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

Abstract

ObjectiveTo 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.MethodsRetrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018.ResultsOur 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.ConclusionsWe 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.

Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies

“…The presence of contrast enhancement at the mesial temporal lobe level in one of our patients is an interesting finding, which was previously reported in Ma2 antibody-associated syndrome. [25][26][27][28] The present study highlights the grim prognosis of patients with Ri-PNS: at 1 year, most of the French patients were unable to walk unassisted, and half of them died within 3 years of disease onset. These findings are in contrast with the favorable prognosis and good functional outcome suggested by others.…”

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum

“…A few patients presenting with irAEs have novel antibody biomarkers such as neurofilament light chain IgG (n = 2) and phosphodiesterase 10A IgG (n = 2) . Other studies have reported detection of Ma2 IgG (n = 6) among CNS irAE with variable cancer subtypes, not compatible with typical oncological association (germ cell tumors) of Ma2 IgG . As indications for cancer immunotherapies grow, cases of classic paraneoplastic phenotypes are also reported; for example, limbic encephalitis in association with anti‐Hu, antineuronal nuclear antibody type‐1, and Lambert–Eaton myasthenia syndrome in association with P/Q type voltage gated calcium channel antibodies .…”

Value of Onconeural Antibodies in Checkpoint Inhibitor‐Related Toxicities

“…Importantly, their clinical manifestations (eg, limbic/diencephalic involvement in anti-Ma2-associated syndromes and sensory neuronopathy/ encephalomyelitis in anti-Hu patients) have been in line with the classical descriptions of these PNSs. 2 The authors did not report whether these antibodies were consistently assessed in their patients. Second, in a mouse model of PNS in which a shared antigen was expressed in both Purkinje cells and implanted breast tumor cells, ICI treatment with anti-CTLA4 was essential to lead to significant T-cell-mediated Purkinje neuron death, 3 as in classical paraneoplastic cerebellar degeneration (PCD), showing also the role of tumor antigen expression.…”

“…The authors mentioned our study, which showed an increased frequency of Ma2-PNSs associated with ICI use in France. 2 They asserted that the associated cancers were not compatible with the typical oncological association (germ cell tumors) of Ma2 antibody. This is not correct.…”