Abstract
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.
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Notes
Details available at the Mayo website: https://www.mayocliniclabs.com/test-catalog/Overview/48401.
The t test can be performed against the mean (0) since z-scores are zero mean and unit variance by definition.
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Funding was provided by the American Academy of Neurology/American Brain Foundation (Clinical Research Training Fellowship to GSD).
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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.
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Appendix 1
Appendix 1
Search strategies
Ovid Medline
Date Searched: 4/3/18
Applied Database Supplied Limits: n/a
Number of Results: 228
Full Search Strategy:
exp Receptors, AMPA/ OR exp alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/ OR (alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid).mp. OR (AMPAR OR AMPAR).mp. OR ((AMPA) ADJ10 (antibod*).mp.) OR ((AMPA OR quisqualate) ADJ2 (receptor*).mp.) AND (exp Encephalitis/ OR (Encephalitis* OR encephalopath* OR encephalomyelitis OR cerebritis OR enkephalitis OR leucoencephalitis OR myeloencephaliti*).mp. OR ((brain) ADJ1 (inflammation).mp.) OR ((allergic) ADJ1 (leucoencephalopath*).mp.) OR ((cerebral) ADJ1 (ventriculitis).mp.))
Embase
Date Searched: 4/3/18
Applied Database Supplied Limits: n/a
Number of Results: 550
Full Search Strategy:
‘AMPA receptor’/exp OR ‘alpha amino 3 hydroxy 5 methyl 4 isoxazolepropionic acid’/exp OR ‘a-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor’ OR (AMPA NEAR/10 antibod*) OR AMPAR OR AMPAR OR ((AMPA OR quisqualate) NEAR/2 (receptor*)) AND (‘encephalitis’/exp OR Encephalitis* OR encephalopathy* OR encephalomyelitis OR cerebritis OR enkephalitis OR leucoencephalitis OR myeloencephaliti* OR ((brain) NEAR/1 (inflammation)) OR ((allergic) NEAR/1 (leucoencephalopath*)) OR ((cerebral) NEAR/1 (ventriculitis)))
Cochrane
Date Searched: 4/3/18
Applied Database Supplied Limits: n/a
Number of Results from each database in Cochrane
-
CDSR: 1
-
CENTRAL: 4
-
DARE:
Full Search Strategy:
([mh “Receptors, AMPA”] OR [mh “alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid”] OR “alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid” OR AMPAR OR AMPAR OR ((AMPA) NEAR/10 (antibody*)) OR ((AMPA OR quisqualate) NEAR/2 (receptor*))) AND ([mh encephalitis] OR Encephalitis* OR encephalopath* OR encephalomyelitis OR cerebritis OR enkephalitis OR leucoencephalitis OR myeloencephaliti* OR ((brain) NEAR/1 (inflammation)) OR ((allergic) NEAR/1 (leucoencephalopath*)) OR ((cerebral) NEAR/1 (ventriculitis)))
Scopus
Date Searched: 4/3/18
Applied Database Supplied Limits: n/a
Number of Results: 455
Full Search Strategy:
TITLE-ABS-KEY(AMPAR OR AMPAR OR “alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid” OR ((AMPA) W/10 (antibody*)) OR ((AMPA OR quisqualate) W/2 (receptor*))) AND TITLE-ABS-KEY(Encephalitis* OR encephalopath* OR encephalomyelitis OR cerebritis OR enkephalitis OR leucoencephalitis OR myeloencephaliti* OR ((brain) W/1 (inflammation)) OR ((allergic) W/1 (leucoencephalopath*)) OR ((cerebral) W/1 (ventriculitis)))
ClinicalTrials.gov
Date Searched: 4/3/18
Number of Results: 0
Report, as accurately as possible, what you did. Searches in Clinicaltrials.gov must be much for simple then those used for other databases.
In expert search: (AMPA receptor OR quisqualate receptor) AND (encephalitis).
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Laurido-Soto, O., Brier, M.R., Simon, L.E. et al. Patient characteristics and outcome associations in AMPA receptor encephalitis. J Neurol 266, 450–460 (2019). https://doi.org/10.1007/s00415-018-9153-8
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DOI: https://doi.org/10.1007/s00415-018-9153-8