What is the evidence for methylene blue in ifosfamide-induced encephalopathy?

Comment by InpharmD Researcher

The evidence is limited to case reports and single-arm retrospective studies, which report mixed results on whether methylene blue is effective for ifosfamide-induced encephalopathy. Due to heterogeneity between studies and treatment protocol, it is unsure if certain treatment strategies carry more benefit or harm. Use of methylene blue does not appear to be harmful, but there are reports of low-grade neurotoxicity.

  

Pubmed: ("ifosfamid"[All Fields] OR "ifosfamide"[MeSH Terms] OR "ifosfamide"[All Fields]) AND ("brain diseases"[MeSH Terms] OR ("brain"[All Fields] AND "diseases"[All Fields]) OR "brain diseases"[All Fields] OR "encephalopathies"[All Fields] OR "encephalopathy"[All Fields]) AND ("methylene blue"[MeSH Terms] OR ("methylene"[All Fields] AND "blue"[All Fields]) OR "methylene blue"[All Fields]) = 63 results

Background

A 2020 retrospective study of patients treated with methylene blue (MB) for ifosfamide-induced encephalopathy (IIE) also performed a literature review for other relevant studies. Lacking any inclusion of prospective randomized controlled trials, a total of 38 patients treated with MB were included. Of the 38 patients, 28 (75.6%) responded favorably. Some case reports describe a combination of thiamine, dexmedetomidine, or clonazepam with MB infusion. Others provided continuous hemodiafiltration or intubation until symptoms improved. [1]

A 2006 literature review reported the results of several case reports and one retrospective chart review for the use of MB to treat IIE. The dosing strategy from the retrospective review consisted of MB 50 mg 6 doses per day starting immediately upon the diagnosis of IIE. Of the 8 patients treated, all recovered within 72 hours, with two patients developing low-grade neurotoxicity. Four other untreated patients were mentioned to have had their IIE resolved spontaneously within 48 hours. Individual patient cases are mixed on the efficacy and place of therapy for MB. Patients either responded immediately to MB treatment, required several days to recover, or did not respond to treatment. Methylene blue may be effective as secondary prophylaxis, but the authors believe the evidence is insufficient to use. Doses of MB that have reported positive results can range from a single dose of 50-60 mg up to 6 times daily. [2]

A 2007 review presents available evidence on the use of MB as a treatment or prevention modality for IIE (see Table 1). When implementing doses from 50 to 300 mg daily, methylene blue has resulted in the time to recovery ranging from 10 minutes to 8 days. The largest referenced study of 8 patients (Pelgrims et al.) suggests intravenous (IV) MB at the dosage of 50 mg every 4 hours daily (1% aqueous solution of methylene given over 5 minutes) for treatment of IIE and 500 mg (either IV or oral) every 6 hours daily for secondary prophylaxis. [3], [4]

References:

[1] Abahssain H, Moukafih B, Essangri H, et al. Methylene blue and ifosfamide-induced encephalopathy: Myth or reality?. J Oncol Pharm Pract. 2021;27(1):143-149. doi:10.1177/1078155220971843
[2] Patel PN. Methylene blue for management of Ifosfamide-induced encephalopathy. Ann Pharmacother. 2006;40(2):299-303. doi:10.1345/aph.1G114
[3] Ajithkumar T, Parkinson C, Shamshad F, Murray P. Ifosfamide encephalopathy. Clin Oncol (R Coll Radiol). 2007;19(2):108-114. doi:10.1016/j.clon.2006.11.003
[4] Pelgrims J, De Vos F, Van den Brande J, Schrijvers D, Prové A, Vermorken JB. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. Br J Cancer. 2000;82(2):291-294. doi:10.1054/bjoc.1999.0917
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is the evidence for methylene blue in ifosfamide-induced encephalopathy?

Level of evidence

D - Case reports or unreliable data  Read more→


Please see Tables 1-5 for your response.

 

Treatment with Methylene Blue in Ifosfamide Encephalopathy 
Reference Number of patients

Ifosfamide dose (g/m2/day)

 Methylene blue dose/day Time to recovery
Kupfer (1994) 1 2.4 x 6 days 50 mg x 3 30 min
Zulian (1995) 1 5 50 mg x 1 10 min
Ferrero (1995) 1 2 x 3 days 100 mg x 1 1 day
Demandt (1996) 1 1.5 x 5 days 50 mg x 2 1 day 
Alonso (1996) 1 1.5-2 x 2 days 60 mg x 1 5 h (partial) 
Koschuth (1996) 1 1.5 x 5 days 50 mg x 2 8 days 
Pelgrims (2000) 8 1.5-4 x 3/4-5 days 50 mg every 4 h 37.5 h (mean) 
Donegan (2001) 1 2 x 3 days 50 mg x 3  72 h 
Turner (2003) 2 1.8 x 5 days and 5 50 mg x 3  24 and 48 h 
Raj (2004) 1 3.5 x 5 days 50 mg every 4 h 72 h 

 

 

References:

Adapted from: Ajithkumar T, Parkinson C, Shamshad F, Murray P. Ifosfamide encephalopathy. Clin Oncol (R Coll Radiol). 2007;19(2):108-114. doi:10.1016/j.clon.2006.11.003

 

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

Design

Retrospective analysis

Objective

To report our experience with methylene blue usage in ifosfamide-induced encephalopathy and review the literature on the role of methylene blue in ifosfamide-induced encephalopathy (IIE) management

Method

From a retrospective analysis, four patients were identified who developed IIE and were treated with methylene blue
  Age, years Pathological diagnosis Chemotherapy protocol/dose Treatment of IIE Time between onset and treatment

Total doses of methylene blue received

 Outcome

Patient 1

46

Chondrosarcoma

 Ifosfamide 9 g/m2 on day 5/doxorubicin 

Methylene blue 50 mg every 4 hours until symptom resolution

Also received hydroxyzine for control of agitation

12 hours

4

Recovered

Patient 2

55

Uterine Sarcoma

 Ifosfamide 5 g/m2 on day 3/doxorubicin 

Methylene blue 50 mg every 4 hours until symptom resolution

Immediately

2

Recovered

Patient 3

62

Non-Hodgkin lymphoma

 Ifosfamide 9 g/m2 on day 5/carboplatin/etoposide

Methylene blue 50 mg every 4 hours until symptom resolution

Immediately

3

No response, died after 2 days due to malignancy progression

Patient 4

65

Uterine Leiomyosarcoma

 Ifosfamide 5 g/m2 on day 3/doxorubicin 

Methylene blue 50 mg every 4 hours until symptom resolution

24 hours

3

Recovered

Study Author Conclusions

Methylene blue can be used as a treatment for IIE owing to the severity of the IIE and the 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.

 

 

References:

Abahssain H, Moukafih B, Essangri H, et al. Methylene blue and ifosfamide-induced encephalopathy: Myth or reality?. J Oncol Pharm Pract. 2021;27(1):143-149. doi:10.1177/1078155220971843

 

Encephalopathy after High-Dose Ifosfamide A Retrospective Cohort Study and Review of the Literature

Design

Single-center, retrospective cohort study

N= 8

Objective

 To estimate the prevalence of encephalopathy, identify characteristics associated with encephalopathy, and evaluate the effectiveness of methylthioninium chloride (methylene blue) in its prevention

Study Groups

 Encephalopathy (N= 8)

Inclusion Criteria

 Diagnosed with soft tissue sarcoma, developed encephalopathy following high-dose ifosfamide

Exclusion Criteria

 N/A

Methods

Patients at a single-institution medical center were identified via reviewing the adverse drug event reports. The study included all patients with soft tissue sarcoma, but only those who developed encephalopathy were analyzed within this table.

Methylene blue was dosed at 50 mg 4-6 times daily as an intravenous bolus in patients who received them. The number of doses administered ranged from 3 to 21 with most patients receiving three doses.

Duration

 January 2000 to December 2004

Outcome Measures

 Methylene blue treatment, symptom duration, received additional chemotherapy that included ifosfamide and recurrence of encephalopathy

Baseline Characteristics

  

Encephalopathy (N= 8)

Age, years

 43.4 ± 12.0

Female

7

White

Black

5

3 

Stage of disease

1

2

4

 

2

2

4

Previous treatment

Surgery

Chemotherapy

Radiation

 

7

1

0

Results

Endpoint

Encephalopathy (N= 8)

Treated with methylene blue

5 (62.5%)

Duration of symptoms, days

Received methylene blue

Not received methylene blue

1.75

2.2

1

Received additional chemotherapy that included isophosphamide

Recurrence of encephalopathy*

5

5

*Patients were given prophylactic methylene blue but still developed encephalopathy

Adverse Events

Not disclosed

Study Author Conclusions

 Methylthioninium chloride did not appear to prevent encephalopathy with subsequent doses of high-dose ifosfamide.

InpharmD Researcher Critique

 The study was not powered to detect a statistically significant benefit with methylene blue use in patients who develop ifosfamide-related encephalopathy. Therefore, the results are speculatory at best. The conclusion by the author is focused on the recurrence of encephalopathy despite secondary prophylaxis. But more robust evidence is needed to confirm these findings.



References:

Sweiss KI, Beri R, Shord SS. Encephalopathy after high-dose Ifosfamide: a retrospective cohort study and review of the literature. Drug Saf. 2008;31(11):989-996. doi:10.2165/00002018-200831110-00003

 

A Novel Case of Prolonged Ifosfamide encephalopathy and long-term treatment with methylene blue

Design

 Case report

Case presentation

An 11-year-old female with a history of autistic spectrum disorder (moderate severity) presented with 4 months of cognitive changes. The patient reported recurrent episodes of severe somnolence for 7 months following Ifosfamide therapy for her Non‐Germinomatous Germ Cell Tumor (GCT). She received six cycles of induction chemotherapy (alternating cycles of carboplatin/etoposide and ifosfamide/etoposide) and craniospinal radiation with a boost to the tumor bed. For the ifosfamide cycle, the dose was initiated at 1800 mg/m2/day for 5 days. During the 4th course of chemotherapy (ifosfamide/ etoposide), she experienced ifosfamide-induced encephalopathy (grade 2/3) and received intravenous methylene blue (MB) 1 mg/kg BID resulting in improved orientation within hours of MB initiation. Ifosfamide treatment continued with close monitoring and concurrent use of MB. Although during the 6th cycle, MB was used prophylactically from a day before chemotherapy initiation, on day 4th of this cycle, somnolence was reported and electroencephalogram (EEG) revealed mild encephalopathy both before and after MB.

Finally, after receiving MB within 30 minutes of initiation of multiple readmissions, no clinical deterioration was reported and the patient was fully alert and orientated following this course of treatment. Further neurocognitive testing continued to show episodes of recurrent somnolence with significant cognitive deficits affecting behavior and memory. Brain MRI and spine showed no evidence of disease and blood/CSF markers remained negative. The patient continues to be in remission.

Study Author Conclusions

In conclusion, Ifosfamide-induced encephalopathy is a well-described toxicity that usually lasts for a period of days to weeks following treatment. MB is described as a therapy for this encephalopathy, but prolonged encephalopathy and treatment with MB after several months of cessation of treatment with Ifosfamide has not been previously reported. 
References:

Chain G, Kalia M, Kestenbaum K, et al. A novel case of prolonged Ifosfamide encephalopathy and long-term treatment with methylene blue: a case report and review of literature. BMC Pediatr. 2022;22(1):76. Published 2022 Feb 2. doi:10.1186/s12887-022-03144-1

 

Ifosfamide-induced encephalopathy: the EEG with frontal intermittent delta activity, and rapid resolution with methylene blue: A case report

Design

 Case report 

Case presentation

A 71-year-old woman diagnosed with a high-grade right triceps pleomorphic sarcoma developed metastases to the lung and mediastinum and was subsequently treated with ifosfamide and mesna due to further disease progression. Past medical history included hypertension, hysterectomy for menorrhagia, and appendectomy. Her medications on admission for ifosfamide treatment were lercanidipine, losartan, hydrochlorothiazide, potassium supplement, enoxaparin (thrombosis prophylaxis), senna, domperidone, aprepitant, Fortisip Compact Fibre, Procal Shot, multivitamin, and evening primrose oil (not administered due to unknown possible drug interactions).

On day 3, within 4 hours of receiving chemotherapy, the patient was difficult to arouse and vital signs were within normal ranges, along with a potassium of 2.7 mmol/L; all other abnormality was reported. Suspected of ifosfamide encephalopathy, an electroencephalogram (EEG) was taken while the patient was encephalopathic and showed a rare finding of frontal intermittent rhythmic delta activity (FIRDA). The decision was made to administer methylene blue 50 mg intravenous (IV) slow push, and she experienced a remarkable resolution of drowsiness within 10 min of administration. Oral thiamine was administered and the patient was admitted to the intensive care unit for monitoring. An EEG performed after resolution of symptoms demonstrated recovery of all previously observed encephalopathy. 

Study Author Conclusions

This case is interesting as it adds to evidence of the methylene blue benefit in the management of ifosfamide-induced encephalopathy, and also demonstrates the rarely observed EEG phenomenon of FIRDA during the ifosfamide-induced encephalopathy.
References:

Hamilton JE, Alexander M, Kelleher FC. Ifosfamide-induced encephalopathy: the EEG with frontal intermittent delta activity, and rapid resolution with methylene blue: A case report. Clin Sarcoma Res. 2020;10(1):25. Published 2020 Nov 28. doi:10.1186/s13569-020-00147-3