Case Report: Immune checkpoint inhibitor-triggered anti-Ma2 paraneoplastic encephalitis in sarcomatoid pleural mesothelioma: a fatal case

Frontiers in Oncology 2026 March 9 [Link]

Ilker Nihat Okten, Tuba Baydaş

Abstract

Background: Neurological immune-related adverse events (N-irAEs) represent rare but potentially fatal complications of immune checkpoint inhibitor (ICI) therapy. Among these, encephalitis associated with paraneoplatic neuronal antibodies poses a major diagnostic and therapeutic challenge, as it blurs the distinction between drug-induced toxicity and tumor-driven autoimmunity.

Case presentation: We report a 61-year-old male diagnosed with unresectable sarcomatoid pleural mesothelioma who was treated with first-line nivolumab plus ipilimumab. Following the third treatment cycle, the patient developed progressive hyperphagia, central sleep apnea, and autonomic dysfunction. Serum testing revealed strong positivity for anti-Ma2/Ta antibodies, while brain magnetic resonance imaging was unremarkable. Despite discontinuation of immunotherapy and treatment with high-dose corticosteroids and intravenous immunoglobulin, the patient experienced relentless neurological deterioration. Notably, follow-up positron emission tomography demonstrated complete metabolic tumor response. The patient ultimately died from progressive brainstem dysfunction.

Discussion: Anti-Ma2-associated encephalitis is classically categorized as a paraneoplastic neurological syndrome mediated by cytotoxic T-cell responses against intracellular neuronal antigens. Recent evidence suggests that ICIs can unmask or accelerate latent paraneoplastic autoimmunity by amplifying pre-existing immune responses. In this context, our case is best interpreted as an ICI-triggered paraneoplastic neurological syndrome rather than a primary immune-related adverse event.

Conclusion: This case highlights a fatal neurological complication occurring in parallel with complete oncologic remission, underscoring the paradox of effective cancer immunotherapy precipitating catastrophic immune-mediated neurotoxicity. Early recognition of prodromal neurological symptoms and heightened awareness of paraneoplastic syndromes in the ICI era are critical to improving patient outcomes.