Fronto-striatal damage may contribute to resistance to fatigue-lowering medications in multiple sclerosis

Commonly used fatigue-lowering medications have not been proven effective in treating multiple sclerosis (MS)-related fatigue. A neuroanatomical basis for treatment-resistant fatigue in MS has not been explored. The aim of this study was to investigate the association between brain diffusion abnormality patterns and resistance to fatigue-lowering treatment.

Retrospective patient stratification: 1. treatment-resistant (n = 22) received anti-fatigue and/or anti-depressant and/or anxiolytic medication and the latest two Modified Fatigue Impact Scale (MFIS) score≥38; 2. responder (n = 16): received anti-fatigue and/or antidepressant and/or anxiolytic medication while the latest MFIS was <38, and minimum one previous MFIS was ≥38; 3. non-treated never-fatigued (n = 26): received none of the above-mentioned medications and MFIS was always<38 (over minimum four years assessed with MFIS every 1-2 years). 3T brain MRI was used to perform a cross-sectional voxel-wise comparison of fractional anisotropy (FA) between the groups.

Treatment-resistant versus responder patients showed more extensive brain damage (ie, lower FA) favoring the fronto-striatal pathways. Both groups showed more widespread brain damage than non-treated never-fatigued patients. A mean fronto-striatal FA value of 0.26 could perfectly predict response to modafinil/armodafinil.

Fronto-striatal damage may play a role in the development of resistance to fatigue-lowering treatment. Fronto-striatal FA may serve as a biomarker to predict response to fatigue-lowering medications in MS.