
3. phase that patients are admitted to hospital.
4. Memory impairment – in particular anterograde amnesia.
5. Dyskinesias (especially orofacial) and seizures (often tonic clonic but not associated with epileptiform activity as assessed by electroencephalography).
6. Loss of responsiveness, low Glasgow Coma Scale (GCS).
7. Hypoventilation/central respiratory depression.
8. Autonomic instability (e.g. variations in blood pressure and salivation rates).
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). 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.
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, 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.
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.
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 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.
( Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis,2010 )
NMDA (N-methyl D-aspartate) is a type glutamate receptors in the brain. The NMDA receptor consists of two NR1 and two NR2 subunits and is important for synaptic «learning» through LTP (long term potentiation). In a normally functioning receptor nerve impulses pass through the synaptic cleft by glutamate being released from presynaptic vesicles and binding itself to postsynaptic glutamate receptors. The NMDA receptor, which is also dependent on glycine, becomes active only when the membrane has been partly depolarised by another glutamate receptor, the AMPA receptor, which transmits the main signal. Ca2+ is normally let through the NMDA receptor. This induces an intracellular signalling cascade which prepares the receptor for modifying the signalling power of the active synapse. The antibodies that cause anti-NMDA receptor encephalitis are directed towards the glutamate binding site on the NR1 subunit.
NMDAR Antibodies in Herpes Simplex Encephalitis
It was made a study to determine the presence and kinetics of antibodies against synaptic proteins in patients with herpes simplex virus encephalitis (HSE). The methods were retrospective analysis of 44 patients with polymerase chain reaction-proven HSE for the presence of a large panel of onconeuronal and synaptic receptor antibodies. The effect of patients’ serum was studied in cultures of primary mouse hippocampal neurons. The results were that NMDAR antibodies of the immunoglobulin (Ig) subtypes IgA, IgG, or IgM were detected in 13 of 44 patients (30%) in the course of HSE, suggesting secondary autoimmune mechanisms. NMDAR antibodies were often present at hospital admission, but in some patients developed after the first week of HSE. Antibody-positive sera resulted in downregulation of synaptic marker proteins in hippocampal neurons. The interpretation could be that some patients with HSE develop IgA, IgG, or IgM autoantibodies against NMDAR. Sera from these patients alter the density of neuronal synaptic markers, suggesting a potential pathogenic disease-modifying effect. These findings have implications for the understanding of autoimmunity in infectious diseases, and prospective studies should reveal whether the subgroup of patients with HSE and NMDAR antibodies may benefit from immunotherapy. Herpes simplex encephalitis (HSE) is the most frequent fatal encephalitis in Western countries. Despite its substantially improved prognosis since the advent of selective antiviral therapy with acyclovir, about 35% of patients still suffer an unfavorable outcome, with severe neurological residual symptoms or even death. However, in patients with HSE, not all symptoms result from direct virus invasion and neuronal cell lysis. The observation of a more severe disease course in immuno-competent as compared to immunocompromised patients suggests a role for secondary autoimmune mechanisms in the pathogenesis of HSE. This hypothesis is in line with studies demonstrating a beneficial effect on the outcome when combining acyclovir with corticosteroids. Additionally, direct viral cytotoxicity is probably not the major pathogenic mechanism in relapses of HSE. During clinical workup of encephalitis patients, was identified an HSE case that had high-titer immunoglobulin (Ig)A antibodies against NMDARs, raising the question of whether some symptoms in HSE might be related to secondary immunological phenomena, such as generation of antibodies against neuronal cell surface antigens. These could include prolonged symptoms after acyclovir treatment, the presence of unusual clinical presentations, and the beneficial effect of steroids in some patients. To get an unbiased estimation of the true prevalence of antibodies against a wide range of NMDARs (different subtypes and epitopes) and other synaptic proteins in HSE, it is performed a blinded retrospective study analyzing a large archived cohort of consecutive serum and cerebrospinal fluid (CSF) samples from patients with a definite diagnosis of HSE.
At the end of all this you might think that there is a similarity between an antigen of herpes simplex virus 1 and the attachment site for the antibody on NMDAR.
( N-Methyl-d-Aspartate Receptor Antibodies in Herpes Simplex Encephalitis,2012 )
Indirect immunofluorescence
Diagnosis of anti-NMDA receptor encephalitis is based on the detection of highly specificautoantibodies directed against glutamate receptors of type NMDA in serum or cerebrospinal fluid. These autoantibodies are detected with high sensitivity and specificity in indirect immunofluorescence using a human recombinant cell line expressing the major target antigen (receptor subunit NR1). The determination of antibodies against glutamate receptors (type NMDA) is of high significance in patients with encephalitis where no pathogen has been detected, as well as in suspected cases of limbic encephalitis. The new cell substrate can be combined with various tissue substrates that are relevant for differential diagnostics (e.g. hippocampus and cerebellum) as BIOCHIP Mosaics, allowing the detection of further autoantibodies associated with limbic encephalitis.
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.
In the media
Susannah Cahalan wrote a book called "Brain on Fire: My Month of Madness" about her experience with the disease.
In this memoir Cahalan describes how she crossed the line between sanity and insanity after an unknown pathogen invaded her body and caused an autoimmune reaction that jump-started brain inflammation, paranoia, and seizures. For months she was confined to the hospital, about which she remembers nothing. One wonderful doctor, noticing that she walked and talked like a late-stage Alzheimer’s patient, was determined to get to the bottom of her medical mystery. Luckily, she was insured, because her treatment cost $1 million. Cahalan expertly weaves together her own story and relevant scientific and medical information about autoimmune diseases, which are about two-thirds environmental and one-third genetic in origin. So, she writes, an external trigger, such as a sneeze or a toxic apartment, probably combined with a genetic predisposition toward developing aggressive antibodies to create her problem. A compelling health story.
Video
( Anti-NMDAR encephalitis )
