Anti-N-methyl-D-aspartic acid receptor encephalitis
Anti N-methyl-D-aspartic acid (NMDA) receptor encephalitis is an autoimmune encephalitis with antibodies against the NMDA receptors. It is sometimes considered a form of autoimmune limbic encephalitis. It usually affects young patients particularly young females, in about 60% of whom ovarian teratoma is present. Patients present with psychiatric symptoms but eventually develop seizures or movement abnormalities.
Young patients are most commonly affected with a female to male ratio of 4:1 1,3. In young females, in particular, up to 58% are associated with ovarian teratoma 3.
An initial viral-like prodromic phase often occurs, followed by prominent psychiatric symptoms ranging from anxiety to psychosis. Subsequently, signs of temporal lobe dysfunction can occur such as seizures and amnesia. With time, severe neurological deficits can develop such as abnormal movements, dysautonomia, catatonia, and coma 8.
An interesting feature in those patients who survived is an amnesia to the entire illness. This is thought to be due to disruption of synaptic plasticity which is important in the memory and learning process.
Anti N-methyl-D-aspartic acid (NMDA) receptor encephalitis is an autoimmune encephalitis due to antibodies against NR1–NR2 heteromers of the NMDA receptor, in particular, extracellular N-terminal domain of the NR1 subunit. These antibodies result in marked reduction of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites 1. An underlying tumor is only detected in approximately 60% of patients, mostly teratomas. Anti-NMDA NR2 antibodies are also found in approximately 15-35% patients with SLE and approximately 80% of SLE patients with severe neuropsychiatric illness. CSF shows pleomorphism. Serum titers of anti-NMDA antibodies are elevated and correlate well with the severity of the disease.
Imaging findings are highly variable and perhaps dependent upon the underlying cause of anti-NMDA receptor encephalitis. Namely, features might differ in pediatric versus adult patients and also depending on if the encephalitis is associated with a paraneoplastic or nonparaneoplastic cause. Of note, initial MRI can be normal in up to 89% of patients 8. FDG PET-CT might be more sensitive in detecting subtle abnormalities.
Findings are non-specific. Abnormal FLAIR or T2 hyperintensity can be seen in the medial temporal lobe, cerebral/cerebellar cortex, basal ganglia, and brainstem 1,2. Typically there is no abnormal enhancement or hemorrhage 8.
FDG-PET may show either hyper- or hypo-metabolism in the affected region depending on time of presentation and severity of neurological deficits. Patterns of involvement are variable, but can affect the cortex in any lobe, namely the temporal region 3. Anomalies may be either symmetrical or asymmetrical. Recently, hypo-metabolism in the medial occipital lobes has been described as a specific biomarker useful in differentiating anti-NMDA receptor encephalitis from other forms of autoimmune encephalitis.
Treatment and prognosis
Medical therapy is usually a combination of immunotherapies including corticosteroids, intravenous immunoglobulins, and/or plasma exchange 1. Further workup of anti-NMDA receptor encephalitis is necessary with whole body CT and pelvic US for detection of associated tumor / ovarian dermoid 1. Surgical excision of any ovarian dermoid is performed with concurrent commencement of immunotherapy.
Estimated 4% reported mortality for anti-NMDA receptor encephalitis mainly from respiratory or cardiac complication during intensive care stay 1. Early diagnosis and treatment have been shown to improve outcome and reduce the number of relapses markedly.
An autobiography titled "Brain on Fire: My Month of Madness" by Susannah Cahalan describes her personal experience with the disease 4.
- 1. Dalmau J, Lancaster E, Martinez-Hernandez E et-al. The Lancet Neurology. 2011;10 (1): . doi:10.1016/S1474-4422(10)70253-2
- 2. Azizyan A, Albrektson JR, Maya MM et-al. Anti-NMDA Encephalitis: An Uncommon, Autoimmune Mediated Form of Encephalitis. J Radiol Case Rep. 2014;8 (8): 1-6. doi:10.3941/jrcr.v8i8.1566 - Free text at pubmed - Pubmed citation
- 3. Pillai SC, Gill D, Webster R et-al. Cortical hypometabolism demonstrated by PET in relapsing NMDA receptor encephalitis. Pediatr. Neurol. 2010;43 (3): 217-20. doi:10.1016/j.pediatrneurol.2010.04.019 - Pubmed citation
- 4. Cahalan S. Brain on Fire. Particular Books. ISBN:1846147395. Read it at Google Books - Find it at Amazon
- 5. Lau CG, Zukin RS. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat. Rev. Neurosci. 2007;8 (6): 413-26. doi:10.1038/nrn2153 - Pubmed citation
- 6. Levite M. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate rec. J Neural Transm (Vienna). 2014;121 (8): 1029-75. doi:10.1007/s00702-014-1193-3 - Pubmed citation
- 7. John C. Probasco, Lilja Solnes, Abhinav Nalluri, Jesse Cohen, Krystyna M. Jones, Elcin Zan, Mehrbod S. Javadi, Arun Venkatesan. Decreased occipital lobe metabolism by FDG-PET/CT. (2017) Neurology - Neuroimmunology Neuroinflammation. 5 (1): e413. doi:10.1212/NXI.0000000000000413
- 8. B.P. Kelley, S.C. Patel, H.L. Marin, J.J. Corrigan, P.D. Mitsias, B. Griffith. Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis. (2017) American Journal of Neuroradiology. doi:10.3174/ajnr.A5086 - Pubmed