Patient characteristics and outcome associations in AMPA receptor encephalitis
Antibody-mediated encephalitis defines a class of diseases wherein antibodies directed at cell-surface receptors are associated with behavioral and cognitive disturbances. One such recently described encephalitis is due to antibodies directed at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). This entity is exceptionally rare and its clinical phenotype incompletely described. We present findings from two cases of AMPAR encephalitis that exemplify variability in the disease spectrum, and summarize findings in published cases derived from a systematic literature review. When all patients are considered together, the presence of psychiatric symptoms at presentation portended a poor outcome and was associated with the presence of a tumor. Furthermore, we provide evidence to suggest that the topography of magnetic resonance imaging abnormalities in reported cases mirrors the distribution of AMPARs in the human brain. The potential for neurological improvement following immunomodulatory therapy together with the favorable outcome reported in most cases emphasizes the importance of testing for autoantibodies against neuronal cell-surface proteins, including AMPAR, in patients with clinical and neuroimaging findings suggestive of autoimmune encephalitis. Close attention to the clinical phenotype may inform the presence of malignancy and long-term prognosis.
KeywordsAutoimmune encephalitis Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor Paraneoplastic encephalitis Limbic encephalitis
Funding was provided by the American Academy of Neurology/American Brain Foundation (Clinical Research Training Fellowship to GSD).
Compliance with ethical standards
Conflicts of interest
On behalf of all authors, the corresponding author states that there are no conflicts of interest. Dr. Bucelli receives an annual gift from a patient's family for Parsonage-Turner research; served on an advisory board for MT Pharma; and has equity in Neuroquestions, LLC. Dr. Day has served as a topic editor on dementia for DynaMed Plus (EBSCO Industries, Inc) and as clinical director for the Anti-NMDA Receptor Encephalitis Foundation (uncompensated). Dr. Day receives research/grant support from The American Academy of Neurology/American Brain Foundation, Avid Radiopharmaceuticals, the Foundation for Barnes Jewish Hospital, and the National Institutes of Health (P01AG03991, R56AG057195, U01AG057195) and holds stock in ANI Pharmaceuticals, Inc. Dr. Day has provided record review and expert medical testimony on legal cases pertaining to management of Wernicke encephalopathy. All other authors have no relevant disclosures to report.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
- 2.Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA (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. Clin Infect Dis 54(7):899–904. https://doi.org/10.1093/cid/cir1038 CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Titulaer MJ, McCracken L, Gabilondo I et al (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12(2):157–165. https://doi.org/10.1016/S1474-4422(12)70310-1 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Castillo-Gómez E, Oliveira B, Tapken D et al (2017) All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class. Mol Psychiatry 22(12):1776–1784. https://doi.org/10.1038/mp.2016.125 CrossRefPubMedGoogle Scholar
- 23.Joubert B, Kerschen P, Zekeridou A et al (2015) Clinical spectrum of encephalitis associated with antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor: case series and review of the literature. JAMA Neurol 72(10):1163–1169. https://doi.org/10.1001/jamaneurol.2015.1715 CrossRefPubMedGoogle Scholar
- 34.Lahiri S, Coad SD (2013) Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor mediated limbic encephalitis in a fourteen-year-old (P05.114). Neurology 80(7 Supplement):P05.114Google Scholar
- 35.Liu HS, Ren HT, Zhou LX et al (2017) Clinical analysis of paraneoplastic neurological syndrome associated with thymoma. J Chin Med Assoc 97(35):2770–2774. https://doi.org/10.3760/CMA.J.ISSN.0376-2491.2017.35.013 CrossRefGoogle Scholar
- 46.Zaeem Z, Luk C, Anderson D, Blevins G, Siddiqi Z (2018) AMPA-R limbic encephalitis associated with systemic lupus erythematosus. Neurology 90(15 Supplement):P5.386Google Scholar
- 48.Pinto L, Simabukuro M, Spera R et al (2016) AMPA receptor antibody encephalitis in a young man associated with atypical findings. Case report. Neurology 86(16 Supplement):P2-265Google Scholar
- 49.Takahashi C, Holmes S, Wong M (2017) A rare case of AMPA-R antibody positive paraneoplastic limbic encephalitis. Neurology 88(16):SupplementGoogle Scholar