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

Neurol Neuroimmunol Neuroinflamm. 2019 Aug 7;6(6):e604. doi: 10.1212/NXI.0000000000000604. Print 2019 Nov.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / adverse effects*
  • Antigens, Neoplasm / immunology*
  • Antineoplastic Agents, Immunological / adverse effects*
  • Encephalitis / chemically induced*
  • Encephalitis / immunology*
  • Humans
  • Immunologic Factors / adverse effects*
  • Ipilimumab / adverse effects*
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Nerve Tissue Proteins / immunology*
  • Nivolumab / adverse effects*
  • Paraneoplastic Syndromes, Nervous System / chemically induced*
  • Paraneoplastic Syndromes, Nervous System / immunology*
  • Retrospective Studies


  • Antibodies, Monoclonal, Humanized
  • Antigens, Neoplasm
  • Antineoplastic Agents, Immunological
  • Immunologic Factors
  • Ipilimumab
  • Ma2 antigen
  • Nerve Tissue Proteins
  • Nivolumab
  • pembrolizumab