Encephalitis and AMPA receptor antibodies

Abstract

Objective: We report the clinical features, comorbidities, and outcome of 22 newly identified patients with antibodies to the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). 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 5 0.009). Methods: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. The recent characterization of autoimmune synaptic disorders has led to the identification of subtypes of limbic, multifocal, or generalized encephalitis that often respond to immunotherapy. One of the antibodies targets the GluA1 or GluA2 (previously called GluR1 or GluR2) subunits of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), an ionotropic receptor that belongs to the family of glutamate receptors. AMPAR mediates most of the fast excitatory synaptic transmission in the brain, and is important for synaptic plasticity, memory, and learning.1 The initial description of the encephalitis associated with these antibodies was published in 2009 and included 10 patients, all with limbic encephalitis (LE) who had CSF and serum antibodies that reacted with the neuropil of rat brain and the cell surface of cultures of rat hippocampal neurons, leading to precipitate and characterize the target antigens as

Autoimmune Encephalitides

“…Further studies by the same authors [164] in a larger cohort highlighted the presence of prominent neuropsychiatric features.…”

“…The disorder was paraneoplastic in association with thymoma, SCLC, and breast cancer [163], so noted in seven patients, including 5 diagnosed by the time of initial episode of LE, and 2 patients at first relapse of LE. Other cancers in addition included ovarian teratoma and thymus carcinoid tumors [164].…”

Management of Immune-Mediated Paraneoplastic Neurological Disorders

“…Patients with Abs to surface antigens have a much better prognosis, except for cases with additional classical paraneoplastic Abs [33,34]. LE is most frequently associated with NMDAR-, LGI1-and Caspr2-Abs; treatment of these forms of encephalitis will be discussed individually.…”

“…Relapses are frequent and occur unrelated to tumor recurrence. In most cases, relapses can be prevented by treatment with rituximab and cyclophosphamide [34].…”

“…Relapses are frequent and occur unrelated to tumor recurrence. In most cases, relapses can be prevented by treatment with rituximab and cyclophosphamide [34].Anti-GABAbR-Abs typically cause limbic encephalitis and less often ataxia. In 50 % of cases a tumor (frequently small cell lung cancer) is detected [70].…”