Fatal neuroleptic malignant syndrome: a forensic case series on postmortem diagnostic challenges

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal adverse reaction to antipsychotic and other dopamine-modulating medications and remains one of the most challenging diagnoses in forensic pathology. Postmortem findings are typically nonspecific and toxicological analyses often demonstrate therapeutic drug concentrations; therefore, accurate cause-of-death determination requires integrated medico-legal evaluation. A retrospective forensic case series was evaluated using the national forensic death investigation system of the Council of Forensic Medicine of Türkiye. First Forensic Medicine Board (FFMB) reports between 2013 and 2024 (n = 53,677) obtained via the National Judiciary Informatics System (UYAP) were screened. Cases in which NMS or malignant hyperthermia was considered underwent detailed manual review, and only those in which the FFMB established NMS or malignant hyperthermia as the final cause of death were included. Demographic characteristics, medication exposure, clinical course, laboratory investigations, autopsy findings, histopathology, toxicological analyses, and final forensic determinations were systematically evaluated. Seventeen deaths met the inclusion criteria, of which fourteen deaths were attributed to NMS associated with antipsychotic therapy and three deaths were attributed to anesthesia-related malignant hyperthermia. Most NMS decedents had underlying psychotic disorders and were receiving antipsychotic treatment, frequently in the setting of psychotropic polypharmacy or depot formulations. A recurring clinical pattern of hyperthermia, neuromuscular abnormalities, altered mental status, autonomic instability, and marked creatine kinase elevation was observed. Autopsy findings were predominantly nonspecific, most commonly demonstrating visceral congestion and pulmonary edema. Toxicological analyses identified prescribed psychotropic medications at therapeutic or near-therapeutic concentrations without evidence of lethal intoxication. Final cause-of-death determination relied on integrated forensic evaluation and systematic exclusion of competing hyperthermic syndromes. Fatal NMS represents a diagnostically challenging functional drug-related cause of death for which neither autopsy nor toxicological analysis alone is sufficient. Accurate forensic diagnosis requires comprehensive integration of clinical history, medication exposure, laboratory investigations, autopsy findings, toxicological results, and exclusion of competing hyperthermic syndromes. Recognition of these recurring clinical and forensic patterns may facilitate more accurate medico-legal cause-of-death determination in suspected NMS-related deaths.