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Toxicology Rounds

Toxicology Rounds: A Catastrophic Diagnosis You Probably Don't Know

Gussow, Leon MD

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doi: 10.1097/01.EEM.0000459000.96697.4e
    The limbic system comprises the hippocampus, amygdala, cingulate gyrus, fornix, hypothalamus, and thalamus.

    Anti-NMDA-receptor encephalitis may be the most important neurologic disease you've never heard of.

    Anti-NMDAR encephalitis, first described in 2007, causes devastating, progressive neurologic and cognitive deterioration, ending with catatonia and sometimes death. The diagnosis is often delayed or not suspected at all because many physicians do not know of it. Patients will often respond dramatically — even completely — to specific immunotherapy, so missing the diagnosis can be catastrophic.

    The body for some reason begins producing antibodies against a subunit of the NMDA receptor, resulting in inflammation of regions in the brain where that receptor is abundant. The precipitating factor is not clear in all cases, but anti-NMDAR encephalitis is often associated with specific tumors such as ovarian teratomas. Sometimes the early manifestations are flu-like, suggesting a link to an initial viral infection.

    The NMDA receptor is a glutamate receptor that in mammalian brains regulates synaptic transmission. NMDA receptors are present throughout the brain, but are especially prominent in the parts of the limbic system that create memories, regulate autonomic functions, and modulate emotions. They are also concentrated in the area of the frontal cortex involved in cognition, decision-making, and personality.

    Presentation can vary, but the disease generally develops in four stages that may meld into one another. About half of patients in the prodrome phase present with fever, headache, upper respiratory symptoms, vomiting, and diarrhea, according to a series of 32 patients. (Ann Neurol 2009;66[1]:11.) It is not clear if this represents the initial manifestations of the condition or a precipitating infection.

    Common symptoms in the psychotic phase include personality changes, bizarre behavior, agitation, paranoia, hallucinations, and delusions. Patients may complain of memory difficulties and sleep disturbance. It is not uncommon for patients in this phase to be admitted for psychiatric treatment when the diagnosis of anti-NMDAR encephalitis is not considered. Additional features of this phase can include seizure activity as well as muscle rigidity, dyskinesias, and repetitive movements of the mouth and tongue.

    Hyperthermia, hypertension, hypotension, tachycardia, and bradycardia have all been reported in cases of anti-NMDAR encephalitis in the autonomic instability phase. Then inflammation intensifies and the disease progresses, with speech slowing down and becoming impoverished in the catatonia phase. Decreasing consciousness and marked central hypoventilation may require intubation and mechanical ventilation.

    Tests can help rule out more common causes of encephalitis, but most standard lab tests remain normal or nonspecific. The cerebral spinal fluid may show a mildly increased number of lymphocytes and the presence of oligoclonal bands. Head CT and MRI exams remain unremarkable. A definitive diagnosis can be made from serum or CSF sent to specific outside laboratories to detect NDMAR autoantibodies.

    The goal of therapy is to reduce inflammation and suppress autoantibody production. Initial interventions usually include steroids, IV immunoglobulin, and plasma exchange. Second-line drugs when indicated include rituximab and cyclophosphamide. Evidence suggests, of course, that clinical outcome is better the earlier the diagnosis is suspected and treatment started.

    The disease is far more common than one might think. Analysis of data from the California Encephalitis Project found that anti-NMDAR encephalitis was identified more than four times as frequently as encephalitis caused by herpes simplex virus type 1, varicella, or West Nile virus in patients under age 30. (Clin Infect Dis 2012;54[7]:899.)

    Medical toxicologists may be consulted about toxic etiologies, especially during the psychotic phase when bizarre behavior, agitation, and hallucinations could suggest drug intoxication or withdrawal. Mentioning anti-NMDAR encephalitis as a potential cause if these are ruled out may reduce the time to diagnosis and improve outcome.

    Not infrequently, patients are treated with neuroleptic agents such as haloperidol during the agitated psychotic phase of the disease. Neuroleptic malignant syndrome may be suspected when patients present with dystonia, muscle rigidity, and autonomic dysfunction. Again, the consulting toxicologist is key in including anti-NMDAR encephalitis on the differential, especially if symptoms don't resolve when exposure to neuroleptic agents is stopped.

    I highly recommend the book Brain on Fire by Susannah Cahalan, a New York Post reporter who recovered from anti-NMDAR encephalitis, and provides a riveting case study from a patient's point of view.

    Correction: I incorrectly stated that marijuana edibles contain pure THC in my September column. The psychoactive compounds in edibles are extracted from the cannabis plant, so other cannabinoids are also present, although only the THC content is listed on the label.

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