The relationship between diffuse axonal damage and fatigue in multiple sclerosis
Tartaglia MC, Narayanan S, Francis SJ, Santos AC, De Stefano N, Lapierre Y and Arnold DL;
Commented by , 28 Jul 2004
Background
Fatigue is a common symptom in MS and one of the most disabling symptoms as well. The pathophysiology of fatigue has not been revealed, but depression and cerebral inflammation has been associated with the symptom. The evidence for a neuronal CNS component is growing and both reduced brainstem activation and widespread neuronal death has been considered. The current study takes advantage of MRI N-acetylaspartate (NAA) measurements as a marker of neuronal integrity, and correlates these findings with fatigue.
Aim
To test the hypothesis that cerebral axonal damage is associated with fatigue in MS.
Methods
The study was cross-sectional, retrospective and included 73 MS patients who completed a Fatigue Severity Scale (FSS) questionnaire. The patients were divided into a high fatigue group (FSS ³ 5; n = 34) and a low fatigue group (FSS £ 4; n = 26) leaving 13 patients in a between-group. Clinical disability was assessed using the Expanded Disability Status Scale (EDSS).
Combined proton magnetic resonance imaging and magnetic resonance spectroscopy imaging (MRS) of the brain were conducted. PD-weighted, T1 and T2-weighted images were used to position an MRS volume of interest of approximately 90x90x20 mm covering the corpus callosum and periventricular white matter. Metabolite intensities of NAA, choline (Cho), and creatinine (Cr) were determined. The metabolite signals were expressed as ratios to Cr in the same voxel.
Results
The NAA/Cr-ratio was significantly lower in the high fatigue group compared with the low fatigue group (t test, p=0.003).
An analysis of covariance controlling for age and EDSS also showed a statistical difference in NAA/Cr between the two groups.
A negative correlation was found between FSS and NAA/Cr ratio (r = -0.361; p = 0.02 Bonferroni corrected). EDSS, age, disease duration, and T2 lesion volume did not correlate with FSS.
Depression was not formally assessed. All patients with a diagnosis of depression or patients who received antidepressants, anxiolytics or fatigue modulating drugs were excluded. This analysis included 49 patients and showed similar results regarding NAA/Cr ratio and fatigue.
Discussion
The study indicates that neuronal/axonal loss causes fatigue in MS. It is the first study to demonstrate a major candidate explaining the etiology of this complex symptom. There are other factors that obviously may contribute or worsen fatigue, although the degree of inflammation, EDSS or disease duration, do not seem to be not closely associated with the symptom.
A joker in this game is depression, and the current study does not control for this in a convincing manner. A simple rating of depression, would have been an easy way to demonstrate the effect, and should have been carried out.
The observed axonal loss seem to be widespread and not related to the frontal lobes, as neurophysiological and PET measurements have indicated. The authors hypothesize that fatigue is a consequence of the neural compensation that take place following axonal/neuronal loss, which seem to go well in hand, with the clinical impression of a possible etiology of the symptom.
The study provides new interesting insight into the pathophysiology of this troubling symptom.