The Zebra Hunter: Anti-NMDAR Encephalitis

The Gist:  anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is probably a more common cause of encephalitis in young individuals than previously thought, according to a California study published in Clinical Infectious Diseases in January 2012.  Providers should consider this autoimmune cause of encephalitis, especially in young women, during the workup of altered mental status and suspected encephalitis and send off the test on the CSF fluid as CSF fluid typically is uninteresting.

Clinical Features of Encephalitis

• Altered Mental Status:  Stupor, Coma, Irritability
• Hallucinations, psychosis, and catonia more prevalent in anti-NMDAR encephalitis
• Seizures
• Neurologic Abnormalities
• Movement disorders, choreoathetoid movements, echolalia, or opisthonic posturing in anti-NMDAR encephalitis
• +/- Fever, Nausea, Vomiting, Malaise
• Stiff neck

Causes:  Traditionally, most cases of encephalitis have been attributed to viruses.  The California Encephalitis Project (CEP) study analyzed cases of suspected encephalitis in individuals <30 years old from 2007-2011.  A total of 761 cases met criteria for inclusion (age <30, 1 sign of encephalitis, hospitalization, reported to the CEP, etc).  The authors reported that among this cohort, the leading single cause of encephalitis was anti-NMDAR.  However, upon further review, only 79 cases among this 761 patient cohort had identified causes reported.  Among those 79 cases, 32 were diagnosed as anti-NMDAR encephalitis, outranking HSV-1 (1).  Thus, most cases are probably attributable to undetected viral entities. 

• Viruses
• Herpes Simplex -1
• Enteroviruses 
• Arthropod borne diseases - West Nile
• Varicella zoster
• Auto-immune
• Teratomas (anti-NMDAR in females and anti-Ma2 in males)
• Small cell lung cancer (anti-Hu)

Differential Diagnosis

• Meningitis
• Brain Abscess
• Toxoplasmosis
• Tick Borne Diseases: Lyme, Rocky Mountain Spotted Fever
• Hypoglycemia
• Tuberculosis
• Hemorrhage

Diagnosis of anti-NMDAR Encephalitis

• The usual encephalitis workup, at a minimum:  glucose, CBC, CMP, CT head, LP with viral panel serology/cultures
• Cerebrospinal fluid (CSF) demonstrates pleocytosis
• Protein and leukocyte count is usually lower in anti-NMDAR encephalitis compared with much higher values in the viral encephalopathies
• Auto-antibodies to the NR1 subunit of the NMDAR present in the CSF
• Presence of an ovarian teratoma (not required for the diagnosis)

Treatment of anti-NMDAR Encephalitis

• Removal of teratoma
• Glucocorticoids (Methylprednisolone 1g IV x 5 days)
• IVIG
• +/- Plasmapheresis
• +/- Cyclophosphamide or Rituximab (monoclonal antibody to CD20) (2)

Why Does This Zebra Matter?

• Individuals undergoing a workup for encephalitis are subjected to extensive tests
• As the CEP demonstrates, these diagnostic evaluations often fail to produce an identifiable cause.  A CSF test for anti-NMDAR encephalitis may increase the number of cases with a known cause.
•  Note:  one of the authors of the aforementioned paper is a patent holder for the anti-NMDAR CSF test. 
• Anti-NMDAR encephalitis has a different treatment course than viral encephalitis and may be reversible with teratoma resection 

References:

1.  Gable M, Sheriff H, Dalmu J, Tilley D, Glaser C.  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. Clin Infect Dis. (2012) 54 (7):899-904.doi: 10.1093/cid/cir1038

2.  Dalmau J, Rosenfeld M.  Paraneoplastic and autoimmune encephalitis. Uptodate