Fatigue in multiple sclerosis: The contribution of occult white matter damage

Mult Scler. 2016 Nov;22(13):1676-1684. doi: 10.1177/1352458516628331. Epub 2016 Feb 4.


Background: A functional cortico-subcortical disconnection has been recognized in fatigued multiple sclerosis (MS) patients. Normal appearing white matter (NAWM) damage might contribute to the abovementioned disconnectivity.

Objectives: To assess the relationship between fatigue and microstructural NAWM damage in relapsing-remitting (RR) MS.

Methods: Sixty RRMS patients and 29 healthy controls (HC) underwent a magnetic resonance imaging (MRI) protocol including diffusion tensor imaging (DTI). Patients with a mean Fatigue Severity Scale (FSS) score ⩾ 4 were considered fatigued (fatigued MS (F-MS)). Tract-based spatial statistics were applied for voxel-wise analysis of DTI indices. A correlation analysis was performed between FSS score and DTI indices in the entire MS group.

Results: Thirty MS patients were F-MS. Compared to HC, F-MS patients showed a more extensive NAWM damage than not fatigued MS (NF-MS) patients, with additional damage in the following tracts: frontal and occipital juxtacortical fibers, external capsule, uncinate fasciculus, forceps minor, superior longitudinal fasciculus, cingulum, and pons. No differences were found between F-MS and NF-MS patients. Fatigue severity correlated to DTI abnormalities of corona radiata, cingulum, corpus callosum, forceps minor, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, thalamus and anterior thalamic radiation, cerebral peduncle, and midbrain.

Conclusions: Fatigue is associated to a widespread microstructural NAWM damage, particularly in associative tracts connected to frontal lobes.

Keywords: Multiple sclerosis; diffusion tensor imaging; fatigue; magnetic resonance imaging; normal appearing white matter; tract-based spatial statistics.

MeSH terms

  • Adult
  • Diffusion Tensor Imaging / methods
  • Fatigue / diagnostic imaging
  • Fatigue / etiology
  • Fatigue / pathology*
  • Female
  • Humans
  • Magnetic Resonance Imaging / methods*
  • Male
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting / complications
  • Multiple Sclerosis, Relapsing-Remitting / diagnostic imaging
  • Multiple Sclerosis, Relapsing-Remitting / pathology*
  • White Matter / diagnostic imaging
  • White Matter / pathology*
  • Young Adult