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Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody EncephalitisA Meta-analysis

Educational Objective
To investigate the most effective treatments for N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis.

1 Credit CME

JAMA Neurology

Published Online: September 20, 2021

Original Investigation

Article Information and Disclosures

Margherita Nosadini, MD, PhD^1,2;

Michael Eyre, MD^3,4;

Erika Molteni, PhD^3,5;

et al

Terrence Thomas, MD⁶;

Sarosh R. Irani, MD, PhD^7,8;

Josep Dalmau, MD, PhD^9,10,11;

Russell C. Dale, MD, PhD¹²;

Ming Lim, MD, PhD^4,13;

and the International NMDAR Antibody Encephalitis Consensus Group

Author Affiliations

¹Paediatric Neurology and Neurophysiology Unit, Department of Women’s and Children’s Health, University Hospital of Padova, Padova, Italy
²Neuroimmunology Group, Paediatric Research Institute “Città della Speranza,” Padova, Italy
³School of Biomedical Engineering and Imaging Sciences, King’s College London, London, United Kingdom
⁴Children’s Neurosciences, Evelina London Children’s Hospital at Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom
⁵Centre for Medical Engineering, King’s College London, London, United Kingdom
⁶Department of Paediatrics, Neurology Service, KK Women’s and Children’s Hospital, Singapore
⁷Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
⁸Department of Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
⁹Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain
¹⁰Department of Neurology, University of Pennsylvania, Philadelphia
¹¹Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
¹²Kids Neuroscience Centre, The Children’s Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Westmead, Australia
¹³Department of Women and Children’s Health, School of Life Course Sciences (SoLCS), King’s College London, London, United Kingdom

International NMDAR Antibody Encephalitis Consensus Groupand the

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Key Points

Question What are the most effective treatments for N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis?

Findings In this meta-analysis of individual patient data including 1550 cases, treatment factors at first event that were significantly associated with good functional outcome 12 months from disease onset included first-line treatment with therapeutic apheresis alone, corticosteroids in combination with intravenous immunoglobulin (IVIG), or corticosteroids in combination with IVIG and therapeutic apheresis, while lack of immunotherapy within 30 days of disease onset was significantly associated with poor outcome. Rituximab and long-term IVIG use were significantly associated with nonrelapsing disease course.

Meaning Separate treatment factors are associated with functional outcomes and relapsing disease biology in those with NMDAR antibody encephalitis.

Abstract

Importance Overall, immunotherapy has been shown to improve outcomes and reduce relapses in individuals with N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis (NMDARE); however, the superiority of specific treatments and combinations remains unclear.

Objective To map the use and safety of immunotherapies in individuals with NMDARE, identify early predictors of poor functional outcome and relapse, evaluate changes in immunotherapy use and disease outcome over the 14 years since first reports of NMDARE, and assess the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score.

Data Sources Systematic search in PubMed from inception to January 1, 2019.

Study Selection Published articles including patients with NMDARE with positive NMDAR antibodies and available individual immunotherapy data.

Data Extraction and Synthesis Individual patient data on immunotherapies, clinical characteristics at presentation, disease course, and final functional outcome (modified Rankin Scale [mRS] score) were entered into multivariable logistic regression models.

Main Outcomes and Measures The planned study outcomes were functional outcome at 12 months from disease onset (good, mRS score of 0 to 2; poor, mRS score greater than 2) and monophasic course (absence of relapse at 24 months or later from onset).

Results Data from 1550 patients from 652 articles were evaluated. Of these, 1105 of 1508 (73.3%) were female and 707 of 1526 (46.3%) were 18 years or younger at disease onset. Factors at first event that were significantly associated with good functional outcome included adolescent age and first-line treatment with therapeutic apheresis, corticosteroids plus intravenous immunoglobulin (IVIG), or corticosteroids plus IVIG plus therapeutic apheresis. Factors significantly associated with poor functional outcome were age younger than 2 years or age of 65 years or older at onset, intensive care unit admission, extreme delta brush pattern on electroencephalography, lack of immunotherapy within the first 30 days of onset, and maintenance IVIG use for 6 months or more. Factors significantly associated with nonrelapsing disease were rituximab use or maintenance IVIG use for 6 months or more. Adolescent age at onset was significantly associated with relapsing disease. Rituximab use increased from 13.5% (52 of 384; 2007 to 2013) to 28.3% (311 of 1100; 2013 to 2019) (P < .001), concurrent with a falling relapse rate over the same period (22% [12 of 55] in 2008 and earlier; 10.9% [35 of 322] in 2017 and later; P = .006). Modified NEOS score (including 4 of 5 original NEOS items) was associated with probability of poor functional status at 1 year (20.1% [40 of 199] for a score of 0 to 1 points; 43.8% [77 of 176] for a score of 3 to 4 points; P = .05).

Conclusions and Relevance Factors influencing functional outcomes and relapse are different and need to be considered independently in development of evidence-based optimal management guidelines of patients with NMDARE.

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Article Information

Accepted for Publication: July 30, 2021.

Published Online: September 20, 2021. doi:10.1001/jamaneurol.2021.3188

Corresponding Author: Ming Lim, MD, PhD, Children’s Neurosciences, Evelina London Children’s Hospital at Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, United Kingdom (ming.lim@gstt.nhs.uk).

The International NMDAR Antibody Encephalitis Consensus Group: Banu Anlar, MD; Thaís Armangue, MD, PhD; Susanne Benseler, MD; Tania Cellucci, MD, MScCH; Kumaran Deiva, MD; William Gallentine, DO; Grace Gombolay, MD; Mark P. Gorman, MD; Yael Hacohen, MD, PhD; Yuwu Jiang, MD; Byung Chan Lim, MD; Eyal Muscal, MD, MS; Alvin Ndondo, MD; Rinze Neuteboom, MD, PhD; Kevin Rostásy, MD; Hiroshi Sakuma, MD; Stefano Sartori, MD, PhD; Suvasini Sharma, MD; Silvia Noemi Tenembaum, MD; Heather Ann Van Mater, MD; Elizabeth Wells, MD; Ronny Wickstrom, MD, PhD; Anusha K. Yeshokumar, MD.

Affiliations of The International NMDAR Antibody Encephalitis Consensus Group: Neuroimmunology Group, Paediatric Research Institute “Città della Speranza,” Padova, Italy (Sartori); Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain (Armangue); Hacettepe University, Ankara, Turkey (Anlar); Sant Joan de Déu (SJD) Children’s Hospital, University of Barcelona, Barcelona, Spain (Armangue); Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada (Benseler); McMaster University, Hamilton, Ontario, Canada (Cellucci); Assistance Publique-Hôpitaux de Paris, University Hospitals Paris Saclay, Bicêtre Hospital, Paris, France (Deiva); French Reference Network of Rare Inflammatory Brain and Spinal Diseases, Paris, France (Deiva); European Reference Network-RITA, Paris, France (Deiva); Stanford University and Lucile Packard Children’s Hospital, Palo Alto, California (Gallentine); Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia (Gombolay); Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts (Gorman); Queen Square MS Centre, UCL Institute of Neurology, University College London, London, United Kingdom (Hacohen); Department of Paediatric Neurology, Great Ormond Street Hospital for Children, London, United Kingdom (Hacohen); Peking University First Hospital, Beijing, China (Jiang); Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (Lim); Section Rheumatology, Texas Children’s Hospital, Baylor College of Medicine, Houston (Muscal); Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, South Africa (Ndondo); Faculty of Health Sciences, University of Cape Town Neuroscience Institute, Cape Town, South Africa (Ndondo); Erasmus Medical Center, Rotterdam, the Netherlands (Neuteboom); Children’s Hospital Datteln, University Witten/Herdecke, Witten, Germany (Rostásy); Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (Sakuma); University Hospital of Padova, Padova, Italy (Sartori); Lady Hardinge Medical College and Associated Kalawati Saran Children’s Hospital, New Delhi, India (Sharma); National Pediatric Hospital Dr J. Garrahan, Buenos Aires, Argentina (Tenembaum); Duke University, Durham, North Carolina (Van Mater); Children’s National Medical Center, Washington, DC (Wells); Karolinska University Hospital, Stockholm, Sweden (Wickstrom); Icahn School of Medicine at Mount Sinai, New York, New York (Yeshokumar).

Author Contributions: Drs Nosadini and M. Lim had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Nosadini and Eyre contributed equally to this work.

Study concept and design: Nosadini, Eyre, Molteni, Dale, M. Lim, Anlar, Ndondo, Sartori, Sharma.

Acquisition, analysis, or interpretation of data: Nosadini, Eyre, Molteni, Thomas, Irani, Dalmau, Dale, M. Lim, Armangue, Benseler, Cellucci, Deiva, Gallentine, Gombolay, Gorman, Hacohen, Jiang, B. Lim, Muscal, Neuteboom, Rostásy, Sakuma, Sartori, Tenembaum, Van Mater, Wells, Wickstrom, Yeshokumar.

Drafting of the manuscript: Nosadini, Eyre, Molteni, Irani, Dale, M. Lim, Ndondo.

Critical revision of the manuscript for important intellectual content: Nosadini, Eyre, Molteni, Thomas, Dalmau, Dale, M. Lim, Anlar, Armangue, Benseler, Cellucci, Deiva, Gallentine, Gombolay, Gorman, Hacohen, Jiang, B. Lim, Muscal, Ndondo, Neuteboom, Rostásy, Sakuma, Sartori, Sharma, Tenembaum, Van Mater, Wells, Wickstrom, Yeshokumar.

Statistical analysis: Eyre, Molteni, Dale, M. Lim, Benseler.

Obtained funding: Molteni.

Administrative, technical, or material support: Irani, Dale, Cellucci, Gombolay, Jiang.

Study supervision: Dalmau, Dale, M. Lim, Deiva, Sakuma, Sartori, Sharma.

Conflict of Interest Disclosures: Dr Molteni has received grants from the UK Medical Research Council Fellowship Scheme. Dr Irani has received grants from CSL Behring, UCB Pharma, and Ono Pharmaceutical; personal fees from UCB Pharma and ADC Therapeutics; and is a coapplicant and receives royalties on patent application WO/210/046716. Dr Dalmau has received royalties from Euroimmun and grants from SAGE. Dr Ming Lim has received consultation fees from CSL Behring, Novartis, Octapharma, and Roche; grants from Boston Children’s Hospital Research Funds, Great Ormond Street Hospital grant, and Great Ormond Street Hospital/Guy’s and St Thomas’ Trust/St Mary’s Hospital Charity; and has received travel grants from Merck Serono; and was awarded educational grants to organize meetings by Novartis, Biogen Idec, Merck Serono, and Bayer. Dr Armangue has received personal fees from Biogen and Novartis. Dr Cellucci has received personal fees from Novartis Canada. Dr Deiva has received personal fees from Novartis, Biogen, Sanofi, and Viela and nonfinancial support from Novartis. Dr Gombolay receives part-time salary support from the US Centers for Disease Control and Prevention to review acute flaccid myelitis cases for surveillance. Dr Gorman has received research funding from Pfizer and Roche. Dr Neuteboom participates in treatment studies in pediatric multiple sclerosis by Novartis and Sanofi-Genzyme and has received consultation fees from Novartis, Zogenix, and Sanofi-Genzyme. Dr Rostásy participates in treatment studies in pediatric multiple sclerosis by Roche. Dr Tenembaum has received personal fees from Biogen Idec Argentina, Genzyme, Novartis Pharma, Novartis Argentina, Genentech-Roche, and Alexion Pharmaceuticals. Dr Wickstrom has received grants from the Stockholm City Council and Hjärnfonden; consultation fees from Roche, Novartis, and Octapharma; and personal fees from Octapharma, Roche, GW Pharma, and Biogen. Dr Yeshokumar has received personal fees from Bristol Myers Squibb. No other disclosures were reported.

Funding/Support: Dr Eyre is supported by Action Medical Research and the British Paediatric Neurology Association. Dr Molteni is supported by the Medical Research Council Skills Development Fellowship Scheme. Dr Armangue is supported by research grants from Instituto Carlos III/FEDER, Spain (PI18/00486), and Generalitat de Catalunya PERIS (SLT006/17/00362). Dr Irani is supported by the Wellcome Trust (104079/Z/14/Z), the UCB-Oxford University Alliance, BMA Research Grants, Vera Down grant (2013) and Margaret Temple grant (2017), Epilepsy Research UK (P1201), the Fulbright UK-US Commission (Multiple Sclerosis Society research award), and the National Institute for Health Research Oxford Biomedical Research Centre. Dr Dale is supported by National Health and Medical Research Council Investigator grant (Australia) and Petre Foundation. Dr Ming Lim receives research grants from Action Medical Research, the Dancing Eye Syndrome Society, the Great Ormond Street Hospital Charity, the National Institute for Health Research, the Multiple Sclerosis Society UK, and the Sparks Charity; and receives research support grants from the London Clinical Research Network and the Evelina Appeal.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: This study was supported and endorsed by the Autoimmune Encephalitis Alliance. Thank you to Kimberley de Haseth, BSc (Autoimmune Encephalitis Alliance, Durham, North Carolina), for support and advice. She was not compensated for her contribution.

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AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody EncephalitisA Meta-analysis

Use and Safety of Immunotherapeutic Management of N-Methyl-D-Aspartate Receptor Antibody Encephalitis

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