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Original research
Central nervous system complications associated with immune checkpoint inhibitors
  1. Alberto Vogrig1,2,3,
  2. Sergio Muñiz-Castrillo1,2,3,
  3. Bastien Joubert1,2,3,
  4. Geraldine Picard1,2,3,
  5. Veronique Rogemond1,2,3,
  6. Cécile Marchal4,
  7. Anne Marie Chiappa5,
  8. Eve Chanson6,
  9. François Skowron7,
  10. Amelie Leblanc8,
  11. François Ducray1,2,3,
  12. Jerome Honnorat1,2,3
  1. 1Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques, Hospices Civils de Lyon, Lyon, France
  2. 2Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France
  3. 3University Claude Bernard Lyon 1, Université de Lyon, Lyon, France
  4. 4Service de Neurologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
  5. 5Service de Pneumologie, CH Cornouaille, Quimper, France
  6. 6Service de Neurologie, Centre Hospitalier Universitaire Gabriel Montpied, Clermont-Ferrand, France
  7. 7Service de Dermatologie, CH Valence, Valence, France
  8. 8Service de Neurologie, CHRU Cavale-Blanche, Brest, France
  1. Correspondence to Professor Jerome Honnorat, Centre de Référence National pour les Syndromes Neurologiques Paranéoplasiques et Encéphalites Autoimmunes, Hospices Civils de Lyon, Hôpital Neurologique, 59 Boulevard Pinel, Bron Cedex 69677, France; jerome.honnorat{at}chu-lyon.fr

Abstract

Objective To describe the spectrum and outcome of central nervous system complications associated with immune checkpoint inhibitors (CNS-ICI).

Methods Patients with CNS-ICI were identified and their characteristics compared with ICI-related peripheral neuropathy (PN-ICI).

Results We identified 19 patients with CNS-ICI. The patients were receiving nivolumab (n=8), pembrolizumab (n=6), a combination of ipilimumab-nivolumab (n=3), ipilimumab-durvalumab (n=1), or atezolizumab (n=1). Underlying malignancies included non-small-cell lung cancer (n=8), melanoma (n=3), and other less common tumours (n=8). Neurological phenotypes were limbic encephalitis (n=8), meningoencephalitis (n=4) and cerebellitis (n=4). Two patients developed isolated confusion and one parkinsonism. Associated autoantibodies included onconeural (Ma2, n=7; Hu, n=1), astrocytic (glial fibrillar acidic protein, n=2) and neuronal surface (contactin-associated protein-like 2, n=1) specificities. ICIs were withheld and corticosteroid treatment was given in all cases. Five patients received intravenous immunoglobulin, two rituximab, one plasmapheresis and one infliximab. Overall, six patients died. Readministration of ICI was attempted in three patients, without further relapses. Non-small-cell lung cancer was significantly more frequent in patients with CNS-ICI (p<0.01), while melanoma and ipilimumab treatment were more common in PN-ICI (p<0.01 and p=0.01). Conversely, CNS-ICI cases were more frequently antibody-positive than PN-ICI (p<0.01) and showed a strong trend towards poorer outcome (p=0.053).

Conclusion Three main clinical phenotypes characterise CNS complications of ICIs, each with distinct immunological background, disease course and response to treatment. Other clinical manifestations (including parkinsonism and steroid-responsive confusion) are also possible. Underlying cancers, antibody prevalence and outcome appear different from those of patients with PN-ICI.

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Footnotes

  • Contributors Study concept and design: AV, JH. Acquisition of data: AV, SM-C, BJ, GP, VR, CM, AMC, EC, FS, AL, FD, JH. Analysis and interpretation of data: AV, SM-C, BJ, GP, VR, CM, AMC, EC, FS, AL, FD, JH. Drafting of the manuscript: AV. Critical revision of the manuscript for important intellectual content: AV, SM-C, BJ, GP, VR, CM, AMC, EC, FS, AL, FD, JH. Study supervision: JH.

  • Funding This study is supported by research grants from ANR (ANR-14-CE15-0001- MECANO) and FRM (Fondation pour la recherche médicale, DQ20170336751). This work has been developed within the BETPSY project, which is supported by a public grant overseen by the French National Research Agency (ANR), as part of the second 'Investissements d'Avenir' programme (reference ANR-18-RHUS-0012).

  • Competing interests AV reported receiving a fellowship grant from the European Academy of Neurology (EAN). No other disclosures were reported.

  • Patient consent for publication Obtained.

  • Ethics approval The study was approved by the Institutional Review Board of the University Claude Bernard Lyon 1 and Hospices Civils de Lyon.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Patient-related data will be shared upon request from any qualified investigator, maintaining anonymisation of the individual patients.

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