Methylene blue and ifosfamide-induced encephalopathy: Myth or reality?

Abstract

Background Ifosfamide-induced encephalopathy (IIE) is a rare and serious adverse reaction. Thus far, no standard medication has been documentedto be efficient in the reversal of IIE, and while ifosfamide infusion interruption and hydration are recommended, methylene blue (MB) administration remains controversial. Methods We retrospectively reviewed medical records to assess cases with IIE after ifosfamide infusion. We included all patients having received an ifosfamide infusion during their hospitalization in the medical oncology unit of the National Institute of Oncology in Rabat, Morocco, between September 2016 and September 2017. We subsequently conducted a literature review to determine the role of MB in IIE by searching PubMed using the terms “Methylene Blue” and “Ifosfamide”. Results A total of 88 patients received ifosfamide, and four patients had IIE. Ifosfamide infusion was stopped immediately after the IIE occurrence, and patients underwent renal function correction with hydration. All patients received MB infusion, and three patients had an improvement of their neurological status. As regards the literature review, 34 articles were reviewed and 16 items were included in the review. Overall, 38 (65.5%) patients received MB infusion and 28 (75.6%) patients responded favorably to the treatment. Conclusions Methylene blue can be used as a treatment for IIE owing to the severity of the IIE as well as absence of standard medication. Nonetheless, side effects such as serotonergic syndrome should be investigated. More broadly, prospective studies and controlled trials are needed to explore the contribution of MB in IIE management and encourage its use.

Methylene Blue

“…Ifosfamide is an alkylating agent that is used for treatment of malignant tumors. 10 There are many well-studied adverse side effects for this drug, notably hemorrhagic cystitis, nephrotoxicity, myelosuppression, and neurotoxicity. 11 The most concerning neurotoxic effect is ifosfamide-induced encephalopathy.…”

“…The clinical findings of ifosfamide-induced encephalopathy can be moderate to severe, from somnolence, agitation, confusion, hallucinations, extrapyramidal symptoms, seizures, to CNS depression, coma, and death. 7,10,11 The literature states the incidence of ifosfamide-induced encephalopathy varies between 10% and 40% of patients. 10 The onset of symptoms for this reaction can occur between 2 and 96 hours after the initial administration.…”

“…7,10,11 The literature states the incidence of ifosfamide-induced encephalopathy varies between 10% and 40% of patients. 10 The onset of symptoms for this reaction can occur between 2 and 96 hours after the initial administration. Symptoms are usually transient and resolve after 48 to 72 hours; however, studies show that in some cases, long-term serious neurologic dysfunction may persist.…”

“…Symptoms are usually transient and resolve after 48 to 72 hours; however, studies show that in some cases, long-term serious neurologic dysfunction may persist. [10][11][12] For patients who do not have resolution, there is no standard medication that has been proven to reverse the neurotoxic effects. 10 There are various predisposing factors reported for ifosfamideinduced encephalopathy, including hyponatremia, renal failure, female sex with bulky disease, and hypoalbuminemia, and previous cisplatin use.…”

Encephalopathy Associated with Ifosfamide Use in the Treatment of Patient with Diffuse Large B Cell Lymphoma

“…In addition, electrolyte abnormalities should be corrected, IV albumin should be administered for patients with low serum albumin, and all other drugs with potential CNS side effects, such as opioids and sedatives, should be discontinued [40]. Despite a lack of randomized prospective controlled trials proving its efficacy in IRE, MB has been commonly used in patients with moderate to severe cases of IRE, as MB can shorten the duration and severity of neurotoxic symptoms [41,42]. It has been proposed that MB may act as an electron acceptor agent and substitute for the inhibited flavoprotein.…”