Chrono-Immune Neuropathy During PD-1 Blockade: A Report of a Fatal Case and Hypothesis on Circadian Modulation of Neurotoxicity

Immune checkpoint inhibitors can cause a wide spectrum of immune-related adverse events, including rare but severe neurological complications. This report describes a fatal case of progressive immune-mediated neuropathy in a melanoma patient treated with PD-1 blockade, in whom worsening neuropathic pain and functional decline coincided with irregular, non-aligned timing of immunotherapy infusions. PET-CT imaging, MRI, and laboratory testing excluded metastatic, infectious, metabolic, and paraneoplastic causes. Longitudinal evaluation revealed fluctuations in inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), with peaks occurring shortly after late-afternoon infusions. Earlier infusions were associated with fewer symptoms. Although causality cannot be established from a single case, this temporal association raises the possibility that circadian desynchronization may amplify immune activation and contribute to neurotoxicity. Based on these observations, the concept of "Chrono-Immune Neuropathy" is proposed, suggesting that disrupted temporal regulation of treatment may influence the severity of neurologic immune-related adverse events. This case highlights the potential importance of consistent, circadian-aware scheduling in immunotherapy and supports further investigation into time-of-day-sensitive treatment strategies aimed at reducing toxicity and improving patient outcomes.