The relationship between diffuse axonal damage and fatigue in multiple sclerosis

Background: Fatigue is a common and distressing symptom for patients with multiple sclerosis (MS). There is growing evidence that fatigue in MS has a central nervous system component. We hypothesized that diffuse cerebral axonal damage could be associated with fatigue and used proton magnetic resonance spectroscopy to non-invasively measure axonal damage or loss in the brains of patients with MS. Objective: To assess the strength of the relationship between central brain N-acetylaspartate and fatigue. Design: Data from 73 patients who had undergone proton magnetic resonance spectroscopy imaging and completed the Fatigue Severity Scale questionnaire were analyzed. Results: The N-acetylaspartate-creatine ratio (NAA/Cr) was significantly lower in the high-fatigue group than the low-fatigue group (mean +/-SD, 2.69+/-0.29 and 2.99+/-0.33, respectively. P=.003). Independent of the Kurtzke Expanded Disability Status Scale, T2 lesion volume, age, and disease duration, NAA/Cr was significantly lower in the high-fatigue group as compared with the low-fatigue group. There was a statistically significant linear correlation between the Fatigue Severity Scale scores and NAA/Cr (Spearman rank p=-0.361, P=.02). Conclusions: The results of this study, combined with those of others, suggest that widespread axonal dysfunction is associated with fatigue in MS. Increased recruitment of cortical areas and pathways in response to brain injury may be responsible for the patient's sense that the effort required to perform actions is disproportionately high.