Anti-N-methyl-D-aspartate (Anti-NMDA) Receptor Encephalitis – A Synopsis
Anti- N-methyl-D-aspartate (NMDA) receptor encephalitis is a fascinating disorder that was first described in 2007. Initially thought to be exclusively a paraneoplastic disorder occurring in young females with an ovarian teratoma, it is now recognised that this syndrome can occur in children and adults with or without a tumour. 
The disorder has garnered media attention after the book by Susannah Cahalan, Brain on Fire, which was made into a movie.
According to the Dalmau, one of the authors of the original publication describing Anti-NMDAR encephalitis  –
In my experience, the answer started to be revealed in December 2003 after we saw a young woman with encephalitis of unknown cause who had been in the Intensive Care Unit for several weeks. She was brought to the hospital for the acute onset of change in behaviour and prominent psychiatric symptoms that progressed rapidly to unconsciousness and central hypoventilation. All diagnostic investigations had been negative except for the presence of a small ovarian teratoma that was believed to be unrelated to her disease and owing to her poor clinical condition, it was not removed. She was given empiric immunotherapy and eventually recovered.
The trial of encephalitis with prominent psychiatric symptoms and hypoventilation in a young woman with an ovarian teratoma and the recovery with immunotherapy were crucial in linking a clinical picture to that of another three young women with an identical syndrome who also had ovarian teratomas.
Despite the remarkable syndrome resemblance amongst the four patients and their clinical and CSF features suggesting an immune-mediated encephalitis, their serum and CSF were negative for all neuronal antibodies known at the time.
It took six months to optimise the tissue processing until it showed a unique pattern of neuropil reactivity with the patient samples. The identity of the antigen (NMDA receptor R was obtained two years later). Nowadays the entire discovery process would just take a few weeks. (Dalmau, 2016)
As Anti -NMDAR encephalitis is a relatively recent discovery, there is often a delay in diagnosis because of the lack of knowledge and clinical experience about the disorder.
Furthermore, the presence of pronounced psychiatric symptoms can often result in a misdiagnosis of functional psychosis or schizophrenia.
In anti- NMDAR encephalitis, IGG autoantibodies directed against the GluN1a subunit of the NMDA Receptor are frequently detected in patients. 
The NMDA is an ionotropic glutamate receptor which when activated, mediate excitatory neurotransmission via passage of sodium and calcium ions through the channel. 
Glutamate receptors are activated when the following steps happen simultaneously.
First depolarisation resulting in the removal of the magnesium plug which usually maintains the NMDA receptor (NMDAR) in a non-activated state and secondly, glutamate and glycine binding to their respective sites.
This results in the opening of the channel and the passage of sodium and calcium ions resulting in activation of the NMDAR which includes not only long-term potentiation of synaptic plasticity but also excitotoxicity.
The significance of NMDA receptor in psychosis and schizophrenia.
It is well known that NMDAR antagonists like phencyclidine can mimic symptoms of schizophrenia.
The NMDAR is implicated in the pathogenesis of schizophrenia in both the positive and the negative symptoms of schizophrenia.
Normally, excitatory glutamate stimulates NMDAR receptors in the interneuron resulting in GABA release and GABA, in turn, inhibits the release of dopamine from the mesolimbic pathway. Thus the glutamatergic pathway acts as a break on the mesolimbic dopamine pathway.
If NMDA receptors are hypoactive, then the tonic inhibition on the mesolimbic dopamine pathway will not occur, resulting in hyperdopaminergia and an increase in the dopamine in the mesolimbic system resulting in positive symptoms.
In anti-NMDAR encephalitis, antibodies bind the NMDA receptor, leading to its internalization from the cell surface and a state of relative NMDA receptor hypofunction.
This removes the tonic inhibition on dopamine released in the mesolimbic pathway resulting in psychosis.
Brain tissue studies showed progressive binding of human NMDAR antibodies to neurons, mainly in the hippocampus, along with a progressive decrease of the density of synaptic NMDAR clusters. These effects occurred in parallel with memory and other behavioral deficits and improved after the infusion of patients’ antibodies stopped, leading to restoration of NMDAR levels and reversibility of the symptoms. (Dalmau, 2016)
CLINICAL FEATURES OF ANTI-NMDAR ENCEPHALITIS
The disorder predominantly occurs in individuals below the age of 45 with a female to male predominance (4:1 ratio) with a high association with ovarian teratoma (found in approx 50% of cases of patients over 18 years of age). 
1. Prodromal phase (Phase 1) – Symptoms such as headaches or a viral-like fever (headaches, respiratory, and gastrointestinal symptoms) are highly common in more than 80% of patients.
2.Illness Phase (Phase 2)
Psychiatric phase – Approximately two weeks after the initial phase, psychiatric symptoms occur which are highly variable.
- Delusional thoughts including paranoid ideation
- Perceptual disturbances
- Disorganised thoughts and behaviours
- Anxiety, agitation and fear
- Cognitive deterioration
- Progressive decline in speech and language which may include alogia, echolalia, perseveration
- Paediatric population often manifests with manic symptoms, irritability, behavioural outbursts, sleep dysfunction, hyperactivity and hypersexuality
- Abnormal movements or facial dyskinesias, dystonic posturing, choreoathetoid movement of the limbs and autonomic instability and in some cases progress to hypoventilation requiring ventilatory support.
- Seizures (partial or complex) are also a feature of the anti-NMDAR encephalitis contributing to greater than 25% of female patients between 18 to 45 with new-onset epilepsy.
3.Recovery and relapse phase (Phase 3) :
- Some patients have a prolonged course of illness but can show spontaneous neurological improvement.
- Cognitive and psychiatric functions are the slowest to improve.
- Anti-NMDAR encephalitis has a relapse rate of 20% to 25%.
4. Late Phase (Phase 4):
- Approximately 85% of patients who make a full recovery of significant cognitive behavioural abnormalities on the hospital discharge, may have deficits in executive function, impulsivity, behavioural disturbance and abnormal sleep patterns.
A systematic literature review of PubMed and EMBASE of all published cases (706 cases) of anti-NMDA receptor encephalitis was published in 2018 focusing on the characteristics of the psychiatric syndrome. 
- Cases were typically young (mean age 22.6 years, SD 14.8), female (F : M ratio 3.5 : 1) and presented with significant behavioural disturbance.
- Reported behaviour was most commonly severe agitation and aggression, abnormal speech, and catatonia.
- Psychosis occurred in 45.8% of cases. Investigation results were inconsistent (MRI abnormal in 35.6%, EEG abnormal in 83.0%) and non-specific.
- Psychiatric treatment often required multiple psychotropics, and there may be increased risk of significant side-effects such as neuroleptic malignant syndrome.
- Prognosis was usually good; however, cognitive and behavioral symptoms remained prominent during recovery, and psychiatrist involvement was required in this period.
A prospective study of 100 patients aiming to determine the behavioural hallmarks of Anti-NMDA receptor encephalitis (ANMDARE) showed: [Espinola-Nadurille et al, 2022]
Our study supports the notion of a neurobehavioral phenotype of ANMDARE characterized by a fluctuating course with psychotic and affective symptoms, catatonic signs, and global cognitive dysfunction, often accompanied by seizures and dyskinesia. The catatonia–delirium comorbidity could be a distinctive neurobehavioral phenotype of ANMDARE.
THE FORMES FRUSTES GROUP
Since 75% of patients with Anti-NMDAR encephalitis first present to a psychiatrist, it becomes especially important for psychiatrists to be vigilant for the disorder to avoid a misdiagnosis of substance use, psychosis, mania or schizophrenia.
The formes frustes group represent the milder forms of the disorder which can be purely psychiatric and can easily be missed. 
For example, the parents of a 19-year-old man who had been diagnosed with pure mania indicated that for several weeks he had had memory problems at school. They denied abnormal movements, but when showed several forms of oculofacial dyskinesias, they indicated that, along with memory problems, the patient had profuse eye blinking, a symptom they attributed to being anxious. (Dalmau et al., 2011)
IMMUNOLOGICAL TRIGGERS OF ANTI-NMDAR ENCEPHALITIS
Since 50% of women with anti-NMDAR encephalitis have an ovarian teratoma one of the postulated theories is that the neural tissue in the teratoma acts as an immunological trigger.
It is postulated that antigen released by apoptotic tumour cells is taken up by antigen presenting cells (APC) and then presented to the immunological system in the regional lymph nodes where memory B cells are generated, and the antibody production by plasma cells is initiated.
The memory B cells after crossing the blood-brain barrier (BBB), undergo maturation into antibody-producing plasma cells. The plasma cells continue a prolonged synthesis of antibodies within the CNS. (you can learn more about neuroinflammation here)
Thus it is postulated that the intrathecal production of CNS produced antibodies is known for the pathogenic effects in anti-NMDAR encephalitis. 
The other immunological trigger is possibly the Herpes Simplex viral antigen. Approximately 20% of patients with Herpes simplex encephalitis develop antibodies against the NMDAR.
The following are investigations that aid in the diagnosis of Anti-NMDAR encephalitis , , 
- CSF lymphocytic pleocytosis and elevated protein. Oligoclonal bands may be found in 60% of the cases. A conclusive diagnosis is made by demonstrating CSF IgG antibodies against the GluN1 subunit of the NMDA receptor
- In 50% of patients, the findings are normal whereas in 50% of patients there are bilateral T2 or FLAIR signal hyperintensities in the medial temporal lobe, frontal cortex, cerebellar cortex, medulla oblongata, and spinal cord.
- A recent imaging study of 53 patients with Anti-NMDAR encephalitis showed that normal brain MRI findings were observed in half of the patients. 
- Lesions in the hippocampus were the most common abnormal finding.
- The presence of hippocampal lesions is the main predictor of poor prognosis in patients with anti-N-methyl-D-aspartate receptor encephalitis.
- The EEG shows a slow and disorganised activity in the delta and theta range with superimposed EEG seizures. Although 90% of cases have abnormal EEG, these data are often non-specific.
- Detection of autoantibodies in the serum using either a tissue-based or cell-based assay form a reliable part of any confirmatory diagnostic test.
- Antibody studies should include CSF analysis as a risk of false-negative, or false-positive diagnoses exists if only serum is used.
- For example, we published a case of a patient with Wernicke-Korsakoff Syndrome who showed serum positive Anti-NMDA-Receptor Antibodies.
Recently, Graus has suggested the following 3 criteria to assist with the diagnosis of probable Anti-NMDAR encephalitis in the absence of antibody testing :
Diagnosis can also be made in the presence of three of the above groups of symptoms accompanied by a systemic teratoma
A diagnosis of definite anti-NMDA receptor encephalitis can be made in the presence of one or more of the six major groups of symptoms AND IgG anti-GluN1 antibodies, after reasonable exclusion of other disorders.
WHICH PATIENTS SHOULD BE TESTED FOR ANTINEURONAL ANTIBODIES?
The recent Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders  and others  have recommended testing patients with first episode of psychosis for anti-neuronal antibodies.
The rationale for this is that early therapy for autoimmune encephalitis is associated with better outcomes.
Scott et al. suggested that appropriate testing must take into account the clinical presentation and specified key clinical features in early psychosis for whom antineuronal antibody testing (including NMDAR antibodies) should always be performed. 
Read more about the clinical features that should increase clinical suspicion of autoimmunity in psychiatry in the article on autoimmune disorders masquerading as psychiatric disorders.
MANAGEMENT OF ANTI-NMDAR ENCEPHALITIS
The first line of treatment for patients involves tumour resection (if present), supportive care, and immunotherapy. , , 
- Corticosteroids, intravenous immunoglobulins and plasma exchange are the first line treatments that have been shown to have significant efficacy once the tumour has been removed.
- 80% of patients with a tumour (mostly teratomas) had substantial improvement after tumour removal and first-line immunotherapy.
- Rituximab or cyclophosphamide (or both) is often necessary particularly if there is no underlying tumour. 48 % respond to first-line immunotherapy, and 65% will respond to second-line immunotherapy.
- In patients without a tumor (in whom relapse is more
common), continued immunosuppression with mycophenolate mofetil or azathioprine is recommended for at least 1 year and periodic screening for an ovarian teratoma over 2 years.
- ECT has also shown to be a safe and effective option (particularly in catatonia) in cases of anti-NMDA encephalitis in addition to the above. 
- High dose dopamine blockade can exacerbate dyskinetic and dystonic movements.
- In some cases, antipsychotic medication can result in a clinical presentation indistinguishable from neuroleptic malignant syndrome (NMS).
- Quetiapine is an appropriate choice to treat psychosis. Valproate is an effective mood stabiliser and offers seizure prophylaxis.
- Recovery tends to occur in reverse order of symptom presentation. Once treated, patients’ autonomic functions stabilise, and their dyskinesia-related symptoms subside during the early stages of recovery.
- Approximately 75% of patients have full recovery or mild deficits, while 25% remain severely disabled or die; mortality is estimated to be 4%.
- Patients tend to need close supervision for several months to encourage complete physical and behavioural rehabilitation as well as treat potential psychotic episodes, which can reappear during this time.
You can read a clinical case of a young girl who presented with mania in whom anti-neuronal antibodies (Not Anti-NMDAR) were identified and illness remission was obtained through immunotherapy.
This case highlights that there may be many other anti-neuronal antibodies to be discovered.
Anti-NMDAR encephalitis is a relatively newly discovered condition which should be suspected in any individual, usually younger than 50 years and especially a child or a teenager, who develops a rapid change of behaviour or psychosis, abnormal postures or movements (mostly orofacial and limb dyskinesias), seizures, and variable signs of autonomic instability, hypoventilation, or both.
The condition is also closely associated with ovarian teratomas in 50% of cases.
If detected and diagnosed correctly, the long-term prognosis is good, but increased dissemination of knowledge about the disorder is required for improved accuracy and rapidity of treatment.
It is also important to recognise that there are currently 16 known disorders with IgG autoantibodies against cell surface or synaptic proteins. Anti-NMDAR encephalitis is one of those 16 disorders.
Thus, this suggests there may be many more autoimmune disorders waiting to be discovered allowing us to understand better the functioning of the brain leading to new treatments.
VIDEO LECTURE SUMMARY
Lennox BR, Palmer-Cooper EC, Pollack T, et al. (2017) Prevalence and clinical characteristics of serum neuronal cell surface antibodies in
first-episode psychosis: A case-control study. Lancet Psychiatry 4: 42–48.