Anti-NMDAr Encephalitis

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Introduction

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. However, neoplasms of the mediastinum (extragonadal teratoma), lymphoma, testicular cancer, and pontine glioma have also been described. 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 judgment, 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.

Causes

anti-NMDAr encephalitis is triggered by tumor, as most commonly noted above an ovarian teratoma in females, and may also be triggered by infection. Other less common neoplastic triggers include testicular cancers, Hodgkin lymphoma, lung, and breast cancers. It may also be triggered by infection, occurring as a para-infectious phenomenon, seen most commonly after herpes simplex-1 encephalitis.

​Presentation

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. Patients have a diverse range of neuropsychiatric symptoms- apathy, anxiety, fluctuating sensorium, bizarre behaviors, hypersexuality, wandering,  aphasia, amnesia, apraxia, sleep-wake cycle disruption with severe insomnia, delusion. Compared with adults, children more often present initially with insomnia, abnormal movements, or seizures, both focal and generalized. Seizures can be resistant to antiepileptic drugs(AEDs) and may evolve to status epilepticus or even refractory status epilepticus. 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 (mutism), memory deficit, prominent movement disorders becomes evident. The classic movement disorder is oro-lingual dyskinesias with lip-smacking, tongue protrusion, jaw movements, but a diverse range of movement disorders can present. Autonomic instability manifested as excess salivation, hyperthermia, fluctuations of blood pressure, tachycardia, or central hypoventilation. Decreased motor activity and catatonia follow. Following the unresponsive phase, some patients require admission to the ICU and in some instances, use of mechanical ventilation and cardiac pacemaker. 

​Treatment

Treatment recommendations are based largely on retrospective series and expert opinion since few clinical trials have been conducted.

The current approach includes immunotherapy and removal of the immunologic trigger, such as teratoma, which occur in 58% of females, or other tumor, when applicable. Early tumor removal is particularly important in achieving a good outcome. 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.  About 85% of patients respond to immunotherapy (and removal of an associated tumor if it applies), but it often takes several months or more than 1 year for patients to recover. For the 47% of patients who do not respond to first-line treatments, 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 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. After immunotherapy and supportive care, the patients may enter the recovery phase after months of treatment. Recovery of language function and behavioral symptoms occurs at the end. 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 within two years of initial presentation but usually with a less severe presentation. To prevent relapses, immunosuppressive treatment can be continued with mycophenolate mofetil or azathioprine for 1 year. 

Prognosis

There is an association of higher CSF titers for teratoma and higher CSF titers 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. There are some independent predictors of worse outcome: Requirement of ICU stay, treatment delay over four weeks, no improvement after four weeks of treatment, abnormal brain MRI, and white blood cell greater than 20 cells/microL. All these variables can be given one point each to form a functional score (see: The anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score below).  A higher score is associated with poor functional status at one year from the disease onset, but this should not be used to guide therapy or determine the final prognosis as one-third of the patients with poor functional status at one year may improve at two years. 

Recovery is slow, greater than two years, and occurs in inverse order of symptom development.  More commonly reported long term deficits involve attention, memory, and executive dysfunctions that can last for a long time; some of which they may not recover.

Overall, 20% of patients develop focal deficits or die from the anti NMDAR encephalitis.

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The anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score

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Our website is not a substitute for independent professional medical advice. Nothing contained on our website is intended to be used as medical advice. No content is intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for your own health professional's advice. Although THE INTERNATIONAL AUTOIMMUNE ENCEPHALITIS SOCIETY  provides a great deal of information about AUTOIMMUNE ENCEPHALITIS, all content is provided for informational purposes only. The International Autoimmune Encephalitis Society  cannot provide medical advice.


International Autoimmune Encephalitis Society is a charitable non-profit 501(c)(3) organization founded in 2016 by Tabitha Andrews Orth, Gene Desotell and Anji Hogan-Fesler. Tax ID# 81-3752344. Donations raised directly supports research, patients, families and caregivers impacted by autoimmune encephalitis and to educating healthcare communities around the world. Financial statement will be made available upon request.

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