Methadone-Induced Toxic Leukoencephalopathy: MR Imaging and MR Proton Spectroscopy Findings

Discussion

Substitute drugs such as methadone are widely used both in medication-assisted therapy of drug abuse/dependence as well as in the management of intractable pain. Nevertheless, due to its increasing use and availability, methadone overdose has been reported as a growing problem.¹

Most of the available literature on imaging of illicit substances deals with the neurotoxic changes induced by heroin, a morphine agonist, administered either intravenously or through (repeated) inhalation.^2–7 There are only a few reported cases of severe methadone-induced toxic leukoencephalopathy that include imaging findings.^8–10

The imaging findings in our patient are similar, though not identical, to previously reported MR imaging and spectroscopic white matter changes observed in heroin-vapor-inhalation toxicity (a practice known as “chasing the dragon”).^2–4,6,7 In general, the different case reports mention similar symmetric and confluent high-signal-intensity changes in the cerebral white matter observed on T2-weighted and FLAIR images with, as also observed in our patient, sparing of the subcortical U-fibers. In our patient, there was no evidence of heroin abuse in any form or involvement of any other recreational drug.

However, most previously published reports on heroin-induced neurotoxicity also mention white matter changes in the cerebellum and brain stem, which were absent in our patient. Furthermore, the few case reports with CT and MR imaging findings describing brain damage after a methadone overdose all reported cerebellar swelling with subsequent development of acute hydrocephalus.^8–10 In these reports, all the patients were children with a maximum age of 3 years. However, to the best of our knowledge, this is the first case report of methadone intoxication in an adult.

Some investigators have hypothesized that the neurotoxicity of heroin may be due to a contaminant or additive to the drug.^4,11 However, in our patient, there was no such a component. Similarly, a previous study by Wolters et al¹¹ failed to clearly identify a neurotoxic contaminant or additive responsible for the inflicted white matter damage after heroin inhalation. Furthermore, Nanan et al¹² described white matter changes in a young girl after intoxication with morphine sulfate tablets, a noncontaminated pure morphine agonist, which could not be fully explained by a hypoxic-ischemic event.

Mitochondrial dysfunction and damage can explain the decrease in NAA and the increase in lactate. Choline is a marker in the synthesis and breakdown of cell membranes. Lactate is a marker for anaerobic metabolism. The proton MR spectroscopy findings revealed a decreased NAA peak and an increase in the lactate peak, similar to findings in previous reports of inhaled heroin neurotoxicity.^6,7 As stated by Vella et al,¹³ these findings may indicate a mixed pathologic process of hypoxia and mitochondrial damage, with axonal injury but without demyelination.

In conclusion, the MR imaging and proton MR spectroscopy findings of methadone-induced neurotoxicity in our patient are similar but not identical to those in previous reports of heroin-induced brain damage. Techniques like proton MR spectroscopy of the involved areas can be of assistance in further work-up. Additional studies are, nevertheless, needed to understand the underlying pathophysiology adequately.