Clinical Characterization and Long-Term Outcome in Children and Adults With Anti-AMPA Receptor Encephalitis

Chiara Milano^{1

2

3}, Ezgi Saylam⁴, Claudia Papi^{1

2

5}, Laura Marmolejo^{1

2}, Alexandra Sankovic⁴, Raphael Reinecke⁶, Jeroen Kerstens⁷, Chiara Pizzanelli³, Mateus Mistieri Simabukuro⁸, Marie Benaiteau⁹, Bastien Joubert⁹, Matteo Gastaldi¹⁰, Lívia Almeida Dutra¹¹, Frank Leypoldt^{12

13}, Mareike Jansen¹², Izumi Kawachi^{14

15}, Hisanao Akiyama¹⁶, Nikolas Boy¹⁷, Silvia Bozzetti¹⁸, Peter Broegger Christensen¹⁹, Pietro Businaro^{10

20}, Alessandro Dinoto²¹, Tal Friedman-Korn²², Urara Fujiwara²³, Tatsuya Fukumoto²⁴, Kenshiro Fuse²⁵, Sam Ishmael Hooshmand²⁶, Lauren Hurst⁴, Raffaele Iorio^{5

27}, Isabelle Korn-Lubetzki²⁸, André Filipe Lucchi Rodrigues⁸, Sara Mariotto²¹, Johannes Michael²⁹, Yuko Morimoto³⁰, Rinze Frederik Neuteboom⁷, Amanda L Piquet³¹, Andrea O Rossetti³², Sabine Rumpler-Kreiner³³, Jonathan D Santoro³⁴, Florian Schwendinger³⁵, Brenda Shen⁴, Steffen Syrbe³⁶, Johannes Troger³⁷, Ingrid Wagner³⁸, Christian G Bien^{39

40}, Eugenia Martinez-Hernandez^{1

2}, Thais Armangue^{1

2

41}, Romana Höftberger⁶, Takahiro Iizuka⁴², Maarten J Titulaer⁷, Jerome Honnorat⁹, Francesc Graus¹, Josep O Dalmau^{1

2

43

44}, Setty Magaña⁴, Marianna Spatola^{1

2}

Affiliations

¹ Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain.
² Caixa Research Institute, Barcelona, Spain.
³ Department of Clinical and Experimental Medicine, University of Pisa, Italy.
⁴ Department of Pediatrics, Division of Neurology, Nationwide Children's Hospital, Columbus, OH.
⁵ Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy.
⁶ Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria.
⁷ Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁸ Division of Neurology, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
⁹ Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, MELIS institute UMR Inserm 1314, CNRS, Université Claude Bernard Lyon 1, France.
¹⁰ Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy.
¹¹ Instituto do Cérebro, Hospital Israelita Albert Einstein, São Paulo, Brazil.
¹² Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Germany.
¹³ Department of Neurology, Christian-Albrechts-University Kiel, Germany.
¹⁴ Department of Neurology, Brain Research Institute, Niigata University, Chuo-ku, Japan.
¹⁵ Medical Education Center, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-ku, Japan.
¹⁶ Department of Internal Medicine, Division of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan.
¹⁷ Division for Neuropediatrics and Metabolic Medicine, Medical Faculty of Heidelberg, Center for Child and Adolescent Medicine, Clinic 1, Heidelberg University, Germany.
¹⁸ Department of Neurology, San Maurizio Provincial Hospital, Bolzano, Italy.
¹⁹ Department of Neurology, Aalborg University Hospital, Denmark.
²⁰ Department of Brain and Behavioral Sciences, University of Pavia, Italy.
²¹ Neurology Unit, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Italy.
²² Department of Neurology and Laboratory of Neuroimmunology at the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
²³ Department of Neurology, National Hospital Organization Beppu Medical Center, Japan.
²⁴ Department of Neurology, University of Tokushima Graduate School of Biomedical Sciences, Japan.
²⁵ Department of Neurology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Japan.
²⁶ Department of Neurology, Medical College of Wisconsin, Milwaukee.
²⁷ Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
²⁸ Department of Neurology, Shaare Zedek Medical Center, Jerusalem, Israel.
²⁹ Department of Neurology, Clinic Donaustadt, Vienna, Austria.
³⁰ Department of Neurology, Chikamori Hospital, Kochi, Japan.
³¹ Department of Neurology, University of Colorado, Aurora.
³² Department of Neurology, Lausanne University Hospital (CHUV) and University of Lausanne, Switzerland.
³³ Department of Neurology, Clinic Oberwart, Austria.
³⁴ Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, CA.
³⁵ Department of Neurology, LKH Feldkirch, Feldkirch, Austria.
³⁶ Division of Pediatric Epileptology, Medical Faculty of Heidelberg, Center for Child and Adolescent Medicine, Clinic 1, Heidelberg University, Germany.
³⁷ Department of Neurology, Klinikum Klagenfurt, Austria.
³⁸ Department of Neurology, Hospital of the Brothers of St John, Eisenstadt, Austria.
³⁹ Department of Epileptology, Krankenhaus Mara, Bethel Epilepsy Center, Medical School OWL, Bielefeld University, Germany.
⁴⁰ Laboratory Krone, Bad Salzuflen, Germany.
⁴¹ Pediatric Neurology Unit, Neurology Department, Sant Joan de Deu Children's Hospital, Barcelona, Spain.
⁴² Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan.
⁴³ Department of Neurology, University of Pennsylvania, Philadelphia, United States; and.
⁴⁴ Centro de Investigación Biomédica en Red, Enfermedades Raras (CIBERER), Madrid, Spain.

PMID: 40680249
PMCID: PMC12275903
DOI: 10.1212/NXI.0000000000200453

Clinical Characterization and Long-Term Outcome in Children and Adults With Anti-AMPA Receptor Encephalitis

Chiara Milano et al. Neurol Neuroimmunol Neuroinflamm. 2025 Sep.

. 2025 Sep;12(5):e200453.

doi: 10.1212/NXI.0000000000200453. Epub 2025 Jul 18.

Authors

Affiliations

¹ Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain.
² Caixa Research Institute, Barcelona, Spain.
³ Department of Clinical and Experimental Medicine, University of Pisa, Italy.
⁴ Department of Pediatrics, Division of Neurology, Nationwide Children's Hospital, Columbus, OH.
⁵ Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy.
⁶ Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria.
⁷ Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁸ Division of Neurology, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
⁹ Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, MELIS institute UMR Inserm 1314, CNRS, Université Claude Bernard Lyon 1, France.
¹⁰ Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy.
¹¹ Instituto do Cérebro, Hospital Israelita Albert Einstein, São Paulo, Brazil.
¹² Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Germany.
¹³ Department of Neurology, Christian-Albrechts-University Kiel, Germany.
¹⁴ Department of Neurology, Brain Research Institute, Niigata University, Chuo-ku, Japan.
¹⁵ Medical Education Center, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-ku, Japan.
¹⁶ Department of Internal Medicine, Division of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan.
¹⁷ Division for Neuropediatrics and Metabolic Medicine, Medical Faculty of Heidelberg, Center for Child and Adolescent Medicine, Clinic 1, Heidelberg University, Germany.
¹⁸ Department of Neurology, San Maurizio Provincial Hospital, Bolzano, Italy.
¹⁹ Department of Neurology, Aalborg University Hospital, Denmark.
²⁰ Department of Brain and Behavioral Sciences, University of Pavia, Italy.
²¹ Neurology Unit, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Italy.
²² Department of Neurology and Laboratory of Neuroimmunology at the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
²³ Department of Neurology, National Hospital Organization Beppu Medical Center, Japan.
²⁴ Department of Neurology, University of Tokushima Graduate School of Biomedical Sciences, Japan.
²⁵ Department of Neurology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Japan.
²⁶ Department of Neurology, Medical College of Wisconsin, Milwaukee.
²⁷ Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
²⁸ Department of Neurology, Shaare Zedek Medical Center, Jerusalem, Israel.
²⁹ Department of Neurology, Clinic Donaustadt, Vienna, Austria.
³⁰ Department of Neurology, Chikamori Hospital, Kochi, Japan.
³¹ Department of Neurology, University of Colorado, Aurora.
³² Department of Neurology, Lausanne University Hospital (CHUV) and University of Lausanne, Switzerland.
³³ Department of Neurology, Clinic Oberwart, Austria.
³⁴ Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, CA.
³⁵ Department of Neurology, LKH Feldkirch, Feldkirch, Austria.
³⁶ Division of Pediatric Epileptology, Medical Faculty of Heidelberg, Center for Child and Adolescent Medicine, Clinic 1, Heidelberg University, Germany.
³⁷ Department of Neurology, Klinikum Klagenfurt, Austria.
³⁸ Department of Neurology, Hospital of the Brothers of St John, Eisenstadt, Austria.
³⁹ Department of Epileptology, Krankenhaus Mara, Bethel Epilepsy Center, Medical School OWL, Bielefeld University, Germany.
⁴⁰ Laboratory Krone, Bad Salzuflen, Germany.
⁴¹ Pediatric Neurology Unit, Neurology Department, Sant Joan de Deu Children's Hospital, Barcelona, Spain.
⁴² Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan.
⁴³ Department of Neurology, University of Pennsylvania, Philadelphia, United States; and.
⁴⁴ Centro de Investigación Biomédica en Red, Enfermedades Raras (CIBERER), Madrid, Spain.

PMID: 40680249
PMCID: PMC12275903
DOI: 10.1212/NXI.0000000000200453

Abstract

Background and objectives: Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (anti-AMPAR) encephalitis manifests as limbic encephalitis in adults and is often associated with cancer. Although some reports suggest that it may occur in children, the clinical features in this population, as well as the prognostic factors and long-term outcomes in children and adults, are unknown.

Methods: We performed a retrospective, international collaborative study of patients with anti-AMPAR encephalitis. Clinical information was reviewed, together with data from published pediatric patients. Clinical features of children and adults were compared with nonparametric tests. Survival rates (Kaplan-Meier curves) were compared using log-rank tests. Prognostic factors of poor outcome (modified Rankin Scale score >2) were identified using logistic regression models.

Results: A total of 115 patients were included, of whom 84 (71 adults, 13 children) had only AMPAR antibodies and 31 (27 adults, 4 children) had additional concurrent neural antibodies. Among patients with AMPAR antibodies alone, tumors were identified in 37 adults (56%) and none of the children (p < 0.0001). Children were more likely than adults to have behavioral/psychiatric symptoms (5/13, 39%, vs 8/71, 11%, p = 0.026) at onset, cerebellar dysfunction (6/13, 46%, vs 7/68, 10% p = 0.005) or movement disorders (5/13, 39%, vs 8/67, 12%, p = 0.032) during the disease course, and extratemporal brain MRI lesions (4/9, 44%, vs 5/44, 11%, p = 0.035). Among 34 patients with prolonged follow-up (>24 months), long-term neurocognitive sequelae were reported in 23 (68%), all adults. Failure to respond to first-line immunotherapy at multivariable analysis predicted a poor outcome (OR 8.0, 95% CI 1.1-59.2, p = 0.043). Among the 31 patients with concurrent neural autoantibodies, 22 (79%) had a tumor; those with high-risk antibodies had lower survival rates (p = 0.008).

Discussion: Children and adults with anti-AMPAR encephalitis show distinct clinical-radiologic features. At long-term follow-up, 68% of patients, all adults, have neurologic sequelae, with failure to respond to first-line immunotherapy being associated with worse outcomes.

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Conflict of interest statement

C. Milano receives research support from Spanish National Health Institute Carlos III and co-funded by the European Union (Rio-Hortega grant CM24/00055). C. Papi receives research support from Spanish National Health Institute Carlos III (FIS grant PI23/01366) and 2023 European Academy of Neurology Research Training Fellowship. L. Marmolejo receives research support from Spanish National Health Institute Carlos III (predoctoral research grant FI24/00021). M. Spatola receives research support from La Caixa Foundation (Junior Leader) and Spanish National Health Institute Carlos III (ISCIII) and co-funded by the European Union (FIS grant PI23/01366). J. Dalmau receives research support from CaixaResearch Health 2022 (HR22-00221), Spanish National Health Institute Carlos III (ISCIII) and co-funded by the European Union (FIS grant PI23/00858), Pla estratègic de recerca i innovació en salut (PERIS)/Generalitat de Catalunya (SLT028/23/000071), Fundació Clínic per a la Recerca Biomèdica (FCRB) Programa Multidisciplinar de Recerca, Generalitat de Catalunya Department of Health (SLT028/23/000071), E.J. Safra Foundation. He receives royalties from Euroimmun for the use of NMDA as an antibody test. He received a licensing fee from Euroimmun for the use of GABAB receptor, GABAA receptor, DPPX and IgLON5 as autoantibody tests; he has received a research grant from Sage Therapeutics. J. Honnorat, M. Benaiteau, and B. Joubert are supported by a public grant overseen by the Agence Nationale de la Recherche (ANR; French research agency) as part of the Investissements d'Avenir program (ANR-18-RHUS-0012), also performed within the framework of the Laboratory of Excellence (LABEX) CORTEX of the Universitè Claude Bernard Lyon 1 (program Investissements d'Avenir, ANR-11- LABX-0042, operated by the ANR) and supported by the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA). S.I. Hooshmand has received compensation for serving on the Scientific Advisory Boards and/or for speaking engagements for EMD Serono, Genentech, TG Therapeutics, and Sanofi-Genzyme. A.L. Piquet reports research grants from the University of Colorado, Rocky Mountain Multiple Sclerosis Center, and the Foundation for Sarcoidosis; consulting fees from Genentech/Roche, UCB Pharma, EMD Serono, Kyverna and Alexion; and honorarium from MedLink and publication royalties from Springer as co-editor of a medical textbook. M.J. Titulaer and J. Kerstens are supported by the Erasmus Medical Center Trust Foundation. M.J. Titulaer, R.F. Neuteboom, and J. Kerstens are part of the European Reference Network RITA. Dr Peter Brøgger Christensen is deceased; to the best of our knowledge, he had no relevant disclosures. All the other authors report no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures.

Figures

**Figure 1. Comparison of Clinical Features Between Pediatric and Adult Patients With Only AMPAR Antibodies**
(A) Proportion of children and adults with the indicated first symptom at disease onset (A) and during the course of the disease (B). Note that some symptoms were not experienced by children or adults at onset (A) but were developed only during the disease course (B). Only p values < 0.05 are indicated (in bold). AMPAR = alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor.

**Figure 2. Brain MRI and Anatomopathologic Specimen From Patients With Only AMPAR Antibodies and Extratemporal Involvement**
(A) On the left panel, brain MRI of a pediatric patient (#6 in eTable 1) presenting with a predominant cerebellar phenotype, showing meningeal contrast enhancement and T2/FLAIR hyperintensities in the right cerebellar hemisphere. On the right panel, biopsy of the cerebellar lesion (red insert), showing lymphocytic perivascular infiltrates (hematoxylin-eosin staining), containing prominent CD4⁺ T cells and rare CD8⁺ T cells, and CD20⁺ B-cell infiltrates forming leptomeningeal aggregates (immunohistochemistry staining). (B) Brain MRI of an adult woman (age range 60–70) with limbic encephalitis who had T2/FLAIR hyperintensities in the left insula (not shown), bilateral medial temporal lobes (left > right), and the left frontal cortex and operculum. All abnormalities substantially improved at follow-up MRI 1 year later (not shown). (C) Brain MRI of an adult woman (age range 70–80) with focal motor status epilepticus and cognitive deficits showing T2/FLAIR hyperintense lesion in the left pulvinar region and left parieto-occipital cortex. There is marked parieto-occipital cortical diffusion restriction (left > right). AMPAR = alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor; FLAIR = fluid-attenuated inversion recovery.

**Figure 3. Kaplan-Meier Curves**
(A) Kaplan-Meier curves showing survival rates for pediatric (green) and adult (red) patients with only AMPAR antibodies, (B) for non-paraneoplastic (blue) and paraneoplastic (orange) cases with only AMPAR antibodies, (C) for patients with only AMPAR antibodies (purple) and patients with additional antibodies (light blue), (D) for paraneoplastic cases with only AMPAR antibodies (violet) and paraneoplastic cases with AMPAR plus additional antibodies (light pink), (E) for patients without high-risk antibodies (pink) and patients with high-risk antibodies (gray), and (F) for paraneoplastic cases with high-risk antibodies (dark red) and paraneoplastic cases without high-risk antibodies (dark green). Ab = antibodies; AMPAR = alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor; HR = high-risk.

See this image and copyright information in PMC

References

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Clinical Characterization and Long-Term Outcome in Children and Adults With Anti-AMPA Receptor Encephalitis

Affiliations

Clinical Characterization and Long-Term Outcome in Children and Adults With Anti-AMPA Receptor Encephalitis

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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Medical