Kerstin Pilling1 and Roger F Butterworth2*
Fatigue in Multiple Sclerosis [MS] is one of the most disabling symptoms having a negative impact on disability scores and on Health-Related Quality of Life [HRQOL] occurring more frequently and with increasing severity in patients with primary or secondary-progressive disease compared to those with a relapsing-remitting presentation. With the advent of modern neuroimaging and spectroscopic methods, new insights into the pathophysiology of fatigue in MS are starting to appear in support of predominantly centrally-mediated changes. For example, abnormalities of motor-evoked potentials [MEPs] and the burden of Magnetic Resonance Imaging [MRI] lesions are independently correlated with fatigue severity in patients with MS consistent with a central origin. Moreover, the subsequent use of 18-Fluorodeoxyglucose Positron Emission Tomography [PET] and 1-H-Magnetic Resonance Spectroscopy [MRS] were employed to demonstrate that metabolic dysfunction in specific brain regions such as frontal cortex and basal ganglia were implicated and that a striatalthalamic- frontal cortical network may play a key role in MS-related fatigue. Major hypotheses involving an imbalance in the dopamine systems in the CNS or of the pro-inflammatory cytokine TNFa were proposed as key central mediators. Electronic and manual searches of databases including PubMed, Medline, Embase and relevant journals using appropriate keywords yielded 6 systematic reviews on amantadine for fatigue in MS, 2 of which had associated meta-analyses. The reviews were based on the results of 11 Randomized Controlled Trials [RCTs], 8 of which were placebo-controlled. Six trials compared the efficacy of amantadine with other active agents. Beneficial effects of amantadine were reported in 9/11 trials compared to placebo for MS patients with fatigue of either chronic progressive or relapsing remitting phenotypes. Amantadine was rated superior to modafinil [2 trials], pemoline [1 trial], Acetyl-L-Carnitine [ALCAR, 1 trial], and ondansetron [1 trial] for fatigue treatment. Doses of amantadine shown to be effective for the treatment of fatigue in MS were generally in the 100-200 mg/d for periods of 4 weeks. Clinical Practice Guidelines published by NICE [UK] in 2019 and The German MS Society concluded that amantadine was recommended for the pharmacological management of MS-related fatigue. An important highlight of the present review came in the form of the results of a key study based upon a novel standardized repetitive fatiguing task in patients with MS which resulted in the identification of the precise mechanism by which amantadine exerts its beneficial effects on fatigue in these patients. Treatment with amantadine [200 mg/d, 3 months] led to significant improvements in levels of intracortical inhibition of motor cortex by a process involving the re-balancing of GABA: Glutamate ratios and consequent improvements of central fatigue scores.