Royal College of Surgeons in Ireland
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Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors

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journal contribution
posted on 2022-05-09, 15:24 authored by Amanda C Guidon, Leeann B Burton, Bart K Chwalisz, James Hillis, Teilo H Schaller, Anthony A Amato, Allison Betof Warner, Priscilla K Brastianos, Tracey A Cho, Stacey L Clardy, Justine V Cohen, Jorg Dietrich, Michael Dougan, Christopher T Doughty, Divyanshu Dubey, Jeffrey M Gelfand, Jeffrey T Guptill, Douglas B Johnson, Vern C Juel, Robert Kadish, Noah Kolb, Nicole R LeBoeuf, Jenny Linnoila, Andrew L Mammen, Maria Martinez-Lage, Meghan J Mooradian, Jarushka NaidooJarushka Naidoo, Tomas G Neilan, David A Reardon, Krista M Rubin, Bianca D Santomasso, Ryan J Sullivan, Nancy Wang, Karin Woodman, Leyre Zubiri, William C Louv, Kerry L Reynolds
Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.


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The original article is available at This article has an Erratum that can be found at

Published Citation

Guidon AC, et al. Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors. J Immunother Cancer. 2021;9(7):e002890.

Publication Date

19 July 2021

PubMed ID



  • Beaumont Hospital
  • Medicine


BMJ Publishing Group Ltd & Society for Immunotherapy of Cancer


  • Published Version (Version of Record)