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

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.

Figure 1. Results of paraclinical studies in patients with anti-Ma2 encephalitis triggered by immune checkpoint inhibitors [ICIs]

Brain MRI (fluid-attenuated inversion recovery sequences) in 2 patients with anti-Ma2 encephalitis triggered by ICIs. Note the prominent limbic (A, axial view) and diencephalic (B, sagittal view) involvement (arrowheads).

Figure 2. Proportion of variation in antibody detection between 2017 and 2018 vs 2015 and 2016 at the French Reference Center for Paraneoplastic Neurological Syndromes

Note the 112% increase in Ma2-associated paraneoplastic neurologic syndrome detection observed after immune checkpoint inhibitor introduction. No other onconeural antibody (Ab) targeting intracellular antigens demonstrated a similar increment. A lower increment is observed for the recently implemented neural surface Abs, ranging from 30% to 50%, probably reflecting their relatively novel adoption in clinical practice if compared with the former group.