UvA-DARE (Digital Academic Repository) Treating fatigue in post-polio syndrome Koopman, F.S. Link to publication

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1 UvA-DARE (Digital Academic Repository) Treating fatigue in post-polio syndrome Koopman, F.S. Link to publication Citation for published version (APA): Koopman, F. S. (2016). Treating fatigue in post-polio syndrome General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 24 Sep 2018

2 Chapter 6 No reduction of severe fatigue in patients with post-polio syndrome by exercise therapy or cognitive behavioral therapy: results of an RCT Fieke S. Koopman, Eric L. Voorn, Anita Beelen, Gijs Bleijenberg, Marianne de Visser, Merel A. Brehm and Frans Nollet. Neurorehabil Neural Repair 2015; [Epub ahead of print]

3 Chapter 6 Exercise therapy and cognitive behavioural therapy in PPS: results of an RCT ABSTRACT Background: People with post-polio syndrome (PPS) commonly experience severe fatigue that persists over time and negatively impacts functioning and the health-related quality of life (HRQoL). Objectives: To study the efficacy of exercise therapy (ET) and cognitive behavioral therapy (CBT) on reducing fatigue and improving activities and HRQoL in patients with PPS. Methods: We conducted a multicenter, single-blinded, randomized controlled trial. Over four months, severely fatigued patients with PPS received ET, CBT, or usual care (UC). The primary endpoint (fatigue) was assessed using the subscale subjective experience of fatigue of the Checklist Individual Strength (CIS-F). Secondary endpoints included activities and HRQoL, which were assessed with the Sickness Impact Profile and the 36-Item Short-Form, respectively. Endpoints were measured at baseline and at 4, 7, and 10 months. Results: Sixty-eight patients were randomized. No differences were observed between the intervention groups and UC group for fatigue (mean differences in CIS-F score: 1.47, 95%CI to 5.79 for ET versus UC; and 1.87, 95%CI to 5.98 for CBT versus UC), activities, or HRQoL. Conclusions: Our results demonstrate that neither ET nor CBT were superior to UC in reducing fatigue in severely fatigued PPS patients. Further research should investigate explanations for the lack of efficacy of these two currently advised approaches in clinical practice, which may provide clues to improve treatment aimed at reducing fatigue in PPS. 158

4 INTRODUCTION People with post-polio syndrome (PPS) commonly experience severe fatigue that persists over time 1-3 and negatively impacts functioning and the health-related quality of life (HRQoL). 4,5 This experienced fatigue is typically described as tiredness or lack of energy that increases with physical activity and decreases with rest. 6 The etiology of fatigue in PPS is poorly understood and it is presumed that fatigue is multifactorial. Biological, physical, psychological and cognitive-behavioral factors are known to be associated with fatigue in PPS. 1,7 Because of this multidimensional character of experienced fatigued, a variety of interventions aimed at alleviating it have been studied. However, due to insufficient good quality data and lack of randomized studies no definite conclusions can be made on their effectiveness. 8 Exercise therapy (ET) and cognitive behavioral therapy (CBT) are interventions that have been found to successfully reduce fatigue in other disorders by targeting two different fatigue-related factors. The rationale for ET is based on the assumption that it can interrupt the vicious cycle of fatigue leading to physical inactivity and, consequently, reduction of physical capacity. Reduced physical capacity results in an increased effort to perform daily activities, 9,10 which, in turn, leads to more fatigue. ET aims to improve physical capacity. The rationale for CBT is based on the assumption that cognitive and behavioral factors play a significant role in perpetuating or worsening fatigue. 11,12 By challenging the meaning of these dysfunctional cognitions and eliciting more realistic cognitions, emotions and behaviors might be changed and consequently fatigue might be reduced. Evidence on the effectiveness of ET and CBT in PPS is limited. A systematic review on ET for neuromuscular diseases included ten studies on patients with PPS, five of which demonstrated positive effects on muscular strength and aerobic capacity. 13 A more recent study showed improvement in fatigue and HRQoL in PPS; however, no comparison with a control group was made and long-term effectiveness was not evaluated. 14 Evidence for CBT in PPS is currently limited to an uncontrolled study of cognitive behavioral strategies incorporated in a multidisciplinary rehabilitation program. 15 Although a reduction in fatigue was found, it is unclear whether this can be ascribed to the cognitive behavioral components of the intervention. This study aimed at investigating the efficacy of ET and CBT in patients with PPS. We hypothesized that both approaches would lead to a sustained reduction of fatigue and improvement of activities and HRQoL compared with usual care (UC). The primary research questions for this study in patients with PPS were: (1) Does ET lead to a sustained reduction of fatigue and an improvement in activities and HRQoL compared with UC? and (2) Does CBT lead to a sustained reduction of fatigue and an improvement in activities and HRQoL compared with UC? 159

5 Chapter 6 Exercise therapy and cognitive behavioural therapy in PPS: results of an RCT METHODS We performed a stratified multi-center, single-blinded randomized controlled trial (RCT) with equal allocation across treatment arms and follow-up over six months. Patients were randomized to one of three treatment arms: ET, CBT, or UC. Randomization was stratified by center. The randomization scheme was computer-generated and random blocks of sequences were created with variable block sizes of three and six. An independent investigator performed the randomization. The investigator responsible for the inclusion and the two experimenters who performed the outcome assessments were blinded to the group allocation. Standard protocol approvals, registrations, and patient consents Our study protocol 16 was approved by the Medical Ethics Committee of the Academic Medical Centre in Amsterdam and all participating centers granted approval to participate. The RCT was registered at the Netherlands National Trial Register (NTR1371). Informed consent was obtained from all participants. Participants Patients were recruited from seven hospitals and rehabilitation centers in the Netherlands. Medical files were screened for potentially eligible patients. Patients willing to give signed consent were evaluated by a physician to check the inclusion and exclusion criteria. Inclusion criteria were: diagnosis of PPS according to the criteria of the March of Dimes which includes a gradual or sudden onset of progressive and persistent muscle weakness or abnormal muscle fatigability after a period of stable neurologic function; 17 severe perceived fatigue (subscale subjective experience of fatigue of the Checklist Individual Strength (CIS-F) 35); 18 age between 18 and 75 years; life-expectancy longer than one year i.e. absence of life threatening comorbidity; walking-ability at least indoors with or without a walking aid; and ability to cycle on a ergometer against a load of at least 25 Watts. Each patient included in the trial completed a Physical Activity Readiness Questionnaire 19 and was approved safe for exercise by the screening physician. Exclusion criteria are described elsewhere. 16 Interventions UC: In all allocation groups, patients received UC at the discretion of their treating physician, which could include the use of assistive devices and/or orthoses, physical therapy, and medication. Patients were not restricted in their activities. Co-interventions were monitored throughout the study. ET: ET was designed specifically to enhance patient s physical capacity. The intervention lasted four months and consisted of (1) a home-based aerobic training program three times 160

6 weekly and (2) a supervised group-training program once a week. Physiotherapists who were trained in the protocol supervised the therapy. (1) The home-based interval training program included aerobic exercise on a cycle ergometer. Patients were supplied with a cycle ergometer and logbook with training instructions at their home. During training, the heart rate was continuously monitored. Training intensity was gradually increased from 60% to 70% heart rate reserve (HRR) 20 and the training duration was gradually increased from 28 to 38 minutes per session. The feasibility of the training schemes was checked weekly by one of the therapists by reading the heart rate monitors and checking the logbooks. (2) The supervised group-training program consisted of individually tailored muscle strengthening and functional exercises in 1-hour group sessions. Only muscle groups with a MRC-score 21 3 were selected for the strengthening exercises. Functional exercises aimed to improve the interplay of cognitive, perceptual, and motor functions. 22 Compliance with ET was assessed by recording the number of home-based training sessions and group-training attendance, as monitored by the physiotherapists. All adverse events (such as severe muscle fatigue, joint pain, or other events considered to be related to ET) were recorded. Adverse events were followed until they abated or until a stable situation had been reached. CBT: CBT was directed at perpetuating factors of fatigue in slowly progressive neuromuscular disorders. 11 These involve dysfunctional cognitions with respect to the disease itself, pain, or fatigue; 7 dysfunctional attention to pain and fatigue symptoms; deregulation of sleep; 7,23 deregulation of physical, social, and/or mental activities; 7,23 and low social support and negative social interactions. 24 For each factor a standardized module was available as part of the intervention. To determine which modules were appropriate, each perpetuating factor was assessed with specific questionnaires, as to customize the CBT to the individual patient. 16 The number of CBT sessions was dependent on the number of modules used and the time necessary to reach the goals of the conducted module. Sessions lasted one hour and were planned within a four-month period. Certified cognitive behavioral therapists, who were highly trained in the protocol, treated the patients. Attendance of CBT was monitored by recording the number of treatment sessions as given by the therapists. A more detailed description of both interventions is available elsewhere. 16 Outcomes Outcomes were assessed at study entry (pre-treatment), at 4 months (post-treatment), at 3 months follow-up (short-term), and at 6 months follow-up (long-term). The primary endpoint was fatigue, assessed with the eight-item subscale CIS-F. 18 Secondary endpoints included self-perceived activity limitations (Sickness Impact Profile [SIP-68]; domains mobility control, 161

7 Chapter 6 Exercise therapy and cognitive behavioural therapy in PPS: results of an RCT social behavior, mobility range 25 ) and HRQoL (Short-Form 36 [SF-36]; Physical Component Summary [PCS], Mental Component Summary [MCS] 26 ). Exploratory endpoints included pain (Visual Analogue Scale, VAS), total mood disturbance (Profile of Mood States, POMS), sleep disturbances (Nottingham Health Profile, NHP-sleep), illness cognitions (Illness Cognitions Questionnaire, ICQ), coping (Coping Inventory for Stressful Situations, CISS-21), and general self-efficacy (Dutch version of the Self-Efficacy Scale, AL- COS-16). In addition, we assessed cardio-respiratory fitness (submaximal heart rate during exercise [HRsubmax]), muscle strength (maximal isokinetic voluntary torque of quadriceps muscles [MVT]), functional capacity (timed-up-and-go test [TUG] and 2-minute walk test [2MWT]), and actual daily physical activity level (monitored on seven consecutive days [StepWatch Activity Monitor; Orthocare Innovations, Oklahoma City, OK]). Descriptions and references of all outcomes are available elsewhere. 16 Statistical Analyses The sample size for this RCT was based on the comparison treatment (ET or CBT) versus UC and four repeated measurements, using an estimated correlation coefficient of the repeated measurements of 0.79 (based on unpublished data from a reproducibility study in 37 PPS patients); a clinical relevant decline of eight points on the CIS-F (for both treatments); 27 and an estimated SD in each treatment group of 9.3. The total sample size needed to detect an 8-point difference in CIS-F at a 5% level of significance (two-tailed) with a power of 90% was 24 subjects in each group. 28 We expected a maximum dropout rate of 10%, based on a previous trial in this patient group. 29 Therefore, a total sample size of 81 patients was planned. To check for selective lost-to-follow-up, differences between participants who completed the trial and those who were lost-to-follow-up were examined (two-tailed independent t-tests, Mann-Whitney U-tests, χ2-tests). We assessed the primary, secondary, and exploratory endpoints with linear mixed models, with group and pre-treatment score of the outcome as covariates (primary analyses). The models incorporated random intercepts for participants. To allow estimates at the individual time points, we added time and time-by-group interaction to the model (secondary analyses). Analyses were performed blinded for group allocation and based on the intention-to-treat (ITT) sample. No imputation of missing data was performed, under the assumption that data were missing at random. Additionally, per protocol analyses were performed including only patients that attended more than 47 of 63 possible treatment sessions for ET (75%) or completed the CBT intervention according to the protocol. All analyses were done with SPSS Statistics 21. An alpha level of 0.05 was used for all tests of significance. 162

8 RESULTS Participant flow and recruitment The phases of the trial are depicted in Figure 1. In total, 490 patients were invited to participate. Of these 490 patients, 129 did not respond, 200 declined to participate, and 93 were excluded. The major reasons for exclusion were; not being severely fatigued and having co-morbidities. From June 2009 to September 2012, 68 patients were enrolled. One patient allocated to ET withdrew consent after the pre-treatment assessment; hence, the ITT-sample consisted of 67 patients (22 in UC, 22 in ET, and 23 in CBT). Sociodemographic and polio characteristics of these 67 patients are shown in Table 1. Fifty-one patients were included in the per-protocol analyses (22 in UC, 14 in ET, and 15 in CBT). There were no significant differences between participants who were not lost-to-follow-up (n=60) and those who were (n=7) on pre-treatment CIS-F-scores, treatment allocation, or any of the pre-treatment sociodemographic or polio characteristics (p>0.08). Figure 1: Flow diagram 163

9 Chapter 6 Exercise therapy and cognitive behavioural therapy in PPS: results of an RCT Table 1. Sociodemographic and polio characteristics for the intention-to-treat population. Sociodemographic characteristics UC (n=22) ET (n=22) CBT (n=23) Female, n (%) 11 50% 13 59% 13 57% Mean age (SD), y Caucasian ethnicity, n (%) 18 82% 19 87% 22 96% Married or partner, n (%) 18 82% 17 77% 17 74% College or university degree, n (%) 11 50% 7 32% 10 44% > 20 h/week paid work, n (%) 6 27% 9 41% 4 17% Polio characteristics Median age of acute polio (range), y Body sites with residual paresis, (n), % upper extremity, unilateral 0 0% 1 5% 5 22% upper extremity, bilateral 1 5% 2 9% 2 9% lower extremity, unilateral 17 77% 12 55% 17 74% lower extremity, bilateral 5 23% 7 32% 4 17% trunk, neck, face and/or throat 1 5% 4 18% 3 13% Mean time since new symptoms (SD), y Mean time since new general fatigue (SD), y New or increased muscle weakness, % 18 82% 20 87% n (%) New or increased muscle atrophy, 3 14% 0 0% 6 26% n (%) New or increased muscle pain, n (%) 7 32% 10 46% 13 57% New or increased muscle fatigue, 14 64% 15 68% 16 70% n (%) MMT sum score legs, median (range) a MMT sum score arms, median (range) b Present walking distance, n (%) c around the house 9 41% 6 27% 8 35% seldom further than 1 km 8 36% 11 50% 12 52% regularly further than 1 km 5 23% 5 23% 3 13% a Sum score for muscle strength of the legs was calculated by adding the scores of 16 muscle 164

10 groups. Each muscle group had a score between 0 and 5, sum score ranged from 0 to b Sum score for muscle strength of the arms was calculated by adding the scores of 10 muscle groups. Each muscle group had a score between 0 and 5, sum score ranged from 0 to c Walking distance was classified into three categories: around the house; seldom further than 1 km; regularly further than 1 km. Abbreviations: UC = usual care; ET = exercise therapy; CBT = cognitive behavioral therapy; MMT = manual muscle testing. Implementation of interventions Median number of overall treatment sessions for the ITT-sample was 57 (range 8-63) for ET and 7 (range: 0-12) for CBT. Co-interventions The number of patients who were prescribed new co-interventions during the whole study period was 10 (50%) for the UC-group, 6 (38%) for the ET-group, and 10 (48%) for the CBT-group. The newly prescribed co-interventions are summarized in Table 2. Table 2. Newly prescribed co-interventions during the ten-month study period. UC (n=20) ET (n= 16) CBT (n = 21) Medication aimed at reducing PPS related symptoms 5 (25%) 5 (31%) 2 (10%) Physical therapy with exercise 0 (0%) 0 (0%) 1 (5%) Physical therapy without exercise 3 (15%) 0 (0%) 4 (19%) Psychological counseling 1 (5%) 0 (0%) 0 (0%) Assistive devices 5 (25%) 2 (13%) 4 (19%) Orthoses 1 (5%) 1 (6%) 1 (5%) Therapeutic footwear 1 (5%) 0 (0%) 0 (0%) One or more of the above mentioned co-interventions 10 (50%) 6 (38%) 10 (48%) Values are the number of patients (percentages). Outcomes The results of the linear mixed modeling for the primary and secondary endpoints are shown in Table 3. Primary analyses showed no differences in fatigue (CIS-F), self-perceived activity limitations (SIP-68), and HRQoL (SF-36) for ET or CBT compared with UC. Secondary analyses also showed no differences in primary and secondary endpoints between the interventions and UC 165

11 Chapter 6 Exercise therapy and cognitive behavioural therapy in PPS: results of an RCT Table 3. Effects of exercise therapy and cognitive behavioral therapy compared to usual care for primary and secondary endpoints. T1 T2 T3 T4 Mean SD n Mean SD n Mean SD n Mean SD n Beta (95% CI) CIS20-F (8 56) UC ET (-2.84 to 5.79) CBT (-2.24 to 5.98) SIP-68 Mobility control (0 12) UC ET (-1.47 to 0.37) CBT (-1.18 to 0.58) SIP-68 Social behavior (0 12) UC ET (-0.92 to 1.08) CBT (-0.84 to 1.08) SIP-68 Mobility range (0 10) UC ET (-0.59 to 0.77) CBT (-0.34 to 0.95) SF-36 Physical component score (0 100) UC ET (-0.86 to 4.70) CBT (-0.46 to 4.80) SF-36 Mental component score (0 100) UC

12 T1 T2 T3 T4 Mean SD n Mean SD n Mean SD n Mean SD n Beta (95% CI) ET (-6.90 to 1.10) CBT (-5.51 to 2.13) Abbreviations; CIS-F= subscale subjective experience of fatigue of the Checklist Individual Strength (higher scores indicating more fatigue); SIP-68= Sickness Impact Profile 68 (higher scores indicating more health-related behavioral problems); SF-36= Short-Form 36 (higher scores indicating higher Health Related Quality of Life); T1= pre-treatment; T2 = post-treatment; T3= short-term follow-up; T4 = long-term follow-up. 167

13 Chapter 6 Exercise therapy and cognitive behavioural therapy in PPS: results of an RCT on the individual time points, except for a significantly higher long-term CIS-F score for ET compared with UC (5.37, 95% CI: 0.19 to 10.56). The efficacies of the interventions compared with UC on the exploratory endpoints are summarized in the supplementary Table 1. For ET, analyses showed no differences in cardio-respiratory fitness and muscle strength when compared to UC (overall mean difference in HRsubmax 2.72 bpm, 95% CI to 7.85 and MVT strongest leg 5.31 Nm, 95% CI to respectively). Also for CBT no differences were found for any of the exploratory endpoints compared with UC,, except for a lower score on the domain Emotional Coping of the CISS-21 at long-term follow-up for CBT compared with UC (-2.77, 95% CI: to -0.38). Per-protocol analyses showed similar results as ITT-analyses (mean differences in CIS-F score: 2.29, 95%CI to 6.94 for ET versus UC; and 1.03, 95%CI to 5.71 for CBT versus UC). Adverse events Three adverse events were reported in the ET group (joint pain at the knee and elbow, and trochanteric bursitis). This led to discontinuation of the intervention in one patient. All three adverse events were resolved. DISCUSSION This RCT did not demonstrate a beneficial effect of exercise therapy (ET) or cognitive behavioral therapy (CBT) on fatigue, activities, or health-related quality of life (HRQoL) compared with usual care (UC) in patients with post-polio syndrome (PPS). These results are consistent with the absence of positive effects on any of the exploratory endpoints investigated in this study. Although the required sample size was not reached, we are confident that this is not the reason for the negative study, considering the magnitude of the estimated effects of ET and CBT. Had the pattern of change noted in the included patients continued, the extra precision in estimates from another 14 patients would not have generated a statistically significant result for either intervention. Moreover, when a larger sample size would have led to significant differences, these differences would not be considered clinically relevant, as the lower limits of the 95%CIs are, for both interventions, well below the clinical relevant decline of 8 points on the CIS-F. 27 Furthermore, the estimated effects are well below the effects found in an identical trial (with a sample size of 77 patients) investigating these interventions in patients with facioscapulohumeral dystrophy (mean differences in CIS-F score: -9.1, 95%CI to -5.8 for ET versus UC; and -13.3, 95%CI to for CBT versus UC). 30 Additional newly prescribed co-interventions varied between the groups, however it seems unlikely this could explain the absence of positive effects of the interventions. Slightly more new 168

14 co-interventions were prescribed in the UC-group during the study period compared with the intervention-groups, but these were almost never specifically targeted at alleviating fatigue. Moreover, we did not find a reduction in fatigue-scores within the UC-group. While, in this study a number of patients had insufficient exposure to the interventions for reasons related and unrelated to the treatments, the per-protocol analyses and ITT-analyses gave similar estimated effects for both interventions, instead of effects leading more in the direction of favoring ET or CBT. Therefore it is unlikely that underexposure did influence the results of this study. Regarding ET, only three adverse events were reported and these were all resolved, indicating that this intervention was safe. The absence of effects on fatigue, activities, and HRQoL in the ET group compared with UC is in line with three previous studies in PPS that reported no effects of ET on fatigue and activities, and also they are consistent with the absence of any physiological changes in cardio-respiratory fitness and muscle strength. To our knowledge only one study 14 showed positive effects of a hospital-based aerobic training program on cardio-respiratory fitness (VO2peak), fatigue and HRQoL. One possible explanation for the dissimilarity in results may be related to the fact that severe fatigue was not a prerequisite for inclusion in that study. It may be hypothesized that increasing cardio-respiratory fitness and muscle strength in severely fatigued PPS-patients is not possible because they already have adapted muscle function optimally as a result of performing daily life activities with their reduced muscle mass. This hypothesis is supported by findings of a recent study showing that in a sample of fatigued PPS-patients there was no deconditioning of the knee extensor muscles as compared to healthy individuals. 34 The lack of efficacy of CBT in our study is in contrast with the positive results found in studies evaluating its effectiveness in other patient populations, such as post-cancer fatigue, chronic fatigue syndrome, multiple sclerosis, and facioscapulohumeral dystrophy. 27,30,35,36 People affected with PPS have spent a lifetime managing the challenges of living with functional limitations and have experienced long durations of fatigue. This may have led to a relatively high degree of acceptance of fatigue symptoms. This assumption is supported by the fact that, although all patients included in the study did indeed experience severe fatigue, a number of patients did not prioritize fatigue as a treatment goal and therefore the CBT intervention was not initiated (n = 5). Furthermore it may be hypothesized that patients with PPS have developed different patterns of dysfunctional cognitions and behavior related to fatigue compared to patient populations with a symptom onset later on in their lives. These differences might, at least in part, explain the lack of efficacy of CBT in PPS. Strengths and limitations This is the first study evaluating the effect of CBT on reducing fatigue in PPS and the effect of 169

15 Chapter 6 Exercise therapy and cognitive behavioural therapy in PPS: results of an RCT ET in a randomized controlled design with patients receiving UC as the control group. A principal strength of this study is that we used standardized treatment protocols of which a detailed description is available. 16 Furthermore, we evaluated patients over a long-term period and utilized a broad arsenal of outcome measures from different domains of the International Classification of Functioning, Disability, and Health (ICF), including patient-reported outcomes. Generalizability of our study results to the PPS-population at large may be considered a limitation, since only a small proportion of the total number of patients assessed for eligibility in this study (almost 500) was included. Nevertheless, patients were recruited from different centers throughout the Netherlands and the sociodemographic and disease characteristics in our sample are comparable to that in previous cohort-studies in polio survivors in the Netherlands 37 and other countries. 7,38 Conclusion Our results demonstrate that neither ET nor CBT were superior to UC in reducing fatigue or improving activities and HRQoL in severely fatigued PPS patients. Considering the negative results of these two substantially different interventions, which have been proven effective in other patient populations 27,30,35,36,39,40 and the wide range of other interventions that were unsuccessful, 8 it seems that fatigue in severely fatigued PPS patients is quite resistant to therapy. Further research should investigate explanations for the lack of efficacy of these two currently advised approaches in clinical practice, 41 which may provide clues to improve treatment aimed at reducing fatigue in PPS. 170

16 REFERENCES 1. Tersteeg IM, Koopman FS, Stolwijk-Swuste JM, Beelen A, Nollet F. A 5-year longitudinal study of fatigue in patients with late-onset sequelae of poliomyelitis. Arch Phys Med Rehabil 2011;92: Schanke AK, Stanghelle JK. Fatigue in polio survivors. Spinal Cord. 2001;39: Nollet F, Beelen A, Prins MH, et al. Disability and functional assessment in former polio patients with and without postpolio syndrome. Arch Phys Med Rehabil 1999;80: On AY, Oncu J, Atamaz F, Durmaz B. Impact of post-polio-related fatigue on quality of life. J Rehabil Med 2006;38: Jensen MP, Alschuler KN, Smith AE, Verrall AM, Goetz MC, Molton IR. Pain and fatigue in persons with postpolio syndrome: independent effects on functioning. Arch Phys Med Rehabil 2011;92: Berlly MH, Strauser WW, Hall KM. Fatigue in postpolio syndrome. Arch Phys Med Rehabil 1991;72: Trojan DA, Arnold DL, Shapiro S, et al. Fatigue in Post-poliomyelitis Syndrome: Association With Disease-Related, Behavioral, and Psychosocial Factors. Phys Med Rehabil 2009;1: Koopman FS, Uegaki K, Gilhus NE, Beelen A, de Visser M, Nollet F. Treatment for postpolio syndrome. Cochrane Database Syst Rev 2011;2:CD Brehm MA, Nollet F, Harlaar J. Energy demands of walking in persons with postpoliomyelitis syndrome: relationship with muscle strength and reproducibility. Arch Phys Med Rehabil 2006;87: Nollet F, Beelen A, Sargeant AJ, de Visser M, Lankhorst GJ, de Jong BA. Submaximal exercise capacity and maximal power output in polio subjects. Arch Phys Med Rehabil 2001;82: Kalkman JS, Schillings ML, Zwarts MJ, van Engelen BG, Bleijenberg G. The development of a model of fatigue in neuromuscular disorders: a longitudinal study. J Psychosom Res 2007;62: van Kessel K, Moss-Morris R. Understanding multiple sclerosis fatigue: a synthesis of biological and psychological factors. J Psychosom Res 2006;61(5): Cup EH, Pieterse AJ, ten Broek-Pastoor JM, et al. Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review. Arch Phys Med Rehabil 2007;88: Oncu J, Durmaz B, Karapolat H. Short-term effects of aerobic exercise on functional capacity, fatigue, and quality of life in patients with post-polio syndrome. Clin Rehabil 2009;23: Davidson AC, Auyeung V, Luff R, Holland M, Hodgkiss A, Weinman J. Prolonged benefit in post-polio syndrome from comprehensive rehabilitation: a pilot study. Disabil Rehabil 2009;31: Koopman FS, Beelen A, Gerrits KH, et al. Exercise therapy and cognitive behavioural therapy to improve fatigue, daily activity performance and quality of life in postpoliomyelitis syndrome: 171

17 Chapter 6 Exercise therapy and cognitive behavioural therapy in PPS: results of an RCT the protocol of the FACTS-2-PPS trial. BMC Neurol 2010;10: March of Dimes. International Conference on post-polio syndrome. Identifying Best Practices in Diagnosis & Care. New York: White Plains, Dittner AJ, Wessely SC, Brown RG. The assessment of fatigue: a practical guide for clinicians and researchers. J Psychosom Res 2004;56: Shephard RJ. PAR-Q, Canadian Home Fitness Test and exercise screening alternatives. Sports Med. 1988;5: Birk TJ. Polio and Post-Polio Syndrome. In: Durstine JL, Moore GE (ed) Exercise Management for Persons with Chronic Diseases and Disabilities. Champaign: Human Kinetics, 2003: Medical Research Council. Aids to the examination of the peripheral nervous system. London: Her Majesty s Stationary Office, Mulder T. A process-oriented model of human motor behavior: toward a theory-based rehabilitation approach. Phys Ther 1991;71: Ostlund G, Wahlin A, Sunnerhagen KS, Borg K. Vitality among Swedish patients with post-polio: a physiological phenomenon. J Rehabil Med 2008;40: Schanke AK. Psychological distress, social support and coping behaviour among polio survivors: A 5-year perspective on 63 polio patients. Disabil Rehabil 1997;19: de Bruin AF, Diederiks JP, de Witte LP, Stevens FC, Philipsen H. The development of a short generic version of the Sickness Impact Profile. J Clin Epidemiol 1994;47: Aaronson NK, Muller M, Cohen PD, et al. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol 1998;51: Gielissen MF, Verhagen S, Witjes F, Bleijenberg G. Effects of cognitive behavior therapy in severely fatigued disease-free cancer patients compared with patients waiting for cognitive behavior therapy: a randomized controlled trial. J Clin Oncol 2006;24: Twisk, JWR. Applied longitudinal data analysis for epidemiology: a practical guide. Cambridge: University Press, Horemans HL, Nollet F, Beelen A et al. Pyridostigmine in postpolio syndrome: no decline in fatigue and limited functional improvement. J Neurol Neurosurg Psych 2003;74: Voet N, Bleijenberg G, Hendriks J, et al. Both aerobic exercise and cognitive-behavioral therapy reduce chronic fatigue in FSHD: An RCT. Neurology 2014;83: Willen C, Sunnerhagen KS, Grimby G. Dynamic water exercise in individuals with late poliomyelitis. Arch Phys Med Rehabil 2001; 82: Ernstoff B, Wetterqvist H, Kvist H, Grimby G. Endurance training effect on individuals with postpoliomyelitis. Arch Phys Med Rehabil 1996; 77: Murray DHF, Campion A, Vance R, Meldrum D, Orla H. The effects of a home-based arm ergometry exercise programme on physical fitness, fatigue and activity in polio survivors; a randomised controlled trial [abstract]. J Rehabil Med 2014;46: Voorn EL, Beelen A, Gerrits KH, Nollet F, de Haan A. Fatigue resistance of the knee extensor 172

18 muscles is not reduced in post-polio syndrome. Neuromuscular Disord 2013;23: van Kessel K, Moss-Morris R, Willoughby E, Chalder T, Johnson MH, Robinson E. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom Med. 2008;70: Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev 2008;3:CD Stolwijk-Swuste JM, Beelen A, Lankhorst G, et al. Impact of age and co-morbidity on the functioning of patients with sequelae of poliomyelitis: a cross-sectional study. J Rehabil Med 2007; 39: Winberg C, Flansbjer UB, Carlsson G, Rimmer J, Lexell J. Physical activity in persons with late effects of polio: a descriptive study. Disabil Health J 2014;7: Pilutti LA, Greenlee TA, Motl RW, Nickrent MS, Petruzzello SJ. Effects of exercise training on fatigue in multiple sclerosis: a meta-analysis. Psychosom Med 2013;75: Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 2012;11:CD Gonzalez H, Olsson T, Borg K. Management of postpolio syndrome. Lancet Neurol.2010;9:

19 Chapter 6 Exercise therapy and cognitive behavioural therapy in PPS: results of an RCT Supplementary table 1. Effects of exercise therapy and cognitive behavioral therapy compared to usual care for exploratory endpoints. T1 T2 T3 T4 Mean SD n Mean SD n Mean SD n Mean SD n Beta (95% CI) Pain (VAS (0 10 cm)) UC ET (-1.00 to 1.58) CBT (-1.24 to 1.04) Total Mood Disturbance (POMS ( )) UC ET (-7.10 to 8.39) CBT (-9.38 to 5.38) Sleep disturbances (NHP-sleep (0 100)) UC ET ( to 10.36) CBT (-9.38 to 9.99) Cardiorespiratory fitness (HR submax (bpm)) UC ET (-2.41 to 7.85) CBT (-7.20 to 2.72) Muscle strength (MVT strongest leg (Nm)) UC ET (-6.13 to 16.74) CBT ( to 9.15) 174

20 T1 T2 T3 T4 Mean SD n Mean SD n Mean SD n Mean SD n Beta (95% CI) Muscle strength (MVT weakest leg (Nm)) UC ET (-7.23 to 19.56) CBT ( to 14.07) Actual daily physical activity level (daily step count) UC ET (-988 to 1201) CBT (-1235 to 928) Functional capacity (TUG (sec)) UC ET (-1.37 to 0.15) CBT (-0.92 to 0.55) Functional capacity (2-MWT (m)) UC ET (-3.61 to 10.88) CBT (-7.36 to 6.97) Illness cognitions (ICQ Helplessness (6 24)) UC ET (-1.34 to 0.97) CBT (-1.24 to 0.98) 175

21 Chapter 6 Exercise therapy and cognitive behavioural therapy in PPS: results of an RCT T1 T2 T3 T4 Mean SD n Mean SD n Mean SD n Mean SD n Beta (95% CI) Illness cognitions (ICQ Acceptance (6 24)) UC ET (-1.31 to 1.17) CBT (-1.02 to 1.37) Illness cognitions (ICQ Perceived benefits (6 24)) UC ET (-1.28 to 1.61) CBT (-2.10 to 0.71) Coping (CISS-21 Task oriented coping (7 35)) UC ET (-2.30 to 2.22) CBT (-3.21 to 1.10) Coping (CISS-21 Avoidance coping (7 35)) UC ET (-1.00 to 3.74) CBT (-3.47 to 1.04) Coping (CISS-21 Emotional coping (7 35)) UC ET (-2.45 to 1.79) CBT (-3.93 to 0.15) General self-efficacy (ALCOS-16) (16 80)) UC

22 T1 T2 T3 T4 Mean SD n Mean SD n Mean SD n Mean SD n Beta (95% CI) ET (-4.98 to 2.71) CBT (-2.55 to 4.66) Abbreviations; VAS= Visual Analogue Scale (higher scores indicating more pain); POMS= Shortened Profile of Mood States (higher scores indicating more mood disturbances); NHP-sleep= Nottingham Health Profile, domain: sleep (higher scores indicating more sleep problems); MVT = maximal voluntary torque (MVT) of the quadriceps muscles; TUG= Timed-Up-and-Go test; 2-MWT= 2-minute walk test; ICQ= Illness Cognitions Questionnaire (higher scores indicating higher levels of the concerning illness cognition); CISS-21= Coping Inventory for Stressful Situations (higher scores indicating that the particular coping style is used more often); ALCOS-16= General Self Efficacy Scale (higher scores indicating higher self-efficacy; T1= pre-treatment; T2 = post-treatment; T3= short-term follow-up; T4 = long-term follow-up. 177