The anti-NMDAr antibody (ab), was first identified in 2007 by Dr. Josep Dalmau. The incidence of NMDA anti-receptor antibody encephalitis (anti-NMDAR) is estimated at approximately 2-3 cases per million. It is the most common type of autoimmune encephalitis and the second most frequent autoimmune encephalitis, after disseminated acute encephalomyelitis in children.
Some patients experience a prodromal phase when the disease is developing with symptoms of viral-like or flu-like illness that usually presents 1-2 weeks before the development of psychiatric symptoms. It is not known whether the symptoms are due to NMDAR dysfunction, the systemic immune response to autoimmune disease or secondary responses to a viral infection which later precipitate autoimmune disease as seen in herpes simplex virus (HSV). The diagnosis of anti-NMDAR encephalitis is confirmed by the detection of CSF antibodies against the GluN1 subunit of the NMDAR; serum testing is less reliable, with false negative results in up to 14% of cases. Therefore, it is important that both serum (blood) and CSF (spinal fluid) are tested as spinal fluid is 100% accurate to confirm the diagnosis.
Anti-NMDAR encephalitis affects predominantly children and young adults (median age, 21 years), with a predominance of cases in females (4:1) that becomes less evident after the age of 45 years. In patients below the age of 12 or older than 45 years, there is an almost equal proportion of males and females. Up to 58% of affected young female patients have an ovarian teratoma. in men and children, the association with tumors is less frequent. In patients older than 45 years, the clinical picture is similar to that of younger patients, but the outcome is less favorable. In this age group, 23% of patients had an underlying tumor (carcinomas instead of teratomas), and delays in diagnosis and treatment were more frequent than in younger patients.
NMDA receptors are proteins that control electrical impulses in the brain. Their functions are critical for judgement, perception of reality, human interaction, the NMDA receptor is essential for the development of new memory and retrieval of memory so patients later have no memory of certain times in their life while the disease was occurring. Speech production is affected; it is described like aphasia but it does not fit with any type of aphasia. Children may become almost mute. The control of unconscious activities such as breathing and swallowing, also known as autonomic functions, is impaired.
The presentation of NMDAR encephalitis in children with behavioral abnormalities may initially suggest autistic regression, early onset schizophrenia, or childhood disintegrative disorder. Presentations with adults may initially suggest undiagnosed Bipolar disorder, or recreational drug or alcohol abuse. Compared with adults, children more often present initially with insomnia, abnormal movements or seizures, or a change in behavior such as irritability, temper tantrums, agitation, and reduction of verbal output. Then in the ensuing days or weeks progress to develop a syndrome similar to that of the adults. Teenagers and adults more often present with psychiatric symptoms, including agitation, hallucinations, delusions, and catatonia, which may lead to hospital admission for psychosis. The disease progresses in a period of days or weeks to include reduction of speech, memory deficit, orofacial and limb dyskinesias, seizures, decreased level of consciousness, and autonomic instability manifested as excess salivation, hyperthermia, fluctuations of blood pressure, tachycardia, or central hypoventilation.
Most patients with autoimmune encephalitis respond within weeks to first-line treatments, but anti-NMDAR encephalitis patients are the slowest among autoimmune encephalitis to respond. For the 47% of patients who do not respond to first-line treatments, a second-line immunotherapy is started with rituximab or cyclophosphamide or both. The outcome of the second-line immunotherapy in patients is improved in 65% of cases. Generally, the frequency of improvement is better for patients with tumor (80%) when compared to patients without tumor (48%). Patients without tumors consequently require more often a second-line immunotherapy. anti-NMDAR encephalitis patients often develop more severe symptoms and require longer hospitalizations, but 80% achieve a complete or substantial recovery that allows them to return to their usual activities. In addition, young patients with anti-NMDAR encephalitis recover better than older patients (81% versus 64%) had a good prognosis after two years of follow-up. Despite this second-line treatment, relapse can occur in 20%–25% of the case. To prevent relapses, immunosuppressive treatment can be continued with mycophenolate mofetil or azathioprine during 1 year.
There is an association of higher CSF titers for teratoma and higher CSF tiiters and worse outcomes. High CSF titers can also be associated with relapses. Usually when the patients start to recover from the autonomic dysfunction, they start getting better. Recovery is slow, greater than two years, and occurs in inverse order of symptom development. Patients are then left with several executive dysfunctions that can last for a long time; some of which they may not recover.
The anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score
Hallmarks for early recognition of anti-NMDAr
Anti-NMDAr Encephalitis Fact-Sheet
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