Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors

Our plain-English summary of Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors, by A. Vogrig, M. Fouret, B. Joubert, et al (Neurology® Neuroimmunology & Neuroinflammation, 2019).

The study

• Authors: A. Vogrig, M. Fouret, B. Joubert, G. Picard, V. Rogemond, A.L. Pinto, S. Muñiz-Castrillo, M. Roger, J. Raimbourg, C. Dayen, L. Grignou, M. Pallix-Guyot, J. Lannoy, F. Ducray, V. Desestret, D. Psimaras, J. Honnorat
• Journal: Neurology® Neuroimmunology & Neuroinflammation
• Published: 2019;6(6)
• Cited by: 144 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objective: To report the induction of anti-Ma2 antibody-associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation.

Methods: Retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018.

Results: Our series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017-2018 biennium. Eight cases had been detected in the preceding biennium 2015-2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability.

Conclusions: We show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging.

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

In plain English

This French study described six patients who developed anti-Ma2 encephalitis while being treated with immune checkpoint inhibitors, a type of cancer immunotherapy. Anti-Ma2 encephalitis is a rare brain disorder linked to cancer (anti-Ma2 antibody–associated paraneoplastic neurologic syndrome). The authors looked back at all such cases diagnosed in 2017–2018 at the national reference center in Lyon. Five patients were men, and their median age was 63. Four had non-small-cell lung cancer, one had pleural mesothelioma and one had kidney cancer. Symptoms began a median of 4 months after the drugs were started. Compared with 44 patients who developed the disorder without these drugs, no statistically significant differences were seen in sex, age, cancer type or main neurologic syndrome. All six stopped the drugs and received corticosteroids, yet 4 of the 6 died. In the patient with pleural mesothelioma, Ma2 antibodies were found in a blood sample stored before immunotherapy began. The center's Ma2 diagnoses rose from 8 in 2015–2016 to 17 in 2017–2018, which the authors reported as a 112.5% increase. The authors concluded that checkpoint inhibitor use was clearly associated with more frequent anti-Ma2 syndrome, while noting that proof of cause was lacking.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective case series from a national reference center, with a comparison against earlier non-immunotherapy cases and a comparison of diagnosis counts between two-year periods
• Who was studied: 6 patients who developed anti-Ma2 syndrome after immune checkpoint inhibitor treatment in 2017–2018, out of 50 patients with Ma2 syndrome diagnosed between 2002 and 2018 at the French National Reference Center for Paraneoplastic Neurological Syndromes in Lyon. They were compared with the other 44 patients, whose syndrome was unrelated to these drugs.
• Exposure: Immune checkpoint inhibitors: nivolumab (3 patients), pembrolizumab (2), and nivolumab plus ipilimumab (1). The article does not study asbestos exposure.
• Main results:
  • Among the 6 drug-associated cases, 83% were male, with a median age of 63 years (range 47–79)
  • Cancers in the 6 patients: 4 non-small-cell lung cancer, 1 pleural mesothelioma, 1 renal clear cell carcinoma
  • The median time from starting the drug to onset of the neurologic syndrome was 4 months (range 2–8)
  • No statistically significant differences in sex, age at onset, cancer type or main neurologic syndrome were found between the 6 patients and the 44-patient cohort
  • Timing differed: in the overall Ma2 cohort, 77% developed the neurologic syndrome before their cancer was diagnosed, whereas all drug-associated cases already had cancer (p = 0.004)
  • All 6 patients had the drug withdrawn and received corticosteroids
  • 4 of the 6 patients died; the remaining 2 had moderate to severe disability
  • Patient 2, who had pleural mesothelioma according to the article's table, had a serum sample stored before immunotherapy began; when tested later, it already contained Ma2 antibodies
  • In that patient, neurologic symptoms appeared 5 months after treatment with ipilimumab plus nivolumab
  • In 2017–2018 the center diagnosed 17 patients with Ma2 antibodies; the 6 drug-associated cases were 35% of these
  • 8 Ma2 cases were seen in 2015–2016, so the authors reported a 112.5% increase (given as 112% in the abstract and figure)
• The authors' conclusion: The authors concluded that there was a clear association between immune checkpoint inhibitor use in France and an increased frequency of anti-Ma2 syndrome. They acknowledged that final proof of a causal relationship is lacking.
• Limitations the authors state:
  • The authors cite the retrospective design, the small sample size and possible referral bias toward more complex or treatment-refractory cases
  • Final arguments proving that the drugs caused the syndrome are lacking

Topics

Medical terms in this study, explained in our Lexicon: checkpoint inhibitors, Nivolumab (Opdivo), Pembrolizumab (Keytruda), Ipilimumab (Yervoy), Neoplasm, Pleural Mesothelioma, Immunotherapy.

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