International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis

Margherita Nosadini¹, Terrence Thomas¹, Michael Eyre¹, Banu Anlar¹, Thais Armangue¹, Susanne M Benseler¹, Tania Cellucci¹, Kumaran Deiva¹, William Gallentine¹, Grace Gombolay¹, Mark P Gorman¹, Yael Hacohen¹, Yuwu Jiang¹, Byung Chan Lim¹, Eyal Muscal¹, Alvin Ndondo¹, Rinze Neuteboom¹, Kevin Rostásy¹, Hiroshi Sakuma¹, Suvasini Sharma¹, Silvia Noemi Tenembaum¹, Heather Ann Van Mater¹, Elizabeth Wells¹, Ronny Wickstrom¹, Anusha K Yeshokumar¹, Sarosh R Irani¹, Josep Dalmau¹, Ming Lim¹, Russell C Dale²

Affiliations

¹ From the Paediatric Neurology and Neurophysiology Unit (M.N.), Department of Women's and Children's Health, University Hospital of Padova; Neuroimmunology Group (M.N.), Paediatric Research Institute "Città della Speranza," Padova, Italy; Department of Paediatrics (T.T.), Neurology Service, KK Women's and Children's Hospital, Singapore; School of Biomedical Engineering & Imaging Sciences (M.E.), King's College London; Children's Neurosciences (M.E.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, United Kingdom; Department of Pediatric Neurology (B.A.), Hacettepe University, Ankara, Turkey; Neuroimmunology Program (T.A.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona; Pediatric Neuroimmunology Unit (T.A.), Neurology Department, Sant Joan de Déu (SJD) Children's Hospital, University of Barcelona, Spain; Alberta Children's Hospital Research Institute (S.M.B.), Department of Pediatrics, Cumming School of Medicine, University of Calgary; Division of Rheumatology (T.C.), Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; Assistance Publique-Hôpitaux de Paris (K.D.), Pediatric Neurology Department, University Hospitals Paris Saclay, Bicêtre Hospital, France; French Reference Network of Rare Inflammatory Brain and Spinal Diseases (K.D.), Le Kremlin Bicêtre, France and European Reference Network-RITA; Departments of Neurology and Pediatrics (W.G.), Stanford University and Lucile Packard Children's Hospital, Palo Alto, CA; Division of Pediatric Neurology (G.G.), Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA; Department of Neurology (M.P.G.), Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Neuroinflammation (Y.H.), Queen Square MS Centre, UCL Institute of Neurology, University College London; Department of Paediatric Neurology (Y.H.), Great Ormond Street Hospital for Children, London, United Kingdom; Department of Pediatrics (Y.J.), Peking University First Hospital, Beijing, China; Department of Pediatrics (B.C.L.), Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, South Korea; Department of Pediatrics (E.M.), Section Rheumatology, Co-appointment in the Section of Neurology and Developmental Neuroscience, Texas Children's Hospital, Baylor College of Medicine, Houston; Division of Paediatric Neurology (A.N.), Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town; Faculty of Health Sciences (A.N.), University of Cape Town Neuroscience Institute, South Africa; Department of Neurology (R.N.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of Pediatric Neurology (K.R.), Children's Hospital Datteln, University Witten/Herdecke, Germany; Department of Brain and Neural Science (H.S.), Tokyo Metropolitan Institute of Medical Science, Japan; Department of Pediatrics (Neurology Division) (S.S.), Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India; Department of Neurology (S.N.T.), National Pediatric Hospital Dr. J. Garrahan, Buenos Aires, Argentina; Department of Pediatrics (H.A.V.M.), Duke University, Durham, NC; Department of Neurology (E.W.), Children's National Medical Center, Washington, DC; Neuropaediatric Unit (R.W.), Karolinska University Hospital, Stockholm, Sweden; Department of Neurology (A.K.Y.), Icahn School of Medicine at Mount Sinai, New York; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital; Department of Neurology (S.R.I.), Oxford University Hospitals NHS Foundation Trust, United Kingdom; Neuroimmunology Program (J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; Children's Neurosciences (M.L.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust; King's Health Partners Academic Health Science Centre (M.L.); Faculty of Life Sciences and Medicine (M.L.), King's College Hospital, United Kingdom; and Kids Neuroscience Centre (R.C.D.), The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
² From the Paediatric Neurology and Neurophysiology Unit (M.N.), Department of Women's and Children's Health, University Hospital of Padova; Neuroimmunology Group (M.N.), Paediatric Research Institute "Città della Speranza," Padova, Italy; Department of Paediatrics (T.T.), Neurology Service, KK Women's and Children's Hospital, Singapore; School of Biomedical Engineering & Imaging Sciences (M.E.), King's College London; Children's Neurosciences (M.E.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, United Kingdom; Department of Pediatric Neurology (B.A.), Hacettepe University, Ankara, Turkey; Neuroimmunology Program (T.A.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona; Pediatric Neuroimmunology Unit (T.A.), Neurology Department, Sant Joan de Déu (SJD) Children's Hospital, University of Barcelona, Spain; Alberta Children's Hospital Research Institute (S.M.B.), Department of Pediatrics, Cumming School of Medicine, University of Calgary; Division of Rheumatology (T.C.), Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; Assistance Publique-Hôpitaux de Paris (K.D.), Pediatric Neurology Department, University Hospitals Paris Saclay, Bicêtre Hospital, France; French Reference Network of Rare Inflammatory Brain and Spinal Diseases (K.D.), Le Kremlin Bicêtre, France and European Reference Network-RITA; Departments of Neurology and Pediatrics (W.G.), Stanford University and Lucile Packard Children's Hospital, Palo Alto, CA; Division of Pediatric Neurology (G.G.), Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA; Department of Neurology (M.P.G.), Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Neuroinflammation (Y.H.), Queen Square MS Centre, UCL Institute of Neurology, University College London; Department of Paediatric Neurology (Y.H.), Great Ormond Street Hospital for Children, London, United Kingdom; Department of Pediatrics (Y.J.), Peking University First Hospital, Beijing, China; Department of Pediatrics (B.C.L.), Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, South Korea; Department of Pediatrics (E.M.), Section Rheumatology, Co-appointment in the Section of Neurology and Developmental Neuroscience, Texas Children's Hospital, Baylor College of Medicine, Houston; Division of Paediatric Neurology (A.N.), Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town; Faculty of Health Sciences (A.N.), University of Cape Town Neuroscience Institute, South Africa; Department of Neurology (R.N.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of Pediatric Neurology (K.R.), Children's Hospital Datteln, University Witten/Herdecke, Germany; Department of Brain and Neural Science (H.S.), Tokyo Metropolitan Institute of Medical Science, Japan; Department of Pediatrics (Neurology Division) (S.S.), Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India; Department of Neurology (S.N.T.), National Pediatric Hospital Dr. J. Garrahan, Buenos Aires, Argentina; Department of Pediatrics (H.A.V.M.), Duke University, Durham, NC; Department of Neurology (E.W.), Children's National Medical Center, Washington, DC; Neuropaediatric Unit (R.W.), Karolinska University Hospital, Stockholm, Sweden; Department of Neurology (A.K.Y.), Icahn School of Medicine at Mount Sinai, New York; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital; Department of Neurology (S.R.I.), Oxford University Hospitals NHS Foundation Trust, United Kingdom; Neuroimmunology Program (J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; Children's Neurosciences (M.L.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust; King's Health Partners Academic Health Science Centre (M.L.); Faculty of Life Sciences and Medicine (M.L.), King's College Hospital, United Kingdom; and Kids Neuroscience Centre (R.C.D.), The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia. russell.dale@health.nsw.gov.au.

PMID: 34301820
PMCID: PMC8299516
DOI: 10.1212/NXI.0000000000001052

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis

Margherita Nosadini et al. Neurol Neuroimmunol Neuroinflamm. 2021.

. 2021 Jul 22;8(5):e1052.

doi: 10.1212/NXI.0000000000001052. Print 2021 Jul.

Authors

Affiliations

¹ From the Paediatric Neurology and Neurophysiology Unit (M.N.), Department of Women's and Children's Health, University Hospital of Padova; Neuroimmunology Group (M.N.), Paediatric Research Institute "Città della Speranza," Padova, Italy; Department of Paediatrics (T.T.), Neurology Service, KK Women's and Children's Hospital, Singapore; School of Biomedical Engineering & Imaging Sciences (M.E.), King's College London; Children's Neurosciences (M.E.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, United Kingdom; Department of Pediatric Neurology (B.A.), Hacettepe University, Ankara, Turkey; Neuroimmunology Program (T.A.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona; Pediatric Neuroimmunology Unit (T.A.), Neurology Department, Sant Joan de Déu (SJD) Children's Hospital, University of Barcelona, Spain; Alberta Children's Hospital Research Institute (S.M.B.), Department of Pediatrics, Cumming School of Medicine, University of Calgary; Division of Rheumatology (T.C.), Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; Assistance Publique-Hôpitaux de Paris (K.D.), Pediatric Neurology Department, University Hospitals Paris Saclay, Bicêtre Hospital, France; French Reference Network of Rare Inflammatory Brain and Spinal Diseases (K.D.), Le Kremlin Bicêtre, France and European Reference Network-RITA; Departments of Neurology and Pediatrics (W.G.), Stanford University and Lucile Packard Children's Hospital, Palo Alto, CA; Division of Pediatric Neurology (G.G.), Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA; Department of Neurology (M.P.G.), Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Neuroinflammation (Y.H.), Queen Square MS Centre, UCL Institute of Neurology, University College London; Department of Paediatric Neurology (Y.H.), Great Ormond Street Hospital for Children, London, United Kingdom; Department of Pediatrics (Y.J.), Peking University First Hospital, Beijing, China; Department of Pediatrics (B.C.L.), Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, South Korea; Department of Pediatrics (E.M.), Section Rheumatology, Co-appointment in the Section of Neurology and Developmental Neuroscience, Texas Children's Hospital, Baylor College of Medicine, Houston; Division of Paediatric Neurology (A.N.), Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town; Faculty of Health Sciences (A.N.), University of Cape Town Neuroscience Institute, South Africa; Department of Neurology (R.N.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of Pediatric Neurology (K.R.), Children's Hospital Datteln, University Witten/Herdecke, Germany; Department of Brain and Neural Science (H.S.), Tokyo Metropolitan Institute of Medical Science, Japan; Department of Pediatrics (Neurology Division) (S.S.), Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India; Department of Neurology (S.N.T.), National Pediatric Hospital Dr. J. Garrahan, Buenos Aires, Argentina; Department of Pediatrics (H.A.V.M.), Duke University, Durham, NC; Department of Neurology (E.W.), Children's National Medical Center, Washington, DC; Neuropaediatric Unit (R.W.), Karolinska University Hospital, Stockholm, Sweden; Department of Neurology (A.K.Y.), Icahn School of Medicine at Mount Sinai, New York; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital; Department of Neurology (S.R.I.), Oxford University Hospitals NHS Foundation Trust, United Kingdom; Neuroimmunology Program (J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; Children's Neurosciences (M.L.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust; King's Health Partners Academic Health Science Centre (M.L.); Faculty of Life Sciences and Medicine (M.L.), King's College Hospital, United Kingdom; and Kids Neuroscience Centre (R.C.D.), The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
² From the Paediatric Neurology and Neurophysiology Unit (M.N.), Department of Women's and Children's Health, University Hospital of Padova; Neuroimmunology Group (M.N.), Paediatric Research Institute "Città della Speranza," Padova, Italy; Department of Paediatrics (T.T.), Neurology Service, KK Women's and Children's Hospital, Singapore; School of Biomedical Engineering & Imaging Sciences (M.E.), King's College London; Children's Neurosciences (M.E.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, United Kingdom; Department of Pediatric Neurology (B.A.), Hacettepe University, Ankara, Turkey; Neuroimmunology Program (T.A.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona; Pediatric Neuroimmunology Unit (T.A.), Neurology Department, Sant Joan de Déu (SJD) Children's Hospital, University of Barcelona, Spain; Alberta Children's Hospital Research Institute (S.M.B.), Department of Pediatrics, Cumming School of Medicine, University of Calgary; Division of Rheumatology (T.C.), Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; Assistance Publique-Hôpitaux de Paris (K.D.), Pediatric Neurology Department, University Hospitals Paris Saclay, Bicêtre Hospital, France; French Reference Network of Rare Inflammatory Brain and Spinal Diseases (K.D.), Le Kremlin Bicêtre, France and European Reference Network-RITA; Departments of Neurology and Pediatrics (W.G.), Stanford University and Lucile Packard Children's Hospital, Palo Alto, CA; Division of Pediatric Neurology (G.G.), Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA; Department of Neurology (M.P.G.), Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Neuroinflammation (Y.H.), Queen Square MS Centre, UCL Institute of Neurology, University College London; Department of Paediatric Neurology (Y.H.), Great Ormond Street Hospital for Children, London, United Kingdom; Department of Pediatrics (Y.J.), Peking University First Hospital, Beijing, China; Department of Pediatrics (B.C.L.), Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, South Korea; Department of Pediatrics (E.M.), Section Rheumatology, Co-appointment in the Section of Neurology and Developmental Neuroscience, Texas Children's Hospital, Baylor College of Medicine, Houston; Division of Paediatric Neurology (A.N.), Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town; Faculty of Health Sciences (A.N.), University of Cape Town Neuroscience Institute, South Africa; Department of Neurology (R.N.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of Pediatric Neurology (K.R.), Children's Hospital Datteln, University Witten/Herdecke, Germany; Department of Brain and Neural Science (H.S.), Tokyo Metropolitan Institute of Medical Science, Japan; Department of Pediatrics (Neurology Division) (S.S.), Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India; Department of Neurology (S.N.T.), National Pediatric Hospital Dr. J. Garrahan, Buenos Aires, Argentina; Department of Pediatrics (H.A.V.M.), Duke University, Durham, NC; Department of Neurology (E.W.), Children's National Medical Center, Washington, DC; Neuropaediatric Unit (R.W.), Karolinska University Hospital, Stockholm, Sweden; Department of Neurology (A.K.Y.), Icahn School of Medicine at Mount Sinai, New York; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital; Department of Neurology (S.R.I.), Oxford University Hospitals NHS Foundation Trust, United Kingdom; Neuroimmunology Program (J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; Children's Neurosciences (M.L.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust; King's Health Partners Academic Health Science Centre (M.L.); Faculty of Life Sciences and Medicine (M.L.), King's College Hospital, United Kingdom; and Kids Neuroscience Centre (R.C.D.), The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia. russell.dale@health.nsw.gov.au.

PMID: 34301820
PMCID: PMC8299516
DOI: 10.1212/NXI.0000000000001052

Abstract

Objective: To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE).

Methods: After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ≥75% agreement).

Results: Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3-12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided.

Conclusion: These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients.

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Figures

**Figure. International Consensus Recommendations for the Treatment of First Event of Pediatric NMDAR Antibody Encephalitis (NMDARE)**

See this image and copyright information in PMC

References

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International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis

Affiliations

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis

Authors

Affiliations

Abstract

Figures

References

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MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources