Fatigue in multiple sclerosis: a diagnostic and therapeutic challenge

Multiple sclerosis (MS) is the most frequent autoimmune CNS condition in young adults in Western countries. It leads to demyelination and neuroaxonal damage. Classic neurological deficits include – amongst others – motor disability, sensory and gait disturbances, impairment of vision, bladder and bowel dysfunction, and cognitive dysfunction and fatigue. Fatigue is one of the most frequent symptoms; it is often disabling and is a major cause of unemployment [1,2]. Fatigue in MS is characterized by an overwhelming sense of tiredness, lack of energy or feeling of exhaustion [3]. One widely used definition of fatigue is ‘a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities' [4]. The term ‘fatigue' encompasses several clinical aspects such as mental and muscle fatigue. One widely used self-rating questionnaire, the Modified Fatigue Impact Scale (MFIS), aims to display the impact of fatigue on physical, cognitive and psychosocial functioning [5]. Fatigue overlaps with both cognitive dysfunction and depression in a complex way [6,7].

Many underlying conditions can influence and worsen MS-related fatigue; for example, side effects from medication or drug interactions, sleep disorders, spasticity, pain syndromes or depression and affective disorders [8-11]. Thus, it is challenging to differentiate between ‘primary' fatigue related to CNS injury in the autoimmune disease MS and ‘secondary' fatigue associated with other conditions because it is not possible to objectify and quantify pure primary fatigue. To date, owing to the lack of adequate biomarkers or physiological measures of fatigue, the estimation of symptom severity is highly dependent on patients' reports and self-assessed questionnaires [12,13]. Despite the substantial individual burden for the affected patient and the high socioeconomic importance of MS-related fatigue our knowledge on pathophysiology, diagnosis and treatment is still strikingly sparse.

Fatigue is a multifactorial phenomenon. Associations with neuroimaging findings such as brain lesion load or atrophy, neuroendocrine dysregulation, proinflammatory cytokines, sympathetic vasomotor dysfunction, xenotropic murine leukemia virus-related virus (XMRV) infections and melatonin dysregulation have been reported [14-19].

With respect to treatment options, the situation is at least as unsatisfactory. Several pharmaceutical and nonpharmaceutical interventions have been proposed. However, none of these measures has reached a sufficiently high level of evidence and no drug has received approval by the USFDA (FDA), the European Medicines Agency (EMA) or other authorities. To improve the situation for affected patients, the nihilistic attitude that they face when reporting their symptoms to their treating neurologist must be challenged. Fatigue is often seen as an inevitable and intractable side effect that patients must learn to live with and neurologists often do not ask whether fatigue is a burden to the patient.

The first step to improved patient care is to recognize fatigue as a relevant problem in patients' daily lives and to ask specific questions to clarify possible treatable, underlying causes of fatigue. These might be sleep disorders (e.g., restless legs syndrome, obstructive sleep apnea), depression, spasticity, pain syndromes and certain endocrine and metabolic dysregulation (anemia, hypothyroidism, etc.). Improvement of these conditions through tailored approaches will be a great relief for many patients and fatigue is expected to decrease under such measures.

For those remaining with an unknown cause of fatigue (presumably related to the underlying autoimmune condition MS ‘primary fatigue'), the situation is more difficult. However, despite lack of convincing scientific evidence for most of the applied therapeutic measures, it is worth trying to treat fatigue and, if the level of evidence is still not better than ‘best medical practice', then patients deserve best medical practice. It is important to bear in mind that best medical practice also implies avoiding potentially harmful and nonbeneficial treatments.

A review by Amato and Portaccio [20] summarizes the current knowledge on the management of MS-related fatigue, including pharmacological and nonpharmacological options. This comprehensive work emphasizes that fatigue is an underestimated and neglected symptom. The review highlights two important aspects of fatigue management: i) the awareness of treatable causes of fatigue, such as sleep disorders, depression etc.; and ii) the increasing number of well-tolerated nonpharmacological interventions that can help improve fatigue, such as mindfulness training, progressive resistance training and exercise therapy, aerobic training, yoga, cooling therapy and energy conservation [21-23]. This is especially valuable against the background of insufficient pharmacological treatment options. However, there is still a long way to go towards adequate biomarkers for fatigue measurement on the one hand and better and larger therapeutic studies on the other. MS clinical researchers need to further investigate the diagnosis and management of fatigue in daily practice.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Acknowledgment

F Paul is supported by the German Research Foundation (DFG Exc 257).