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Recovery of peripheral muscle function from fatiguing exercise and daily physical activity level in patients with multiple sclerosis: A case-control study

Clinical Neurology and Neurosurgery, pages 97 - 105

Abstract

Objectives

Delayed recovery of muscle function following exercise has been demonstrated in the lower limbs of patients with multiple sclerosis (MS). However, studies examining this in the upper limbs are currently lacking. This study compared physical activity level (PAL) and recovery of upper limb muscle function following exercise between MS patients and healthy inactive controls. Furthermore, the relationship between PAL and muscle recovery was examined.

Methods

PAL of 19 MS patients and 32 controls was measured using an accelerometer for 7 consecutive days. Afterwards, recovery of muscle function was assessed by performing a fatiguing upper limb exercise test with subsequent recovery measures.

Results

Muscle recovery of the upper limb muscles was similar in both groups. Average activity counts were significantly lower in MS patients than in the control group. MS patients spent significantly more time being sedentary and less time on activities of moderate intensity compared with the control group. No significant correlation between PAL and recovery of muscle function was found in MS patients.

Conclusions

Recovery of upper limb muscle function following exercise is normal in MS patients. MS patients are less physically active than healthy inactive controls. PAL and recovery of upper limb muscle function appear unrelated in MS patients.

Keywords: Multiple sclerosis, Muscle recovery, Physical activity, Rehabilitation, Physiotherapy.

1. Introduction

Multiple sclerosis (MS) is a chronic and progressive demyelinating disease of the central nervous system (CNS). The disease is characterized by a demyelination process that expresses itself in inflammation and damage of axons in the CNS. This damage results in an important conduction delay and eventually a conduction block of electrical potentials at the level of the lesions[1], [2], [3], [4], and [5].

MS has a large impact on life, mainly because of the unpredictability in progression and heterogeneous presentation of symptoms. The disease presents with a wide variety of chronic and variable symptoms (including cerebellar-, motor-, sensory-, emotional- or sexual-related symptoms) depending on the affected area in the CNS[1], [2], [3], [6], and [7].

Previous studies demonstrated various central and peripheral muscle alterations in MS during and after fatiguing exercise. Examples of these alterations are an incomplete motor unit recruitment [8] , slowing of muscle contractile properties[9] and [10], decreased muscle oxidative capacity[8] and [11], impaired excitation–contraction response[8], [9], and [10], impaired calcium kinetic properties [9] , and altered muscle metabolic response to exercise such as a larger decrease in intracellular phosphocreatine and pH [11] . All of these can possibly influence recovery of muscle function post-exercise. A study by Sharma et al. [9] showed a delayed muscle recovery in MS patients after a low intensity fatiguing exercise protocol where an electrical stimulus of 50 Hz was given for 240 ms once every 3 s for a total of 9 min. MS patients showed an exaggerated metabolic response to exercise. In contrast to these findings, no difference in muscle recovery was found between MS patients and healthy controls after a short-term high intensity exercise (50 Hz stimulation trains for 500 ms with 1000 ms between the trains for a period of 90 s (60 muscle contractions/90 s)) [10] . These conflicting findings, of studies performed at the level of the lower limbs, might be due to a lack of controlling for daily physical activity level which can potentially bias the study findings. Yet, the authors of the latter study found that the maximal rate of force rise (muscle speed) was still impaired in the MS group after a 9 min recovery period, indicating their excitation–contraction coupling was still impaired [10] . This impairment was also found by Sharma et al. [9] who demonstrated this through a reduced release of calcium from the sarcoplasmatic reticulum, possibly contributing to the described delayed muscle recovery following exercise[9] and [12]. A delayed recovery can limit several physical functions and activities in MS patients[13] and [14].

It is possible that a delayed recovery of muscle function is a consequence of physical deconditioning. MS patients can have different and variable physical limitations, which can result into physical inactivity. Previous studies found that patients who suffer from MS are less physically active compared to healthy active people[15], [16], and [17]and healthy sedentary persons [15] . Sandroff et al. [18] noticed that these studies overrated this difference in physical activity as a result of using non-valid assessment tools, too small sample sizes and no control group matched for age, sex, height and weight. When taking these limitations into account, Sandroff et al. [18] still found a reduced physical activity level in MS patients but this difference was smaller than in the previous studies. Apart from the latter study, to date, there is no other research on this subject with the same study conditions. Therefore, it seems warranted to further study daily physical activity level in MS patients versus matched healthy inactive controls, using a valid measure for real-time physical activity monitoring. Furthermore, examining the time spent on different types of physical activities to get a more precise image of the physical activity pattern in MS patients will provide us with some important information. Moreover, reduced physical activity has negative consequences including an increased risk of secondary conditions such as cardiovascular diseases[18] and [19]. Physical activity is a behavioral component which is modifiable[5] and [18]and may therefore play an important role in the treatment of MS.

The purpose of this study was to examine recovery of upper limb muscle function together with daily physical activity level in MS patients and a healthy age-, body mass index- and sex-matched inactive control group. It is hypothesized that MS patients present with delayed recovery of muscle function and a reduced daily physical activity level compared to the control group. Furthermore, this study investigates for the first time the association between the daily physical activity level and recovery of upper limb muscle function in MS patients and a healthy age-, body mass index- and sex-matched inactive control group. Likewise, these two variables may have an important association with each other. The hypothesized relationship between the two is based on the knowledge about modified muscle adaptations in MS patients, which can influence muscle recovery post-exercise and the knowledge that a prolonged recovery can limit physical functions. Considering the important relationship of physical activity level with both levels of self-reported fatigue and quality of life (QoL) in people with MS, as demonstrated in several previous studies[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], and [23], these factors will be further taken into account.

2. Materials and methods

This study was designed as a blinded case-control study. The study took place at the Pain in Motion research lab of the Artesis University College Antwerp and the Vrije Universiteit Brussel between February 2011 and December 2012. The study protocol was approved by the ethics committees of the University Hospital Brussels/Vrije Universiteit Brussel and the University Hospital Antwerp.

2.1. Participants

Patients with MS were recruited through the neurology department of the University Hospital of Antwerp. No restrictions regarding MS subtype were made for study inclusion, and MS had to be diagnosed according to the McDonald criteria[24] and [25]. All participating MS patients were diagnosed by an experienced neurologist at our university hospital. The diagnosing neurologist is specialized in MS patients. Furthermore, the patients had to have an expanded disability status scale (EDSS) score <6 and had to be relapse-free in the last 3 months.

Healthy control subjects were recruited via MS patients already participating in the study and via students and staff of the research group (friends, family, or acquaintances). Control subjects had to be inactive, pain-free and could not suffer from a (chronic) disease. Inactivity was defined as having a seated occupation and performing a maximum of 3 h of moderate physical activity per week. Moderate physical activity was defined as: “Activity demanding at least the threefold of the energy spent passively” [26] . Subjects of both groups could be men or women between 18 and 65 years old. Pregnancy was not allowed for study participation. All participants were asked not to start new treatments during the study period (in particular medication, rehabilitation or other consultations with paramedics or alternative medicine). Furthermore, every participant was asked not to undertake heavy physical activities and to refrain from the use of substances like caffeine, alcohol, nicotine, and benzodiazepines which could influence physical performance on the day of the second visit.

2.2. Procedure and assessments

Fig. 1 shows the flow diagram of the study. During their first visit, participants were asked to sign an informed consent form. After registering their age, sex, height and weight, they were provided with an accelerometer which they had to wear continuously on the wrist of the non-dominant hand during 7 consecutive days. After these 7 days of accelerometry their second visit was scheduled. On the second assessment day the accelerometer was returned and participants performed a fatiguing exercise test and subsequent recovery measures with a hydraulic hand dynamometer. During the recovery period they filled out the medical outcomes study 36-item short form health survey (SF-36) and the checklist individual strength (CIS). The assessor (K.I.) was blinded for the diagnosis and success of blinding was checked at the end of the second visit by asking the assessor to which group she thought the participant belonged to.

gr1

Fig. 1 Flow chart of the study.*McDonald et al. [24] . MS, multiple sclerosis; SF-36, medical outcomes study 36-item short form health survey; CIS, checklist individual strength.

3. Real-time activity monitoring

Physical activity was measured using an Actical accelerometer (Mini Mitter, Bend, OR, USA) measuring accelerometer activity counts [27] . The Actical contains an omni-directional sensor capable of detecting accelerations in two planes. It identifies low frequency gravity forces common to human movements and registers magnitude and duration of the detected acceleration. An increase in speed and motion produces an increase in voltage. This type of accelerometer is capable of recording movements in all directions [28] . Accelerometers are capable of measuring physical activity objectively. The Actical has a compact size (27 mm × 26 mm × 9 mm), is water-resistant, and is easily worn on the wrist without discomfort [29] . It was set to record activity at 1 min periods over a total activity period of 7 days and was worn at the wrist of the non-dominant hand. The Actical has a moderate reliability for daily activities in a general population with an intraclass correlation coefficient (ICC) of 0.65 [30] . It has a moderate reliability for low and free-living activities and a good reliability for moderate and vigorous activities in an MS population (ICC of 0.75 and 0.85–0.90, respectively) [31] . This type of accelerometer also has a good validity for each type of physical activity (low, moderate and vigorous)[32] and [33].

4. Fatiguing exercise test and recovery measurements

Recovery of upper limb muscle function following a fatiguing exercise was assessed based on the protocol from a previous study conducted by Paul et al. [34] that was performed at the quadriceps muscle. There were some adjustments made to the original protocol by Paul et al. [34] to enable examination of upper limb muscle recovery. The protocol was executed with the help of a hydraulic hand dynamometer (Jamar, Saehan Corporation, Masan, Japan) and the recovery phase was shortened to 45 min after the fatiguing exercise.

First, subjects were instructed to perform 3 consecutive isometric maximal voluntary contractions (MVCs) with their non-dominant hand by gripping the hand dynamometer as hard as possible. Between each effort there was a one-minute break. The best of 3 was registered as their MVCbaseline. Next, each subject performed a fatiguing exercise consisting of 18 isometric MVCs in a 50% duty cycle of 5 s contraction and 5 s rest. After the fatiguing exercise test, a single 5 s isometric MVC was performed during the recovery phase at time intervals of 0, 5, 10, 15, 20, 30 and 45 min post-exercise. These absolute values were converted into percentages of MVCbaseline (with the latter being taken as 100%) to obtain relative data. For statistical analyses these relative recovery data were split into three sections. MVCstart equals the MVC at time interval 0 min post-exercise, MVCmid equals the mean of the MVCs at time interval 5–30 min post-exercise, and MVCend equals the MVC at time interval 45 min post-exercise. While executing all MVCs, the subjects were verbally encouraged in a standardized way to promote the performance of maximal contractions.

MVCs were all measured using the hand dynamometer in a standard testing position. The standard testing position is defined as sitting in a straight-backed chair with the feet flat on the floor, the shoulder adducted and neutrally rotated, the elbow flexed at 90°, the forearm in neutral position, and the wrist between 0 and 30° extension and between 0 and 15° ulnar deviation. In all cases the arm could not be supported. For grip strength measurement, the dynamometer is presented vertically and in line with the forearm to maintain the standard forearm and wrist position [35] .

Hydraulic instruments are the most widely used devices that measure grip strength and register in kilograms/pounds-force (kgf and lbf). The hand dynamometer is a reliable instrument and an objective way for measuring strength in elderly and physically impaired persons. It is reported to have a good test-retest reliability and inter-rater reliability for clinical use (ICCs > 0.90) in healthy subjects[35], [36], and [37]as well as in subjects with muscular dystrophy, cumulative trauma disorders and lateral epicondylitis [35] .

5. Self-reported questionnaires

The SF-36 Dutch version was used to assess quality of life (QoL). This questionnaire can be used in the general healthy population but can also report the health status of several chronic-diseased patients [38] In this study, only the total SF-36 score (SF-36tot) was used. A higher score represents better QoL.

Subjective fatigue was measured with the CIS Dutch version [39] . The CIS consists of 20 statements about fatigue (during the past 2 weeks) to be scored on a seven-point scale ranging from ‘yes, that is true’ to ‘no, that is not true’ [40] . In this study, only the subjective fatigue score (CISfatigue) and activity reduction due to fatigue score (CISactivity) of the CIS were further taken into account. Higher scores represent a higher level of fatigue and activity reduction due to fatigue.

5.1. Statistical analysis

Data analyses were performed using IBM®SPSS®Statistics 20.0 for Windows (IBM Corp., Armonk, NY, USA). All data subsets were assessed for normal distribution using the Kolmogorov–Smirnov goodness of fit test. Demographic data of both groups were compared, using an independent samplesT-test for age, body weight and body length, and a Mann–WhitneyU-test for body mass index (BMI). A Fisher exact test was used to compare sex and a Pearson Chi-Square test to compare occupational situation between groups.

Relative data (percentages) of physical activity level and relative (percentages of MVCbaseline) and absolute data of muscle recovery that were not normally distributed were transformed via a square root transformation.

Physical activity levels were compared between groups using multivariate analysis of covariance (MANCOVA) with fatigue and QoL as covariates. The results of the initial maximal voluntary contraction (MVCbaseline) of both groups were compared using a Mann–WhitneyU-test. Further, to compare recovery of upper limb muscle function between (group: MS and control) and within (time: post-exercise measuring moment) both groups, a 2 × 3 mixed factorial analysis of variance (ANOVA) was used for the relative data and a 2 × 7 mixed factorial ANOVA was used for the absolute data. When a main effect for time was found, subsequent post hoc analyses were conducted using the Bonferroni correction.

To compare the results of the three covariates between the MS group and the control group an independent samplesT-test was used for SF-36tot and CISfatigue and a Mann–WhitneyU-test for CISactivity.

To investigate the relationship between physical activity level and muscle recovery, partial correlations were used while controlling for possible confounders (fatigue and QoL).

We tested two-tailed, except for the partial correlations, and all tests were conducted at a level of significance ofα < 0.05.

6. Results

Nineteen MS patients and 32 healthy controls participated in this study. Demographic data are described in Table 1 . There was no significant difference between MS patients and healthy controls for age (p = 0.916), body length (p = 0.849), body weight (p = 0.414) and BMI (p = 0.639). A significant difference between the two groups was found for occupational situation (p = 0.001), but not for sex (p = 0.980).

Table 1 Demographic data of MS patients (n = 19) and healthy controls (n = 32).

Variable Mean ± SD p-value
Age (years) a MS 39.74 ± 10.67 0.916
CON 39.34 ± 13.85  
 
Body length (cm) a MS 172.89 ± 8.67 0.849
CON 172.47 ± 7.05  
 
Body weight (kg) a MS 71.89 ± 11.62 0.414
CON 75.45 ± 19.23  
 
BMI (kg/m²) b MS 23.42 ± 3.52 0.639
CON 24.69 ± 5.11  
 
Sex (n) (♀/♂) c MS 13/6 0.980
CON 22/10  
 
Occupational situation (n) d MS 5 inactive 0.001
9 part time  
5 full time  
0 students  
CON 7 inactive  
2 part time  
15 full time  
8 students  
 
EDSS score MS 1.64 ± 1.02  
CON 0.00 ± 0.00  
 
Duration of disease (months) MS 83.52 ± 68.50  
CON 0.00 ± 0.00  

a An independent samples T-test was used to compare MS group and control group.

b A Mann–Whitney U-test was used to compare MS group and control group.

c A Fisher exact test test was used to compare MS group and control group.

d A Pearson Chi-Square test was used to compare MS group and control group.

SD, standard deviation; MS, multiple Sclerosis; CON, controls; BMI, body mass index; EDSS, expanded disability status scale.

Statistically significant results are printed in bold.

6.1. Physical activity level

Because of a technical defect of the accelerometer, the physical activity data of 1 healthy subject and 1 MS patient were not registered. These two participants were excluded for further analyses with the physical activity data.

The percentage of time spent being sedentary was significantly higher in the MS group compared with the control group (p = 0.015;p = 0.020;p = 0.008 corrected for SF-36tot, CISfatigue, and CISactivity, respectively), while the percentage of time spent on moderate activities was significantly lower in the MS group than in the control group (p = 0.016;p = 0.025;p = 0.015 corrected for SF-36tot, CISfatigue, and CISactivity, respectively) ( Table 2 ). There was also a significant difference between the MS patients and controls for the average activity counts (AvgAC) when corrected for SF-36tot (p = 0.028) and CISactivity (p = 0.026) but not when corrected for CISfatigue (p = 0.059). MS patients had less AvgAC than the inactive control persons. Both groups were comparable for average energy expenditure (AvgEE), percentage of time spent on light activities and percentage of time spent on vigorous activities (p > 0.05).

Table 2 Comparison of physical activity of MS patients (n = 18) and healthy inactive control persons (n = 31).

Physical activity data   Mean ± SD p-value
Confounder     SF-36tot CISf CISa
AvgEE (kcal/min) MS 0.65 ± 0.22 0.431 0.345 0.308
CON 0.78 ± 0.28      
 
AvgAC (counts/min) MS 265.56 ± 142.20 0.028 0.059 0.026
CON 318.75 ± 88.92      
 
Time sedentary (%) MS 46.80 ± 9.86 0.015 0.020 0.008
CON 41.35 ± 7.08      
 
Time light activity (%) MS 43.96 ± 7.08 0.135 0.103 0.085
CON 46.34 ± 5.94      
 
Time moderate activity (%) MS 9.08 ± 6.18 0.016 0.025 0.015
CON 12.18 ± 4.88      
 
Time vigorous activity (%) MS 0.16 ± 0.48 0.992 0.775 0.861
CON 0.13 ± 0.25      

SD, standard deviation; SF-36tot, short-form 36 health survey total score; CISf, checklist individual strength fatigue; CISa, checklist individual strength activity; AvgEE, average energy expenditure; AvgAC, average activity counts; MS, multiple sclerosis; CON, controls.

Statistically significant results are printed in bold.

6.2. MVC and upper limb muscle recovery from fatiguing exercise

There was no significant difference in MVCbaseline between both groups (p = 0.440). When looking at the relative data of upper limb muscle recovery, a significant main effect for time (p < 0.001) was found, meaning that there was a significant difference between the three parts of the recovery period. The post hoc analyses revealed that MVCstart was significantly lower than MVCmid and MVCend (p < 0.001), and that MVCmid was significantly lower than MVCend (p = 0.008). There was no significant group effect (p = 0.544), nor did we found a significant timexgroup interaction effect (p = 0.712). Fig. 2 depicts the graph of the relative data for upper limb muscle recovery post-exercise in both groups.

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Fig. 2 Relative values of muscle recovery after the fatiguing exercise for the MS patients (n = 19) and control group (n = 32). Values are means ± SD. MVC, maximal voluntary contraction; MS, multiple sclerosis.

To analyze the absolute data of upper limb muscle recovery, there were 7 measurements at a different time during the recovery phase, namely MVC0′, MVC5′, MVC10′, MVC15′, MVC20′, MVC30′ and MVC45′ ( Fig. 3 ). Again, there was a significant main effect for time (p < 0.001). After performing post hoc Bonferroni corrections, we found a significant difference between MVC 0′ and all other 6 measurements during the recovery phase (p < 0.001). Furthermore, there was a significant difference between MVC5′ and MVC15′ (p < 0.001), MVC20′ (p = 0.004), MVC30′ (p < 0.001), and MVC45′ (p < 0.001). There was no significant difference between the other measuring moments (p > 0.05). We did not found a significant main effect for group (p = 0.789), nor did we found a significant timexgroup interaction effect (p = 0.733).

gr3

Fig. 3 Absolute values of muscle recovery after fatiguing exercise for MS patients (n = 19) and control group (n = 32). MS, Multiple sclerosis.

6.3. Fatigue and QoL

Significant differences were found for self-reported QoL (SF-36tot), fatigue (CISfatigue) and activity reduction due to fatigue (CISactivity) (p < 0.001;p < 0.001;p = 0.004, respectively) ( Table 3 ).

Table 3 Comparison of fatigue and QoL of MS patients (n = 19) and healthy inactive control persons (n = 32).

Confounder   Mean ± SD p-value
SF-36tot a MS 520.93 ± 149.40 0.001
CON 678.57 ± 74.25  
 
CISfatigue a MS 36.11 ± 11.36 0.001
CON 23.41 ± 12.25  
 
CISactivity b MS 11.26 ± 5.13 0.004
CON 7.31 ± 4.11  

a An independent samples T-test was used to compare MS group and control group.

b A Mann–Whitney U-test was used to compare MS group and control group.

SD, Standard Deviation; MS, Multiple Sclerosis; CON, Controls.

Statistically significant results are printed in bold.

6.4. Partial correlations between physical activity level and recovery of muscle function

One significant correlation (r = −0.337;p = 0.040) was found between the time spent on light activities and the MVC directly following the fatiguing exercise in the control group. All other correlations between physical activity level and the relative data for muscle recovery in the two groups were not significant (p > 0.05) ( Table 4 ).

Table 4 Correlation coefficient of the partial correlation between physical activity and relative values of muscle recovery for MS patients (n = 18) and control group (n = 32).

    MVCstart MVCmid MVCend
AvgEE MS −0.242 0.079 0.079
CON −0.083 −0.171 −0.054
 
AvgAC MS −0.018 0.214 0.079
CON −0.034 −0.019 0.041
 
%TimeSed MS 0.048 −0.130 −0.049
CON 0.192 0.082 0.186
 
%TimeLight MS −0.081 −0.097 −0.049
CON −0.337 −0.148 −0.253
 
%TimeMod MS −0.094 0.242 0.129
CON 0.040 0.107 0.069
 
%TimeVig MS 0.084 0.202 0.128
CON −0.108 −0.099 0.182
         

MVCstart, maximal voluntary contraction directly following fatiguing exercise; MVCmid, mean MVC of 5 till 30 min after fatiguing exercise; MVCend, MVC 45 min after fatiguing exercise; AvgEE, average energy expenditure; AvgAC, average activity counts; %TimeSed, %time spent being sedentary; %TimeLight, %time spent on light activity; %TimeMod, %time spent on moderate activity; %TimeVig, %time spent on vigorous activity; MS, multiple sclerosis; CON, controls.

Statistically significant results are printed in bold.

Correlations were corrected for QoL (SF-36tot) and fatigue (CISfatigue and CISactivity).

6.5. Success of assessor blinding

In the MS group, the assessor guessed wrong in 15 of the 19 cases. In the control group, she guessed wrong in only 3 of 32 cases. Blinding was good in case of the MS patients but not in case of the healthy persons. The assessor was able to recognize healthy persons in 90% of the cases.

7. Discussion

This study investigated recovery of upper limb muscle function after a fatiguing exercise in MS patients. Furthermore, the study also examined the physical activity level and pattern of MS patients and compared their results to those of a healthy age-, body mass index- and sex-matched inactive control group. Finally, the relationship between physical activity level and recovery of peripheral muscle function was studied for the first time in MS patients.

The results indicate that recovery time and pattern of distal upper limb muscles was similar in MS patients and healthy inactive controls. AvgAC were significantly lower in MS patients than in the control group. MS patients also spent significantly more time being sedentary and less time on activities of moderate intensity compared with the control group. No significant correlation between physical activity level and recovery of muscle function was found in patients with MS.

7.1. Upper limb muscle strength and recovery of muscle function from fatiguing exercise

There are several studies that already investigated muscle force or weakness using MVC in MS patients. However, they mostly examined muscles of the lower extremity such as the quadriceps muscle[9], [10], [41], and [42]or the ankle dorsiflexors[9], [11], [12], [42], [43], and [44]. These previous studies reported significant lower maximal force in MS patients compared to healthy controls, with force differences range from 31% [10] to 38% [9] in the quadriceps muscle and from 30% to 70% in the tibialis anterior muscle[9], [11], [12], [42], [43], and [44]. Furthermore, hamstrings muscles as well are reported to be weaker in MS patients [41] . Some authors[9] and [42]attributed this weakness to a smaller number or size of the activated muscle fibers, while others attributed this to the MS related reduced ability to activate muscle mass[10] and [41]and a combination of MS induced central impairment and muscle atrophy/lower quality of muscle mass[12] and [41].

There are only a few studies[14] and [44]that examined muscles of the hand or upper extremity in MS patients, underscoring the need for the present study. These studies[14] and [44]did not find a significant difference in muscle force in the abductor pollicis brevis muscle, flexor carpi radialis muscle [14] and adductor pollicis muscle [44] between MS patients and healthy controls. Our study results support these findings as we did not find a significant difference in MVC produced by the non-dominant hand before the fatiguing exercise.

Taken together, it appears that lower limb muscle function is more and/or earlier affected than upper limb muscle function in MS patients, and thus that motor functions are better preserved in the upper extremity [45] .

Our findings also show that the upper extremity muscles in both MS patients and healthy controls almost completely recover in the first 10 min following a fatiguing exercise (93% of MVCbaseline in the MS group and 94% of MVCbaseline in the control group). There were no significant differences between both groups, implying that MS patients show the same recovery pattern and have no delayed muscle recovery for the upper extremity compared with healthy inactive controls.

As they used different testing/exercise protocols and tested different muscle groups, previous study findings[8], [9], [10], [11], [14], [44], [46], and [47]provided conflicting results on muscle recovery following exercise. In addition, studies that found a delayed recovery of the maximum force following exercise involved MS patients with a mean EDSS score higher than the mean EDSS score of 1.64 (±1.02) seen in our MS group. Furthermore, these exercise protocols were performed at the ankle dorsiflexors[8], [9], and [11]. Our results show no differences in recovery of muscle function between the MS patients and healthy controls and thereby support results found in studies investigating upper limb muscle recovery in MS patients[44], [46], and [47]. More specifically, it has previously been shown that recovery of force is similar in MS patients and healthy control persons in the adductor pollicis longus [44] and the abductor digiti minimi [46] . Likewise, Iriarte et al. [47] showed preserved recovery of handgrip strength in the dominant hand of MS patients. In the study of the de Ruiter et al. [44] , besides the adductor pollicis longus muscle, the quadriceps muscle was tested as well. The quadriceps muscle of these MS patients, with a mean EDSS score of 3.3, appeared to be weaker and showed a delayed recovery relative to the healthy control group. Our MS group had a lower EDSS score and we did not find a delayed muscle recovery or abnormal recovery pattern either, which supports the results of de Ruiter et al. [44] . These results of preserved muscle recovery of the upper limb and delayed muscle recovery of the lower limb suggest that motor functions, in the upper extremity can be maintained for a longer period in MS patients[14], [44], [45], and [47]. As shown before, next to other mechanisms, muscle oxygenation plays a role in the muscular recovery of healthy subjects [48] . This suggests that it could also be a contributing factor in MS patients’ delayed muscle recovery in the lower limbs. Several muscle alterations observed in MS patients in previous studies, such as impaired oxidative capacity (slowed phosphocreatine recovery and prolonged adenosine diphosphate recovery)[8] and [11], impaired excitation–contraction coupling[8] and [9]and muscle weakness[9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], and [44]can be due to deconditioning and chronically disuse of the muscles and are possible contributing factors in these patients’ delayed muscle recovery in the lower limbs.

7.2. Physical activity level

Physical activity level was registered objectively using an accelerometer. To analyze the physical activity pattern we focused on the average energy expenditure, the average activity counts and the percentage of time spent on a type of physical activity (sedentary, light, moderate, and vigorous). Previous studies in MS patients already showed a relationship between physical activity level and QoL on the one hand and physical activity level and fatigue on the other hand[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], and [23]. Considering these results we included QoL and level of fatigue as covariates in our analysis. The present study results showed significantly less activity counts corrected for QoL and activity reduction due to fatigue (CISactivity) in MS patients. Although our results showed no significant difference in AvgAC between the MS and control group corrected for the subjective feeling of fatigue in general (CISfatigue), there was a tendency toward significance.

Furthermore, we found our MS patients to be significantly more sedentary and spending significantly less time on moderate activities compared with our control group when corrected for each confounder separately. The study results showed no difference among the groups on the time spent on light activities nor on vigorous activities. This can be due to the fact that our control group consisted of inactive persons as described in the inclusion criteria. Also the fact that MS patients had to have an EDSS score less than 6, implying no physical impairment, could have contributed to these findings. Previous studies[15], [16], [17], and [18]already concluded that MS patients are less physically active than control persons. These studies, however, have several limitations (use of non-valid assessment tools, too small sample sizes, and no control group matched for age, sex, height and weight) [18] . Sandroff et al. [18] corrected for these limitations in their study and found that the MS patients were still less physically active than the control persons. Our study went further as we ensured that the control group was inactive and examined different types of physical activity to get a more precise image of the physical activity pattern of MS patients. We found that MS patients were more sedentary en spent less time on moderate activities. This difference with the control group was not as big as reported in previous studies showing that MS patients were about 35% less physically active than sedentary controls. We found that MS patients were about 5.45% more sedentary and spent 3.10% less time on activities of moderate intensity. This large difference among studies can be due to methodological issues, as previous studies used less advanced ways of measuring physical activity patterns and did not control for so many possible confounders as done here [15] .

7.3. Physical activity level and recovery of upper limb muscle function

Our study was the first to investigate the relationship between the daily physical activity level and recovery of upper limb muscle function in MS patients. Likewise, these two variables may have an important association with each other because of the observed modified muscle adaptations in earlier studies[8], [9], [10], and [11]. Hence, we expected to find a significant correlation between physical activity and muscle recovery. More specifically, we even expected to find a positive correlation as this was also found in a study on patients with chronic fatigue syndrome (De Backer, 2012 1 ) and these patients show the same muscle alterations as MS patients, namely an impaired oxidative capacity[10] and [34]. A possible explanation for the absence of a relationship between the physical activity level and muscle recovery in the MS group is that we did not register an abnormal recovery pattern or delayed muscle recovery in MS patients (in contrast to what is seen in patients with chronic fatigue syndrome [49] ).

7.4. Fatigue and quality of life

In 40–60% of MS patients fatigue is the most important disease related problem with major consequences for daily activities and social live [3] . MS patients often get tired during physical and cognitive activities and their recovery takes longer. Several studies showed that physical activity is inversely related to fatigue in MS patients[4], [5], [6], [7], and [19].

Our results show that MS patients report more fatigue (CISfatigue) and more activity reduction due to fatigue (CISactivity) compared with healthy persons. We found that these different dimensions of fatigue have an influence on MS patients’ physical activity level, and more specifically that self-reported physical activity reduction due to fatigue was a stronger confounder than self-reported fatigue in general. These results support the findings of previous studies[4], [5], [6], [7], and [19].

Previous studies indicate that QoL is lower in MS patients compared with the QoL of the general non-diseased population[4], [5], [20], and [50]but also with the QoL of other chronic diseased people[4], [20], [50], [51], and [52]. Different studies concluded that several aspects of MS contribute to this reduced QoL, including a reduced mobility[51] and [53]. Concerning the relation between physical activity and QoL, previous studies showed contradictory results[4], [5], [20], [21], [22], and [23].

In the present study we found that MS patients had lower QoL than healthy inactive controls. Because QoL has an important relationship with physical activity[4], [5], [20], [21], [22], and [23]this factor was further taken into account. Our results showed a significant difference in physical activity level between MS patients and healthy controls corrected for this confounder. Furthermore, QoL seemed to be a stronger confounder for physical activity level than self-reported fatigue in general (CISfatigue), but a weaker confounder than the burden of fatigue for physical activity (CISactivity).

7.5. Study strengths and limitations

The present study has both strengths and a few limitations. First, the number of MS patients studied here is rather small. However, a post hoc power calculation revealed that our study was sufficiently powered to detect a true difference between both groups in physical activity level (1 − β = 0.81) and between the different measuring moments of muscle recovery (1 − β = 1.00). Therefore, further increasing the sample size was deemed unethical.

The measurement of physical activity level was performed over a period of 7 days. In this real-life assessment we have to consider a phenomenon where subjects participating in a study are aware they are being studied and change their behavior; better known as the Hawthorne effect. It is possible that because of this effect some results are altered[54] and [55]. Although Trost et al. [56] describe that for reliable outcomes a 3–5 days monitoring is enough, it would appear to be useful to monitor physical activity over longer periods to minimize behavioral changes.

Previous studies[9], [11], [12], and [14]investigating muscle contractions in MS patients often used electrical stimulation of the muscles in MS patients. This because it is shown that MS patients do not use their full muscle capacity when voluntary contracted [12] . It is possible, when we would have replaced the voluntary contraction with electrical stimulation, we would have found other results. However, this would mean that results would have been less translatable to daily activities because voluntary force production is the only force that patients can rely on during everyday situations.

Besides these limitations, this study also has several strengths. The most important one is that we matched our MS patients to the healthy control persons. Both groups were matched for sex, age and BMI. Healthy control persons had to be inactive because MS patients are known to have a more inactive lifestyle[15], [16], [17], and [18]. For the same reason only MS patients with an EDSS score under 6 were included in this study. As it was shown that functional impairment acts as a confounder in the relationship between the physical activity level and symptoms [57] . To have an EDSS score under 6 was also important for the blinding of this study as we attempted to blind the assessor regarding participants’ disease status.

7.6. Clinical implications and future recommendations

Research on physical activity in MS is an important study area because of the differences in physical activity level already found in previous studies[15], [16], [17], and [18]. An important characteristic of physical activity is that, unlike muscle recovery, (muscle) fatigue, and QoL, it is a behavioral component that is modifiable[5] and [18]and thus it plays an important role in this disease. It has already been proven that the daily physical activity pattern has an important relationship with both fatigue and QoL[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], and [23]. Muscle fatigue in MS is a debilitating symptom occurring as muscle weakness during every physical exercise [46] . This muscle weakness and fatigue is often found in muscles of the lower extremity[8], [9], [10], and [11]. Positive is the observation that muscle strength and recovery in the upper limbs is normal and can be maintained for a longer period [46] .

Several previous studies[58], [59], [60], and [61]investigating different exercise modalities already showed positive effects on different symptoms characteristic of MS, such as muscle weakness, muscle endurance, cardiopulmonary fitness, depression, and fatigue. Importantly, physical activity does not increase the rate or severity of MS exacerbations. MS patients can also benefit from physical activity and minimize their risk on secondary conditions such as cardiovascular and respiratory diseases[18], [19], and [59].

In this study we did not found a relation between physical activity and muscle recovery for the upper extremity in MS patients. It would be interesting to examine this relation for the lower extremity as previous studies found delayed muscle recovery in the lower limbs and the lower limb muscles are found to be weaker in MS patients than in healthy persons. Furthermore, knowing whether there is a relation between physical activity level and muscle recovery and which direction this relationship has, is important for future research. If a specific relationship can be found, it can form the base for further studies examining different physical interventions and their effects on the muscular dysfunctions and the delayed muscle recovery in the lower limbs of MS patients. For the same reasons, examining if cardiopulmonary exertion during physical exercise may (in part) contribute to muscle recovery and fatigue in larger and smaller muscles would be interesting to steer activity interventions. We would also recommend, besides the evaluation of strength and recovery distally (as performed in this study with handgrip strength), further evaluation of proximal upper extremity strength and muscle recovery. Finally, examining upper as well as lower extremity strength and muscle recovery in the same patients using the methods of this paper would be very interesting to draw solid conclusions on the difference between upper and lower extremity muscle strength and recovery in MS patients.

8. Conclusion

MS patients spent more time being sedentary and less time on moderate activities than healthy inactive persons, while both groups spent about the same amount of time on light and vigorous activities.

We did not register any difference in handgrip strength, nor did we observe a delayed recovery of upper limb muscle function or a different recovery pattern in MS patients. Muscle force in the non-dominant hand recovered almost completely in MS patients and healthy controls within the first 10 min following the fatiguing exercise.

The present study also investigated the relation between the physical activity level and recovery of upper limb muscle function and did not find a significant relation between these two variables. We believe there could be a relation between physical activity level and recovery of lower limb muscle function and we recommend that future studies should investigate this.

Acknowledgements

The study was funded by ME Research UK. Mira Meeus is awardee of the 2012 early research career grant of the International Association for the Study of Pain (IASP), funded by the Scan│Design Foundation by INGER & JENS BRUUN. Jo Nijs is holder of the Chair ‘Exercise immunology and chronic fatigue in health and disease’ funded by the European College for Decongestive Lymphatic Therapy, The Netherlands. Kelly Ickmans is a research fellow of ME Research UK, a national charity funding biomedical research into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

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Footnotes

a Pain in Motion Research Group, Departments of Human Physiology and Physiotherapy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Belgium

b Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Belgium

c Pain in Motion Research Group, Division of Occupational Therapy, Artesis University College Antwerp, KU Leuven, Belgium

d Department of Neurology, Faculty of Medicine, Antwerp University , Belgium

e Rehabilitation Sciences and Physiotherapy, Faculty of Medicine, Antwerp University, Belgium

f Rehabilitation Sciences and Physiotherapy, Department of Rehabilitation Sciences and Physiotherapy, Ghent University, Belgium

lowast Corresponding author at: Vrije Universiteit Brussel, Medical Campus Jette, Building F-Kine, Laarbeeklaan 103, BE-1090 Brussels, Belgium. Tel.: +32 24774489; fax: +32 26292876.

1 De Backer F. Dagelijkse activiteitenniveau en spierherstel bij patiënten met het chronisch vermoeidheidssyndroom: een patiënt-controle onderzoek (Unpublished master dissertation). Vrije Universiteit Brussel. 2012.