Encephalitis and AMPA receptor antibodies: Novel findings in a case series of 22 patients

Abstract

Objective: We report the clinical features, comorbidities, and outcome of 22 newly identified patients with antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR).

Methods: This was a retrospective review of patients diagnosed between May 2009 and March 2014. Immunologic techniques have been reported previously.

Results: Patients' median age was 62 years (range 23-81; 14 female). Four syndromes were identified: 12 (55%) patients presented with distinctive limbic encephalitis (LE), 8 (36%) with limbic dysfunction along with multifocal/diffuse encephalopathy, one with LE preceded by motor deficits, and one with psychosis with bipolar features. Fourteen patients (64%) had a tumor demonstrated pathologically (5 lung, 4 thymoma, 2 breast, 2 ovarian teratoma) or radiologically (1 lung). Additional antibodies occurred in 7 patients (3 onconeuronal, 1 tumor-related, 2 cell surface, and 1 tumor-related and cell surface), all with neurologic symptoms or tumor reflecting the concurrent autoimmunity. Treatment and outcome were available from 21 patients (median follow-up 72 weeks, range 5-266): 5 had good response to immunotherapy and tumor therapy, 10 partial response, and 6 did not improve. Eventually 5 patients died; all had a tumor or additional paraneoplastic symptoms related to onconeuronal antibodies. Coexistence of onconeuronal antibodies predicted a poor outcome (p = 0.009).

Conclusion: Anti-AMPAR encephalitis usually manifests as LE, can present with other symptoms or psychosis, and is paraneoplastic in 64% of cases. Complete and impressive neurologic improvement can occur, but most patients have partial recovery. Screening for a tumor and onconeuronal antibodies is important because their detection influences outcome.

Figure 1. Brain MRI findings of anti-AMPAR encephalitis

Brain MRI obtained 6 weeks after symptom onset (patient 4, table 1) shows increased T2/fluid-attenuated inversion recovery (FLAIR) signal abnormalities involving medial temporal lobes (A) and insular cortex (B). In addition, the frontal and parieto-occipital cortex and claustrum show mild focal hyperintensity (B). Diffusion-weighted images of patient 13 (table 1) show widespread involvement of the temporal cortex (C). Similar abnormalities are shown on FLAIR sequences involving the left frontal and right temporal cortex as well as the right putamen (D). AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.

Figure 2. Reactivity of patients' antibodies with GluA1 or GluA2 subunits of AMPAR

Patients' antibodies were identified on HEK293 cells transfected with GluA1 or GluA2 subunits of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Examples of patients with antibodies targeting only GluA1 (patient 9), or GluA2 (patient 15), or both subunits (patient 3) are shown. Patients' antibodies are shown with green fluorescence; commercial monoclonal antibodies against GluA1 or GluA2 are shown with red fluorescence; the blue nuclear staining is shown with 4',6-diamidino-2-phenylindole (DAPI). All panels: ×400.

Figure 3. Survival of patients with paraneoplastic or idiopathic anti-AMPAR encephalitis

(A) Kaplan-Meier survival curves for patients with paraneoplastic anti–α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis (with or without onconeuronal antibodies, red) and patients with idiopathic anti-AMPAR encephalitis (blue). (B) Kaplan-Meier survival curves for 4 patients with paraneoplastic anti-AMPAR encephalitis plus additional onconeural antibodies (dark red) and 10 patients with paraneoplastic anti-AMPAR encephalitis without onconeuronal antibodies (orange). (C) Kaplan-Meier survival curves for all assessable reported patients with paraneoplastic anti-AMPAR encephalitis and onconeuronal antibodies (dark red), paraneoplastic anti-AMPAR encephalitis without onconeuronal antibodies (orange), and idiopathic anti-AMPAR encephalitis (blue).^,,,