Comprehensive review/Revue généraleFatigue in multiple sclerosis – Insights into evaluation and management
Introduction
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) that constitutes the second most common cause of handicap in young adults [39]. Although most patients suffer from recurrent relapses in the initial phase of the illness, they would ultimately face a progressive neurological decline: an unavoidable fate in the vast majority of cases [39]. Throughout the disease course, various symptoms and signs would accumulate, among which fatigue remains particularly disabling and very challenging for the medical community to manage. Since the pioneering work of Freal et al. in 1984, MS fatigue continues to attract the attention of scientists and caregivers [67]. Although Kurtzke did not include fatigue in his famous scale [108], Freal et al. reported, for the first time, that 78% of MS patients they surveyed complained of fatigue and considered it their most annoying symptom [67]. Following these surprising findings, growing literature has proven that fatigue is frequently encountered in the MS population, with 75%–90% of patients reporting it at some point in time [59], [103], [115]. Importantly, MS fatigue can occur at all stages of the disease [99], [104], profoundly alters quality of life, impacts work performance and affects social and family interactions [59].
Despite the high prevalence and debilitating nature of the symptom, its underlying mechanisms are still far from being fully understood. In this regard, studies have highlighted the role of various structural, functional, and immunological factors [61], [62], [82], [116], [179], [188], [205]. In addition, several limitations in fatigue measurement exist, since its evaluation mainly relies on a handful of subjective instruments that were chosen as primary outcomes in the majority of trials. The situation is further complicated by the lack of efficient and satisfactory management protocols. Therefore, in-depth comprehension of the underlying causes and implementation of new therapeutic strategies appear mandatory.
In this review, we aim to:
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define fatigue and present its available classification;
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briefly reappraise its pathophysiological mechanisms;
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suggest a screening/diagnostic approach for daily practice;
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and finally discuss the available treatments, with a particular emphasis on the pharmacological and innovative interventions, namely non-invasive brain stimulation.
Other treatment modalities such as exercise and cognitive behavioural therapies are discussed elsewhere and therefore are beyond the scope of the current work [84], [232]. For this purpose, a systematic research was conducted according to PRISMA guidelines [133]. First, computerized databases indexed in peer-reviewed journals (PubMed, Medline, and Scopus) were consulted between January and October 2016 aiming to identify articles in English and French languages addressing MS fatigue. We combined the following research terms: multiple sclerosis, MS, fatigue, fatigue severity scale, FSS, modified fatigue impact scale, MFIS, evaluation, treatment, management, therapy, axonal loss, inflammation, neurodegeneration, brain atrophy, pathophysiology, imaging, MRI, transcranial direct current stimulation, tDCS, transcranial magnetic stimulation, TMS, noninvasive brain stimulation, NIBS, disability and disease duration. In addition, a second research was conducted combining the names of treatments derived from the first research. Finally, the references of the selected studies were scanned independently by both co-authors in order to look for additional relevant sources.
Section snippets
Definition and classification of multiple sclerosis fatigue
Before discussing the various work-up strategies, it is essential and even crucial to set an agreement on fatigue definition. Indeed, there is no clear consensus in this context, and fatigue description varies among patients, scientists and caregivers. While patients refer to fatigue as “excessive tiredness”, “malaise” or “weakness” [102], this symptom is observed from another perspective by researchers and physicians. For instance, some authors look at fatigue as having its origin in the CNS,
A brief overview of fatigue pathophysiology
The multifactorial nature of MS fatigue makes it challenging for scientists to illustrate its underlying mechanisms. While some authors have explored the role of structural or functional brain abnormalities in the generation of this intractable symptom, others have investigated the contribution of neurochemical imbalance, neuroendocrine dysfunction, neuroimmune dysregulation and peripheral nervous system contribution. In addition, some research has focused on evaluating the influence of
History taking and physical exam
Despite high fatigue prevalence, this symptom is often overlooked in clinical practice. Although clinicians are aware of its presence, they do not necessarily inquire about it at each encounter. Hence, based on the above-mentioned data, we thought of proposing a “road map” for fatigue management that could be of help for care providers. Our aim is to facilitate the diagnosis and guide the therapeutic strategies by searching for all potential fatigue causes and performing the needed work-ups.
The
Pharmacological and alternative interventions
Since MS fatigue is a multi-faceted problem, a multidisciplinary approach and a tailor-made intervention seem necessary and highly recommended. Several molecules and a number of non-pharmacological techniques have been tried so far to reduce symptom intensity and ameliorate patients’ quality of life. Here, we present the rationale behind and the efficacy of each of the proposed therapies.
Conclusion and future perspectives
Taken together, these data highlighted the complex and multifactorial nature of MS fatigue. From an etiological viewpoint, a constellation of mechanisms is incriminated in this context, and no single factor accounts for the occurrence of the symptom. From a therapeutic perspective, the available options are of limited benefit and unsatisfactory responses are usually obtained following monotherapy regimens. To solve this problem, clinicians would need to overcome many obstacles. First, it is
Disclosure of interest
Samar S. Ayache declares having received travel grants or compensation from Genzyme, Biogen, Novartis and Roche. Moussa A. Chalah declares that he has no competing interest.
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