Introduction
The most common neuropathy associated with diabetes mellitus is distal symmetrical polyneuropathy, with a glove-and-stocking distribution of sensory and motor loss [
1]. This form of neuropathy, also known as diabetic peripheral neuropathy (DPN), affects around 12–50% of individuals with diabetes mellitus at any given point in time [
2,
3]. DPN is a known important risk factor for serious adverse sequelae such as foot ulceration and amputation [
4,
5]. Equally importantly, DPN itself is symptomatically distressing to individuals [
6] and is associated with a reduction in health-related quality of life (HRQoL).
Classically, associations between DPN and HRQoL have been studied with respect to positive symptoms, especially pain [
7‐
9]. Most of the randomised controlled trials for improvement of HRQoL in individuals with DPN have also focused on relief from neuropathic pain. However, there is increasing recognition that DPN is associated with reduced HRQoL, even without pain [
2,
10]. We and others have demonstrated that DPN affects all domains of HRQoL, specifically physical functioning and physical role domains of the SF-36 [
2,
10,
11]. In previous work, we found that DPN had the strongest association with reduced scores in the physical domains of HRQoL in individuals with diabetes-related complications, when compared with diabetic individuals without any complications [
2].
It is well known that DPN contributes to reduced functional performance in individuals with diabetes [
12,
13]. Those with DPN have been found to have reduced proprioceptive sense [
14], reduced ankle mobility and range of motion [
15,
16] and decreased muscle strength [
15], especially in ankle and foot plantar and dorsiflexors, leading to reduced balance or postural stability [
17] and alterations in functional gait and mobility [
15,
16]. Evidence from published literature suggests that structured physiotherapy or exercise interventions can help improve mobility and balance in individuals with DPN [
18‐
20]. However, the goal of these studies has been to prevent falls in individuals with DPN, rather than improving HRQoL.
To our knowledge, only one previous study has examined the effect of exercise on HRQoL in individuals with DPN, reporting improvement in neuropathy-specific quality-of-life scores after 8 weeks of an aerobic exercise intervention [
21]. However, the intervention was not designed to target functional performance; nor was this reported. In our previous work examining cross-sectional associations between DPN status, physical functioning and HRQoL, we found that functional measures, including functional performance, balance and balance confidence, partly mediated the observed association between DPN and lower HRQoL [
22]. Other researchers have also reported that non-pain neuropathy symptoms such as unsteadiness and restrictions in daily activities are associated with increased fear of falling and psychological distress [
23]. Targeted interventions to address these functional deficits, including balance confidence, may potentially improve both functional status and HRQoL. With this rationale, we conducted a randomised controlled trial to assess the effectiveness of an intervention focusing on lower-limb deficits that limit balance and functional mobility in individuals with DPN, with the primary aim of improving overall HRQoL and secondary aim of improving functional status.
Methods
Assessments
All participants underwent assessment through planned clinic visits at three time points (at baseline and at 2 months and 6 months after baseline). At each time point, HRQoL was assessed using the SF-36v2 and EQ-5D-5L. The SF-36v2 is a 36-item generic HRQoL instrument that has been validated for use in Singapore [
30]. All SF-36v2 scores were weighted using Singapore general population data before computing individual domain scores, the physical component summary (PCS) score and the mental component summary (MCS) score. The EQ-5D-5L is a generic HRQoL instrument with five items, from which a summary index score was calculated using the Japanese value set [
31].
Functional assessment included measurement of functional mobility, static balance, muscle strength and range of motion. Functional mobility was assessed through the timed up-and-go (TUG) test, five times sit-to-stand (FTSTS) test, functional reach and balance confidence. The TUG test measures the time taken by a participant to stand from a sitting position, walk 3 m, return and sit back down and is a measure of mobility. The FTSTS measures the time taken by a participant to switch from sitting-to-standing five times in a row and is a test of functional strength. Functional reach measures the distance a participant can reach forward with his or her arm outstretched while standing and is a test of balance. For each test, participants completed a practice run before the actual measurement. The activities-specific balance confidence (ABC) scale was used to measure balance confidence. The ABC scale is a 16-item self-administered questionnaire, with each item assessing participants’ confidence (from 0% to 100%) in undertaking a specific task without losing balance. Individual item scores were averaged to compute the total ABC score.
Average body sway velocity, as a measure of static balance, was measured using a balance platform (Accugait; AMTI, Watertown, MA, USA). Participants were instructed to stand on the balance platform with eyes closed for 2 min. The mean from two rounds of testing was used.
Muscle strength at the ankle during dorsiflexion was measured with the participant seated and the knee extended, using a hand-held dynamometer (micro FET3; Hoggan Scientific, Salt Lake City, UT, USA) placed on the dorsum of the foot. Range of motion for dorsiflexion–plantar flexion at the ankle was measured using a hand-held inclinometer (MicroFET3; Hoggan Scientific) positioned on the dorsum of the foot, with the participant seated, the knee extended and the ankle fully plantar-flexed at the start. Range of motion for flexion–extension at the knee was measured using the hand-held inclinometer placed on the lower third of the back of the leg of interest, with the participant standing and starting with a fully extended knee. For each test, the mean from two rounds of testing was used after an initial trial. Muscle strength and range of motion were assessed on both lower limbs.
All assessments were conducted by a trained research assistant who was blinded to the participants’ randomisation status.
Results
A total of 143 participants were enrolled in the study, with 70 randomised to the intervention arm and 73 to the control arm. The CONSORT diagram of participant recruitment and flow is presented in electronic supplementary material (ESM) Fig.
1. Three intervention and six control arm participants were lost to follow-up at 2 months, while two intervention and three control arm participants were lost to follow-up at 6 months. This left 67 participants in each arm available for the intention-to-treat analysis.
The mean age of enrolled participants was 62 years, 80 (56%) were women and most (110, 77%) were of South Asian ethnicity. Mean duration of diabetes at enrolment was 15.3 (SD 10.7) years, with hypertension, hypercholesterolaemia, heart disease and retinopathy being the most common comorbidities reported. Most participants were not symptomatic for DPN; only four participants (two in each arm) had Michigan Neuropathy Screening Instrument history scores of 7 or more. The most common symptoms were leg cramps and numbness. At enrolment, mean BMI was 28.4 (SD 5.7) kg/m
2 and mean HbA
1c was 69 mmol/mol (8.5%). Participants in the intervention and control arms were comparable in terms of demographic and clinical characteristics, except for there being a higher proportion of women in the control arm (ESM Table
1). Table
1 shows the distribution of key outcomes of interest at baseline across both arms, where again both groups were similar.
Table 1HRQoL and functional scores of study participants at baseline
PCS score | 34.1 (12.2) | 35.1 (11.9) | 34.6 (12.0) |
EQ-5D-5L index score | 0.73 (0.16) | 0.71 (0.17) | 0.72 (0.16) |
Functional status |
TUG test, s | 10.9 (3.9) | 12.2 (4.8) | 11.6 (4.4) |
FTSTS test, s | 14.4 (4.0) | 15.6 (5.8) | 15.0 (5.0) |
Functional reach, cm | 24.3 (7.0) | 23.7 (6.9) | 24.0 (6.9) |
Total ABC score, % | 76.3 (20.5) | 73.3 (22.6) | 74.8 (21.6) |
Body sway velocity, eyes closed, mm/s | 1.6 (1.3) | 1.6 (1.1) | 1.6 (1.2) |
Muscle strength, right ankle, N | 49.8 (14.7) | 48.5 (13.3) | 49.4 (13.8) |
Range of motion, |
Right ankle | 78.0 (9.6) | 78.5 (10.8) | 78.2 (10.2) |
Right knee | 104.9 (15.9) | 101.7 (19.8) | 103.3 (18.0) |
Discussion
The current study found no significant difference in overall HRQoL scores between intervention and control arms after 2 months of structured strength and balance training in individuals with DPN. However, we found significantly greater improvement in the body pain domain of HRQoL in the intervention arm as compared with the control arm. In addition, there were significant improvements in several functional status variables in the intervention arm compared with the control arm. These included statistically significant and clinically meaningful improvements in functional task performance, balance confidence, range of motion at knee and muscle strength at ankle. These improvements were sustained for up to 4 months after the end of the intervention.
Our previous cross-sectional study demonstrated significant differences in both EQ-5D-5L scores and functional status between diabetic individuals with and without DPN. Functional measures, specifically FTSTS test results and balance confidence, partially mediated the association between DPN status and HRQoL [
22]. In our current study, we did not demonstrate any effect of our intervention on overall HRQoL scores, either PCS (SF-36v2) or EQ-5D-5L, despite significant gains in FTSTS performance and balance confidence. Based on the previous analysis, one-unit change in balance confidence and FTSTS performance would result in a 0.005 increase in EQ-5D-5L. The magnitude of change observed in EQ-5D-5L scores in our current trial is consistent with this, with greater improvement in EQ-5D-5L scores with improvement in functional measures in participants in the intervention arm. These results suggest that substantially larger changes in functional measures would be needed to meaningfully change HRQoL in these individuals. More intensive physical therapy over a longer period of time may be needed to effect improvement in HRQoL. However, more intensive physical interventions may potentially lead to adverse events, including pain, muscle strain and even ulceration [
33,
34]; careful assessment of the risks vs benefits would be needed for any individual before prescription of intensive physical therapy.
Dixit et al have previously reported significant improvements in overall quality-of-life scores, as well as in pain, sensory motor symptoms, activities of daily living and social relationships scores with 8 weeks of aerobic exercise [
21]. This is in contrast to our findings. However, Dixit et al used a neuropathy-specific instrument to assess quality of life, which would be more sensitive to change compared with the generic instruments we have used. Nevertheless, disease-specific instruments do not allow for a comparison between diseases, which is important for prioritising interventions for resource allocation; this consideration governed our choice of instrument.
HRQoL scores in our study improved over time in both groups and to a similar extent. This may possibly be due to the Hawthorne effect [
35] as participants on both arms had similar contact and support from the study team during the duration of the study. Other treatments and external factors beyond the study may also affect how an individual’s HRQoL changes over time. Among the specific domains of HRQoL, body pain was the only domain that showed significant improvement with intervention. It is possible that the improved physical conditioning in these individuals may have reduced the effect of pain on daily life and activities [
36,
37]. However, it needs to be noted that the body pain domain is not specific to neuropathic pain and participants may have had pain due to other comorbidities that responded to the intervention.
The change in functional variables with the intervention is in line with previously published literature. A variety of exercise interventions enhanced postural stability, functional performance and lower-limb strength in a meta-analysis of such interventions in individuals with diabetes [
38]. Similar improvements have been reported in individuals with DPN [
33]. Richardson et al showed significant improvements in unipedal stance time, functional reach and tandem stance time in ten individuals with peripheral neuropathy who underwent a 3 week exercise intervention as compared with control individuals who did not receive the intervention [
18]. The exercises included range of motion, inversion–eversion and toe and heel raises performed daily. However, there was no significant difference in balance confidence between intervention and control groups [
18]. Allet et al demonstrated significant improvements in walking speed and gait variability in challenging terrains, as well as improvements in balance, strength and mobility in 35 diabetic individuals who received physiotherapy training over 12 weeks compared with 36 control individuals who did not receive physiotherapy [
19,
20]. The physiotherapy intervention consisted of twice weekly group sessions of 60 min, consisting mainly of gait and balance exercises. Improvements in the intervention group were significant both at the end of the 12 week period and at follow-up at 6 months [
19,
20]. However, small sample size has been a consistent limitation of these studies, and our larger-scale trial provides supportive evidence for the positive effect of physical therapy on functional status in DPN.
One important functional measure that improved as a result of the intervention was balance confidence. Low balance confidence has been associated with greater physical difficulties and lower HRQoL [
22,
39]. More importantly, low balance confidence has been shown to predict poorer mobility in the future [
40]. Balance confidence may determine the nature, duration and intensity of physical activities an individual undertakes on a daily basis and a decline in confidence, either due to a previous fall or the fear of falling, may place an individual on a downward spiral of declining physical functioning and further deteriorating balance confidence. Ours is the first randomised controlled trial to demonstrate the effectiveness of structured physical therapy in improving balance confidence in individuals with DPN.
Some limitations of the study need to be acknowledged. As DPN was defined using only simple clinical assessments, the findings may not be applicable to those with early or small-fibre neuropathy. We chose these assessments as they are used routinely in clinics to identify individuals at risk of foot problems due to neuropathy. In addition, we did not assess the severity of DPN in these individuals as the study primarily focused on functional improvement in DPN rather than on reduction of neuropathy progression. Hence, we were unable to comment on the potential effect of the intervention on DPN severity. We used two commonly used generic HRQoL instruments, which may not capture the impact of DPN with sufficient granularity. Therefore, we may have missed subtle changes in HRQoL that a disease-specific instrument may have identified. Generic instruments were chosen in this study as we have demonstrated significant reductions in HRQoL in DPN using both SF-36v2 and EQ-5D-5L previously. In addition, use of generic instruments allows the comparison of intervention effect in HRQoL between conditions. The sample size achieved was smaller than the target sample size, raising the concern that no significant differences in primary outcomes were found due to inadequate sample size. However, the magnitude of change in HRQoL outcomes observed was much smaller than anticipated during sample size calculations and was too small to have been significant even if the target sample size had been achieved. The magnitude of change in HRQoL observed in our trial is consistent with the strength of association between HRQoL and functional status observed previously. Hence, it appears more likely that the failure to detect a difference in the primary outcome in our study is due to lack of effect on quality of life by an intervention of this intensity, rather than a lack of power. The challenge to achieving target sample size was mainly the relatively small pool of patients with clinically evident neuropathy without active foot problems, foot deformities or prior amputations. The bulk of the patients with clinically evident neuropathy had either existing foot conditions or had severe comorbid conditions that precluded them from participation.
The use of a randomised controlled trial design, blinding of the assessor and the low proportion of participants lost to follow-up are key strengths of the study. The study intervention consisted of easy to understand exercises, was delivered at participants’ homes, was individualised to progress and resulted in significant improvements in a number of functional variables, which is another major strength. Other strengths are the comprehensive assessment of functional status and HRQoL, as well as the follow-up of participants for an additional 4 months post-intervention, allowing the examination of sustained improvements in outcomes of interest.
In conclusion, we have demonstrated that short-term structured strength and balance training resulted in sustained improvements in functional status at 6 months in individuals with DPN but that the magnitude of improvement in functional status did not appear to be sufficiently large to impact overall HRQoL. Longer-term and more intensive interventions may be needed to influence HRQoL in these individuals. Nonetheless, an intervention of this nature may help to preserve functional status, improve balance confidence and reduce the likelihood of falls and injuries in individuals with DPN. In addition to improving glycaemic control, the only specific treatments for DPN available in clinical practice are for pain relief [
41]. However, only a subset of individuals with DPN have painful neuropathy, while loss of functional capacity affects almost all individuals. Therefore, such an intervention can be a useful treatment option for patients with DPN in clinical practice, especially for those without pain symptoms, and this should be evaluated in future studies.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.