Introduction
In descriptions of facioscapulohumeral muscular dystrophy (FSHD) pain and fatigue are rarely mentioned as important clinical features of the condition. However, a questionnaire-based survey in 270 French and one in 84 Dutch members of patient support groups indicated that pain is present in 50–75% of patients [
6,
22]. Bushby et al. reported four adult patients with FSHD in whom pain was a presenting complaint and remained their most disabling symptom [
10]. In a recent questionnaire-based survey, 61% of 139 Dutch FSHD patients were severely fatigued [
19]. Their experienced fatigue severity was associated with the severity of functional impairments in daily life. Actually, pain and fatigue seem to be important symptoms in FSHD; and they are not only underreported, but probably also undertreated. In patients with slowly progressive neuromuscular diseases, such as FSHD, combinations of muscle weakness, pain, fatigue, problems with locomotion and body weight can lead to reduced physical activity and a sedentary lifestyle [
26]. Physical inactivity has a negative influence on quality of life and health outcomes [
26].
In FSHD the decline in muscle strength and mass is progressive over years and follows in general a recognizable sequence of muscle involvement. However, there is a large, unexplained, interindividual variability in rate of progression, even within families sharing the same mutation [
30,
36,
41]. The variable course within families and the typical asymmetric weakness has led to the hypothesis that daily exertion might be responsible for disease progression [
9,
18]. Uncontrolled studies on the effects of strength training in neuromuscular disorders, although including only 13 FSHD patients, suggested a positive effect of strength training and did not point towards extra susceptibility for muscle overstrain [
1,
25,
28,
39]. The results of a pilot study and a subsequent randomised, controlled trial in FSHD patients with the β 2-adrenergic agonist albuterol were indicative for an anabolic effect that wears off with prolonged use [
20,
21]. In animals and healthy persons the strength-increasing effect of β
2-adrenergic agonists can be augmented when it is administered in combination with resistance exercise [
11,
14,
16,
42]. We previously reported a randomised controlled trial in which we evaluated the efficacy of a moderate-intensity strength training program and albuterol in FSHD [
35]. Strength training and albuterol were well tolerated and appeared safe interventions with limited positive effects on muscle strength and volume. Contrary to our expectation no synergistic effects between training and albuterol were detected; also no antagonistic effect was observed.
A strength training program could potentially induce muscle soreness caused by exercise-induced muscle damage or pain as a result of increased strain on the tendoskeletal apparatus. The imposed extra physical activity could lead to an increase in experienced fatigue caused by a physical overload, as well as a decrease caused by a better physical condition.
There is no information available on the effects of β
2-adrenergic agonists, such as albuterol, on muscle endurance or on experienced fatigue. Theoretically, albuterol could result in reduced fatigability via increased muscle strength and mass, but also in a decrease in muscle endurance by slow-to-fast muscle fibre type transformation [
43]. Ideally, both interventions—strength training and albuterol—should result in less disability and a better quality of life.
The objectives of this study were: (1) to explore the prevalence, magnitude and other characteristics of pain and experienced fatigue in the group of FSHD patients participating in the previously reported, randomised controlled trial [
35], and (2) to study the effects of albuterol and strength training on self-reported pain, experienced fatigue, functional status and psychological distress in these patients.
Discussion
Eighty percent of the participating FSHD patients reported chronic persistent or periodic pain with a low to moderate intensity, mostly characterized as sore, stabbing, stiff and taut. Pains were most frequently present around the shoulders, neck, lower back and lower legs. There was no relationship between the presence of pain and gender or age. However, if pain was present the reported intensity tended to be slightly higher for female and older patients. Patients with pain appeared to be more fatigued. The outcomes for functional status and psychological distress did not significantly differ between those with and without pain.
Thirty-four percent of the patients were considered to be severely fatigued. There was no relationship between both the presence and the severity of fatigue, and gender or age. Severely fatigued patients had significantly more pain, more disability, more psychological distress, and more depressive feelings. However, our data also indicated relatively moderate sickness-related dysfunction and no indications of abnormal psychological distress in the total group of patients studied.
The two interventions, moderate-intensive strength training and albuterol, did not appear to have a clear positive or negative effect on pain, experienced fatigue, functional status or psychological distress.
The results of the Dutch and French surveys were rather similar with regard to relative frequency, pattern in time, and localization and other characteristics of pain [
6,
22]. Considering the high relative frequency of pain, it is surprising how little attention this complaint has received. For all, it raises questions about the pathophysiology of pain in this disorder. As suggested, part of the multifocal, often asymmetrical pains—especially those in the shoulder region and around the spine—can probably be attributed to postural problems [
10]. Problems induced by the loss of muscle mass and strength, as pain was most frequently localized in body regions affected early and most severely in the course of the dystrophic process. However, a considerable proportion of our patients reported pain in the thighs and upper legs, and some patients even mentioned facial pains. We do not know if pain in these body parts is more myalgic in nature, as reported previously. Pain is also mentioned in relation to the onset and exacerbations of the disease [
10,
30]. Myalgic pains and periodic pains could be due to—a long debated—inflammatory component in the pathophysiology of FSHD [
4]. Although inflammatory changes in muscle are a frequent histological feature in FSHD [
4,
30], the results of metabolic investigations and muscle biopsies in the previously reported four patients with myalgic pains did not indicate any exceptional inflammatory response [
10]. Moreover, the myalgic pains in these patients hardly responded to conventional first-line analgesics or anti-inflammatory therapy. Unfortunately, pain was not an outcome measure in a 12-week open-label pilot trial with prednisone in eight FSHD patients [
32].
The presence of pain did not seem to have an important influence on disability and psychological distress; as opposed to the presence of severe experienced fatigue, which was clearly associated with more disability, more psychological distress and more depressive feelings. The proportion of patients with a possible depression was significantly higher in the severely fatigued subgroup as compared to the other patients. Severe fatigue could not be seen as merely a sign of depression, as 66% of the severely fatigued patients had normal scores on the depression inventory. However, it appears likely that in the state of depression fatigue related to FSHD is experienced as more severe. So, one should consider a depression in FSHD patients with excessive fatigue.
In a recent questionnaire-based survey 61% (CI: 53–69%) of 139 Dutch FSHD patients were severely fatigued versus 34% (CI: 22–46%) in our study [
19]. Both studies used identical versions of the CIS questionnaire, and defined severe fatigue by the same cutoff score. The difference in the proportion of severely fatigued patients might be due to selection in both studies. The questionnaire-based survey was specifically aimed at problems associated with fatigue, potentially leading to an overestimation if nonresponders tended to be less fatigued. Our study might underestimate fatigue as a problem, as patients were only eligible if they were willing to train if allocated to the training group, and were able to walk independently, potentially excluding the most fatigued and most affected patients. Kalkman et al. also found an association between the experienced fatigue severity and functional impairments in daily life [
19]. Recently, a 12-week low-intensity aerobic exercise program in eight FSHD patients improved their aerobic capacity without signs of muscle damage [
29]. Self-reported fatigue did not change. Regrettably, this small study lacked a randomised controlled or casecontrolled design, and fatigue severity was not quantitated.
Experienced fatigue has been defined as an overwhelming sense of tiredness, lack of energy and feeling of exhaustion [
23]. It is not the same as muscle weakness or muscle fatigability [
23]. Muscle fatigability has been defined as the failure to sustain the force of muscle contraction, and is also called peripheral fatigue [
12]. We believe that experienced fatigue in patients with a muscle disease is not merely caused by their muscle weakness and muscle fatigability alone. Central fatigue, characterized by an enhanced perception of effort and limited endurance of sustained physical and mental activities, might play a part as well [
12]. Fatigue might even be an independent determinant of disability. We did not predefine a measure for disease severity, so at this moment we cannot answer the important question on the relations between experienced fatigue, the severity of the dystrophic process and functional disability.
We recently reported the primary and main secondary outcomes of this randomised controlled trial in which we demonstrated that in FSHD strength training and albuterol are well tolerated and safe interventions with limited positive effect on muscle strength and volume [
35]. In the design of this study self-reported pain, experienced fatigue, functional status and psychological distress were predefined as explorative outcome measures.
The very limited positive effects of the strength training program on muscle strength and the absence of any detectable effects on experienced fatigue, functional status and psychological distress could reflect the inability of the diseased neuromuscular and cardiorespiratory system to respond with normal adaptations to the applied training stimulus. However, part of this lack of response could also be due to the specificity of the training [
15,
24]. The physiological adaptations to training are specific to muscle actions involved, speed of movement, range of motion, muscle groups trained, energy systems involved and intensity and volume of training [
3]. This means that a training program with dynamic exercises increases dynamic strength more than isometric strength, and vice versa. This phenomenon of specificity of training also has implications for the sensitivity of the outcome measures: e.g. the positive effect of a dynamic strength training program may be captured by using a dynamic evaluation technique, and might be missed using an isometric strength measure, a functional test (e.g. walking), or a functional disability questionnaire. Of course, the secondary outcomes not demonstrating any relevant or significant changes may also be due to the small number of muscle groups trained. The American College of Sports Medicine recommends exercising eight to ten major muscle groups to come to an effective training stimulus [
2]. All other recommendations to come to an effective, standardized, but safe and individualized exercise prescription were met. Based on our experience guardedly exercising eight to ten major muscle groups in neuromuscular patients does actually seem feasible. And finally, the FSHD population in this study turned out to have relatively moderate sickness-related dysfunction and no indications of abnormal psychological distress, so in retrospect perhaps one could hardly expect relevant changes.
However, in this trial no signs of overuse, such as a decline in strength measures or training-related increase in pain or fatigue, were seen. This is of major clinical importance, because these findings do not support the hypothesis of extra risk for muscle strain in FSHD. Still, an extra liability for overwork weakness in more severely affected FSHD patients is not excluded. Based on our experience we tell our FSHD patients that ‘normal’ participation in sports and work appears not to harm their muscles but there is insufficient evidence to establish that it offers benefit. And, that there is insufficient evidence for general prescription of exercise programmes in FSHD.
Pain and fatigue are indeed frequent and clinically relevant symptoms in FSHD. More work is necessary to understand their pathophysiology, to study their relation with disease severity and functional disability, and to explore possible treatment strategies. Now that concise strength training of a few muscle groups has proven safe, a study on the effect of more comprehensive training programs designed to target goals more meaningful to these patients seems rational. And, although albuterol (SR capsules, 8 mg twice daily) did not have any effect on fatigue, functional status, and psychological distress, the limited positive effect on muscle strength and volume, and the good tolerability are sufficient ground for studies exploring alternative dosing regimens, and combinations with other ergogenic medication.