A novel case of prolonged Ifosfamide encephalopathy and long-term treatment with methylene blue: a case report and review of literature

Abstract

Background Encephalopathy following Ifosfamide treatment is a well-described phenomenon that is typically treated with Methylene Blue (MB). Chloroacetaldehyde, a potentially neurotoxic metabolite of Ifosfamide is hypothesized to cause this encephalopathy. Current guidelines for treatment is to stop Ifosfamide and provide supportive care. MB acts to inhibit Chloroacetaldehyde formation and has been described as a therapy and prophylaxis for Ifosfamide-encephalopathy. MB is effective within 30 min and lasts up to 3 days. Prolonged encephalopathy and MB therapy has not been described in the literature as lasting longer than 30 days following treatment. Case presentation We present the case of an 11-year-old female with autistic spectrum disorder and recurrent episodes of severe somnolence for 7 months following Ifosfamide therapy for her Non-Germinomatous Germ Cell Tumor (GCT). Periods of somnolence occurred prior to receiving cranial RT. Administration of MB gave immediate but limited response, with resolution of somnolence lasting 1-2 days between administrations. The somnolence could not be explained by neuroimaging or laboratory evaluation, but EEG indicated persistent encephalopathy. Conclusion A literature review determines that neurotoxicity is a side effect of Ifosfamide, but this effect has not been described persisting longer than 30 days. Our case continued to require treatment with MB for 7 months following cessation of therapy. We report these novel clinical findings, and hypothesize that there could be a genetic/metabolic component linking this reaction to Ifosfamide with the case patient’s pre-existing autism. This possible association may also correlate to the already-established link between autism and the development of GCTs. This hypothesis leads to further discussion on the suitable usage of Ifosfamide in children with co-morbidities and the necessity of screening prior to its usage.

Rare Delayed Ifosfamide Encephalopathy: A Case Report of Chemotherapeutic Neurotoxicity

“…Symptoms of neurotoxicity include fatigue, drowsiness, hallucination, seizures, coma, and death [ 8 ]. This is thought to be due to the effect of ifosfamide metabolites, primarily chloroacetaldehyde and chloroethylamine, neurotoxic byproducts that are able to cross the blood-brain barrier [ 1 , 9 ]. There are 3 case studies in the literature noting delayed encephalopathy following ifosfamide infusion.…”

“…The authors noted that it took 10 days to administer methylene blue due to lack of knowledge about delayed presentations of encephalopathy [ 7 ]. Lastly, in 2022, Chain et al [ 9 ] described an encephalopathy that lasted 7 months post-infusion in an 11-year-old with a non-germinomatous germ cell tumor and autism spectrum disorder, requiring continuous methylene blue administration.…”

Ifosfamide-Induced Encephalopathy Successfully Prevented by Methylene Blue: A Pediatric Case Report and Review of the Literature

“…IIE occurs within a week after initiation of ifosfamide, and neurological symptoms are usually transient and resolve within 48-72 hours of onset [ 8 ]. However, prolonged neurological symptoms [ 9 ] and death [ 10 ] have also been reported. The mechanism of action of IIE is thought to be that chloroethylamine, a metabolite of ifosfamide, inhibits the mitochondrial respiratory chain, disrupting the intracellular nicotinamide adenine dinucleotide (NAD)/nicotinamide adenine dinucleotide hydride (NADH) balance, leading to the accumulation of NADH and preventing the dehydrogenation of the neurotoxic chloroacetaldehyde (CAA) [ 11 ].…”