Clinical phenotype and outcomes in autoimmune encephalitis after herpes simplex virus encephalitis: A systematic review and meta-analysis

Jonathan Cleaver¹, Renetta Chungath², Amy Gimson³, Christine Strippel¹, Bryan Ceronie¹, Babak Soleimani⁴, Thomas Johnson⁵, Eyal Muscal⁶, Kristen Fisher⁷, Yike Jiang⁸, Timothy A Erickson⁹, Kristy O Murray¹⁰, Siv Tonje Faret Hovet¹¹, Charlotte Aaberg Poulsen¹², Anna Søgaard Magnussen¹³, Pauline Dumez¹⁴, Shannon Ronca¹⁵, Martin Häusler¹⁶, Annegret Quade¹⁶, Andrew Swayne¹⁷, Morten Blaabjerg¹⁸, Mette Nissen¹⁸, Alexander J Sandweiss⁷, Jerome Honnorat¹⁴, Russell Dale¹⁹, Ming Lim²⁰, Michael Eyre²¹, Margherita Nosadini²², Lahiru Handunnetthi²³, Sarosh R Irani²⁴, Adam E Handel²⁵

Affiliations

¹ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK.
² Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
³ Department of Neurology, Southmead Hospital, Bristol, UK.
⁴ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, University of Oxford, Oxford, UK.
⁵ Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, University of Oxford, Oxford, UK.
⁶ Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA; Department of Pediatrics, Section of Rheumatology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
⁷ Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
⁸ Department of Pediatrics, Division of Pediatric Rheumatology, Duke University School of Medicine, Durham, NC, USA.
⁹ Laboratories for Emerging and Tropical Disease Research, Department of Epidemiology & Biostatistics, Texas A&M School of Public Health, College Station, TX, USA.
¹⁰ Department of Pediatrics, Division of Innovation and Research, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹¹ Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark.
¹² Department of Nuclear Medicine, Odense University Hospital, 5000 Odense, Denmark.
¹³ Department of Neurology, Odense University Hospital (OUH), Denmark; Department of Neurosurgery, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
¹⁴ French Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, MeLiS-UCBL-CNRS UMR 5284. INSERM U1314, Université Claude Bernard Lyon 1, Lyon, France.
¹⁵ Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Division of Tropical Medicine, Baylor College of Medicine, Houston, TX, USA.
¹⁶ Department of Pediatrics, Division of Neuropediatrics and Social Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
¹⁷ Mater Centre for Neurosciences, Mater Hospital, Brisbane, Queensland, Australia.
¹⁸ Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark; Department of Neurology, Odense University Hospital (OUH), Denmark.
¹⁹ Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Clinical Neuroimmunology Group, Kids Neuroscience Centre and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; TY Nelson Department of Neurology, Children's Hospital at Westmead, Sydney, NSW, Australia.
²⁰ Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, London, UK; Department of Women & Children's Health, School of School of Life Course & Population Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
²¹ Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, London, UK; Departments of Imaging Physics & Engineering and Early Life Imaging, School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK.
²² Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy; Neuroimmunology Group, Paediatric Research Institute "Città della Speranza," Padova, Italy.
²³ Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, University of Oxford, Oxford, UK; Department of Psychiatry, University of Oxford, Oxford, UK.
²⁴ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Departments of Neurology and Neurosciences, Mayo Clinic, Jacksonville, FL, USA.
²⁵ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK. Electronic address: Adam.Handel@ndcn.ox.ac.uk.

PMID: 40780589
DOI: 10.1016/j.jinf.2025.106566

Free article

Meta-Analysis

Clinical phenotype and outcomes in autoimmune encephalitis after herpes simplex virus encephalitis: A systematic review and meta-analysis

Jonathan Cleaver et al. J Infect. 2025 Sep.

Free article

. 2025 Sep;91(3):106566.

doi: 10.1016/j.jinf.2025.106566. Epub 2025 Aug 6.

Authors

Affiliations

¹ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK.
² Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
³ Department of Neurology, Southmead Hospital, Bristol, UK.
⁴ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, University of Oxford, Oxford, UK.
⁵ Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, University of Oxford, Oxford, UK.
⁶ Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA; Department of Pediatrics, Section of Rheumatology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
⁷ Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
⁸ Department of Pediatrics, Division of Pediatric Rheumatology, Duke University School of Medicine, Durham, NC, USA.
⁹ Laboratories for Emerging and Tropical Disease Research, Department of Epidemiology & Biostatistics, Texas A&M School of Public Health, College Station, TX, USA.
¹⁰ Department of Pediatrics, Division of Innovation and Research, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹¹ Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark.
¹² Department of Nuclear Medicine, Odense University Hospital, 5000 Odense, Denmark.
¹³ Department of Neurology, Odense University Hospital (OUH), Denmark; Department of Neurosurgery, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
¹⁴ French Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, MeLiS-UCBL-CNRS UMR 5284. INSERM U1314, Université Claude Bernard Lyon 1, Lyon, France.
¹⁵ Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Division of Tropical Medicine, Baylor College of Medicine, Houston, TX, USA.
¹⁶ Department of Pediatrics, Division of Neuropediatrics and Social Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
¹⁷ Mater Centre for Neurosciences, Mater Hospital, Brisbane, Queensland, Australia.
¹⁸ Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark; Department of Neurology, Odense University Hospital (OUH), Denmark.
¹⁹ Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Clinical Neuroimmunology Group, Kids Neuroscience Centre and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; TY Nelson Department of Neurology, Children's Hospital at Westmead, Sydney, NSW, Australia.
²⁰ Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, London, UK; Department of Women & Children's Health, School of School of Life Course & Population Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
²¹ Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, London, UK; Departments of Imaging Physics & Engineering and Early Life Imaging, School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK.
²² Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy; Neuroimmunology Group, Paediatric Research Institute "Città della Speranza," Padova, Italy.
²³ Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, University of Oxford, Oxford, UK; Department of Psychiatry, University of Oxford, Oxford, UK.
²⁴ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Departments of Neurology and Neurosciences, Mayo Clinic, Jacksonville, FL, USA.
²⁵ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK. Electronic address: Adam.Handel@ndcn.ox.ac.uk.

PMID: 40780589
DOI: 10.1016/j.jinf.2025.106566

Abstract

Background: Autoimmune encephalitis after herpes simplex virus encephalitis (HSVE-AE) represents the intersection of central nervous system infection and autoimmunity. Defining the phenotype and the safety and effectiveness of immunotherapy in HSVE-AE would help identify immunotherapy candidates, optimise therapeutic strategies, and improve patient outcomes.

Methods: We systematically searched Embase, Medline, PubMed, and Web of Science (2007-2024) for cases meeting consensus criteria for AE after confirmed HSVE. Demographics, phenotype, treatment and outcome data were extracted. Dimensionality reduction, network analysis, and multivariate logistic regression was used to explore age- and diagnosis-specific patterns and outcome predictors.

Results: From 2259 articles screened, 78 studies (225 patients) were included (median age 7.25 years; 52.9% female). Children (0-12 years) experienced more seizures during HSVE (p=0.003) and movement disorders during AE (p<0.001). Older patients (>12 years) had more headaches during HSVE (p=0.003), and speech dysfunction (p=0.02) and neuropsychiatric symptoms (p=0.02) during AE. HSVE-AE (89.3% N-methyl-D-aspartate receptor-antibody encephalitis [NMDAR-AbE]) differed significantly from a canonical NMDAR-AbE cohort (n=1550) in clinical, paraclinical and outcome domains. Poor outcomes were linked to infant and older adult age, neuropsychiatric symptoms, and AE-phase mRS >4. Rituximab independently predicted better outcomes. Disability improved over time (p<0.001), with adverse event rates comparable to NMDAR-AbE.

Conclusions and relevance: This meta-analysis defines novel age-specific HSVE-AE features, outcome predictors, and confirms the safety and improved outcomes of HSVE-AE after immunotherapy.

Keywords: Autoimmune encephalitis; Herpes simplex virus encephalitis; Immunotherapy; Infectious encephalitis; NMDA receptor-antibody encephalitis; Neuroimmunology.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SRI has received honoraria/research support from Amgen, Argenx, UCB, Roche, Janssen, IQVIA, Clarivate, Slingshot Insights, Cerebral therapeutics, BioHaven therapeutics, CSL Behring, and ONO Pharma and is a co-applicant and receive royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders’ and is coinventor on ‘Diagnostic method and therapy’ USP 17/051,930, 2021 and ‘Biomarker’ USP 18/279,624, 2024. AEH has received research support from UCB. M.L. receives/has received consultation fees from CSL Behring, Novartis, Roche and Octapharma; received travel grants from Merck Serono; and received unrestricted educational grants to organise meetings by Novartis, Biogen Idec, Merck Serono and Bayer.

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Clinical phenotype and outcomes in autoimmune encephalitis after herpes simplex virus encephalitis: A systematic review and meta-analysis

Affiliations

Clinical phenotype and outcomes in autoimmune encephalitis after herpes simplex virus encephalitis: A systematic review and meta-analysis

Authors

Affiliations

Abstract

Conflict of interest statement

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LinkOut - more resources

Full Text Sources