Limbic encephalitis due to GABA<sub>B</sub>and AMPA receptor antibodies: a case series

Onugoren, Müjgan Dogan; Deuretzbacher, D; Haensch, Carl-Albrecht; Hagedorn, H J; Halve, S; Isenmann, Stefan; Kramme, Corinna; Lohner, Hanns; Melzer, Nico; Monotti, Rita; Presslauer, Stefan; Schäbitz, Wolf‐Rüdiger; Steffanoni, Sara; Stoeck, Katharina; Strittmatter, M.; Stögbauer, Florian; Trinka, Eugen; Oertzen, Tim J. von; Wiendl, Heinz; Woermann, Friedrich G.; Bien, Christian G.

doi:10.1136/jnnp-2014-308814

Cited by 123 publications

(131 citation statements)

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“…We do not know why patients in the current study had fewer neurologic relapses than those in previous studies (1/21 vs 5/16) 2,5,6,8 ; however, the approach to therapy may be a reason. Indeed, when considering all current and previous cases for which treatment information is available (n 5 37), all clinical relapses were in the group who did not receive aggressive therapy (6 of 18 patients, p 5 0.008).…”

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confidence: 52%

“…The 5 patients who died had one or more of these features along with an underlying tumor. These findings along with the review of previously reported cases with tumor (either with or without an additional paraneoplastic neurologic autoimmunity) 2,5,6,8 suggest that the presence of an additional paraneoplastic autoimmunity is the main prognostic factor for a poor outcome. Indeed, the survival of patients with tumor but without additional paraneoplastic autoimmunity was similar to that of patients without tumor, but the survival of patients with tumor and additional paraneoplastic autoimmunity was significantly worse than that of the other subgroups.…”

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confidence: 98%

“…2,5,6,8 Overall, relapses occurred in 6/37 patients (16%, 1 case in the current study). While 0/19 patients who received aggressive therapy (chemotherapy or rituximab) had relapses, 6/18 who did not receive aggressive therapy had relapses (p 5 0.008).…”

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confidence: 99%

“…In order to assess the significance of the presence of an underlying tumor or additional paraneoplastic antibodies in the clinical outcome (survival and relapse frequency), we reviewed the current data along with all previously reported oncologic or paraneoplastic cases of anti-AMPAR encephalitis. [1][2][3][4][5][6][7][8][9][10][11][12]. Two of these patients developed seizures (nos.…”

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confidence: 99%

“…3,4 Since the initial description of this disorder, few cases with similar antibodies have been reported and therefore the clinical manifestations are largely unknown. [5][6][7][8] We report 22 additional patients and describe the clinical presentation, cancer association, response to treatment, comorbidities, prognostic factors, and outcome. Clinic, University of Barcelona.…”

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confidence: 99%

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Encephalitis and AMPA receptor antibodies

et al. 2015

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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

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confidence: 98%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Encephalitis and AMPA receptor antibodies

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Clinical Spectrum of Encephalitis Associated With Antibodies Against the α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor

et al. 2015

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The clinical features of autoimmune encephalitis associated with antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR-Abs) remain poorly defined.OBJECTIVES To describe 7 patients with encephalitis and AMPAR-Abs and to provide a review of the literature on this disease entity. DESIGN, SETTING, AND PARTICIPANTSThe setting was the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (Lyon, France), and participants were 7 consecutive patients diagnosed as having encephalitis and AMPAR-Abs between January 1, 2010, and December 1, 2014. Patients' clinical data were analyzed, with a median follow-up period of 12 months (range, 2-31 months). Relevant articles were identified in the MEDLINE database using the keywords autoimmune encephalitis and AMPA receptor antibodies until February 15, 2015. MAIN OUTCOMES AND MEASURESModes of onset, full clinical presentations, and cancer prevalence. RESULTSThe patients included 4 women and 3 men (median age, 56 years). Four main modes of encephalitis onset were observed, including confusion (3 patients), epileptic (1 patient), amnestic (1 patient), and a severe form of fulminant encephalitis (2 patients). In contrast with previous reports, we observed only 1 patient with seizures. Two patients had cancer (1 lung carcinoma and the other thymic carcinoma). Analysis of the literature identified 35 published cases of encephalitis and AMPAR-Abs, including 18 with clinical data. The same modes of encephalitis onset were observed, including confusion (12 patients), epileptic (1 patient), amnestic (3 patients), and fulminant encephalitis (2 patients). Eleven patients were initially seen with a neoplasm (lung, breast, thymoma, or ovary). CONCLUSIONS AND RELEVANCEThe clinical spectrum of AMPAR encephalitis is variable. Cancer was found in 13 of 27 patients (48%) with known cancer status. Most patients are seen with symptoms suggestive of autoimmune limbic encephalitis, although they can be paucisymptomatic or may manifest severe panencephalitis that evolves to a minimally conscious state and diffuse cortical atrophy. Patients suspected of having autoimmune encephalitis should undergo screening for serum and cerebrospinal fluid AMPAR-Abs.

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Neuropathological Insights into Unexpected Cognitive Decline in Epilepsy

Reimers

Helmstaedter

Elger

et al. 2022

Annals of Neurology

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Objective Some patients unexpectedly display an unfavorable cognitive course after epilepsy surgery subsequent to any direct cognitive sequelae of the surgical treatment. Therefore, we conducted in‐depth neuropathological examinations of resective specimens from corresponding patients to provide insights as to the underlying disease processes. Methods In this study, cases with significant cognitive deterioration following a previous postoperative assessment were extracted from the neuropsychological database of a longstanding epilepsy surgical program. An extensive reanalysis of available specimens was performed using current, state‐of‐the‐art neuropathological examinations. Patients without cognitive deterioration but matched in regard to basic pathologies served as controls. Results Among the 355 operated patients who had undergone more than one postoperative neuropsychological examination, 30 (8%) showed significant cognitive decline in the period after surgery. Of the 24 patients with available specimens, 71% displayed further neuropathological changes in addition to the typical spectrum (ie, hippocampal sclerosis, focal cortical dysplasias, vascular lesions, and low‐grade tumors), indicating (1) a secondary, putatively epilepsy‐independent neurodegenerative disease process; (2) limbic inflammation; or (3) the enigmatic pathology pattern of "hippocampal gliosis" without segmental neurodegeneration. In the controls, the matched individual principal epilepsy‐associated pathologies were not found in combination with the secondary pathology patterns of the study group. Interpretation Our findings indicate that patients who unexpectedly displayed unfavorable cognitive development beyond any direct surgical effects show rare and very particular pathogenetic causes or parallel, presumably independent, neurodegenerative alterations. A multicenter collection of such cases would be appreciated to discern presurgical biomarkers that help with surgical decision‐making. ANN NEUROL 2023;93:536–550

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Limbic encephalitis due to GABA_Band AMPA receptor antibodies: a case series

Abstract: GABA(B)R and AMPAR abs are well associated with LE. GABA(B)R abs lead to severe clinical, neuroradiological and EEG abnormalities with poorer outcome.

Cited by 123 publications

References 26 publications

Encephalitis and AMPA receptor antibodies

Encephalitis and AMPA receptor antibodies

Clinical Spectrum of Encephalitis Associated With Antibodies Against the α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor

Neuropathological Insights into Unexpected Cognitive Decline in Epilepsy

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Limbic encephalitis due to GABABand AMPA receptor antibodies: a case series

Abstract: GABA(B)R and AMPAR abs are well associated with LE. GABA(B)R abs lead to severe clinical, neuroradiological and EEG abnormalities with poorer outcome.

Cited by 123 publications

References 26 publications

Encephalitis and AMPA receptor antibodies

Encephalitis and AMPA receptor antibodies

Clinical Spectrum of Encephalitis Associated With Antibodies Against the α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor

Neuropathological Insights into Unexpected Cognitive Decline in Epilepsy

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Limbic encephalitis due to GABA_Band AMPA receptor antibodies: a case series