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Anti-NMDA-Receptor Encephalitis

2018-01-30T02:37:16+00:00

EncephalitisAnti-NMDA-receptor encephalitis is a severe and treatable immune-mediated disorder which presents with a rapid progression of  psychiatric and neuropsychiatric symptoms. Although only first reported as a diagnosis in 2007, an exponential number of cases have since been described, suggesting that the disease is not rare but rather under-diagnosed. Emergency physicians play an important role in recognizing this disorder, as prognosis is largely dependent on early treatment with immunotherapy.

Case

A 47 year old man was brought to the ED after 2 witnessed seizures. Further history revealed the patient did not have a history of epilepsy, but had a seizure 1-week prior preceded by a viral prodrome. His workup at a neighboring hospital for the first-time seizure included a normal CT and EEG study and discharge after 24 hours. Since discharge, his wife, parents, and friends report that he has had unusual behavior. His wife mentions that “he has been more inward”, and his friend who brought him to the ED says “he seemed subdued.”

During current ED visit, he is initially afebrile, yet later develops an oral temperature of 100.4F. His heart rate is 93 bpm, respiratory rate 20 bpm, blood pressure 144/76, and SaO2 (RA) is 98%. On exam, he is unresponsive but breathing spontaneously. Pupils are equal and reactive, and there is no sign of head trauma. Heart sounds are normal, lungs are clear to auscultation, and his abdomen is soft, nontender, and not distended. He has equal, strong pulses in all extremities. His left arm is in a sling from a clavicle injury he sustained during his first seizure, but otherwise there is no deformity or tenderness to his extremities. On a limited neurological exam, he is nonverbal, does not follow commands, and has notable rigidity of his extremities. There are no rashes or markings on his skin. During the patient’s stay in the ED, he is noted to be catatonic, with several episodes of facial twitching.

ED workup included a normal head CT. CSF analysis was suggestive of viral encephalitis. The remainder of his lab studies, including a CBC, BMP, UA, ABG and later blood culture were otherwise unremarkable. The patient was admitted to the hospital for further neurological workup with the working diagnosis of encephalitis, specifically concerning for Anti-N-methyl D-aspartate (Anti-NMDA) receptor encephalitis.

Anti-NMDA-Receptor Encephalitis

Anti-NMDA-receptor encephalitis is a severe form of immune-mediated encephalitis first described in the neurology literature in 2007. 1,2  In an analysis of 100 cases, the median age was found to be 23, with a range from 5-76 years. The disease predominately affects women (91 of the 100 patients). All patients presented with psychiatric symptoms or memory problems, with seizures being reported in 75 of the cases. Decreased mentation as well as autonomic dysfunction was also common. Ovarian teratomas were found in half of the cases, and these patients had better outcomes with removal of the tumor.2

Retrospective studies report a multi-stage presentation, with prodromal symptoms of headache and low-grade fevers present for 0-2 weeks on average. This viral prodrome is followed by the rapid progression of psychiatric and neuropsychiatric symptoms which usually bring the patient to seek medical attention and hospital admission. These symptoms include personality changes, memory problems, unresponsiveness, dyskinesia, seizures, autonomic instability, central hypoventilation, and cardiac dysrhythmias.3 Given the wide spectrum of presentation and unfamiliarity with this disorder, many patients will have a delayed diagnosis. Diagnosis is often suspected when patients do not respond properly to treatment of their presumed diagnosis, such as alcohol withdrawal, seizure disorder, neurotropic viruses like HSV encephalitis, or intoxication. 4,5

Further workup usually reveals an abnormality on EEG, MRI, or CSF analysis. Once a diagnosis is suspected, patients may undergo testing for specific autoantibodies in the serum or cerebrospinal fluid. Early recognition is imperative as patients often respond to proper immunotherapy or complete tumor removal, if an ovarian teratoma is known. 6

In the past year, EM:RAP, and TPR have brought attention to anti-NMDA-receptor encephalitis, making ED providers more aware of this often under-recognized diagnosis. This week ALiEM Book Club discussed “Brain on Fire – My Month of Madness,” a personal account of a young woman diagnosed with anti-NMDA-receptor encephalitis.

 Image credit

1.
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld M, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10(1):63-74. [PubMed]
2.
Dalmau J, Gleichman A, Hughes E, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-1098. [PubMed]
3.
Wandinger K, Saschenbrecker S, Stoecker W, Dalmau J. Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. J Neuroimmunol. 2011;231(1-2):86-91. [PubMed]
4.
Armangue T, Petit-Pedrol M, Dalmau J. Autoimmune encephalitis in children. J Child Neurol. 2012;27(11):1460-1469. [PubMed]
5.
Punja M, Pomerleau A, Devlin J, Morgan B, Schier J, Schwartz M. Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis: an etiology worth considering in the differential diagnosis of delirium. Clin Toxicol (Phila). 2013;51(8):794-797. [PubMed]
6.
Titulaer M, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165. [PubMed]

Expert Peer Review

The emergency physician has a key role making the diagnosis of anti-NMDA-receptor encephalitis and facilitating early treatment with IV immunoglobulin and steroids — interventions that are known to improve prognosis. This fascinating but still under-recognized disease progresses in several general phases:

  1. prodromal phase — nonspecific symptoms of viral infection or URI
  2. psychotic phase — personality changes, paranoia, bizarre behavior, hallucinations, memory deficits
  3. catatonic phase — decreased level of consciousness, lethargy, movement disorders, autonomic instability, slow impoverished speech

Seizures can occur at almost any stage.

Because of psychotic features early on, these patients are often admitted to the psychiatric service, a mistake that can significantly delay making the correct diagnosis. In addition, they are frequently treated with neuroleptic antipsychotic drugs such as haloperidol. Autonomic instability and dyskinesia supervene as the disease process evolves, making it all too easy to anchor on a mistaken diagnosis of neuroleptic malignant syndrome, delaying the diagnosis further. Both emergency practitioners and medical toxicologists should be aware of this pitfall.

Therefore, any patient — especially a young patient — who has new onset psychotic manifestations, especially if accompanied by seizures and/or hallucinations, should be suspected of having anti-NMDAR-encephalitis. Examination of the CSF will show increased lymphocytes and oligoclonal bands in most cases. Definitive diagnosis is made by detection of anti-NMDAR antibodies in the serum and CSF.

As pointed out in Dr. Haber\'s excellent discussion of this interesting case, anti-NMDAR encephalitis is not really a rare disease. In fact, data from the California Encephalitis Project suggested that it is more than four times as common as encephalitis attributed to HSV-1, varicella, or West Nile Virus in patients 30 years of age of less.

One open question involves the role of empiric therapy with IV-Ig and steroids in patients suspected of having anti-NMDAR encephalitis. Should these be started as soon as the diagnosis is suspected? After other diagnoses have been ruled out? Or only when the diagnosis is confirmed by the presence of specific antibodies? The question may become less important as antibody testing becomes more readily available.

Leon Gussow, MD FACEP
Board-certified in Emergency Medicine & Internal Medicine; Medical consultant to the Illinois Poison Center; “Toxicology Rounds” columnist for Emergency Medicine News; Medical Editor of The Poison Review.
Jordana Haber, MD

Jordana Haber, MD

Director of Clinical Education
University Medical Center, Las Vegas