“A Whole Herd of Zebras:” Anti-NMDA Receptor Encephalitis

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Author: Jonathan Morgan, OMSIII
Medical Student
Lake Erie College of Osteopathic Medicine-Bradenton

In 2005 neuro-oncology researchers at the University of Pennsylvania first described a strange neurologic syndrome, found in a group of young women with ovarian teratomas, which consisted of acute psychosis followed by the development of motor symptoms and ventilatory failure. Two years later they determined that the etiology of the disorder was the formation of antibodies against NMDA receptors and named the new disorder anti-NMDA-receptor encephalitis (ANMDARE).[1]

Initially, ANMDARE was thought to be a paraneoplastic syndrome found only in the company of ovarian teratomas. However, reports of ANMDARE in patients without tumors began to accumulate, and it now seems that the disease exists in both genders and sometimes in the absence of a tumor or any other obvious causative factor.

At first glance, this disease may seem like a rarity better left to neurologists or other consultants, and not a disease worth worrying about in the ED. However, there is some evidence that ANMDARE is, in actuality, an often unrecognized but relatively common cause of encephalitis. This includes data provided by the California Encephalitis Project (CEP), a group charged with studying the epidemiology and etiology of encephalitis. In 2011 CEP reported on the ultimate diagnosis in the cases referred to them between 2007 and 2011. Of the 761 cases referred to the CEP, 32 cases were diagnosed as ANMDARE. This may seem like a small number, but in comparison only 30 were diagnosed with enterovirus encephalitis, a mere 7 patients had HSV-1, and only 5 patients each had either West Nile Virus or VZV.[2]

These other etiologies are commonly considered, and sometimes empirically treated, during the workup of a patient with encephalitis in the ED. Given the potential for ANMDARE to be even more common, it is worth keeping on the differential for patients presenting with acute psychosis or encephalitis.[4] This may be particularly important in patients with new onset psychosis being referred to a psychiatric facility, especially if they presented with any neurologic symptoms.

Another compelling reason to consider the diagnosis in the ED is that ANMDARE is a treatable disease, and seems to respond better to early treatment. There are numerous reports of patients who demonstrated improvement immediately following immunosuppressant therapy or tumor resection, and one large study has found that good outcome is associated with early treatment.[4,5-7]

ANMDARE is generally characterized by three phases, although detection during the first phase is unlikely.

Phase 1
The first phase of the disease is a nonspecific prodrome with symptoms of low fever, myalgia, and fatigue.[6]

Phase 2
The second phase is characterized by neurologic and psychiatric symptoms. Adult patients often show overt psychosis with different combinations of psychomotor agitation, delusions, catatonia, violence and aggression.[1] One case report describes a previously normal male patient who was admitted to a psychiatric ward after throwing a man through a glass door.[2] Dyskinesia is almost universal in ANMDARE, and may be present at this phase or may first appear during phase three. It seems very likely that these patients will pass through an ED, and unfortunately many case reports of ANMDARE describe patients who presented to a physician in phase two and were diagnosed with either organic or drug-induced psychotic disorders and referred to psychiatric institutions.

Phase 3
During phase three ANMDARE patients often present with hemodynamic instability and hypoventilation. Again, patients are likely to present to an ED in this stage, from either home or a psychiatric institution. Almost half of ANMDAE patients will require ICU admission and mechanical ventilation. Many develop autonomic dysregulation including combinations of tachycardia, bradycardia, hypertension, hypotension, hypothermia, or hyperthermia.[2] Also common is the development of seizure like motor activity, although EEG typically does not show changes consistent with epileptic activity.

Diagnosis and Treatment
The initial workup will be the same as for any encephalitis, including LP and probably imaging, with the addition of serum and CSF tests for anti-NMDA-receptor antibodies. CSF will usually show a lymphocytic pleocytosis with elevated protein. Imaging does not seem to be helpful in making the diagnosis.[1] The diagnosis is ultimately confirmed by the exclusion of an infectious cause of encephalitis and the presence of antibodies in either the CSF or the serum.

Other than performing the appropriate tests, initial ED treatment for ANMDARE will focus on airway management and hemodynamic support, especially given the predilection of ANMDARE to cause autonomic dysregulation and respiratory failure – a distinguishing feature from other causes of encephalitis.

Since antibody results are not likely to be rapidly available, definitive diagnosis and treatment may not occur until the patient is in the ICU, but it may be helpful to be aware of the specific treatment options. First line treatment consists of prompt removal of a tumor, if one can be found, and administration of IVIG or immunosuppression with methylprednisolone. Plasma exchange is also an option. If there is no improvement rituximab and cyclophosphamide will likely be started as second line therapy.[4] Prophylactic immunosuppression for one year with mycophenolate or azathioprine will probably be recommended once those therapies are ended.

Recovery is prolonged, with patients sometimes requiring months or years in the ICU and prolonged periods on a ventilator. Reports of mortality vary, but 75% of patients will eventually make a good recovery, and some reports of mortality in treated patients are as low as 3%.[3]

ANMDARE is a new disease, and understanding of the syndrome is still evolving. Nevertheless, ANMDARE is worth considering when faced with a patient displaying the appropriate psychiatric or neurologic symptoms. There are multiple reports of individuals in whom the diagnosis was missed and who subsequently languished in psychiatric wards, only to become seriously ill but still remain undiagnosed for several months despite a mind-boggling array of tests. Considering the diagnosis in the ED may spare patients from such inappropriate dispositions and reduce delays, allowing for earlier treatment and hopefully improving the ultimate outcome.

Why it matters in the ED: Under recognized. May be more common than other etiologies of encephalitis such as HSV or VZV. Better outcome if treated early.

Recognition: Disease of the young: mean age around 18, usually under 40 [3,4]

  • Phase 1: “Take two aspirin and call me in the morning.”
    • Nonspecific flu-like illnesses
    •  Myalgia 
    • Minimally elevated temperature 
    • Fatigue
  • Phase 2: “Admit to psych/who gave this patient ketamine?”
    • Overt psychosis: dissociative state “similar to that elicited by ketamine”[3]
    • Dyskinesia, most often facial[6]
  • Phase 3: “Medically Cleared No More.” 
    • Autonomic Dysregulation
    • Hypoventilation/hypoxia 
    • Fluctuating blood pressure 
    • Fever or hypothermia 
    • Tachycardia or bradycardia (sometimes requiring pacing) 
    • Dyskinesia 
    • Seizure like activity 
    • Coma 
    • Hyper salivation that may interfere with airway management 
    • No memory for events 
    • Often long ICU stays, prolonged ventilator requirements


  • CSF: lymphocytic pleocytosis in 90% of cases, lower values than viral etiologies (~20 WBC/mm3 vs 70 WBC/mm3)[2]
  • 20% have increased protein 
  • 25% have oligoclonal bands 
  • May have tumors: especially ovarian teratomas in young women. Men get testicular teratomas and small cell lung cancer. Younger patients are less likely to have tumors.[5] 
  • Neuroimaging normal or nonspecific[1,3] 
  • Definitive test is IgG anti-NMDA antibodies in either serum or CSF


  • Tumor resection, if one is present
  • 1st Line: IVIG 0.4g/kg per day for 5 days PLUS methylprednisolone 1g/day for 5 days. Plasma exchange optional.[8] 
  • 2nd line: rituximab 375mg/m2 every week for 4 weeks PLUS cyclophosphamide 750mg/m2 monthly.[8]


1. Dalmau, J., Tüzün, E., Wu, H., Masjuan, J., Rossi, J. E., Voloschin, A., Lynch, D. R. (2007). Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Annals of Neurology, 61(1), 25–36. doi:10.1002/ana.21050

2. Gable, M. S., Sheriff, H., Dalmau, J., Tilley, D. H., & Glaser, C. A. (2012). The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 54(7), 899–904. doi:10.1093/cid/cir1038

3. Young, P. J., Baker, S., Cavazzoni, E., Erickson, S. J., Krishnan, A., Kruger, P. S., Wibrow, B. A. (2013). A case series of critically ill patients with anti- N-methyl-D-aspartate receptor encephalitis. Critical Care and Resuscitation: Journal of the Australasian Academy of Critical Care Medicine, 15(1), 8–14.

4. Titulaer, M. J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T.,Dalmau, J. (2013). Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. The Lancet. Neurology, 12(2), 157–165. doi:10.1016/S1474-4422(12)70310-1

5. Wandinger, K.-P., Saschenbrecker, S., Stoecker, W., & Dalmau, J. (2011). Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. Journal of Neuroimmunology, 231(1-2), 86–91. doi:10.1016/j.jneuroim.2010.09.012

6. Dalmau, J., Gleichman, A. J., Hughes, E. G., Rossi, J. E., Peng, X., Lai, M.,Lynch, D. R. (2008). Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. The Lancet Neurology, 7(12), 1091–1098. doi:10.1016/S1474-4422(08)70224-2

7. Luca, N., Daengsuwan, T., Dalmau, J., Jones, K., deVeber, G., Kobayashi, J., Benseler, S. M. (2011). Anti-N-methyl-D-aspartate receptor encephalitis: a newly recognized inflammatory brain disease in children. Arthritis and Rheumatism, 63(8), 2516–2522. doi:10.1002/art.30437

8. Dalamu, J, Rosenfeld, M. (2014). Paraneoplastic and Autoimmune Encephalitis In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2014. Retrieved: September 27, 2014.