Severe Ifosfamide-Associated Encephalopathy Requiring Mechanical Ventilation With Gradual Neurological Recovery During Methylene Blue Therapy: A Case Report

Background: Ifosfamide-induced encephalopathy (IIE) is a well-recognized complication of ifosfamide therapy, typically presenting as mild and reversible neurocognitive dysfunction. Severe, life-threatening cases requiring mechanical ventilation are rare and pose significant diagnostic challenges in complex oncology patients with multiple competing etiologies for altered mental status. Furthermore, evidence guiding the optimal dosing, duration, and safety monitoring of methylene blue therapy in refractory presentations remains extremely limited. Case Description: A 44-year-old man with metastatic retroperitoneal spindle cell sarcoma and normal baseline renal and hepatic function was admitted for chemotherapy. His clinical picture was confounded by a recent complicated urinary tract infection treated with ciprofloxacin, which precipitated mild prodromal delirium. However, within 24 hours of receiving combination chemotherapy with doxorubicin and ifosfamide (cumulative ifosfamide dose ~16.6 g), he experienced an abrupt, catastrophic neurological decline culminating in coma and requiring mechanical ventilation. Non-contrast brain computed tomography was unremarkable. Cerebrospinal fluid analysis revealed mild lymphocytic pleocytosis; however, comprehensive infectious, autoimmune, and paraneoplastic evaluations were negative, rendering immune checkpoint inhibitor encephalopathy from prior pembrolizumab exposure less likely. Continuous electroencephalography (EEG) demonstrated diffuse generalized delta–theta slowing with frontal predominance. Given the precipitous post-infusion decline, severe IIE was diagnosed. Following mandatory screening confirming the absence of glucose-6-phosphate dehydrogenase (G6PD) deficiency and concomitant serotonergic medications, intravenous methylene blue (50 mg every 8 hours) was initiated. Despite no neurological improvement during the first 72 hours, the extended 5-day therapeutic course was temporally associated with progressive clinical recovery and parallel EEG background normalization, ultimately resulting in successful extubation. Conclusions: This case illustrates a rare, life-threatening presentation of IIE requiring mechanical ventilation and demonstrates that neurological recovery following methylene blue therapy may be delayed in severe cases. Prolonged methylene blue administration, guided by clinical course and serial EEG monitoring, may be beneficial when early response is absent. Increased recognition of severe IIE and further study of treatment duration and response predictors are warranted.