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Aerobic exercise capacity in post-polio syndrome

Voorn, E.L.

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Eric Voorn


Eric Voorn


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Eric Voorn

AEROBIC EXERCISE CAPACITY

IN POST-POLIOSYNDROME

Op vrijdag 16 januari 2015 om 10:00 uur

In de Agnietenkapel van de Universiteit van

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Oudezijds Voorburgwal 2311012 EZ Amsterdam

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AEROBIC EXERCISE CAPACITY INPOST-POLIO SYNDROME

Eric Voorn

Voorn, E.Aerobic exercise capacity in post-polio syndrome.

Academisch proefschrift, Universiteit van Amsterdam.

ISBN/EAN 978-94-6108-867-3

Cover design by: Eric Voorn.Photography cover by: Felix Schmidt.Printed by: Gildeprint - The Netherlands.

© 2014, Eric Voorn, The Netherlands.No parts of this thesis may be reproduced or transmitted in any form or by any means, electronically or mechanically, including photocopying, recording or any information storage and retrieval system, without prior permission from the author.

AEROBIC EXERCISE CAPACITY INPOST-POLIO SYNDROME

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. D.C. van den Boom

ten overstaan van een door het college voor promoties

ingestelde commissie,

in het openbaar te verdedigen in de Agnietenkapel

op vrijdag 16 januari 2015, te 10:00 uur

door

Eric Lukas Voorngeboren te Elburg

Promotiecommissie:

Promotores: Prof. dr. F. Nollet

Prof. dr. A. de Haan

Co-promotores: Dr. J.A.J.M. Beelen

Dr. K.H.L. Gerrits

Overige leden: Prof. dr. R.H.H. Engelbert

Prof. dr. A.C.H. Geurts

Prof. dr. T.W.J. Janssen

Prof. dr. W. van Mechelen

Prof. dr. J.H. Ravesloot

Prof. dr. M. de Visser

Faculteit der Geneeskunde

The studies presented in this thesis were financially supported by:The Netherlands Organisation for Health Research and Development (ZonMw)The Prinses Beatrix SpierFonds (PBF)The RevalidatiefondsRevalidatie NederlandNetherlands Society of Physical and Rehabilitation MedicineDepartment of Rehabilitation, Academic Medical Center Amsterdam

Printing of this thesis was financially supported by:Academic Medical Center Amsterdam | www.amc.nlLode B.V. | www.lode.nlProCare B.V. | www.procarebv.nlNoppe Orthopedietechniek | www.noppeorthopedie.nlMotekforce Link | www.motekforcelink.comLivit Orthopedie | www.livit.nl

CONTENTS

Chapter 1 General introduction 9

Chapter 2 Reliability of contractile properties of the knee extensor 19 muscles in individuals with post-polio syndrome

Chapter 3 Fatigue resistance of the knee extensor muscles is not 35 reduced in post-polio syndrome

Chapter 4 Determining the anaerobic threshold in post-polio 49 syndrome: comparison with current guidelines for training intensity prescription

Chapter 5 RCT on exercise therapy and cognitive behavioral 63 therapy to reduce fatigue in post-polio syndrome

Chapter 6 Aerobic exercise training in post-polio syndrome: process 81 evaluation of the FACTS-2-PPS trial

Chapter 7 General discussion 99

Summary / Nederlandse samenvatting 113

Dankwoord 121

List of publications 127

Curriculum vitae / Portfolio 131

Chapter 1

GENERAL INTRODUCTION

1

1

10

Chapter 1

At its peak in the 1940s and 1950s, polio paralyzed or killed over half a million people worldwide every year. Due to the introduction of routine vaccination in the late 1950s, and in 1988, the Global Polio Eradication Initiative spearheaded by the World Health Organi-zation (WHO), Rotary International, UNICEF and the Center for Disease Control (CDC), the number of polio cases per year declined dramatically, from over 350,000 new cases in 1988 to 406 in 2013.

Polio has become a rare and almost forgotten disease in the Western world. The virus is however still endemic in some developing countries (Pakistan, Afghanistan and Nigeria).1 Virus spread from these countries remains a significant risk for polio reintroduction and periodically causes outbreaks in other countries, including Syria most recently.2

Despite the low number of new polio cases, there are still many individuals suffering from the late effects of polio. The WHO estimates the number of polio survivors worldwide at 20 million.1 In the Netherlands the last large epidemic, with 2,206 cases notified to the health authorities, dates from 1956. Since then, some sporadic cases and small outbreaks have occurred in 1978 (110 cases) and 1992/1993 (71 cases), mainly in communities that re-fuse vaccination on religious grounds.3 Most polio survivors of the epidemics in the Nether-lands are now in their late fifties or aged above. However, due to immigration, our country is today home to younger polio survivors as well.

ACUTE POLIO AND THE RECOVERYPoliomyelitis is a highly contagious viral disease that spreads by faeco-oral route with

humans as the only host. In most cases, the infection passes by unnoticed without symp-toms. Due to an immune response the infected person develops immunity for the polio virus. In 4–8% of all infections, polio results in mild, flue-like symptoms, such as fever, sore throat, nausea or diarrhoea. However in approximately 0.1 to 2% of the infected persons, the virus invades the central nervous system leading to destruction of the motor neurons in the anterior horns of the spinal cord. This results in an acute, usually asymmetrically dis-tributed, flaccid paresis of a varying number of muscle groups.4

The acute paralytic phase, which may last for several weeks, is followed by a recovery period. Restoration of motor function mainly occurs within the first 3 months, but may continue for several years. There are several mechanisms that contribute to this recovery. Some motor neurons survive and regain their function, usually within 1 month.5 Dener-vated muscle fibers from permanently lost motor neurons are reinnervated by means of collateral sprouting from intact axons leading to the formation of giant motor units that can increase up to 10 times in size.6,7 Furthermore, strength increases as a result of muscle fiber hypertrophy, in response to exercise and performing activities of daily life.

Full restoration of function may be achieved with apparently normal strength, but with a reduced number of enlarged motor units.8 In many cases, however, the recovery is in-complete, leaving patients with greatly varying clinical presentations, from local residual paresis in one extremity to severe residual paresis of all four extremities, trunk and bul-bar muscles. Usually, this is accompanied by bony deformities and limb length deficiencies which develop during growth. From then on, muscle function and functioning remain sta-ble for many years.

11

Introduction

1

THE POST-POLIO SYNDROMEFor a long time it was believed that the residual neurological deficits resulting from

polio would remain stable throughout life. However in the late 1970s and early 1980s polio survivors were found to develop new symptoms related to the polio they had contract-ed many years before.9 The combination of these late symptoms are referred to as the post-polio syndrome (PPS) and include new or increased muscle weakness, abnormal mus-cle fatigability, generalized fatigue, muscle atrophy, muscle and joint pain, muscle cramps and cold intolerance.10 The prevalence of PPS has been reported from 15% to 80% of all individuals with previous paralytic polio depending on the criteria applied and population studied.11 Nearly 60% of a sample of Dutch survivors of the 1956 outbreak experienced late onset polio sequelae about forty years after the acute stage of polio.12

FATIGUE AND FUNCTIONAL DECLINE IN POST-POLIO SYNDROMEIndividuals with PPS report fatigue and a decline in their functional abilities, especially

walking outdoors, standing, and climbing stairs, as their major problems.13 An important factor that contributes to the symptoms of fatigue and increased difficulties in performing (sustained) activities is a reduced muscle strength, primarily caused by a reduced muscle mass.14,15 Another factor that is assumed to contribute is the severely diminished aerobic capacity found in these patients. Aerobic capacity is defined as the (maximum) amount of oxygen the body can use during a specified period. It is a function both of cardiorespiratory performance and the maximum ability to extract and utilize oxygen from circulating blood in the muscles.

Previous studies have shown that individuals with PPS have a lower aerobic capacity than healthy persons, mainly due to the reduced muscle mass.16-18 The gradual loss of mus-cle strength in PPS leads to a decline in functional abilities and may induce a relatively sedentary lifestyle. This decrease in physical activity leads to deconditioning, which causes even more difficulties in performing sustained activities. Consequently, two factors may contribute to the diminished aerobic capacity in PPS: (1) alteration of muscle function due to the disease process itself, and (2) deconditioning due to a sedentary lifestyle.

MUSCLE ADAPTATIONS AND FATIGUE IN POST-POLIO SYNDROMEIn addition to the reduced muscle mass, alterations of the intrinsic properties of the re-

maining muscle fibers and peripheral circulation may lead to early muscle fatigue, thereby limiting the aerobic capacity in these patients.

Several muscular alterations have been described in polio survivors. Muscle biopsy studies of polio subjects have found mean muscle fiber cross-sectional area to be about twice as large in PPS compared to healthy subjects, probably due to excessive use of re-maining fibers.19 Secondary to hypertrophy, a reduced capillary supply in relation to fiber area was observed, that might impair diffusion capacity, leading to shortage of substrate during work. This is accompanied by a low aerobic enzyme activity of the muscle fibers.20 A low capillary density in combination with decreased aerobic enzyme capacity would lim-

12

Chapter 1

it muscle endurance. Furthermore, a muscle fiber transformation from type II fibers to type I fibers was reported in polio survivors, most likely also resulting from overuse of the reduced muscle mass.20 Given that type I fibers better resist fatigue than type II fibers, this would, contrary to the other adaptations, favor muscle endurance, unless type I fiber characteristics in PPS differ from those in healthy subjects. Therefore, it remains uncer-tain whether the combination of these opposite adaptations leads to early muscle fatigue, thereby limiting the aerobic capacity in individuals with PPS.21 Although there have been a few studies investigating fatigability of muscles in PPS, results were contradictory, empha-sizing the need for further research in this area.

Muscle fatigue depends on several factors that may reside in the brain or spinal cord (here defined as central fatigue), and/or in the muscles themselves (here defined as periph-eral fatigue) and can be quantified using different techniques and devices.22 Previous stud-ies indicate that the contribution of central fatigue in PPS is only limited.15,23 In combination with the adaptations that have been described above, it seems therefore likely that mainly peripheral mechanisms, such as the muscle’s aerobic capacity, fiber type composition and capillary supply, are involved in muscle fatigue.15,23 Investigation of contractile properties can therefore help to understand the origin of fatigue.24,25 These can be investigated by electrically evoked muscle contractions; an experimental condition that completely re-moves central mechanisms. In this thesis we used this technique to study whether dif-ferences in contractile properties between individuals with PPS and healthy subjects may account for the increased muscle fatigue perceived by many individuals with PPS, thereby contributing to the diminished aerobic capacity.

AEROBIC EXERCISE TRAINING IN POST-POLIO SYNDROMESecondary to the muscular adaptations due to the disease process itself, a diminished

aerobic capacity may as well arise from deconditioning due to the low physical activity lev-els of many individuals with PPS.26,27 Although there is strong scientific evidence confirming the health benefits of regular physical activity, there is a lack of high quality evidence of similar benefits for people with PPS and other neuromuscular diseases.28-30 It is therefore important that interventions aimed at maximizing health among polio survivors are devel-oped, to improve physical functioning and perceived health and reduce lifestyle related risk factors.

Although the evidence base is limited, physical therapy recommendations for individu-als with PPS include aerobic exercise.31 The studies that have been conducted so far show inconsistent results with respect to the efficacy of aerobic exercise in PPS, which may, at least in part, be explained by the limited methodological quality of most studies.28,29 Fur-ther research is therefore required to draw definite conclusions on the effectiveness of this intervention. Another important factor explaining the inconsistent results may relate to the problems therapists experience when designing training schedules for individuals with PPS; exercise levels should be sufficiently intense to stimulate a training effect, yet avoid muscular overload.32

13

Introduction

1

INDIVIDUALIZING AEROBIC TRAINING INTENSITY IN POST-POLIO SYNDROME

Guidelines for aerobic exercise training in healthy subjects recommend training inten-sities relative to the individual’s maximal capacity. In PPS, however, a true maximum ox-ygen consumption or maximal heart rate is often not reached because the leg muscles frequently fatigue before the cardiorespiratory system reaches its maximum. Therefore, in this patient group, maximal heart rate is often estimated based on age. Another method to prescribe training intensity uses ratings of perceived exertion (RPEs), and is preferred in individuals using beta-blocking agents.33 Our experience is that, when applying these guidelines, physical therapists often have to adjust the training intensity. This is probably due to the fact that none of these guidelines makes use of measures of someone’s aerobic capacity, resulting in exercise prescription to be insufficiently tailored to the individual.

The anaerobic threshold (AT), a direct indicator of aerobic capacity, may be useful to overcome this problem. The AT is widely used for setting target intensity for aerobic train-ing in healthy subjects,34 as well as individuals with chronic diseases such as multiple scle-rosis,35 coronary heart disease,36 hypertension,37 and obesity.38 Usually, the AT is assessed through graded maximal exercise testing. In PPS and other neuromuscular diseases, max-imal exercise testing is not feasible in all individuals because performance is often symp-tom-limited. Furthermore, maximal exercise may provoke muscle complaints and excessive fatigue, with a prolonged recovery, and should thus be avoided. Therefore, the AT should preferably be obtained from submaximal exercise testing. Whether this is possible in indi-viduals with PPS is still uncertain and was investigated in this thesis. Furthermore, realizing that the expensive gas analysis equipment that is necessary for determining the AT, is often not available in physical therapy practices, we also compared commonly used markers for training intensity prescription with the AT.

THE FITNESS AND COGNITIVE BEHAVIORAL THERAPIES FOR FATIGUE AND ACTIVITIES IN POST-POLIO SYNDROME TRIAL–FACTS-2-PPS

Based on the knowledge that current evidence regarding exercise therapy in PPS is re-stricted to studies of limited methodological quality, we designed the FACTS-2-PPS trial.39 The FACTS-2-PPS trial (Dutch trial register NTR1371) is a multicenter randomized controlled trial (RCT), in which the effectiveness of exercise therapy and cognitive behavioral therapy on fatigue, daily activities and health-related quality of life in patients with PPS was studied. In this study, the Academic Medical Center in Amsterdam collaborated with other universi-ty hospitals and rehabilitation centers throughout the country. The exercise therapy had a duration of 4 months and was designed specifically to enhance aerobic capacity. The cogni-tive behavioral therapy, also lasting 4 months, is outside the scope of this thesis.

The primary purpose of the FACTS-2-PPS trial was to investigate the effect of both in-terventions on reducing fatigue and improving activities and quality of life. Next to this, we investigated in more detail the working mechanisms underlying the exercise intervention. It is known from literature that there is a large variability in the way individuals respond to exercise training. This may be the result of several factors such as the initial training status,

14

Chapter 1

exercise capacity and psychological factors.40 An important factor for the effectiveness of exercise in PPS may be the training dose (i.e. intensity and duration) and most of the previ-ous studies on aerobic exercise in PPS report the designated training dose for their program quite well.41-46 Precise quantification of the actually realized training dose, its relationship with the subsequent training response and the working mechanisms of improvement are however unknown. This information will provide better insight in the potential role of aer-obic exercise and will help to provide more effective training methods to alleviate fatigue symptoms in PPS.

AIMS OF THIS THESISThis thesis aims to improve our understanding of the diminished aerobic capacity of in-

dividuals with PPS. The first objective of this thesis was to investigate whether, besides the reduced muscle mass, altered intrinsic properties of the muscle fibers and peripheral circu-lation result in early muscle fatigue, thereby contributing to the limited aerobic capacity in these individuals. The second objective was to obtain more knowledge about aerobic ex-ercise in PPS: in particular on determining the appropriate individual training intensity and evaluating the effectiveness of an aerobic exercise intervention in the FACTS-2-PPS trial.

OUTLINE OF THIS THESISChapter 2 describes a study in which we established test-retest reliability of some

fundamental contractile properties derived from electrically evoked contractions of the knee extensor muscles. Accordingly, in chapter 3, these measures were used to investi-gate whether differences in contractile properties between individuals with PPS and age-matched healthy subjects may account for the increased muscle fatigue perceived by many individuals with PPS, thereby contributing to the diminished aerobic capacity.

In chapter 4 we determined whether the AT could be identified through submaximal exercise testing in PPS. In addition, we compared commonly used markers for training in-tensity based on estimated heart rate reserve (HRR) and RPEs according to current guide-lines, with the AT.

Chapter 5 describes the results of the FACTS-2-PPS trial we performed to study the efficacy of exercise therapy and cognitive behavioral therapy for reducing fatigue and im-proving activities and quality of life in individuals with PPS. Additionally, in chapter 6, we investigated whether the exercise program as conducted in the FACTS-2-PPS trial had fa-vorable effects on cardiorespiratory fitness and muscle function. We also quantified the actually achieved training dose and its relationship with the subsequent training response.

The general discussion, in chapter 7 reflects on the main findings and discusses the clinical implications. Finally, some methodological considerations of the study and recom-mendations for future research together with an overall conclusion are described.

15

Introduction

1

REFERENCES

1. World Health Organization (WHO). Poliomyelitis fact sheet. Available at: http://www.who.int/mediacentre/factsheets/fs114/en/. Accessed September 25, 2014.

2. Razum O, Muller O. Polio eradication: where are we now? Lancet 2013;382:1979.

3. Oostvogel PM, Van der Avoort HGAM, Mulders MN et al. Poliomyelitis outbreak in an unvacci-nated community in the Netherlands, 1992-93. The Lancet 1994;344:665-670.

4. Morens DM, Pallansch MA, Moore M. Polioviruses and other enteroviruses. Text Book of Hu-man Virology, Mosbey Year Books 1991;427-497.

5. Bodian D. Poliomyelitis; neuropathologic observations in relation to motor symptoms. J Am Med Assoc 1947;134:1148-1154.

6. Einarsson G, Grimby G, Stalberg E. Electromyographic and morphological functional compensa-tion in late poliomyelitis. Muscle Nerve 1990;13:165-171.

7. Stalberg E, Grimby G. Dynamic electromyography and muscle biopsy changes in a 4-year fol-low-up: study of patients with a history of polio. Muscle Nerve 1995;18:699-707.

8. Halstead LS, Rossi CD. Post-polio syndrome: clinical experience with 132 consecutive outpa-tients. Birth Defects Orig Artic Ser 1987;23:13-26.

9. Halstead LS, Rossi CD. New problems in old polio patients: results of a survey of 539 polio sur-vivors. Orthopedics 1985;8:845-850.

10. March of Dimes. International conference on post-polio syndrome. Identifying Best Practices in Diagnosis & Care. White Plains, NY, USA; 2000.

11. Farbu E, Gilhus NE, Barnes MP et al. EFNS guideline on diagnosis and management of post-polio syndrome. Report of an EFNS task force. Eur J Neurol 2006;13:795-801.

12. Ivanyi B, Nollet F, Redekop WK et al. Late onset polio sequelae: disabilities and handicaps in a population-based cohort of the 1956 poliomyelitis outbreak in The Netherlands. Arch Phys Med Rehabil 1999;80:687-690.

13. 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;80:136-143.

14. Beelen A, Nollet F, de Visser M, de Jong BA, Lankhorst GJ, Sargeant AJ. Quadriceps muscle strength and voluntary activation after polio. Muscle Nerve 2003;28:218-226.

15. Grimby G, Stalberg E, Sandberg A, Sunnerhagen KS. An 8-year longitudinal study of muscle strength, muscle fiber size, and dynamic electromyogram in individuals with late polio. Muscle Nerve 1998;21:1428-1437.

16. Stanghelle JK, Festvag L, Aksnes AK. Pulmonary function and symptom-limited exercise stress testing in subjects with late sequelae of poliomyelitis. Scand J Rehabil Med 1993;25:125-129.

17. Willen C, Cider A, Sunnerhagen KS. Physical performance in individuals with late effects of po-lio. Scand J Rehabil Med 1999;31:244-249.

18. Nollet F, Beelen A, Sargeant AJ, de Visser M, Lankhorst GJ, de Jong BA. Submaximal exercise ca-pacity and maximal power output in polio subjects. Arch Phys Med Rehabil 2001;82:1678-1685.

19. Grimby G, Einarsson G, Hedberg M, Aniansson A. Muscle adaptive changes in post-polio sub-jects. Scand J Rehabil Med 1989;21:19-26.

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Chapter 1

20. Borg K, Henriksson J. Prior poliomyelitis-reduced capillary supply and metabolic enzyme content in hypertrophic slow-twitch (type I) muscle fibres. J Neurol Neurosurg Psychiatry 1991;54:236-240.

21. Thomas CK, Zijdewind I. Fatigue of muscles weakened by death of motoneurons. Muscle Nerve 2006;33:21-41.

22. Allen DG, Lamb GD, Westerblad H. Skeletal muscle fatigue: cellular mechanisms. Physiol Rev 2008;88:287-332.

23. Allen GM, Middleton J, Katrak PH, Lord SR, Gandevia SC. Prediction of voluntary activation, strength and endurance of elbow flexors in postpolio patients. Muscle Nerve 2004;30:172-181.

24. Burke RE, Levine DN, Tsairis P, Zajac FE. Physiological types and histochemical profiles in motor units of the cat gastrocnemius. J Physiol 1973;234:723-748.

25. Harridge SD, Bottinelli R, Canepari M et al. Whole-muscle and single-fibre contractile proper-ties and myosin heavy chain isoforms in humans. Pflugers Arch 1996;432:913-920.

26. Klein MG, Braitman LE, Costello R, Keenan MA, Esquenazi A. Actual and perceived activity levels in polio survivors and older controls: a longitudinal study. Arch Phys Med Rehabil 2008;89:297-303.

27. Rekand T, Korv J, Farbu E et al. Lifestyle and late effects after poliomyelitis. A risk factor study of two populations. Acta Neurol Scand 2004;109:120-125.

28. 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;88:1452-1464.

29. Koopman FS, Uegaki K, Gilhus NE, Beelen A, de Visser M, Nollet F. Treatment for postpolio syn-drome. Cochrane Database Syst Rev 2011;CD007818.

30. Rimmer JH, Chen MD, McCubbin JA, Drum C, Peterson J. Exercise intervention research on persons with disabilities: what we know and where we need to go. Am J Phys Med Rehabil 2010;89:249-263.

31. Farbu E, Gilhus NE, Barnes MP et al. Post-polio syndrome. European Handbook of Neurological Management 2010;2:311-319.

32. Nierse CJ, Abma TA, Horemans AM, van Engelen BG. Research priorities of patients with neuro-muscular disease. Disabil Rehabil 2013;35:405-412.

33. Birk TJ, Nieshoff EC. Polio In: Lemura LM, von Duvillard SP, editors. Clinical Exercise Physiology: Application and Physiological Principles. Philedelphia: Lippincott Williams & Wilkins, 2004;p. 269-284.

34. Londeree BR. Effect of training on lactate/ventilatory thresholds: a meta-analysis. Med Sci Sports Exerc 1997;29:837-843.

35. Mostert S, Kesselring J. Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis. Mult Scler 2002;8:161-168.

36. Sullivan M, Ahnve S, Froelicher VF, Meyers J. The influence of exercise training on the ventilato-ry threshold of patients with coronary heart disease. Am Heart J 1985;109:458-463.

37. Kiyonaga A, Arakawa K, Tanaka H, Shindo M. Blood pressure and hormonal responses to aero-bic exercise. Hypertension 1985;7:125-131.

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38. Tan S, Yang C, Wang J. Physical training of 9- to 10-year-old children with obesity to lactate threshold intensity. Pediatr Exerc Sci 2010;22:477-485.

39. 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: the protocol of the FACTS-2-PPS trial. BMC Neurol 2010;10:8.

40. Borresen J, Lambert MI. The quantification of training load, the training response and the effect on performance. Sports Medicine 2009;39:779-795.

41. Dean E, Ross J. Effect of modified aerobic training on movement energetics in polio survivors. Orthopedics 1991;14:1243-1246.

42. Ernstoff B, Wetterqvist H, Kvist H, Grimby G. Endurance training effect on individuals with post-poliomyelitis. Arch Phys Med Rehabil 1996;77:843-848.

43. Jones DR, Speier J, Canine K, Owen R, Stull GA. Cardiorespiratory responses to aerobic training by patients with postpoliomyelitis sequelae. JAMA 1989;261:3255-3258.

44. Kriz JL, Jones DR, Speier JL, Canine JK, Owen RR, Serfass RC. Cardiorespiratory responses to upper extremity aerobic training by postpolio subjects. Arch Phys Med Rehabil 1992;73:49-54.

45. 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;23:155-163.

46. Willen C, Sunnerhagen KS, Grimby G. Dynamic water exercise in individuals with late poliomy-elitis. Arch Phys Med Rehabil 2001;82:66-72.

Chapter 2

RELIABILITY OF CONTRACTILE PROPERTIES OF THE KNEE EXTENSOR MUSCLES IN INDIVIDUALS WITH POST-POLIO SYNDROME

PloS one 2014; 9: e101660

Eric L. VoornMerel A. Brehm

Anita BeelenArnold de Haan

Frans NolletKarin H.L. Gerrits

2

2

20

Chapter 2

ABSTRACTObjective: To assess the reliability of contractile properties of the knee extensor muscles in 23 individuals with post-polio syndrome (PPS) and 18 age-matched healthy individuals.Methods: Contractile properties of the knee extensors were assessed from repeated elec-trically evoked contractions on 2 separate days, with the use of a fixed dynamometer. Re-liability was determined for fatigue resistance, rate of torque development (MRTD), and early and late relaxation time (RT50 and RT25), using the intraclass correlation coefficient (ICC) and standard error of measurement (SEM, expressed as % of the mean).Results: In both groups, reliability for fatigue resistance was good, with high ICCs (>0.90) and small SEM values (PPS: 7.1%, healthy individuals: 7.0%). Reliability for contractile speed indices varied, with the best values found for RT50 (ICCs>0.82, SEM values <2.8%). We found no systematic differences between test and retest occasions, except for RT50 in healthy subjects (p=0.016).Conclusions: In PPS and healthy individuals, the reliability of fatigue resistance, as obtained from electrically evoked contractions is high. The reliability of contractile speed is only moderate, except for RT50 in PPS, demonstrating high reliability.Significance: This was the first study to examine the reliability of electrically evoked con-tractile properties in individuals with PPS. Our results demonstrate its potential to study mechanisms underlying muscle fatigue in PPS and to evaluate changes in contractile prop-erties over time in response to interventions or from natural course.

21

Reliability of contractile properties in PPS

2INTRODUCTION

Post-polio syndrome (PPS) is a complex of late onset neuromuscular symptoms with new or increased muscle weakness and muscle fatigability as key symptoms.1 PPS often affects the lower limbs, and many individuals experience increased difficulty with walking, standing, climbing stairs and other activities of sustained endurance.2-4 Therefore, inter-ventions aimed at reducing lower limb muscle fatigue are important components in the management of PPS.5-7

Muscle fatigue depends on several factors that may reside in the brain or spinal cord (central fatigue), and/or in the muscles themselves (peripheral fatigue).8 Since previous studies suggest that the contribution of central fatigue in PPS is only limited, the focus is on peripheral fatigue.6,9 Peripheral fatigue is largely determined by the muscle’s aerobic capacity and fiber type composition, and investigation of contractile properties can help to understand the origin of fatigue.10,11 Two fundamental contractile properties are the resis-tance to fatigue and contractile speed. Both properties can be investigated by electrically evoked muscle contractions.

Despite recent findings indicating that resistance to fatigue and contractile speed in individuals with PPS do not seem to differ from age-matched healthy individuals, a marked variability was observed, expressed by the large SD, underscoring the heterogeneity in con-tractile properties between individuals.12 This implies that contractile functioning is im-paired in part of the individuals with PPS, and intervention programs aimed at reducing muscle fatigue in this subgroup might therefore be useful. Obviously, the application of measurements of contractile properties, for example to evaluate changes following an in-tervention, requires information about the reliability.

Surprisingly, despite the frequent use of electrically evoked muscle contractions to as-sess fatigue resistance and contractile speed in healthy subjects and individuals with im-paired neuromuscular function13 only limited information is available about the reliability of these measures. Based on studies containing small numbers of healthy subjects and individuals with spinal cord injury, reliability seems acceptable.14-18 However, variability may differ between study populations,19 requiring the reliability to be specifically established in individuals with PPS. Furthermore, most studies either addressed reliability with the intra-class correlation coefficient,16,18 or with parameters of measurement error.14 Yet, to cover reliability in full, information about both these aspects is required.20,21

The purpose of our study was to establish the reliability of fatigue resistance and con-tractile speed indices of the knee extensor muscles obtained from electrically evoked con-tractions in individuals with PPS and in healthy individuals. We hypothesized that the re-liability of fatigue resistance and contractile speed indices would be high in both groups.

METHODS

Subjects

Subjects were recruited from the Dutch expert center for polio survivors of the Ac-ademic Medical Center in Amsterdam and were all diagnosed with PPS according to the

22

Chapter 2

criteria as published by the March of Dimes.1 They all had a confirmed history of acute poliomyelitis affecting the lower limbs, new symptoms after a period of functional stabili-ty, and no other diseases that could explain their reduced muscle strength. Furthermore, subjects were capable of walking with or without walking aids, and had minimum knee extensor strength of at least 30 Newton meter (Nm) in one leg, which was assumed to represent minimal muscle strength for functional use. Thirteen subjects performed the measurements as part of an ongoing clinical trial,22 and the remaining subjects responded to an invitation after chart review for eligibility. In addition, healthy individuals (matched for age and gender) who never had polio or any other neurological disease served as con-trols. Control subjects were employees of the university or volunteers who had responded to a recruitment advertisement. The study was approved by the medical ethics committee of the Academic Medical Center (University of Amsterdam, The Netherlands) and written informed consent was obtained from all subjects before inclusion.

Instrumentation

Contractile properties of the knee extensor muscles were assessed from isometric contractions with the knee and hip angle set at 60° and 80° (0°=full extension), respec-tively, with the use of a specially designed fixed dynamometer. The subjects’ upper body and pelvis were restrained to the dynamometer chair with adjustable belts, to prevent the hip from extending during testing. The lower leg was tightly strapped to a lever arm, immediately proximal to the malleoli. The torque applied by the knee extensor muscles was displayed on a screen, digitized (1,000 HZ), and stored on disk for off-line analysis. In individuals with PPS, measurements were performed on the leg subjects felt was limiting performance during daily life activities the most. However, if knee extensor strength in this leg was <30 Nm, measurements were performed on the other leg. In healthy subjects, the leg that was measured was selected randomly.

Electrical stimulation of the knee extensor muscles was delivered through two self-ad-hesive surface electrodes (8×13 cm, Schwa-medico, Leusden, The Netherlands). The cath-ode was placed on the midline of the thigh, 15 cm distal to the anterior superior iliac spine, and the anode was positioned 8 cm proximal to the superior border of the patella. A cus-tom-made software program controlled the frequency and number of square-wave pulses (200 µs), which were delivered by a constant-current high voltage stimulator (model DS7H, Digitimer Ltd., Welwyn Garden City, UK).

Procedure

Subjects were tested on 2 different occasions, using exactly the same protocol, with a maximum of 3 weeks between the 2 occasions (median interval: 7 days). Test (T1) and retest (T2) measures were performed at the same time of the day, and the same trained researcher performed all measurements and analyses. After anthropometrics were taken, subjects were asked to perform 3 maximal voluntary isometric knee extensions. Subjects received visual feedback regarding the torque they produced, and were verbally encour-aged to exert maximal isometric torque for approximately 3 s, with 1 min of rest between contractions. The highest torque was taken as the maximal voluntary torque (MVT). Sub-

23


2sequently, electrical bursts (150 Hz, to ensure maximal activation) of 1 s duration were delivered to the muscle with increasing current, until ~30% of MVT was reached, sufficient to activate a representative part of the muscle mass.19 After a 5-min resting period, fatigue resistance was determined by a series of electrically evoked isometric tetanic contractions (50 Hz) of 1 s duration and 1 s of rest in between, for a period of 5 min (150 contractions). At this 50 Hz frequency, considerable torque is generated,12 and high frequency fatigue is prevented.8 The latter was confirmed by visual inspection of the raw data.

Data analysis

Off-line analysis of torque records was performed using a custom-written Matlab script (version R2007a, The Mathworks Inc., S. Natick, MA, USA). Each torque signal was filtered with a low-pass fourth order Butterworth filter with a 50 Hz cut-off frequency. Fatigue resistance was expressed as the torque at the end of the fatigue protocol divided by that at the start of the protocol: fatigue resistance [% torque remaining] = (average last 30 con-tractions/first contraction) × 100%).16,23

In addition to fatigue resistance and the maximal voluntary torque (MVT), we estab-lished 3 indices of contractile speed: i) the maximal rate of torque development, calculated as the highest value of the differentiated torque signal, expressed relative to the highest torque during that contraction (MRTD [s-1])24; ii) early half-relaxation time, defined as the time taken for torque to decline from the value at the end of stimulation to 50% of that value (RT50 [ms])8; and iii) late half-relaxation time, i.e. the time needed for torque to fall from 50% to 25% (RT25 [ms]).8 Contractile speed indices were determined from the first contraction of the fatigue protocol.

Statistical analysis

Descriptive data were expressed as mean and standard deviation (demographic data) or as median and range (polio characteristics). Differences between individuals with PPS and healthy subjects regarding demographic data were analyzed with the Student t test for normally distributed data; in case of nonnormally distributed data, the Mann-Whitney U test was used. Dichotomized variables were analyzed with the Fisher exact test.

Test-retest reliability25 was assessed with the intraclass correlation coefficient (ICC2,1) and the 95% confidence intervals (CI), by use of a random effects two-way analysis of vari-ance (ANOVA). A lower CI limit of the ICC ≥ .75 was considered to indicate excellent reliabil-ity.26 Systematic changes between test occasions together with the 95% CI were analyzed with paired t tests. A systematic change is a nonrandom change that occurs if the subject systematically performs better (or worse) on the second test occasion as a result of, for example, a change in behavior or a learning effect.

Measurement error25 was calculated according to the equations proposed by Euser et al.27 (see Appendix S1), which is based on ANOVA. Measurement error was expressed ei-ther in the actual units of the measurements (standard error of measurement (SEM) and absolute limits of agreement (ALoA)) or as a proportion of the measured values (coefficient of variation based on log transformed variables (CV) and ratio limits of agreement (RLoA)). The CV and RLoA were used in case of heteroscedasticity, implying that measurement er-

24

Chapter 2

ror was dependent of the parameter mean. Data was denoted heteroscedastic if the cor-relation coefficient (Kendall’s τ) between the absolute differences and the corresponding means was > 0.1.28 Bland-Altman graphs were plotted for visual interpretation of the data.

To determine the influence of measurement error on sample size estimation for an ef-fect study comparing 2 independent groups, we calculated the minimal number of subjects per group needed (n) to find a significant difference in change of fatigue resistance from n > 2(Zα + Zβ)

2 σ2/ δ2, with Z values based on tables of standard normal curves (Zα+Zβ=3.242 for a=.05 and b=.10), σ as the standard deviation of the difference, and δ as the minimal differ-ence in effect that is considered of clinical interest.29 Because it is unknown what changes are considered clinically relevant, we included 3 sample size estimations based on different change scores (i.e. 10%, 15% and 20%).

For all tests, the significance level was set at p<.05. Statistical analyses were performed with the SPSS statistical software package (version 20.0.0.1, IBM Company, Armonk, NY, USA).

RESULTSTwenty-nine individuals with PPS and 20 healthy subjects participated. Two healthy sub-

jects and 4 PPS subjects prematurely aborted the measurements due to discomfort of the electrical stimulation. Furthermore, in 2 individuals with PPS, targeted stimulated torque levels were not achieved despite high current levels. Therefore, analyses were performed on 23 individuals with PPS (9 men) and 18 healthy individuals (6 men). Characteristics of both groups are presented in Table 1. None of the demographic variables presented in Ta-ble 1 differed significantly between both groups (p>0.072).

Table 1. Subject characteristics.

PPS

(n=23)

Control

(n=18)

Demographic characteristics

Gender (male/female) 9/14 6/12

Age (yrs) 59.9±6.3 58.5±6.8

Weight (kg) 77.3±12.7 74.7±8.5

BMI (kg/m2) 26.4±2.8 24.7±2.9

Polio characteristics

Age at acute polio (yrs) 1.0 (0.9)

Time since new symptoms (yrs) 15 (3–33)

Present walking distance* 3 (2–4)

Measured leg (most/less affected) 13/10

Values for demographic data are mean ± SD; values for polio characteristics are median (range).Abbreviations: PPS, post-polio syndrome; BMI, body mass index.*Walking distance was defined as the daily distance walked and was classified in 4 categories: 1 (indoors only), 2 (around the house), 3 (seldom >1km), and 4 (regularly >1km).

25


2The mean difference in fatigue resistance between both tests was -0.28% and 2.06%

for individuals with PPS and healthy subjects, respectively, with no systematic differences observed (Table 2). The ICC values and corresponding 95% CIs were high and comparable in PPS (ICC = 0.90 [95% CI: 0.77–0.96]) and healthy subjects (0.91 [0.77–0.97]).

For contractile speed indices and MVT, differences between the means of outcomes on the two occasions can be found in Table 2. Only for RT50 in healthy subjects, a systematic difference between test scores was observed (2.67 ms, p=0.016).

Test-retest reliability varied between outcomes, both in PPS and in healthy individuals. For example, in individuals with PPS, ICCs ranged from 0.10 for RT25 [95% CI: -0.33–0.48] to 0.97 for MVT [0.92–0.99].

Table 2. Results on test and retest for individuals with PPS and healthy subjects.

n Test (T1) Retest (T2) Δ T2–T1 95% CIΔ ICC2,1 (95%CIICC)

Fatigue resistance

Fatigue resistance (% torque remaining)

PPS 19 48.0±10.3 47.7±11.6 -0.28±4.90 -2.64–2.08 0.90 (0.77–0.96)

Control 16 51.6±12.9 53.7±12.2 2.06±4.98 -0.60–4.71 0.91 (0.77–0.97)

MVT and contractile speed indices

MVT (Nm)

PPS 23 116.8±47.3 114.2±48.9 -2.54±12.51 -7.95–2.86 0.97 (0.92–0.99)

Control 18 177.7±33.8 176.1±32.7 -1.67±9.10 -6.20–2.85 0.96 (0.91–0.99)

MRTD (s-1)

PPS 23 15.4±7.9 15.0±6.4 -0.35±6.55 -3.18–2.48 0.59 (0.24–0.81)

Control 18 16.6±9.4 15.2±8.3 -1.39±6.11 -4.43–1.65 0.76 (0.48–0.90)

RT50 (ms)

PPS 23 125.0±8.3 125.2±8.4 0.22±3.92 -1.48–1.91 0.89 (0.77–0.95)

Control 18 122.6±8.2 125.2±7.6 2.67±4.23 0.56–4.77 0.82 (0.49–0.93)

RT25 (ms)

PPS 23 28.0±3.5 28.9±3.5 0.87±4.69 -1.16–2.90 0.10 (-0.33–0.48)

Control 18 31.9±6.1 30.6±5.1 -1.33±4.80 -3.72–1.06 0.63 (0.25–0.84)

The score on the two visits and the difference (Δ) are presented as mean ± SD. Missing data are due to the difficulty of some subjects to relax the leg during the stimulated protocol, resulting in unworkable signals, and leading to different numbers of observations for different parameters. Abbreviations: ICC, intraclass correlation coefficient; CI, confidence interval; PPS, post-polio syndrome; RT50, relaxation time 50%; MVT, maximal voluntary torque; Nm, Newton meter; MRTD, maximal rate of torque de-velopment; RT25, relaxation time 25%; ms, milliseconds.

26

Chapter 2

Table 3 and Figure 1 present the results on measurement error and the Bland-Altman graphs for all variables. In PPS, the SEM for fatigue resistance was 3.38% and the ALoA ranged from -9.9 to 9.3%, indicating a real difference at individual level of 9.6%. This rep-resents 20% of the mean fatigue resistance of T1 and T2 (i.e. 9.6%/47.9%). Similar results were found for healthy subjects. In both groups, measurement error for RT50 was much smaller compared to the values found for the other indices of contractile speed and for MVT (Table 3).

Table 3. Results for measurement error for individuals with PPS and healthy subjects.

τ-correlation

coefficient

SEM

(% of mean)

ALoA CV RLoA

Fatigue resistance

Fatigue resistance (% torque remaining)

PPS -0.065 (p=0.700) 3.38 (7.1%) -9.9–9.3 – –

Control -0.059 (p=0.752) 3.70 (7.0%) -7.7–11.8 – –

MVT and contractile speed indices

MVT (Nm)

PPS -0.138 (p=0.355) 8.83 (7.6%) -27.1–22.0 – –

Control -0.033 (p=0.850) 6.36 (3.6%) -19.5–16.2 – –

MRTD (s-1)

PPS 0.518* (p=0.001) – – 30.0% 0.42–2.28

Control 0.399* (p=0.021) – – 26.8% 0.44–1.96

RT50 (ms)

PPS 0.009 (p=0.957) 2.71 (2.2%) -7.5–7.9 – –

Control -0.042 (p=0.816) 3.46 (2.8%) -5.6–11.0 – –

RT25 (ms)

PPS 0.123 (p=0.437) – – 11.6% 0.75–1.42

Control 0.338 (p=0.063) – – 10.2% 0.73–1.27

Abbreviations: SEM, standard error of measurement; ALoA, absolute limits of agreement; CV, coefficient of variation; RLoA, ratio limits of agreement; PPS, post-polio syndrome; RT50, relaxation time 50%; MVT, maximal voluntary torque; Nm, Newton meter; MRTD, maximal rate of torque development; RT25, relaxation time 25%; ms, milliseconds.*Significant correlation (p<.05, two tailed) using Kendall’s τ-correlation coefficient.

27


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28

Chapter 2

Table 4 shows the results of the sample size estimations based on different change scores. For example, assuming that a 10% change in fatigue resistance between two groups of individuals with PPS is clinical relevant, the total number of subjects for an intervention study would be 44 (i.e. 2 groups of 22 subjects).

Table 4. Sample size estimation for an effect study to detect improvement in fatigue resistance between 2 independent groups of individuals with PPS.

Minimal number of subjects per group needed (n)

Assumed clinically relevant change

10% 22

15% 10

20% 6

We calculated the minimal number of subjects per group (n) needed to find a significant change of fatigue resistance from n > 2(Zα + Zβ)2 σ2/ δ2, with Z values based on tables of standard normal curves (Zα+Zβ=3.242 for a=.05 and b=.10), σ as the standard deviation of the difference (4.90%), and δ as the minimal difference in effect that is considered of clinical interest. Because it is unknown what change is considered clinically relevant we estimated sample size based on different change scores (i.e. 10%, 15% and 20%).

DISCUSSIONTo our knowledge, this is the first study that assessed both test-retest reliability and

measurement error of contractile properties obtained from electrically evoked contrac-tions in a patient population. Our results indicate that both in individuals with PPS and in healthy individuals, the reliability of fatigue resistance is high and sensitive to detect changes at group level. The reliability of contractile speed indices is only moderate, except for RT50 in PPS, demonstrating high reliability. Considering these results, the assessment of fatigue resistance and RT50 seems suitable for clinical use, for example to evaluate changes in contractile properties following interventions aimed at reducing muscle fatigue in PPS.

In the present study we found high ICC values for fatigue resistance and RT50, both in individuals with PPS and healthy persons, indicating adequate test-retest reliability. Our results with respect to fatigue resistance are similar to those reported in previous studies in healthy subjects (with ICCs ranging from 0.78 to 0.92).15-18 Results regarding contractile speed indices cannot be directly compared, because this was the first study that assessed the test-retest reliability of these measures, based on the ICC. We found that test-retest re-liability of RT50 is better than the test-retest reliability of the two other indices of contrac-tile speed, both in individuals with PPS and in healthy persons. Considering these results, it may be hypothesized that late half-relaxation time (RT25) and rate of torque development (MRTD) are influenced more by additional voluntary muscle activity that possibly occurred during the stimulated contractions than early half-relaxation time (RT50).30 However, there is no evidence to support this hypothesis. Taken together, the high ICCs as found in the present and in previous studies indicate that the test-retest reliability of fatigue resistance and RT50 to discriminate between persons with different levels of muscle fatigue is ade-quate.

Adequate reliability in terms of a high ICC does not directly imply that the outcome

29


2measure is suitable for clinical use. In addition, measurement error should be small enough to detect clinically relevant changes. In the present study, measurement error for fatigue resistance (SEM<3.70%, representing 7.0% of the mean) and RT50 (SEM<3.46 ms, 2.8% of the mean) were low. These values are in agreement with those established in other pa-tient groups (e.g. spinal cord injury),14 and, moreover, they indicate that measurements can be made reliably for a group of individuals with PPS. Unfortunately, it is not known what changes in contractile properties of the knee extensor muscles in individuals with PPS are considered clinically relevant, and future research is therefore required. Nevertheless to in-terpret the measurement error values found in our study, we related our data to previously established training effects for contractile properties. We found two studies reporting on changes in volitional fatigue resistance of the knee extensors following exercise training in PPS, ranging from 10 to 21%.5,31 Combined with the sample size estimations, based on the current reliability data, this indicates that feasible sample sizes are required to detect im-provement in fatigue resistance between two independent groups of individuals with PPS.

While our results suggest that electrically evoked contractions can be used to detect changes in fatigue resistance and RT50 at group level, we consider this method insuffi-ciently sensitive to detect changes in single individuals. For example, based on the limits of agreement, it appeared that the relative change in fatigue resistance should exceed 20% to indicate a real change at individual level. Only when larger therapeutic benefits are expect-ed, this outcome measure is useful for this purpose.

Limitations

Our study is limited by the relatively small sample size, restricting generalizability of our results to the population of individuals with PPS and healthy individuals in general. Another limitation is that we performed measurements solely on the knee extensor muscles and not on other muscle groups. Although from the literature it is known that the effects of polio are widespread and not necessarily restricted to one muscle group,32 we have chosen to investigate this muscle group. This because muscle weakness in PPS often affects the lower limbs, and also measurements can be easily performed on this muscle group that is of major importance during locomotion-related activities.33 Nonetheless, even though we believe it is legitimate that we performed measurements only on the knee extensor mus-cles, it must be realized that results cannot simply be generalized to other muscle groups.

Conclusion

Both in individuals with PPS and in healthy individuals, the reliability of fatigue resis-tance, as obtained from electrically evoked contractions of the knee extensor muscles is high. The reliability of contractile speed indices is only moderate, except for RT50 in PPS, demonstrating high reliability. Considering these results, the assessment of contractile properties in PPS is sufficiently reliable to identify those patients with impaired contrac-tile functioning of their knee extensor muscles, and, accordingly, to evaluate changes over time or following interventions in this patient group. Based on its potential in PPS, future research may also focus on the feasibility of this method in other slowly progressive neuro-muscular diseases where muscle fatigue is a major problem.

30

Chapter 2

Appendix S1

Reliability measures regarding measurement error.

Measurement error was assessed based on a two-way analysis of variance (ANOVA). The three components of variance that were estimated with this analysis included the in-ter-subject variance (vars), the variance related to the repeated sessions (occasion variance, varo), and the error variance (vare). These latter two were used to calculate the standard error of measurement (SEM) and coefficient of variation (CV).

SEM ( )eo varvar +

Where ( )eo varvar + is the spread of original measurements from different occasions.

CV 100% × ln(10) ( )eo varvar +

Where ( )eo varvar + is the spread of the log-transformed measurements from different occasions. The ln(10) is used, because we considered the 10-log transformation.

ALoA Mean difference ± 1.96 × SD difference

Where SD difference is the standard deviation of the differences between the original measurements.

RLoA Antilog (Mean difference log ± 1.96 × SD difference log)

Where mean difference log and SD difference log are the mean and standard deviation of the differences between the log-transformed measurements.

Abbreviations: SEM, standard error of measurement; varo, occasion variance; vare, error variance; CV, coefficient of variation; ALoA, absolute limits of agreement; SD, standard deviation; RLoA, ratio limits of agreement.

31


2REFERENCES


2. Ivanyi B, Nelemans PJ, de Jong R, de Ongerboer V, de Visser M. Muscle strength in postpolio patients: a prospective follow-up study. Muscle Nerve 1996;19:738-742.

3. Halstead LS. Assessment and differential diagnosis for post-polio syndrome. Orthopedics 1991;14:1209-1217.


5. Agre JC, Rodriquez AA, Franke TM. Strength, endurance, and work capacity after muscle strengthening exercise in postpolio subjects. Arch Phys Med Rehabil 1997;78:681-686.


7. Hildegunn L, Jones K, Grenstad T, Dreyer V, Farbu E, Rekand T. Perceived disability, fatigue, pain and measured isometric muscle strength in patients with post-polio symptoms. Physiother Res Int 2007;12:39-49.





12. Voorn EL, Beelen A, Gerrits KH, Nollet F, de Haan A. Fatigue resistance of the knee extensor muscles is not reduced in post-polio syndrome. Neuromuscul Disord 2013;23:892-898.

13. Millet GY, Martin V, Martin A, Verges S. Electrical stimulation for testing neuromuscular func-tion: from sport to pathology. Eur J Appl Physiol 2011;111:2489-2500.

14. Gerrits HL, Hopman MT, Sargeant AJ, de Haan A. Reproducibility of contractile properties of the human paralysed and non-paralysed quadriceps muscle. Clin Physiol 2001;21:105-113.

15. Maffiuletti NA, Jubeau M, Munzinger U et al. Differences in quadriceps muscle strength and fatigue between lean and obese subjects. Eur J Appl Physiol 2007;101:51-59.

16. McDonnell MK, Delitto A, Sinacore DR, Rose SJ. Electrically elicited fatigue test of the quadri-ceps femoris muscle. Description and reliability. Phys Ther 1987;67:941-945.

17. Morris MG, Dawes H, Howells K, Scott OM, Cramp M. Relationships between muscle fatigue characteristics and markers of endurance performance. Journal of Sports Science and Medicine 2008;7:431-436.

18. Snyder-Mackler L, Binder-Macleod SA, Williams PR. Fatigability of human quadriceps femoris muscle following anterior cruciate ligament reconstruction. Med Sci Sports Exerc 1993;25:783-789.

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19. Gerrits HL, de Haan A, Hopman MT, van der Woude LH, Jones DA, Sargeant AJ. Contractile properties of the quadriceps muscle in individuals with spinal cord injury. Muscle Nerve 1999;22:1249-1256.

20. Lexell JE, Downham DY. How to assess the reliability of measurements in rehabilitation. Am J Phys Med Rehabil 2005;84:719-723.

21. Mokkink LB, Terwee CB, Patrick DL et al. The COSMIN checklist for assessing the methodologi-cal quality of studies on measurement properties of health status measurement instruments: an international Delphi study. Qual Life Res 2010;19:539-549.


23. Burnley M. Estimation of critical torque using intermittent isometric maximal voluntary con-tractions of the quadriceps in humans. J Appl Physiol 2009;106:975-983.

24. de Ruiter CJ, Kooistra RD, Paalman MI, de Haan A. Initial phase of maximal voluntary and elec-trically stimulated knee extension torque development at different knee angles. J Appl Physiol 2004;97:1693-1701.

25. de Vet HC, Terwee CB, Mokkink LB, Knol DL. Measurement in Medicine: A Practical Guide. 2011. Cambridge: Cambridge University Press.

26. Lee J, Koh D, Ong CN. Statistical evaluation of agreement between two methods for measuring a quantitative variable. Comput Biol Med 1989;19:61-70.

27. Euser AM, Dekker FW, le Cessie S. A practical approach to Bland-Altman plots and variation coefficients for log transformed variables. J Clin Epidemiol 2008;61:978-982.

28. Atkinson G, Nevill AM. Statistical methods for assessing measurement error (reliability) in vari-ables relevant to sports medicine. Sports Med 1998;26:217-238.

29. Friedman LM, Furberg CD, DeMets DL. Sample size. In: Fundamentals of clinical trials. St Louis, Mosby-Year Book 1996;p. 94-129.

30. Hunter S, White M, Thompson M. Techniques to evaluate elderly human muscle function: a physiological basis. J Gerontol A Biol Sci Med Sci 1998;53:B204-B216.


32. Luciano CA, Sivakumar K, Spector SA, Dalakas MC. Electrophysiologic and histologic studies in clinically unaffected muscles of patients with prior paralytic poliomyelitis. Muscle Nerve 1996;19:1413-1420.

33. Grimby G, Jonsson AL. Disability in poliomyelitis sequelae. Phys Ther 1994;74:415-424.

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2

Chapter 3

FATIGUE RESISTANCE OF THE KNEE EXTENSOR MUSCLES IS NOT REDUCED IN POST-POLIO SYNDROME

Neuromuscular Disorders 2013; 23: 892–898© Reprinted with permission from Elsevier

Eric L. VoornAnita Beelen

Karin H.L. GerritsFrans Nollet

Arnold de Haan

33

36

Chapter 3

ABSTRACTThe present study investigated whether intrinsic fatigability of the muscle fibers is re-

duced in patients with post-polio syndrome (PPS). This may contribute to the muscle fa-tigue complaints reported by patients with PPS. For this purpose, we assessed contractile properties and fatigue resistance of the knee extensor muscles using repeated isometric electrically evoked contractions in 38 patients with PPS and 19 age-matched healthy sub-jects. To determine whether any difference in fatigue resistance between both groups could be attributed to differences in aerobic capacity of the muscle fibers, 9 patients with PPS and 11 healthy subjects performed the same protocol under arterial occlusion. Results showed that fatigue resistance of patients with PPS was comparable to that in controls, both in the situation with intact circulation and with occluded blood flow. Together, our findings suggest that there are no differences in contractile properties and aerobic muscle capacity that may account for the increased muscle fatigue perceived in PPS.

37

Fatigue resistance in PPS

3

INTRODUCTIONPost-polio syndrome (PPS) is a complex of late onset neuromuscular symptoms with

new or increased muscle weakness and abnormal muscle fatigability as key symptoms.1,2 Knowledge about the origin of the muscle fatigue perceived by patients with PPS is pres-ently limited. The muscle fatigue may result from the motor unit reorganization and the altered pattern of activity and function of the remaining muscle fibers that occurred during recovery from the acute polio and the secondary decline.3

Several adaptations have been described that may change the fatigue resistance of the muscle fibers in PPS.4-6 Mean muscle fiber cross-sectional area was found to be about twice as large in patients with PPS compared to healthy subjects, probably due to excessive use of remaining fibers.6 Secondary to this hypertrophy, a reduced capillary supply in relation to fiber area was observed, that might impair diffusion capacity, leading to shortage of substrate during muscle work. This assumption is supported by the low aerobic enzyme activity of the muscle fibers.5 A low capillary density in combination with decreased aer-obic enzyme capacity would reduce fatigue resistance of the muscle fibers. Furthermore, a muscle fiber transformation from type II fibers to type I fibers was reported, most likely also resulting from overuse of the reduced muscle mass. Contrary to the other adaptations, this would enhance fatigue resistance.4-6 Therefore, it remains unclear whether the combi-nation of these opposite adaptations will enhance or reduce the fatigue resistance of the muscle fibers in patients with PPS compared to healthy subjects.3

The few studies on fatigability of muscles in PPS reported contradictory results. Some have shown that muscles of patients with PPS are more fatigable than muscles of healthy subjects, irrespective of strength,7-9 while other studies reported no differences.10-13 All these studies have in common that voluntary contractions were used to induce fatigue. Because fatigue is influenced by both central neural and peripheral muscle factors, the use of voluntary contractions complicates the search for the relative contribution of each of these factors. The use of electrically evoked contractions, an experimental situation that completely removes the volitional element, allows studying the intrinsic fatigability of the muscle fibers.14,15

Our primary objective was to investigate fatigue resistance of the knee extensor mus-cles in patients with PPS during electrically evoked muscle contractions in comparison with healthy subjects. The knee extensor muscles were chosen, because muscle weakness in PPS often affects the lower limbs, and measurements can accurately be performed on this muscle group that is of major importance during locomotion-related activities.16 The sec-ond objective was to determine whether differences in fatigability between both groups could be attributed to differences in blood flow or aerobic capacity of the muscle. There-fore, we compared fatigue with an intact circulation with fatigue under ischaemic condi-tions, during which the ability for aerobic energy regeneration was largely eliminated.17 If differences in fatigue resistance between PPS and healthy subjects during the protocol with an intact circulation are attributed to differences in aerobic muscle capacity or blood flow then no differences will be evident when the blood supply is occluded.

38

Chapter 3

MATERIALS AND METHODS

Subjects

A sample of 38 former polio patients who were diagnosed with PPS according to the criteria published by the March of Dimes participated in this study.1 The criteria for PPS are as following: (1) prior paralytic poliomyelitis with evidence of motor neuron loss, as confirmed by history of the acute paralytic illness, signs of residual weakness, and atrophy of muscles on neurological examination, and signs of denervation on electromyography (EMG), (2) a period of partial or complete functional recovery after acute paralytic polio-myelitis, followed by an interval (usually 15 years or more) of stable neurologic function, (3) gradual or sudden onset of progressive and persistent muscle weakness or abnormal muscle fatigability (decreased endurance), with or without generalized fatigue, muscle at-rophy, or muscle and joint pain, (4) symptoms persist for at least 1 year, and (5) exclusion of other neurologic, medical, and orthopedic problems as causes of symptoms. Patients were recruited from the Dutch expert center for polio survivors of the Academic Medical Center in Amsterdam. Twenty-eight of these patients performed the measurements as part of an ongoing clinical trial of the efficacy of exercise therapy and cognitive behavioral therapy to improve fatigue, daily activity performance, and quality of life in PPS.18 The remaining 10 patients responded to an invitation after chart review for eligibility. All patients were capa-ble of walking with or without walking aids and had minimum knee extensor strength of 30 Nm in at least one leg, assumed as minimal muscle strength for functional use. In addition, healthy individuals, matched for age and gender, who never had polio or any other neuro-logical disease served as controls. The control subjects were recruited from employees of the university and others who had responded to a recruitment advertisement for the study. The study was approved by the medical ethics committee of the Academic Medical Center (University of Amsterdam, The Netherlands), and written informed consent was obtained from all participants.

Instrumentation

Isometric torque recordings were made of maximal voluntary and electrically evoked contractions of the knee extensor muscles. Subjects were seated in a specially designed dynamometer with a knee angle of 60° and a hip angle of 100°. The upper body and pelvis were restrained with adjustable belts to prevent the hip from extending when the knee ex-tensor muscles contracted. The lower leg was tightly strapped to a lever arm, immediately proximal to the malleoli. The torque applied by the knee extensor muscles was displayed on a screen, digitized (1,000 HZ), and stored on disk for off-line analysis.

Electrical stimulation of the knee extensor muscles was delivered through two self-ad-hesive surface electrodes (8×13 cm, Schwa-medico, Leusden, The Netherlands) placed over the proximal and distal part of the anterior thigh. A personal computer running cus-tom-made software controlled the frequency and number of square-wave pulses (200 µs) delivered by a constant-current high voltage stimulator (model DS7H, Digitimer Ltd., Wel-wyn Garden City, UK).

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3

Procedure

In patients with PPS measurements were performed on the leg which they felt was most limiting performance during activities in daily life. However, if maximum knee exten-sor strength in this leg was <30 Nm, measurements were performed on the other leg. In healthy subjects, the leg on which measurements were performed was selected randomly. Subjects performed 3 maximal voluntary isometric knee extensions. They received visual feedback of the torque and were verbally encouraged to exert maximal isometric torque for approximately 3 s, with 1 min of rest between contractions. The highest torque was taken as the maximal voluntary torque (MVT). Subsequently, electrical bursts (150 Hz, to ensure maximal activation) of 1 s duration were delivered to the muscle with increasing current until ~30% of MVT was reached, sufficient to activate a representative part of the muscle mass.19 After a 5-min resting period, the resistance to fatigue was determined by a series of electrically evoked isometric contractions (50 Hz) of 1 s duration and 1 s of rest in between for a period of 5 min (150 contractions). At this 50 Hz frequency, torque is approx-imately 80–85% of the torque attained at 150 Hz, and high frequency fatigue is prevented.20 Subjects were instructed to relax the muscles as much as possible during the protocol. Recovery of fatigue, which depends to a great extent on the aerobic capacity of the muscle fibers,21 was also monitored. This was done by applying similar 1 s contractions (50Hz) at different times (15, 30, 45, 90 and 180 s) after the end of the fatigue protocol.

On an additional occasion, a subgroup of subjects, who were willing to participate, per-formed the same fatigue test under arterial occlusion. Three seconds prior to the protocol, the blood flow was occluded by rapid (<3 s) inflation of a cuff (Hokanson SC 10D, Bellevue, WA) to a pressure of ~250 mmHg. The occlusion was applied to prevent the return of blood in the intervals between the stimulated contractions and hence to prevent aerobic energy regeneration.17 To ensure that the cuff did not unwrap, an extra strap was secured around the cuff before inflation. When torque did no longer decline the protocol was stopped and the cuff was deflated.

Data analysis

Off-line analysis of torque records was performed using Matlab (Matlab, the Mathwork Inc., S. Natik, MA, USA). Each torque signal was filtered with a low-pass fourth order But-terworth filter with a 50 Hz cut-off frequency. The 50/150 Hz ratio and half-relaxation time (RT50) were assessed in the pre-fatigue state as indices of contractile speed of the muscle. Those muscles with faster relaxation rates and lower 50/150 Hz ratios are assumed to con-tain a higher proportion of fast twitch fibers and consequently will be less fatigue resis-tant.14,15 RT50 was determined from the first contraction (50 Hz) of the fatigue protocol and was defined as the time taken for torque to decline from the value at the end of stimulation to 50% of that value.

In the present study we focused on two important properties that change during mus-cle fatigue: the decline in torque-generating capacity and the slowing of relaxation.20 Peak torque and RT50 during the fatigue protocol were expressed as a percentage of the values obtained in the first contraction of the protocol (= 100%) to correct for torque differences among subjects. The subsequent recovery of parameters was expressed as a percentage of

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Chapter 3

the difference between the first and the average of the last 15 contractions of the fatigue protocol.

Statistics

Statistical analysis was performed with the SPSS statistical software package (version 19.0.0.1). Descriptive data were expressed as mean and standard deviation (demographic data) or as median and range (polio characteristics). Differences with respect to demo-graphic data and pre-fatigue contractile characteristics (MVT, RT50 and 50/150 Hz ratio) between patients with PPS and healthy subjects were analyzed with the Student’s t test. Dichotomized variables were analyzed with Fisher’s exact test. A two-factor (“PPS” and “gender”) analysis of variance, with repeated measures (“time”) was used to test for signif-icant differences in the course of fatigue and recovery. Gender was added as a factor since there are sex differences in muscle fatigue resistance.22 For the standard fatigue protocol and the fatigue protocol under arterial occlusion, total duration of the protocol was divided into five equal intervals. Peak torque and RT50 values of the contractions corresponding to the resulting six time points were accordingly used for analysis. An alpha level of 0.05 was used for all tests of significance.

RESULTS

Study group

Characteristics of patients with PPS and healthy control subjects, both for the total study group (38 PPS, 19 control), and the subgroup performing the fatigue protocol under occlusion (9 PPS, 11 control), are presented in Table 1. Regular exercise (a minimum of 150 min per week with at least moderate intensity) was reported by 11 healthy subjects and 6 patients with PPS. All patients reported that they suffered from generalized fatigue. Clinical signs of polio residuals in the lower extremities, based on manual muscle testing, were present in all, except 3 patients. No significant differences were found between patients with PPS performing the occlusion measurements and those who did not, with respect to demographic data and polio characteristics.

Some subjects had difficulty in relaxing the leg during the stimulated fatigue protocol. This involuntary activity, judged on basis of visual inspection of the data by experienced investigators, sometimes caused unsteady baseline torque resulting in unreliable mea-surements. These results were therefore not included in the statistical analysis, leading to different numbers of observations for different parameters (the exact numbers used for analysis are given in the legends with the figures).

Pre-fatigue contractile characteristics

The MVT of the knee extensor muscles of patients with PPS was significantly lower com-pared to healthy subjects (mean difference -74 Nm, 95% CI -96 to -51, p≤0.001). In 20 of the 26 female patients MVT was below the lowest value found in the healthy women (128 Nm), and 11 of the 12 male patients had an MVT below the lowest value found in healthy men

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(150 Nm). No significant differences in pre-fatigue state with respect to contractile speed (RT50 and 50/150 Hz ratio) were found between both groups (Table 1).

Table 1. Subject characteristics and pre-fatigue contractile characteristics.

All subjects Subgroup (occlusion)

PPS

(n=38)

Control

(n=19)

PPS

(n=9)

Control

(n=11)

Demographic data

Gender (male/female) 12/26 7/12 4/5 3/8

Age (yrs) 60.0±6.6 59.0±7.0 61.3±6.7 60.3±5.4

Body weight (kg) 76.1±11.9 75.8±9.4 77.3±12.1 74.7±10.1

BMI (kg/m2) 26.4±2.9 24.8±2.8 26.2±1.9 24.8±3.3


Age at acute polio (yrs) 2.0 (0–9) – 2.0 (0–9) –

Present walking distancea 3 (2–4) – 4 (3–4) –

Measured leg clinically affected (yes/no) 27/11 – 5/4 –

Reported abnormal fatigue in measured

leg (yes/no)

23/15 – 6/3 –

MMT knee extension measured leg (0–5) 5 (4- –5) – 5 (4- –5) –

MMT sum score legs (0–80)b 69.4±8.6 – 71.3±5.1 –

Pre-fatigue contractile characteristics

MVT (Nm) 106±42c 179±34 124±69 172±29

RT50 (ms) 127±10 122±8 124±9 124±9

50/150 Hz ratio (%) 79±12 84±10 77±11 85±9

Values for age, body weight, BMI, MMT sum score, and pre-fatigue characteristics are mean ± SD; values for age at acute polio, present walking distance and MMT knee extension are median (range).Abbreviations: BMI, body mass index; MMT, manual muscle testing; MVT, maximal voluntary torque; RT50, half-relaxation time.aWalking distance was classified in 4 categories: 1 = indoors only; 2 = around the house; 3= seldom >1km; 4 = regularly >1km.bSum score for the muscle strength of the legs was calculated by adding 16 muscle groups. Each muscle group had a score between 0 and 5, sum score ranged from 0 to 80.33

cp ≤ 0.001 (PPS versus control subjects, in the total study group).

Fatigue resistance

The relative torque level during the initial contraction of the fatigue protocol was com-parable in PPS and healthy subjects (33.4 ± 9.3 %MVT versus 30.8 ± 5.6 %MVT, p=0.300). No difference was found between both groups with respect to the course of fatigue (p=0.780). During the protocol torque declined to 50.6 ± 10.5% in the last contraction in patients with PPS and to 52.2 ± 11.9% in healthy subjects (Fig. 1A).

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Figure 1. Changes in parameters during the standard fatigue protocol with an intact circulation. Peak torque (A) and half-relaxation time (B) are expressed as percentages of pre-fatigue values (=100%). Mean data ± SD are shown for every fifth contraction for PPS (open squares; n=36) and control subjects (black circles; n=17).

Figure 2. Change in peak torque during the fatigue protocol under arterial occlusion. Values are expressed as percentages of pre-fatigue value (=100%). Mean data ± SD are shown for every fifth contraction for PPS (open squares; n=9) and control subjects (black circles; n=11).

No difference in slowing of relaxation during the fatigue protocol was found between PPS and healthy subjects. After an initial increase in RT50 during the first 40 contractions, muscles of both groups showed a gradual decrease towards the end of the protocol (Fig. 1B). In the last contraction of the protocol, RT50 was increased by 32.5 ± 17.5% in the PPS group compared to 34.2 ± 16.0% in the control group (p=0.366).

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3

All subjects (n=20) continued the protocol under occlusion for at least 70 contractions. Therefore the 70th contraction was used as the last contraction in the analysis (Fig. 2). During the protocol, torque declined to 24.9 ± 14.5% in patients with PPS and to 28.8 ± 7.2% in healthy subjects (p=0.173). When compared to the torque decrease with intact blood circulation, the additional decrease in peak torque as a consequence of the occluded blood flow was similar in the PPS (25.0 ± 11.8% during the last contraction) and control group (31.1 ± 12.0%) (p=0.802).

Recovery

Recovery from the reduction in peak torque during the fatigue protocol was better in patients with PPS compared to healthy subjects (p=0.043). The recovery was however in-complete in both groups. In muscles from healthy subjects, only 54.9 ± 20.4% of the reduc-tion in torque during the fatigue protocol recovered within 3 min, while patients with PPS recovered to 68.9 ± 20.5% of the reduction (Fig. 3A).

Although still incomplete, RT50 recovered to a higher extent compared to torque (Fig. 3B) and no difference was found between PPS and healthy subjects (p=0.138). In patients with PPS 85.9 ± 21.0% of the increase in RT50 during the fatigue protocol recovered within 3 min, compared to 86.7 ± 19.0% in the healthy subjects.

Figure 3. Recovery of parameters following the standard fatigue protocol with an intact circulation. Peak torque (A) and half-relaxation time (B) are expressed as percentages of the change during the fatigue protocol (=100%). Mean data ± SD are shown for every contraction for PPS (open squares; n=34) and control subjects (black circles; n=16).

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Additional analyses

Comparing results of patients reporting abnormal increased muscle fatigability (n=23) in the measured leg to those without this complaint (n=15) revealed no significant differ-ences with respect to any of the studied variables, except for the slowing of relaxation, showing less change in the group with fatigue complaints (p=0.031).

DISCUSSIONContrary to our expectations no differences in fatigue resistance of the knee extensor

muscles between patients with PPS and healthy control subjects were found, indicating that the abnormal muscle fatigue reported by many patients with PPS is most likely ex-plained by factors other than impaired intrinsic fatigability of the muscle fibers.

Fatigue resistance is determined by the interplay of energy utilization and energy pro-duction. During prolonged series of stimulated contractions, the production of energy de-pends largely on aerobic metabolism. Several observations from the present study showed that for the knee extensor muscles in PPS, neither the rate of energy utilization is higher, nor the aerobic energy regeneration capacity is lower compared to normal. The first im-portant observation to support this conclusion is that the rate of fatigue was comparable in patients with PPS and healthy subjects both in the situation with intact circulation and when the blood flow was occluded (Figs. 1A and 2). Contrary to findings in muscle biopsies from patients with PPS that showed a reduced capillary supply and oxidative enzyme ac-tivity,5,23 this indicates that impaired blood flow or reduced aerobic capacity of the muscle fibers does not contribute to the abnormal muscle fatigue perceived by these patients. This is further supported by the recovery measurements, where no differences were found between PPS and healthy subjects with respect to recovery of half-relaxation time, and an even faster and more complete recovery of peak torque in patients with PPS (Figs. 3A and B). Although the explanation for the latter finding remains unclear, these results argue against a compromised aerobic metabolism in PPS muscles, since recovery depends to a large extent on the aerobic capacity of the muscle fibers.21

In addition, we found no indications that the rate at which energy was utilized was higher in knee extensor muscles of patients with PPS compared to healthy subjects. One way to investigate this is by comparing the extent of fatigue under occlusion between both groups. In this situation blood flow to the muscles is restricted and consequently fatigue will be determined primarily by anaerobic energy utilization since aerobic energy regen-eration is no longer possible.17 Our results showed that fatigability under occlusion was comparable in PPS and healthy subjects (Fig. 2) and therefore suggest that the speed of energy utilization is similar in both groups. This is consistent with the findings regarding the half-relaxation time and the 50/150 Hz ratio which were measured in the pre-fatigue state as indices of contractile speed. Compared to type II fibers, type I fibers have a slower speed of contraction and consequently a slower rate of energy consumption. Therefore, the absence of significant differences in these parameters suggests that large dissimilarities in muscle fiber type composition of the tested knee extensor muscles, between PPS and healthy subjects are not likely.

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3

Our findings of no differences in contractile properties and aerobic capacity of the mus-cle fibers between both groups were unexpected given the muscular adaptations and fati-gability complaints that have been described in patients with PPS.4-6 This may indicate that our study group was not representative for the PPS population. However, based on the considerably lower muscle strength, low physical activity level, and complaints of gener-alized fatigue and local muscle fatigue in the majority of patients, which is consistent with characteristics that are known in the literature,24,25 this seems unlikely. The clinical rele-vance of these opposite adaptations has been debated before3,5,6,26 and it may well be that the combination of adaptations, such as the predominance of type I fibers with a decreased oxidative enzyme activity, ultimately has no effect on the fatigability of the muscle fibers in patients with PPS.

A methodological limitation is the small subgroup that performed the occlusion mea-surements. Nevertheless, despite the limited sample size, characteristics of these patients did not differ from the characteristics of the other patients, indicating that they formed a representative subgroup. Furthermore, all patients suffered from generalized fatigue, and MVT of the knee extensor muscles was below the lowest values found in healthy subjects in 82% of the patients, indicating that the majority of measured legs were clinically affect-ed. Part of the patients, however, reported no complaints of abnormal muscle fatigability in the measured leg. Nevertheless, further analyses revealed that, except for the slowing of relaxation, there were no differences between patients with abnormal muscle fatigue complaints in the measured leg compared to those without this complaint. In addition, it should be realized that neuromuscular adaptations have also been found in clinically unaf-fected muscles and therefore this probably did not negatively influence generalizability of results.27-29

With the present study we have shown that the muscle fatigue complaints reported by many patients with PPS are most likely explained by factors other than intrinsic fatiga-bility of the muscle fibers. Previous studies that investigated the contribution of central fatigue indicate that an impaired voluntary activation does not seem to be a major factor as well,8,13 but evidence is limited, and therefore this factor should be considered.3,30 Anoth-er possible explanation, which has been proposed before,3,13,31 is that perceived fatigue is mainly related to a reduced muscle mass. Given the substantially lower maximal isometric knee extensor muscle strength (41%) that we found in PPS compared to healthy subjects, it is reasonable to assume that the relatively higher loading of active muscles contributes to the increase in muscle fatigue in executing daily life activities.32

In conclusion, the present study did not find differences in fatigue resistance of elec-trically activated knee extensor muscles between patients with PPS and a healthy control group. Our findings suggest that there are no differences with respect to contractile prop-erties and aerobic muscle capacity that contribute to the increased muscle fatigue report-ed by many patients with PPS during daily life activities. Probably, this symptom is most likely the result of muscle weakness that requires individuals to perform at higher relative muscle load, inducing early fatigue.

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REFERENCES


2. 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;92:899-904.

3. Thomas CK, Zijdewind I. Fatigue of muscles weakened by death of motoneurons. Muscle Nerve 2006;33:21-41.

4. Birk TJ. Poliomyelitis and the post-polio syndrome: exercise capacities and adaptation--current research, future directions, and widespread applicability. Med Sci Sports Exerc 1993;25:466-472.



7. Allen GM, Gandevia SC, Neering IR, Hickie I, Jones R, Middleton J. Muscle performance, volun-tary activation and perceived effort in normal subjects and patients with prior poliomyelitis. Brain 1994;117 ( Pt 4):661-670.


9. Sharma KR, Kent-Braun J, Mynhier MA, Weiner MW, Miller RG. Excessive muscular fatigue in the postpoliomyelitis syndrome. Neurology 1994;44:642-646.

10. Agre JC, Rodriquez AA. Neuromuscular function: comparison of symptomatic and asymptomat-ic polio subjects to control subjects. Arch Phys Med Rehabil 1990;71:545-551.

11. Samii A, Lopez-Devine J, Wasserman EM et al. Normal postexercise facilitation and depression of motor evoked potentials in postpolio patients. Muscle Nerve 1998;21:948-950.

12. Sunnerhagen KS, Carlsson U, Sandberg A, Stalberg E, Hedberg M, Grimby G. Electrophysiologic evaluation of muscle fatigue development and recovery in late polio. Arch Phys Med Rehabil 2000;81:770-776.





17. Russ DW, Elliott MA, Vandenborne K, Walter GA, Binder-Macleod SA. Metabolic costs of iso-metric force generation and maintenance of human skeletal muscle. Am J Physiol Endocrinol Metab 2002;282:E448-E457.

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19. Gerrits HL, de Haan A, Hopman MT, van der Woude LH, Jones DA, Sargeant AJ. Contractile properties of the quadriceps muscle in individuals with spinal cord injury. Muscle Nerve 1999;22:1249-1256.


21. Blei ML, Conley KE, Odderson IB, Esselman PC, Kushmerick MJ. Individual variation in contrac-tile cost and recovery in a human skeletal muscle. Proc Natl Acad Sci U S A 1993;90:7396-7400.

22. Wust RC, Morse CI, de Haan A, Jones DA, Degens H. Sex differences in contractile properties and fatigue resistance of human skeletal muscle. Exp Physiol 2008;93:843-850.

23. Grimby L, Tollback A, Muller U, Larsson L. Fatigue of chronically overused motor units in prior polio patients. Muscle Nerve 1996;19:728-737.

24. Trojan DA, Cashman NR. Post-poliomyelitis syndrome. Muscle Nerve 2005;31:6-19.

25. Gonzalez H, Olsson T, Borg K. Management of postpolio syndrome. Lancet Neurol 2010;9:634-642.

26. Nordgren B, Falck B, Stalberg E et al. Postpolio muscular dysfunction: relationships between muscle energy metabolism, subjective symptoms, magnetic resonance imaging, electromyog-raphy, and muscle strength. Muscle Nerve 1997;20:1341-1351.

27. Grabljevec K, Burger H, Kersevan K, Valencic V, Marincek C. Strength and endurance of knee extensors in subjects after paralytic poliomyelitis. Disabil Rehabil 2005;27:791-799.


29. McComas AJ, Quartly C, Griggs RC. Early and late losses of motor units after poliomyelitis. Brain 1997;120 ( Pt 8):1415-1421.

30. Abraham A, Drory VE. Fatigue in motor neuron diseases. Neuromuscul Disord 2012;22 Suppl 3:S198-S202.


32. Frey Law LA, Avin KG. Endurance time is joint-specific: a modelling and meta-analysis investiga-tion. Ergonomics 2010;53:109-129.

33. Medical Research Council. Aids to the examination of the peripheral nervous system. Memo-randum no. 45, London: Her Majesty’s Stationary, Office, 1976.

Chapter 4

DETERMINING THE ANAEROBIC THRESHOLD IN POST-POLIO SYNDROME: COMPARISON WITH CURRENT GUIDELINES FOR TRAINING INTENSITY PRESCRIPTION

Archives of Physical Medicine and Rehabilitation 2014; 95: 935–940© Reprinted with permission from Elsevier

Eric L. VoornKarin H.L. Gerrits

Fieke S. KoopmanFrans Nollet

Anita Beelen

44

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Chapter 4

ABSTRACTObjectives: To determine whether the anaerobic threshold (AT) can be identified in individ-uals with post-polio syndrome (PPS) using submaximal incremental exercise testing, and to compare current guidelines for intensity prescription in PPS with the AT. Design: Cohort study.Setting: Research laboratory.Participants: Individuals with PPS (n=82).Interventions: Not applicable.Main outcome measures: Power output, gas exchange variables, heart rate and rating of perceived exertion (RPE) were measured in an incremental submaximal cycle ergometry test. Two independent observers identified the AT. Comparison of current guidelines for training intensity prescription in PPS (40%–60% heart rate reserve [HRR] or RPE of 12) with the AT was based on correlations between recommended heart rate and the heart rate at the AT. In addition, we determined the proportion of individuals that would have been recommended to train at an intensity corresponding to their AT. Results: The AT was identified in 63 (77%) of the participants. Pearson correlation coeffi-cients between the recommended heart rate and the heart rate at the AT were lower in cases of 40% HRR (r=.56) and 60% HRR (r=.50) than in cases of prescription based on the RPE (r=.86). Based on the RPE, 55% of the individuals would have been recommended to train at an intensity corresponding to their AT. This proportion was higher compared with 40% HRR (41%) or 60% HRR (18%) as criterion. Conclusions: The AT can be identified in most individuals with PPS offering an individualized target for aerobic training. If the AT cannot be identified (e.g. because gas analysis equip-ment is not available), intensity prescription can best be based on the RPE.

51

Anaerobic threshold in PPS

4

INTRODUCTIONPhysical therapy recommendations for individuals with neuromuscular diseases (NMDs)

include aerobic exercise training to prevent or reverse deconditioning and preserve muscle endurance for daily life activities.1 Determining the desired training intensity is delicate in NMDs because exercise levels should be sufficiently intense to stimulate a training effect; however, they should avoid muscular overload.2

Most guidelines for aerobic training in healthy subjects recommend training intensities relative to the individual’s maximal capacity in terms of maximum oxygen consumption or maximal heart rate.3 In NMDs, however, a true maximum oxygen consumption or maximal heart rate is often not reached because the leg muscles frequently fatigue before the car-diorespiratory system reaches its maximum. Therefore, in these patient groups, maximal heart rate is often estimated based on age. Another method to prescribe training inten-sity uses ratings of perceived exertion (RPEs), often used in individuals using beta-block-ing agents.4 Our experience with training in individuals with post-polio syndrome (PPS), a slowly progressive NMD, is that when applying these guidelines, physical therapists often have to adjust the intensity. This is probably because none of these guidelines make use of a direct indicator of aerobic capacity, resulting in an exercise prescription insufficiently tailored to the individual.

The anaerobic threshold (AT), a direct indicator of aerobic capacity,5 may be useful to overcome this problem. The AT is widely used for setting target intensity for aerobic train-ing in healthy subjects6 and individuals with chronic disease (e.g. multiple sclerosis,7 coro-nary heart disease,8 hypertension,9 obesity.10). Usually, the AT is assessed through graded maximal exercise testing.11 In PPS and other NMDs, maximal exercise testing is not feasible in all individuals because performance is often symptom limited.12,13 Furthermore, maximal exercise may provoke muscle complaints and excessive fatigue with a prolonged recovery and should, therefore, be avoided.4 Submaximal exercise testing could provide an alterna-tive with reduced physiological stress in at least some individuals; however, the risk lies in insufficient stressing of the cardiorespiratory system to identify the AT.

Our aim was to determine whether the AT in individuals with PPS can be identified through submaximal exercise testing. In addition, we compared commonly used markers for training intensity based on the estimated heart rate reserve (HRR) and RPEs according to current guidelines with the AT. In this process we realized that expensive gas analysis equipment is often not available in physical therapy practices.

METHODS

Participants

Eighty-two individuals with PPS were recruited. Sixty-six participants performed the test as part of an ongoing clinical trial of the efficacy of exercise therapy and cognitive be-havioral therapy to improve fatigue, daily activity performance, and quality of life in PPS.14 The remaining 16 participants performed the test as part of a cross-sectional study inves-tigating the aerobic exercise capacity in individuals with PPS. Participants were recruited

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from Dutch hospitals and rehabilitation centers throughout the country. All eligible partic-ipants were initially screened by a physician. Inclusion criteria were diagnosis of PPS,15 age between 18 and 75 years, life expectancy >1 year, ability to cycle on a bicycle ergometer at an intensity of at least 25 W, and capability of walking with or without walking aids. Exclusion criteria were use of psychotropic drugs or other psychiatric treatment, clinical depression, disabling comorbidity influencing the outcome parameters (including cardio-pulmonary disease, epileptic seizures and poorly regulated diabetes mellitus), respiratory insufficiency, cognitive impairment, and pregnancy. Both studies were approved by the medical ethics committee of the University of Amsterdam, The Netherlands, and written informed consent was obtained from all participants.

Procedure

We collected data on demographic characteristics (age, sex, height, weight) and polio characteristics (age at acute polio, time since new symptoms, present walking distance). Furthermore, we determined muscle strength of the lower limbs by manual muscle testing according to the Medical Research Council Scale.16

Submaximal exercise test

Participants performed an incremental exercise test on a cycle ergometera with con-tinuous recording of gas exchange variables using the COSMED K4b2, a portable breath-by-breath gas analysis system.b Heart rate was measured with a Polar RS400 heart rate monitor.c The test protocol started with the measurement of resting energy expenditure during 3 min while sitting in a chair. The exercise test consisted of 3 min unloaded cycling, after which the workload was increased by 10 W every minute. Using this 1-min step proto-col is recommended for patients, to avoid early termination of the test (because of sudden increases in work rate), and it results in a sufficient quantity of accumulated data.17 During the test, the individuals’ feet were strapped to the pedals with toe clips and extra bands, if necessary. Criteria for stopping the test were the heart rate exceeding 80% of the esti-mated HRR, the pedal frequency dropping <60 revolutions per minute, or the participant’s being unable to continue the test for any reason. The same criteria were used for partici-pants using beta-blocking agents. However, if the RPE exceeded a score of 16 on the Borg Scale before these participants reached their target heart rate, the test was stopped. The HRR was defined as the difference between the maximal heart rate and the heart rate at rest. The maximal heart rate was estimated at 220 minus age,3 and the heart rate at rest was the mean value of the last minute of the 3-min resting measurement. The protocol was completed with 3 min of unloaded cycling. At each work load and at the end of the exercise test, participants rated their perceived exertion on the Borg Scale (range, 6–20).18 Gas exchange and heart rate data were stored on a computer for offline analysis with the COSMED K4b2 software.

Data analysis

Power output, heart rate, gas exchange values, and the RPE were determined from the highest achieved increment. Two independent experienced researchers determined the

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4

AT through visual inspection of the gas exchange plots using the V-slope method (Fig 1).11 In participants where the AT could be identified, power output, heart rate, gas exchange values, and the RPE were determined at the moment of the AT. Disagreements between the 2 researchers were discussed and resolved in a consensus meeting.

The relations between recommended target intensity based on current guidelines and the AT were visualized using plots. According to these guidelines, participants of the pres-ent study would have been recommended to start their training program at an intensity of approximately 40% to 60% estimated HRR or an RPE of 12.19,20 The heart rate corresponding to these intensities (40% HRR, 60% HRR, RPE of 12) was determined for every individual and was plotted against the heart rate attained at the AT. Subsequently, we determined the proportion of individuals that would be recommended to train at an intensity below, at, or above the AT. We considered training intensity prescription to correspond to the AT if the recommended heart rate fell within a range of 10 beats per minute (bpm) around the heart rate attained at the AT (±5 bpm). Participants using beta-blocking agents were not included in the HRR and AT relation.

Descriptive data were expressed as mean ± SD (demographic data) or as median and range (polio characteristics). For normally distributed data, differences between the partic-ipants with AT and those without AT were analyzed with the Student t test; in the case of nonnormally distributed data, the Mann-Whitney U test was used. Dichotomized variables were analyzed with the Fisher exact test. Pearson correlation coefficients were calculat-ed to examine the associations between the recommended heart rate based on current guidelines (40% HRR, 60% HRR, RPE of 12) and the heart rate attained at the AT. Systematic differences were analyzed with paired t tests. Statistical analysis was performed with SPSS software (version 20.0.0.1).d An alpha level of .05 was used for all tests of significance.

Figure 1: Gas exchange plot from the submaximal exercise test of a representative participant to illustrate identi-fication of the AT. With the V-slope method, the V̇co2/V̇o2 plot is used to identify the point at which the V̇co2 starts to increase more rapidly than V̇o2. The vertical dashed line represents the AT. V̇co2, carbon dioxide production; V̇o2, oxygen consumption.

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RESULTS

Study group

All 82 participants with PPS included in this study (33 men, 49 women; age range, 25–74y) performed the exercise test. Clinical signs of polio residuals in the lower extremities based on manual muscle testing were found in all except 2 participants (Table 1). Thirteen participants used beta-blocking agents.

Table 1. Participant characteristics.

PPS

(n=82)

Demographic data

Sex (male/female) 33/49

Age (yrs) 59.3±8.0

Weight (kg) 75.9±13.1

BMI (kg/m2) 26.4±3.8


Age at acute polio (yrs) 2.0 (0–40)

Time since new symptoms (yrs) 15 (2–44)

Present walking distance*

Indoors only (n)Around the house (n)Seldom further than 1 km (n)Regularly further than 1 km (n)

1254016

Residual paresis in 1 leg/2 legs 57/23

Values for demographic data are mean ± SD, and values for polio characteristics are median (range); all other values are as otherwise indicated.*Walking distance was defined as the daily distance walked and was classified in 4 categories: 1 (indoors only), 2 (around the house), 3 (seldom >1km), 4 (regularly >1km).

Submaximal exercise test

Thirty-one participants reached the target heart rate of 80% of the estimated HRR. Eight participants, all using beta-blocking agents, reached the endpoint based on perceived exertion (>16 on the Borg Scale). All other participants (n=43) stopped the test because the pedal frequency dropped <60 revolutions per minute (Table 2). None of the participants reported physical complaints in the days after the test.

Anaerobic threshold

The AT could be identified in 63 of the 82 participants (77%) and occurred at a mean power output ± SD of 49 ± 16W and at a mean heart rate ± SD of 110 ± 14 bpm (Table 3).

55


4

Expressed as a percentage of the estimated HRR, the AT occurred at a mean of 42 ± 13% (range, 17%–73%).

Table 2. Exercise parameters during the final increment of the exercise test and the reasons for stopping.

All

(n=82)

AT

(n=63)

No AT

(n=19)

Mean difference between

AT and no AT (95% CI)

P*

Exercise parameters (end of test)

Power Output (W) 80±28 85±27 62±23 24 (10 to 37) ≤.001

Peak heart rate (bpm)

Patients without beta blockers†

134±19

137±18

136±18

139±18

128±20

130±20

8 (-2 to 18)

9 (-2 to 19)

.114

.093

Oxygen consumption (mL/min/kg) 19.1±4.7 19.8±4.2 17.1±5.6 2.7 (0.3 to 5.0) .024

Minute ventilation (L/min) 51±16 54±16 39±13 15 (7 to 23) ≤.001

Respiratory exchange ratio 1.03±0.10 1.06±0.09 0.95±0.08 0.11 (0.06 to 0.15) ≤.001

Borg Scale 17±2 17±2 16±2 1 (0 to 2) .098

Reasons for stopping

Heart rate >80% HRR 31 26 5 NA .289

RPE ≥ 16‡ 8 8 0 NA .188

Revolutions per minute < 60 43 29 14 NA .040

Values are mean ± SD or as otherwise indicated. Abbreviations: CI, confidence interval; NA, not applicable.There are missing data in heart rate recording for 4 AT and 1 no AT.*Student’s t test for exercise parameters and Fisher exact test for reasons for stopping. †Heart rate values for patients without beta blockers (n=69; AT: n=52; no AT: n=17). ‡Only applicable to patients with beta blockers and not reaching a heart rate >80% HRR.

Table 3. Exercise parameters at the moment of the AT.

AT

(n=63)

Exercise parameters

Power Output (W) 49±16

Heart rate (bpm)

Patients without beta blockers*

110±14

112±14

Oxygen consumption (mL/min/kg) 14.1±2.4

Minute ventilation (L/min) 29±6

Respiratory exchange ratio 0.88±0.06

Borg Scale 12±2

Values are mean ± SD. There is missing data for heart rate recording in 4 patients.*Heart rate value for patients without beta blockers (n=52).

56

Chapter 4

No differences were found for demographic variables, beta-blocking agent use, and po-lio characteristics between the group of participants in whom the AT could be identified and the group without the AT. Participants without the AT stopped more often because they could no longer maintain the pedal frequency (p<.05). The power output during the final increment of the exercise test was significantly higher in the AT group than the group without AT (85 ± 27W vs 62 ± 23W, p<.001). Furthermore, oxygen consumption, minute ventilation, and the respiratory exchange ratio during the final increment were all signifi-cantly higher in the group of participants in whom the AT could be identified (Table 2). No significant difference was found regarding the RPE at the end of the exercise test between the 2 groups.

Figure 2. Heart rate corresponding to 40% HRR (A) and 60% HRR (B) plotted against the heart rate attained at the AT for all individuals, except those using beta-blocking agents. The solid line represents the situation in which the recommended training heart rate based on the HRR exactly equals the heart rate attained at the AT. We consid-ered training intensity prescription to correspond with the AT if the recommended heart rate fell within a range of 10 bpm around the heart rate attained at the AT (dashed lines represent +5 bpm (upper) and -5 bpm (lower), respectively).

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4

Recommended training intensity based on current guidelines compared with the AT

In cases of prescription based on an RPE, more individuals with PPS would have been recommended to train at an intensity corresponding to their AT than in cases of prescrip-tion based on the HRR (Figs. 2A, 2B, 3; Table 4).

The mean heart rate corresponding to 60% HRR was significantly higher than the mean heart rate at the AT (mean difference, 14.6 ± 12.4 bpm; p<.001), whereas we found no systematic differences between mean heart rates corresponding to 40% HRR and the AT (-2.9 ± 11.9 bpm, p=.090) and between an RPE of 12 and the AT (-1.1 ± 9.1 bpm, p=.365). Correlation coefficients between current guidelines and the AT were lower in cases of 40% HRR (r=.56, p<.001) and 60% HRR (r=.50, p<.001) than in cases of prescription based on RPE (r=.86, p<.001).

Table 4. The proportion of individuals that would be recommended to train at an intensity below, at, or above their AT.

Below AT (%) AT (%)* Above AT (%)

Current guidelines

40% HRR 35 41 24

60% HRR 6 18 76

RPE of 12 26 55 19*We considered training intensity prescription based on current guidelines to correspond to an intensity of the AT if the recommended heart rate fell within a range of 10 bpm around the heart rate attained at the AT (±5 bpm).

Figure 3. Heart rate corresponding to an RPE of 12 plotted against the heart rate attained at the AT for individuals with (black circles), and without beta-blocking agents (open squares). The solid line represents the situation in which the recommended training heart rate based on RPE exactly equals the heart rate attained at the AT. We considered training intensity prescription to correspond with the AT if the recommended heart rate fell within a range of 10 bpm around the heart rate attained at the AT (dashed lines represent +5 bpm (upper) and -5 bpm (lower), respectively).

58

Chapter 4

DISCUSSIONThe present study demonstrates that the AT can be identified in most (77%) individu-

als with PPS with submaximal incremental exercise testing. This finding is of importance because it implies that the AT can be assessed in most individuals while avoiding maximal exertion, which might provoke muscle complaints. Furthermore, for those individuals for whom it is not possible to determine the AT, our results suggest that exercise prescription should, preferably, be based on RPEs instead.

It appeared that almost half of the participants met 1 of the submaximal stopping criteria used. In this population, the AT could be identified in the vast majority (87%), implying that even though these participants could continue their exercise test, this was not necessary to determine the AT. It demonstrates that sufficient data points beyond the AT were obtained, which is necessary to identify the change in slope, indicating the AT, in the gas exchange plots. In 5 participants, however, the AT could not be identified despite reaching their tar-get HRR. This finding may indicate that in these participants, the AT would have occurred at an intensity close to or above 80% HRR, hampering identification of a clear threshold. Another explanation is that their actual maximal heart rate was underestimated, and their exercise intensity did not reach the AT. Because the validity of the estimated age-related maximal heart rate for individuals can be questioned, it remains uncertain what the actu-al exercise stress for each participant was during the exercise test.21 Nevertheless, even though intensity levels might have been insufficient to determine the AT in some cases, the proportion of participants in which the AT was identified (77%) is comparable with results using the conventional method (72%) where all participants exercised until exertion.12

The absence of the AT in part of the individuals with PPS (23%) may be related to re-duced muscle function of the lower limbs, as indicated by the significantly lower power out-put during the final increment of the exercise test in this group compared with the group with the AT. However, other factors (e.g. fear of physical complaints, not being accustomed to cycling, lack of motivation) probably caused some participants to stop the exercise test prematurely, despite having sufficient muscle strength.13,22 Further knowledge about the inability to identify the AT is essential for physical therapists in designing training programs. If this absence is caused by reduced muscle functioning, other exercise modes may be con-sidered for aerobic exercise training and testing. In other cases, adapting the testing proce-dure (e.g., habituation sessions) may suffice to determine the AT.

Furthermore, our results indicate that current guidelines for training intensity prescrip-tion in PPS based on RPEs correspond better to the AT than prescription based on estimated HRR. From our results it appears that recommended training intensity is above the AT in many individuals when prescription is based on the HRR, even in cases of 40% HRR (24%). Besides the fact that this is probably unnecessary to induce aerobic training effects23,24, it may, for most individuals, be too exhausting to sustain these exercise intensities during training. This latter assumption is supported by our own experiences and earlier studies investigating the effectiveness of aerobic training in PPS. For example, in studies by Jones,25 Kriz,26 and colleagues, the training intensity was set at 70% to 75% of the HRR, which ap-peared unfeasible for several participants and had to be adjusted. The observation that the target intensity was apparently not appropriate for all individuals is corroborated by

59


4

results from Kriz26 who showed that the mean heart rate achieved during their training pro-gram represented only 50% of the HRR. Together our results indicate that based on current guidelines, the recommended intensity is overestimated in a substantial part of the indi-viduals with PPS. Moreover, they confirm earlier reports emphasizing the need for training programs tailored to the individual’s aerobic capacity, instead of prescription based on a fixed percentage of the HRR for a group of patients.27

Even though intensity prescription based on RPEs corresponds better to the AT than based on the HRR, it is important to realize that, for part of the individuals with PPS (19%), recommended target intensity is still above their AT. However, most will have a recom-mended intensity at or near the AT. This close relation between RPEs and the AT is con-sistent with the literature, showing that although there is clearly some variation between individuals, the perception of work at the AT is quite similar among subjects within the same population. This makes it a useful alternative for training intensity prescription.28-30

Study limitations

A limitation to our findings is that we selected individuals who could cycle on an ergom-eter. Therefore, despite the relatively large sample size, generalizability of the study to all survivors of polio may be compromised. Another limitation is that the AT was not identified in some of the individuals. As a consequence, it is unclear whether results that were found in the group of individuals in which we identified the AT are applicable to the group of indi-viduals without AT as well.

Conclusions

Submaximal incremental exercise testing can be used for assessment of the AT in most individuals with PPS who can cycle on an ergometer and enables physical therapists to bet-ter individualize exercise intensity for aerobic training. If the AT cannot be identified (e.g. because gas analysis equipment is not available) training prescription, should, preferably be based on RPEs. A next step is to study the feasibility of training at the AT in individuals with PPS and in other NMDs.

Suppliers

a. Lode BV, Zernikepark 16, 9747 AN Groningen, The Netherlands.b. Cosmed Srl, Via dei Piani di Monte Savello 37, PO Box 3, Pavona di Albano, Rome, I-00040, Italy.c. Polar Electro Oy, HQ Professorintie 5, FIN-90440 Kempele, Finland.d. SPSS Inc, 233 S Wacker Dr, 11th Fl, Chicago, IL 60606.

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Chapter 4

REFERENCES



3. American College of Sports Medicine. Resource manual for guidelines for exercise testing and prescription. Lippincott Williams & Wilkins. Seventh edition, 2012;p 466-482.

4. Birk TJ, Nieshoff EC. Neuromuscular diseases and disorders In: Lemura LM, von Duvillard SP, editors. Clinical Exercise Physiology: Application and Physiological Principles. Philedelphia: Lip-pincott Williams & Wilkins, 2004;p. 205-299.

5. Faude O, Kindermann W, Meyer T. Lactate threshold concepts: how valid are they? Sports Med 2009;39:469-490.

6. Davis JA, Frank MH, Whipp BJ, Wasserman K. Anaerobic threshold alterations caused by endur-ance training in middle-aged men. J Appl Physiol Respir Environ Exerc Physiol 1979;46:1039-1046.



9. Kiyonaga A, Arakawa K, Tanaka H, Shindo M. Blood pressure and hormonal responses to aero-bic exercise. Hypertension 1985;7:125-131.


11. Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp BJ. Principles of exercise testing and interpretation; including pathophysiology and clinical applications. Lippincott Williams & Wil-liams, 2005;p. 146-150.


13. Noonan V, Dean E. Submaximal exercise testing: clinical application and interpretation. Phys Ther 2000;80:782-807.


15. March of Dimes. International conference on post-polio syndrome. Identifying Best Practices in Diagnosis & Care. White Plains, NY, USA, 2000.

16. Medical Research Council. Aids to examination of the peripheral nervous system. Memoran-dum no. 45. London: Her Majesty’s Stationary Office, 1976.

17. Zhang YY, Johnson MC, Chow N, Wasserman K. Effect of exercise testing protocol on parame-ters of aerobic function. Med Sci Sports Exerc 1991;23:625-630.

18. Borg G. Perceived exertion as an indicator of somatic stress. Scand J Rehabil Med 1970;2:92-98.

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19. Birk TJ, Nieshoff EC. Polio In: Lemura LM, von Duvillard SP, editors. Clinical Exercise Physiology: Application and Physiological Principles. Philedelphia: Lippincott Williams & Wilkins, 2004;p. 269-284.

20. Birk TJ. Polio and Post-Polio Syndrome. In: Durstine, J.L., Moore, G.E., editors. Exercise Man-agement for Persons with Chronic Diseases and Disabilities. Human Kinetics, 2009;chapter 43.

21. Whaley MH, Kaminsky LA, Dwyer GB, Getchell LH, Norton JA. Predictors of over- and under-achievement of age-predicted maximal heart rate. Med Sci Sports Exerc 1992;24:1173-1179.

22. Alba A, Block E, Adler JC, Chikazunga C. Exercise testing as a useful tool in the physiatric man-agement of the post-polio survivor. Birth Defects Orig Artic Ser 1987;23:301-314.

23. Belman MJ, Gaesser GA. Exercise training below and above the lactate threshold in the elderly. Med Sci Sports Exerc 1991;23:562-568.





28. Boutcher SH, Seip RL, Hetzler RK, Pierce EF, Snead D, Weltman A. The effects of specificity of training on rating of perceived exertion at the lactate threshold. Eur J Appl Physiol Occup Physi-ol 1989;59:365-369.

29. Demello JJ, Cureton KJ, Boineau RE, Singh MM. Ratings of perceived exertion at the lactate threshold in trained and untrained men and women. Med Sci Sports Exerc 1987;19:354-362.

30. Purvis JW, Cureton KJ. Ratings of perceived exertion at the anaerobic threshold. Ergonomics 1981;24:295-300.

Chapter 5

RCT ON EXERCISE THERAPY AND COGNITIVE BEHAVIORAL THERAPY TO REDUCE FATIGUE IN POST-POLIO SYNDROME

Submitted

Fieke S. KoopmanEric L. VoornAnita Beelen

Gijs BleijenbergMarianne de Visser

Merel A. BrehmFrans Nollet

55

64

Chapter 5

ABSTRACTObjectives: To study the efficacy of exercise therapy (ET) and cognitive behavioral therapy (CBT) on reducing fatigue and improving activities and health-related quality of life (HRQoL) in patients with post-polio syndrome (PPS).Methods: We conducted a multicenter, single-blinded, randomized controlled trial. Over 4 months, severely fatigued patients with PPS received ET, CBT, or usual care (UC). The primary endpoint (fatigue) was assessed using the subscale fatigue severity of the Checklist Individual Strength (CIS20-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 CIS20-F score: 1.47, 95%CI -2.84 to 5.79 for ET versus UC; and 1.87, 95%CI -2.24 to 5.98 for CBT versus UC), ac-tivities, or HRQoL. Conclusions: Our results demonstrate that neither ET nor CBT were superior to UC in re-ducing fatigue in severely fatigued PPS patients.

65

Exercise therapy and cognitive behavioral therapy in PPS

5

INTRODUCTIONPeople with post-polio syndrome (PPS) commonly experience severe fatigue that per-

sists over time1-3 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 Since fatigue is a multidimensional symptom with both physical and psychological factors,1,7 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 Fatigue may be reduced by enhancing physical capacity through exercise therapy (ET) and chang-ing cognitions and behavior related to fatigue through cognitive behavioral therapy (CBT); although, evidence on the effectiveness of these interventions 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.9 A more recent study showed improvement in fatigue and HRQoL in PPS; howev-er, a comparison with a control group was not made and long-term effectiveness was not evaluated.10

Evidence for CBT in PPS is currently limited to an uncontrolled study of cognitive be-havioral strategies incorporated in a multidisciplinary rehabilitation program.11 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 to investigate the efficacy of ET and CBT in patients with PPS. We hypothesized that both approaches would lead to a sustained reduction of fatigue and im-provement 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?

METHODSWe performed a stratified multi-center, single-blinded randomized controlled trial (RCT)

with equal allocation across treatment arms and follow-up over 6 months. Patients were randomized to 1 of 3 treatment arms: ET, CBT, or UC. Randomization was stratified by cen-ter. The randomization scheme was computer-generated and random blocks of sequences were created with variable block sizes of 3 and 6. An independent investigator performed the randomization. The investigator responsible for the inclusion and the 2 experimenters who performed the outcome assessments were blinded to the group allocation.

Standard protocol approvals, registrations, and patient consents

Our study protocol12 was approved by the Medical Ethics Committee of the Academic Medical Center in Amsterdam and all participating centers granted approval to participate. The RCT was registered at the Dutch Trial Register (NTR1371). Informed consent was ob-tained from all participants.

66

Chapter 5

Participants

Patients were recruited from 7 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. Inclu-sion 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 ab-normal muscle fatigability after a period of stable neurologic function;13 severe perceived fatigue (subscale fatigue severity of the Checklist Individual Strength (CIS20-F) ≥ 35);14 age between 18 and 75 years; life-expectancy longer than 1 year; walking-ability at least in-doors with or without a walking aid; and ability to cycle on an ergometer against a load of at least 25 Watts. Exclusion criteria are described elsewhere.12

Interventions

UC: In all allocation groups, patients received UC at the discretion of their treating phy-sician, 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 mon-itored throughout the study.

ET: ET was designed specifically to enhance patient’s physical capacity. The intervention lasted 4 months and consisted of (1) a home-based aerobic training program 3 times week-ly 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 er-gometer. Patients were supplied with a cycle ergometer and logbook with training instruc-tions at their home. During training, the heart rate was continuously monitored. Training intensity was gradually increased from 60% to 70% heart rate reserve (HRR)15 and the train-ing duration was gradually increased from 28 to 38 min per session. The feasibility of the training schemes was checked weekly by 1 of the therapists by reading the heart rate mon-itors 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-score16 ≥3 were selected for the strengthening exercises. Functional exercises aimed to improve the interplay of cognitive, perceptual, and motor functions.17

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 sit-uation had been reached.

CBT: CBT was directed at perpetuating factors of fatigue in slowly progressive neuro-muscular disorders.18 These involve dysfunctional cognitions with respect to the disease itself, pain, or fatigue;7 dysfunctional attention to pain and fatigue symptoms; deregulation of sleep;7,19 deregulation of physical, social, and/or mental activities;7,19 and low social sup-port and negative social interactions.20 For each factor a standardized module was avail-able as part of the intervention.12 Therapy was customized to each individual due to the

67


5

variability of relevant perpetuating factors in PPS patients. To determine which modules were appropriate, each perpetuating factor was assessed with specific questionnaires.12

The number of CBT sessions was dependent on the number of modules used. Each session lasted 1 hour during a 4 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.12

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 8-item subscale CIS20-F.14 Secondary endpoints included self-perceived activity limitations (Sickness Impact Profile [SIP-68]; domains mo-bility control, social behavior, mobility range21) and HRQoL (Short-Form 36 [SF-36]; Physical Component Summary [PCS], Mental Component Summary [MCS]22).

Exploratory endpoints included pain (Visual Analogue Scale, VAS), total mood distur-bance (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-Effica-cy Scale, ALCOS-16).

In addition, we assessed cardiorespiratory fitness (submaximal heart rate during ex-ercise [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.12

Statistical Analyses

The sample size for this RCT was based on the comparison treatment (ET or CBT) ver-sus UC and 4 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 improvement of 8 points on the CIS20-F (for both treatments);23 and an estimated SD in each treatment group of 9.3. The total sample size needed to detect an 8-point difference in CIS20-F at a 5% level of significance (two-tailed) with a power of 90% was 24 subjects in each group.24 We expected a maximum dropout rate of 10%, based on a previous trial in this patient group.25 Therefore, a total sample size of 81 patients was planned.

To check for selective lost-to-follow-up, differences between participants who complet-ed 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 mod-els, with group and pre-treatment score of the outcome as covariates (primary analyses).

68

Chapter 5

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 (sec-ondary 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 anal-yses were done with SPSS Statistics 21. An alpha level of 0.05 was used for all tests of significance.

RESULTS

Participant flow and recruitment

The phases of the trial are depicted in Figure 1. From June 2009 to September 2012, 68 patients were enrolled. Recruitment was stopped for logistical and financial reasons, although our sample size goal (n = 81) was not achieved. One patient allocated to ET with-drew 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

Figure 1. Flow diagram.

69


5

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-treat-ment CIS20-F-scores, treatment allocation, or any of the pre-treatment sociodemographic or polio characteristics (p>0.08).

Table 1. Sociodemographic and polio characteristics for the intention-to-treat population.

UC

(n=22)

ET

(n=22)

CBT

(n=23)

Sociodemographic characteristics

Female, n (%) 11 50% 13 59% 13 57%

Mean age (SD), y 60.1 7.4 56.7 8.9 60.1 8.2

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%


Median age of acute polio (range), y 3 1–40 2 0–16 3 0–7

Body sites with residual paresis, (n), %

Upper extremity, unilateralUpper extremity, bilateralLower extremity, unilateralLower extremity, bilateralTrunk, neck, face and/or throat

01

1751

0%5%

77%23%5%

12

1274

5%9%

55%32%18%

52

1743

22%9%74%17%13%

Mean time since new symptoms (SD), y 13.2 7.7 14.6 9.5 17.2 9.8

Mean time since new general fatigue (SD), y 11.7 8.5 16.1 9.4 12.3 6.6

New or increased muscle weakness, n (%) 22 100% 18 82% 20 87%

New or increased muscle atrophy, n (%) 3 14% 0 0% 6 26%

New or increased muscle pain, n (%) 7 32% 10 46% 13 57%

New or increased muscle fatigue, n (%) 14 64% 15 68% 16 70%

MMT sum score legs, median (range)a 67.8 41.8–80.0 69.6 43.0–80.0 70.3 45.5–79.3

MMT sum score arms, median (range)b 50.0 32.0–50.0 50.0 16.8–50.0 50.0 37.8–50.0

Present walking distance, n (%)c

Around the houseSeldom further than 1kmRegularly further than 1km

985

41%36%23%

6115

27%50%23%

8123

35%52%13%

aSum score for muscle strength of the legs was calculated by adding the scores of 16 muscle groups. Each mus-cle group had a score between 0 and 5, sum score ranged from 0 to 80.16

bSum 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 50.16

cWalking distance was classified into three categories: around the house; seldom >1km; regularly >1km.Abbreviations: UC, usual care; ET, exercise therapy; CBT, cognitive behavioral therapy; MMT, manual muscle testing.

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Chapter 5

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.

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 (CIS20-F), self-per-ceived activity limitations (SIP-68), and HRQoL (SF-36) for ET or CBT compared with UC. Sec-ondary analyses also showed no differences in primary and secondary endpoints between the interventions and UC on the individual time points, except for a significantly higher long-term CIS20-F score for ET compared with UC (5.37, 95%CI: 0.19 to 10.56). The effica-cies of the interventions compared with UC on the exploratory endpoints are summarized in Table-e1. Primary and secondary analyses showed no differences in exploratory end-points for ET and CBT 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: -5.16 to -0.38). Per-protocol analyses showed similar results as ITT-analyses (mean differences in CIS20-F score: 2.29, 95%CI -2.36 to 6.94 for ET versus UC; and 1.03, 95%CI -3.65 to 5.71 for CBT versus UC).

Table 2. Newly prescribed co-interventions during the 10-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).

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 1 patient. All 3 adverse events were resolved.

71


5

Tabl

e 3.

Ove

rall-

time

effec

ts o

f exe

rcise

ther

apy

and

cogn

itive

beh

avio

ral t

hera

py c

ompa

red

to u

sual

car

e fo

r prim

ary

and

seco

ndar

y en

dpoi

nts.

T1T2

T3T4

Mea

nSD

nM

ean

SDn

Mea

nSD

nM

ean

SDn

Beta

(95%

CI)

CIS2

0-F

(8–5

6)

UC

38.0

8.4

2236

.111

.219

38.3

10.4

2034

.412

.719

ET41

.48.

322

37.2

8.7

1739

.38.

916

39.9

9.8

161.

47 (-

2.84

to 5

.79)

CBT

39.6

9.4

2339

.38.

422

39.8

9.2

2139

.58.

422

1.87

(-2.

24 to

5.9

8)

SIP-

68 M

obili

ty c

ontr

ol (0

–12)

UC

5.6

2.2

226.

41.

919

6.0

2.5

205.

83.

019

ET5.

22.

222

4.9

2.2

185.

42.

216

5.3

1.9

16-0

.55

(-1.4

7 to

0.3

7)

CBT

5.1

1.9

235.

32.

022

5.2

2.5

215.

51.

622

-0.3

0 (-1

.18

to 0

.58)

SIP-

68 S

ocia

l beh

avio

r (0–

12)

UC

4.0

2.0

223.

91.

919

4.3

2.0

203.

92.

019

ET4.

62.

422

4.6

2.7

184.

52.

516

4.1

2.2

160.

08 (-

0.92

to 1

.08)

CBT

3.5

2.2

233.

62.

222

4.0

2.7

214.

02.

322

0.12

(-0.

84 to

1.0

8)

SIP-

68 M

obili

ty ra

nge

(0–1

0)

UC

0.6

1.3

220.

81.

519

0.8

1.3

200.

50.

719

ET1.

01.

622

1.2

1.4

181.

01.

616

1.0

1.1

160.

09 (-

0.59

to 0

.77)

CBT

0.8

1.1

230.

81.

522

1.4

2.1

211.

11.

922

0.31

(-0.

34 to

0.9

5)

SF-3

6 Ph

ysic

al c

ompo

nent

sco

re (0

–100

)

UC

35.7

6.7

2233

.66.

719

33.2

7.8

2034

.58.

018

ET33

.97.

522

35.4

7.8

1834

.37.

016

35.8

6.9

161.

92 (-

0.86

to 4

.70)

CBT

35.6

8.7

2334

.97.

222

36.0

8.1

2136

.17.

422

2.17

(-0.

46 to

4.8

0)

SF-3

6 M

enta

l com

pone

nt s

core

(0–1

00)

UC

51.0

11.1

2252

.512

.119

51.7

10.3

2052

.410

.118

ET50

.210

.322

52.4

8.7

1849

.810

.516

48.0

12.7

16-2

.90

(-6.

90 to

1.1

0)

72

Chapter 5

T1T2

T3T4

Mea

nSD

nM

ean

SDn

Mea

nSD

nM

ean

SDn

Beta

(95%

CI)

CBT

53.6

7.5

2353

.67.

522

53.0

8.2

2149

.310

.622

-1.6

9 (-5

.51

to 2

.13)

Abbr

evia

tions

; CIS

20-F

, sub

scal

e fa

tigue

seve

rity o

f the

Che

cklis

t Ind

ivid

ual S

tren

gth

(hig

her s

core

s ind

icati

ng m

ore

fatig

ue);

SIP-

68, S

ickn

ess I

mpa

ct P

rofil

e 68

(hig

her s

core

s in

dica

ting

mor

e he

alth

-rel

ated

beh

avio

ral p

robl

ems)

; SF-

36, S

hort

-For

m 3

6 (h

ighe

r sco

res i

ndic

ating

hig

her H

ealth

Rel

ated

Qua

lity

of L

ife).

Tabl

e e1

. Ove

rall-

time

effec

ts o

f exe

rcise

ther

apy

and

cogn

itive

beh

avio

ral t

hera

py c

ompa

red

to u

sual

car

e fo

r exp

lora

tory

end

poin

ts.

T1T2

T3T4

Mea

nSD

nM

ean

SDn

Mea

nSD

nM

ean

SDn

Beta

(95%

CI)

Pain

(VA

S (0

–10

cm))

UC

2.5

2.0

203.

02.

415

3.4

2.1

173.

72.

315

ET3.

72.

519

3.8

2.3

134.

03.

09

4.1

2.4

90.

29 (-

1.00

to 1

.58)

CBT

2.2

2.2

213.

22.

317

3.0

2.4

183.

12.

516

-0.1

0 (-1

.24

to 1

.04)

Tota

l Moo

d D

istu

rban

ce (P

OM

S (-2

0–10

8))

UC

8.4

14.1

2111

.518

.619

10.2

14.7

1811

.922

.919

ET17

.020

.222

12.4

17.6

1814

.921

.716

13.2

20.0

160.

64 (-

7.10

to 8

.39)

CBT

11.0

17.8

2310

.518

.322

7.6

18.6

2015

.617

.422

-2.0

0 (-9

.38

to 5

.38)

Slee

p di

stur

banc

es (N

HP-

slee

p (0

–100

))

UC

25.5

27.0

2230

.532

.919

22.0

25.9

2032

.231

.518

ET34

.528

.422

32.2

30.0

1836

.024

.115

37.5

27.2

16-0

.02

(-10.

41 to

10.

36)

CBT

21.7

19.9

2326

.626

.422

23.1

27.0

2126

.727

.121

0.30

(-9.

38 to

9.9

9)

Card

iore

spira

tory

fitn

ess (

HR su

bmax

(bpm

))

UC

115.

416

.622

114.

116

.821

113.

019

.921

112.

014

.720

ET11

5.5

16.6

2111

7.8

11.7

1811

3.1

15.5

1611

4.1

15.2

172.

72 (-

2.41

to 7

.85)

CBT

117.

416

.322

111.

015

.322

109.

814

.119

110.

413

.621

-2.2

4 (-7

.20

to 2

.72)

73


5

T1T2

T3T4

Mea

nSD

nM

ean

SDn

Mea

nSD

nM

ean

SDn

Beta

(95%

CI)

Mus

cle

stre

ngth

(MV

T st

rong

est l

eg (N

m))

UC

82.0

51.5

2184

.650

.320

79.0

47.7

1986

.046

.619

ET94

.340

.719

100.

242

.817

92.9

33.0

1499

.746

.114

5.31

(-6.

13 to

16.

74)

CBT

106.

454

.123

104.

050

.022

106.

149

.821

98.8

41.1

19-1

.74

(-12.

62 to

9.1

5)

Mus

cle

stre

ngth

(MV

T w

eake

st le

g (N

m))

UC

62.7

35.7

1465

.034

.714

62.7

31.0

1464

.733

.114

ET69

.841

.113

77.3

43.5

1274

.437

.510

83.1

42.9

106.

16 (-

7.23

to 1

9.56

)

CBT

82.4

46.5

1780

.447

.217

88.7

49.2

1677

.940

.614

1.67

(-10

.72

to 1

4.07

)

Actu

al d

aily

phy

sica

l acti

vity

leve

l (da

ily s

tep

coun

t)

UC

6426

2856

1970

5036

1918

6939

2708

1962

0025

4715

ET66

4723

3422

6853

2875

1868

2128

6215

6405

2714

1710

6 (-9

88 to

120

1)

CBT

6803

2636

2264

0425

2018

6832

2595

2062

6825

3318

-153

(-12

35 to

928

)

Func

tiona

l cap

acit

y (T

UG

(sec

))

UC

11.3

2.0

2110

.82.

321

11.0

2.3

2110

.62.

120

ET10

.52.

622

9.6

2.0

199.

91.

716

9.6

2.0

17-0

.61

(-1.3

7 to

0.1

5)

CBT

10.8

4.9

2310

.33.

322

9.7

2.5

2010

.84.

518

-0.1

9 (-

0.92

to 0

.55)

Func

tiona

l cap

acit

y (2

-MW

T (m

))

UC

110.

220

.121

111.

624

.121

111.

824

.221

113.

325

.420

ET11

8.0

23.8

2212

4.0

26.1

1911

5.1

19.5

1612

2.1

24.2

173.

63 (-

3.61

to 1

0.88

)

CBT

122.

427

.423

121.

627

.421

123.

528

.521

122.

428

.919

-0.2

0 (-7

.36

to 6

.97)

Illne

ss c

ogni

tions

(ICQ

Hel

ples

snes

s (6–

24))

UC

11.5

3.3

2211

.53.

919

11.3

3.9

2011

.64.

419

ET12

.24.

021

11.8

3.1

1811

.73.

716

11.0

2.9

16-0

.19

(-1.3

4 to

0.9

7)

CBT

10.7

2.9

2210

.92.

322

10.8

2.8

2110

.42.

421

-0.1

3 (-1

.24

to 0

.98)

74

Chapter 5

T1T2

T3T4

Mea

nSD

nM

ean

SDn

Mea

nSD

nM

ean

SDn

Beta

(95%

CI)

Illne

ss c

ogni

tions

(ICQ

Acc

epta

nce

(6–2

4))

UC

15.8

4.1

2216

.14.

319

14.8

4.3

1915

.24.

719

ET17

.44.

421

18.5

3.2

1817

.73.

816

18.6

3.2

16-0

.07

(-1.3

1 to

1.1

7)

CBT

17.5

3.9

2217

.84.

122

17.9

4.0

2118

.13.

822

0.17

(-1.

02 to

1.3

7)

Illne

ss c

ogni

tions

(ICQ

Per

ceiv

ed b

enefi

ts (6

–24)

)

UC

15.8

4.1

2216

.14.

319

14.8

4.3

1915

.24.

719

ET15

.15.

021

16.4

3.3

1714

.84.

316

15.3

4.2

160.

17 (-

1.28

to 1

.61)

CBT

14.4

4.2

2114

.04.

322

14.3

5.1

2113

.45.

022

-0.7

0 (-2

.10

to 0

.71)

Copi

ng (C

ISS-

21 T

ask

orie

nted

cop

ing

(7–3

5))

UC

25.6

4.5

2226

.05.

419

25.0

6.3

2025

.36.

018

ET24

.53.

521

25.9

3.9

1824

.62.

916

25.4

2.2

16-0

.04

(-2.3

0 to

2.2

2)

CBT

25.5

3.3

2324

.25.

622

25.5

5.5

2124

.85.

022

-1.0

6 (-3

.21

to 1

.10)

Copi

ng (C

ISS-

21 A

void

ance

cop

ing

(7–3

5))

UC

17.9

6.2

2218

.66.

919

18.1

7.3

2016

.26.

018

ET17

.35.

321

18.0

5.4

1817

.85.

816

18.9

5.9

161.

37 (-

1.00

to 3

.74)

CBT

18.2

5.9

2317

.27.

022

17.1

6.0

2116

.57.

222

-1.2

2 (-3

.47

to 1

.04)

Copi

ng (C

ISS-

21 E

moti

onal

cop

ing

(7–3

5))

UC

16.0

4.7

2216

.14.

419

14.3

4.8

2016

.24.

918

ET16

.26.

121

14.8

6.4

1815

.45.

816

14.6

4.5

16-0

.33

(-2.4

5 to

1.7

9)

CBT

17.3

5.3

2314

.85.

222

14.9

4.1

2114

.56.

022

-1.8

9 (-3

.93

to 0

.15)

Gen

eral

sel

f-effi

cacy

(ALC

OS-

16) (

16–8

0))

UC

62.9

7.6

2263

.19.

919

63.0

9.5

2063

.210

.219

ET60

.011

.420

62.0

12.5

1861

.212

.416

62.6

10.4

16-1

.14

(-4.

98 to

2.7

1)

CBT

64.0

8.7

2366

.110

.822

65.8

10.0

2164

.09.

721

1.06

(-2.

55 to

4.6

6)

75


5

Abbr

evia

tions

; VAS

, Visu

al A

nalo

gue

Scal

e (h

ighe

r sco

res i

ndic

ating

mor

e pa

in);

POM

S, S

hort

ened

Pro

file

of M

ood

Stat

es (h

ighe

r sco

res i

ndic

ating

mor

e m

ood

dist

urba

nces

); N

HP-

slee

p, N

otting

ham

Hea

lth P

rofil

e, d

omai

n: s

leep

(hig

her

scor

es in

dica

ting

mor

e sl

eep

prob

lem

s); M

VT, m

axim

al v

olun

tary

torq

ue (M

VT) o

f the

qua

dric

eps

mus

cles

; TU

G, T

imed

-Up-

and-

Go

test

; 2-M

WT,

2-m

inut

e w

alk

test

; ICQ

, Illn

ess

Cogn

ition

s Q

uesti

onna

ire (h

ighe

r sco

res

indi

catin

g hi

gher

leve

ls of

the

conc

erni

ng il

lnes

s co

gniti

on);

CISS

-21,

Cop

ing

Inve

ntor

y fo

r Str

essf

ul S

ituati

ons (

high

er sc

ores

indi

catin

g th

at th

e pa

rticu

lar c

opin

g st

yle

is us

ed m

ore

often

); AL

COS-

16, G

ener

al S

elf E

ffica

cy S

cale

(hig

her

scor

es in

dica

ting

high

er se

lf-effi

cacy

).

76

Chapter 5

DISCUSSIONThis 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 (mean differences in CIS20-F score: 1.47, 95%CI -2.84 to 5.79 for ET versus UC; and 1.87, 95%CI -2.24 to 5.98 for CBT versus UC). 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.

Additional interventions varied between the groups, however it seems unlikely this could explain the absence of positive effects of the interventions. Slightly more new co-in-terventions were prescribed in the UC-group during the study period compared with the in-tervention-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 interven-tions 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 lead-ing 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 3 adverse events were reported and these were all resolved, indicat-ing that this intervention was safe. The absence of effects on fatigue, activities, and HRQoL in the ET group compared with UC is consistent with the absence of positive effects on the different parameters of physical capacity (i.e. cardiorespiratory fitness, muscle strength and functional capacity) as found in our study. These results are in line with the results of 3 studies on the effectiveness of ET in PPS that also reported no effects on fatigue and activities.26-28 To our knowledge only 1 study showed positive effects of a hospital-based aerobic training program on physical capacity, fatigue, and HRQoL.10 The results of that study should be interpreted with caution since they were based on within group-differenc-es. Possible explanations for the dissimilarity in results may be related to the younger age of patients in that study, the different exercise mode used, namely treadmill walking, and/or the training intensity based on ratings of perceived exertion.

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 fa-tigue, chronic fatigue syndrome, and multiple sclerosis.23,29,30 People affected with PPS have spent a lifetime managing the challenges of living with functional limitations and have ex-perienced long durations of fatigue. These factors may explain the differences in results. One could hypothesize that the PPS-population has a relatively high degree of acceptance of fatigue symptoms compared with other diseases. The assumption that alleviation of fa-tigue is not a priority is supported by the finding that for some patients allocated to CBT, the patient and therapist could not identify fatigue-related problems and goals to work on

77


5

and therefore the CBT intervention was not initiated. Furthermore, the treatment protocol for CBT was based on a model of perpetuating factors of fatigue in slowly progressive neu-romuscular disorders in general.18 Since relationships among the factors in the model can be different in PPS, this model might be less valid in this patient population.

This is the first study evaluating the effect of CBT on reducing fatigue in PPS and the effect of 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.12 Furthermore, we evaluated patients over a long-term and utilized a broad arsenal of outcome measures from different domains of the International Classification of Functioning, Disability, and Health (ICF), including patient-re-ported outcomes.

Generalization of the study results to the PPS population is considered to be good, since patients were recruited from different centers throughout the Netherlands and a large pro-portion of the diagnosed PPS-patients in the Netherlands (more than 900) were assessed for eligibility in this study. Furthermore the sociodemographic and disease characteristics in our sample are comparable to that in previous cohort-studies in polio survivors in the Netherlands31 and other countries.7,32

Our results demonstrate that neither ET nor CBT were superior to UC in reducing fa-tigue or improving activities and HRQoL in severely fatigued PPS patients. Considering the negative results of these 2 substantially different interventions, which have been proven effective in other patient populations23,29,30,33,34 and the wide range of other interventions that were unsuccessful,8 it seems that fatigue in PPS is quite resistant to therapy. Further research should investigate explanations for the lack of efficacy of these 2 currently advised approaches in clinical practice,35 which may provide clues to improve treatment aimed at reducing fatigue in PPS.

Acknowledgments

The authors thank the patients; the referring rehabilitation medicine consultants of the participating hospitals and rehabilitation centers (Academic Medical Center Amsterdam; University Medical Center Nijmegen; Roessingh Rehabilitation Center, Enschede; University Medical Center Utrecht; University Medical Center Rotterdam (Erasmus MC); Rehabilitation Center Merem de Trappenberg, Huizen; Rehabilitation Center Leijpark, Libra Zorggroep, Til-burg) and the therapists of the ET and CBT interventions.

78

Chapter 5

REFERENCES

1. Tersteeg IM, Koopman FS, Stolwijk-Swuste JM, et al. A 5-year longitudinal study of fatigue in patients with late-onset sequelae of poliomyelitis. Arch Phys Med Rehabil 2011;92:899-904.

2. Schanke AK, Stanghelle JK. Fatigue in polio survivors. Spinal Cord 2001;39:243-51.

3. 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;80:136-43.

4. On AY, Oncu J, Atamaz F, et al. Impact of post-polio-related fatigue on quality of life. J Rehabil Med 2006;38:329-32.

5. Jensen MP, Alschuler KN, Smith AE, et al. Pain and fatigue in persons with postpolio syndrome: independent effects on functioning. Arch Phys Med Rehabil 2011; 92: 1796-801.

6. Berlly MH, Strauser WW, Hall KM. Fatigue in postpolio syndrome. Arch Phys Med Rehabil 1991;72:115-8.

7. 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;1:442-9.

8. Koopman FS, Uegaki K, Gilhus NE, et al. Treatment for postpolio syndrome. Cochrane Database Syst Rev 2011;2:CD007818.

9. 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;88:1452-64.


11. Davidson AC, Auyeung V, Luff R, et al. Prolonged benefit in post-polio syndrome from compre-hensive rehabilitation: a pilot study. Disabil Rehabil 2009;31:309-17.


13. March of Dimes Birth Defects Foundation. Identifying Best Practices in Diagnosis & Care. Pro-ceedings of the International conference on Post-Polio Syndrome; May 19-2000; Warm Springs, GA. New York, USA: March of Dimes; 2001. Available at: http://www.polioplace.org/sites/de-fault/files/files/MOD-%20Identifying.pdf. Accessed September 25, 2014.

14. Dittner AJ, Wessely SC, Brown RG. The assessment of fatigue: a practical guide for clinicians and researchers. J Psychosom Res 2004;56:157-70.

15. Birk TJ. Polio and Post-Polio Syndrome. In: Durstine JL, Moore GE, eds. Exercise Management for Persons with Chronic Diseases and Disabilities. Champaign: Human Kinetics 2003: 273-80.

16. Medical Research Council. Aids to the examination of the peripheral nervous system. London: Her Majesty’s Stationary Office: 1976.

17. Mulder T. A process-oriented model of human motor behavior: toward a theory-based rehabil-itation approach. Phys Ther 1991;71:157-64.

18. Kalkman JS, Schillings ML, Zwarts MJ, et al. The development of a model of fatigue in neuro-muscular disorders: a longitudinal study. J Psychosom Res 2007;62:571-9.

19. Ostlund G, Wahlin A, Sunnerhagen KS, et al. Vitality among Swedish patients with post-polio: a physiological phenomenon. J Rehabil Med 2008;40:709-14.

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20. Schanke AK. Psychological distress, social support and coping behaviour among polio survivors: A 5-year perspective on 63 polio patients. Disabil Rehabil 1997;19:108-16.

21. de Bruin AF, Diederiks JP, de Witte LP, et al. The development of a short generic version of the Sickness Impact Profile. J Clin Epidemiol 1994;47:407-18.

22. Aaronson NK, Muller M, Cohen PD, et al. Translation, validation, and norming of the Dutch lan-guage version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol 1998;51:1055-68.

23. Gielissen MF, Verhagen S, Witjes F, et al. Effects of cognitive behavior therapy in severely fa-tigued disease-free cancer patients compared with patients waiting for cognitive behavior therapy: a randomized controlled trial. J Clin Oncol 2006;24:4882-7.

24. Twisk, J.W.R. Applied longitudinal data analysis for epidemiology: a practical guide. Cambridge: University Press 2003: 280-5.

25. Horemans HL, Nollet F, Beelen A, et al. Pyridostigmine in postpolio syndrome: no decline in fatigue and limited functional improvement. J Neurol Neurosurg Psychiatry 2003;74:1655-61.

26. Willen C, Sunnerhagen KS, Grimby G. Dynamic water exercise in individuals with late poliomy-elitis. Arch Phys Med Rehabil 2001; 82:66-72.

27. Ernstoff B, Wetterqvist H, Kvist H, et al. Endurance training effect on individuals with postpolio-myelitis. Arch Phys Med Rehabil 1996; 77:843-8.

28. Murray D, Horgan F, Campion A, et al. 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;46:589.

29. Kessel K.van, Moss-Morris R, Willoughby E, et al. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom Med 2008;70:205-13.

30. Price JR, Mitchell E, Tidy E, et al. Cognitive behavior therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev 2008;3:CD001027.

31. Stolwijk-Swuste JM, Beelen A, Lankhorst G, et al. Impact of age and co-morbidity on the func-tioning of patients with sequelae of poliomyelitis: a cross-sectional study. J Rehabil Med 2007; 39:56-62.

32. Winberg C, Flansbjer UB, Carlsson G, et al. Physical activity in persons with late effects of polio: a descriptive study. Disabil Health J 2014;7:302-8.

33. Pilutti LA, Greenlee TA, Motl RW, et al. Effects of exercise training on fatigue in multiple sclero-sis: a meta-analysis. Psychosom Med 2013;75:575-80.

34. Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Co-chrane Database Syst Rev 2012;11:CD006145.


Chapter 6

AEROBIC EXERCISE TRAINING IN POST-POLIO SYNDROME: PROCESS EVALUATION OF THE FACTS-2-PPS TRIAL

To be submitted

Eric L. VoornFieke S. Koopman

Merel A. BrehmKarin H.L. Gerrits

Arnold de HaanAnita BeelenFrans Nollet

66

82

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ABSTRACTObjective: A recent study failed to show improvements in cardiorespiratory fitness through a home-based high intensity aerobic exercise program in post-polio syndrome (PPS). We performed a process evaluation to explore reasons for the lack of efficacy by quantifying actual training dose and evaluating the effect of the program on muscle function.Methods: Forty-four individuals with PPS were randomized to exercise therapy (n=22) or usual care (n=22). Participants exercised 3 times weekly for 4 months on a bicycle ergome-ter (>60% heart rate reserve). We determined the training time spent within the designated target heart rate range, as well as the time at or above the anaerobic threshold (AT). For muscle function, we measured muscle endurance.Results: The attendance rate was high (median 89%), but nobody trained within the target heart rate range >75% of the designated time. Instead, participants exercised at lower in-tensities; around the AT most of the time. We found no improvement in aerobic capacity: muscle endurance (1.6%, 95%CI -10.6 to 13.7) nor cardiorespiratory fitness (submaximal heart rate, -0.3 beats per minute, -7.8 to 7.2) increased in the exercise group, compared to usual care.Conclusions: Individuals with PPS were unable to adhere to a high intensity aerobic training program on a bicycle ergometer. Despite exercise intensities around the AT most of the training period, aerobic capacity did not improve. The lack of efficacy on muscle function does not support the assumption of deconditioning of muscles of the lower extremities in PPS.

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Aerobic exercise training in PPS: process evaluation

6

INTRODUCTIONIndividuals with post-polio syndrome (PPS) generally report fatigue as their main prob-

lem.1,2 This fatigue is known to be multidimensional and consists, besides cognitive and psychological components also of physical aspects.3 One of the factors responsible for physical fatigue may be a reduced aerobic capacity resulting from a lower physical activity level.4,5 Recently, we reported the results of a randomized controlled trial on the efficacy of exercise training (FACTS-2-PPS trial) that failed to show improvements in fatigue through a 4-month exercise therapy intervention with a home-based high intensity aerobic exercise program.6

In the FACTS-2-PPS trial we also observed no change in cardiorespiratory fitness, as-sessed from heart rate response, following the 4-month exercise program.6 This contra-dicts findings of several previous studies, showing the potential of aerobic training in PPS.7,8 Clarifying the reasons for the lack of efficacy of the FACTS-2-PPS exercise program may provide insight in the potential role of aerobic training and optimal training methods for alleviating fatigue symptoms in PPS.

One possible explanation for the lack of efficacy is that individuals could not adhere to the program. During the 4-month program, designated training intensity was gradually increased from 60% heart rate reserve (HRR) to 70% HRR, in accordance with the American College of Sports Medicine (ACSM) guidelines for aerobic training in healthy subjects and persons with chronic diseases.9 In addition, training duration was increased from 28 to 38 minutes. Although it has been reported that individuals with PPS tolerate such high inten-sity programs,7,8,10-13 most of these studies provided incomplete or no insight in the training intensity and duration actually achieved. It is therefore currently still uncertain whether individuals with PPS can adhere to an aerobic training program based on these guidelines.

Also, the optimal training dose (in terms of intensity and duration), its relationship with the subsequent training response and the mechanisms of improvement are currently still unknown in PPS. It is well known that regular aerobic training induces both central (i.e. car-diorespiratory) and peripheral (i.e. muscular) adaptations.14 Furthermore, it is known that improvement of cardiorespiratory fitness requires involvement of large muscle groups to impose an adequate stimulus for adaptations.15 Possibly, the FACTS-2-PPS exercise program did result in muscular adaptations, which, due to the reduced muscle mass of the lower extremities, did not lead to an increased cardiorespiratory fitness. On the other hand, if no muscular adaptations occurred following the exercise program, this indicates that training dose was apparently insufficient to induce a positive training response.

In the current study we present the results of a process evaluation of the exercise in-tervention of the FACTS-2-PPS trial. We investigated the following research questions: (1) Are individuals with PPS able to adhere to a 4-month high intensity home-based aerobic training? (2) Does a high intensity home-based aerobic training result in improved muscu-lar function? (3) To what extent does actual training dose explain the variance in training response?

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METHODSThe data used in the present study comes from the multicenter FACTS-2-PPS trial on

the efficacy of exercise therapy (ET) and cognitive behavioral therapy (CBT) on reducing fa-tigue, and improving activities and quality of life in PPS. Two previous publications describe the study design16 and the main results6 of the trial. In the present study we compared the group allocated to ET to the usual care (UC) group. Outcomes in both groups were assessed at baseline (pre-treatment) and after 4 months (post-treatment). Two assessors, who were blinded for treatment allocation, tested participants at each occasion.

Participants

Participants were recruited from 7 hospitals and rehabilitation centers throughout the Netherlands. Participants were initially screened by a physician to check the in- and exclu-sion criteria. Inclusion criteria were: diagnosis of PPS according to the criteria as published by the March of Dimes1; severe perceived fatigue (subscale fatigue severity of the Checklist Individual Strength (CIS20-F) ≥35);17 age between 18 and 75 years; life-expectancy longer than 1 year; walking-ability at least indoors with or without walking aid; and ability to cycle on a cycle ergometer against a load of at least 25 Watts. Exclusion criteria are described elsewhere.16 The medical ethics committees of the hospitals and rehabilitation centers in-volved approved the study protocol, and written informed consent was obtained from all participants.

Interventions

UC: The participants in the UC and ET group all received usual care. Usual care for PPS could include the use of assistive devices and/or orthoses, physical therapy, and medication use. Participants were not restricted in their activities.

ET: Exercise therapy lasted 4 months and consisted of (1) a home-based aerobic training program on a bicycle ergometer 3 times weekly and a (2) supervised group training contain-ing muscle strengthening and functional exercises once a week.

(1) Participants were supplied with a bicycle ergometer (Kettler X7, Germany) and a log-book containing the training scheme. In the logbook, participants documented the number and duration of treatment sessions, their perceived exertion of the training on the Borg Scale (range 6–20 )18 and possible complaints after the training session. Training intensity was gradually increased from 60% to 70% of the estimated HRR. The HRR was calculat-ed as the difference between the predicted maximal heart rate (220 minus age)19 and the heart rate at rest. Participants were instructed to monitor the training intensity by check-ing their hear rate (HR), which was continuously measured by HR monitors (Polar RS400, Polar Electro Nederland, Almere, The Netherlands). Duration of the training sessions was gradually increased from 28 to 38 min per session (including 5 min warming-up and 5 min cooling-down) and sessions were divided into prescribed exercise bouts, which were in-terspersed with short rest periods of unloaded cycling. The duration of exercise bouts was increased from 2 min at the start of the program to 13 min at the end of the program. Fea-sibility of the training scheme was checked weekly by one of the therapists by reading the HR monitors and checking the logbooks.

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6

(2) The supervised group training consisted of strengthening exercises and functional exercises in 1-hour group sessions. The therapist selected functionally relevant muscles for strengthening exercise before the start of the program. Functional exercise selection was based on the best expected effects on physical functioning.

Outcomes

Adherence: The attendance rate of ET was assessed by recording the fraction of home-based training sessions as recorded in the participants’ logbooks. To determine whether participants adhered to the designated training program, we used the data from the HR monitors to establish the total time that participants trained in their prescribed target HR range (60% to 70%HRR). Individuals were considered adherent if they exercised >75% of the possible time in their prescribed target HR range.

In addition, we established the total time that participants trained at or above the HR corresponding to their anaerobic threshold (AT). This is of interest because the AT is often used to target training intensity, in healthy subjects20 and individuals with chronic disease.21-23 We recently demonstrated that the recommended training intensity based on current guidelines is above the AT in many individuals with PPS, especially when target intensity is set at 60%HRR or higher.24 Besides evaluating whether individuals with PPS can adhere to a high intensity program, we therefore also established whether they are capable of exercising at or above their AT. We considered this to be the case if individuals trained >75% of the possible time at or above their AT. The AT was determined by 2 independent experienced researchers, through visual inspection of the gas exchange plots from the pre-treatment submaximal incremental exercise test using the V-slope method.25

Muscle function: For muscle function, we assessed both muscle endurance and strength. As a measure of muscle endurance we determined the fatigue resistance of the knee ex-tensor muscles (at 60° knee flexion) by a series of intermittent electrically evoked isometric contractions (150 contractions of 1 s duration and 1 s of rest in between) with the use of a fixed dynamometer. Fatigue resistance was defined as the percentage torque remaining during the last minute of the protocol.26 Measurements were performed on the weakest leg, unless during manual muscle testing grading of knee extension strength was <3, ac-cording to the Medical Research Council Scale (MRC).27 An extensive description of the protocol can be found elsewhere.16,26

For muscle strength we measured the maximal voluntary torque (MVT) of the knee ex-tensor muscles isokinetically between 90° and 30° knee flexion at a velocity of 60°/s using a fixed dynamometer (Biodex System 3, New York, USA). The MVT of each leg was measured separately and we included the best of 3 maximal efforts in the analysis. If the MRC-score was <3, strength measurements were not performed. Data for isokinetic strength measure-ments are presented both for the strongest leg and the weakest leg.

Cardiorespiratory fitness: The previously reported results, indicating no change in the cardiorespiratory fitness following training, solely considered the submaximal HR response as prespecified outcome measure.6 However, other indices of HR and gas exchange out-comes, as well as values of perceived exertion could reveal possible cardiorespiratory ad-aptations.

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From the submaximal incremental cycle ergometry tests,16 we assessed changes in rest-ing heart rate, oxygen consumption at the AT, submaximal oxygen consumption (Vo2submax), submaximal respiratory exchange ratio (RERsubmax), and submaximal ratings of perceived exertion (RPEsubmax). Vo2submax, RERsubmax and RPEsubmax were assessed at the highest similar submaximal workload that was achieved both during the pre- and post-treatment assess-ment (i.e. the workload differed between participants but within participants the same standardized workload was used for comparison).

Adverse effects

All adverse events (such as severe muscle fatigue, joint pain, or other events consid-ered to be related to ET) reported spontaneously by the participants or observed by the therapist were recorded and followed until they abated or until a stable situation had been reached.

To evaluate whether the training program resulted in muscular overload, blood samples were taken to determine serum creatine kinase (CK) activity as an index of muscle dam-age.28 CK activity levels were determined pre-treatment, 5 and 10 weeks after the start of the intervention and post-treatment.

Statistical analysis

Descriptive statistics were used to characterize the sample. For normally distributed data, we used the paired-samples t test to test differences within the groups and the Stu-dent t test to test differences between groups; in case of non-normally distributed data, the Wilcoxon signed-rank test and Mann-Whitney U test were used. To study the course of CK activity levels during the intervention period in the ET group, we used the Friedman test.

Using a linear regression model, we determined the extent to which the actually achieved training dose explained the variance in submaximal HR change (∆HRsubmax). Session training doses (calculated as the duration of the session multiplied by the mean %HRR for that session) were added up for each participant to obtain the total actual training dose.29 We visualized the relationship in a plot. Statistical analyses were performed with the SPSS statistical software package (version 20.0.0.1). An alpha level of 0.05 was used for all tests of significance.

RESULTSIn total 44 participants were included in the analyses (22 in UC and 22 in ET). The flow

of participants through the study is reported elsewhere.6 Table 1 shows the characteristics of participants in the UC and ET group.

Figure 1 shows that the attendance rate for the aerobic exercise sessions at home was high (median 89%). Eight participants (36%) attended <75% of the possible sessions. The 3 most frequently reported reasons for missing a training session were fatigue, illness and muscle pain.

Three participants used beta blockers. In addition, due to technical problems, HR data was incomplete in 5 other participants. HR data in the remaining participants (n=14) showed

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6

that nobody trained within their designated target HR range >75% of the possible time (Fig. 2). Group mean values for the mean duration achieved during the sessions for each week of the program are presented in Figure 3A, illustrating that training duration increased in accordance with the protocol. Figure 3B shows the group mean values for the mean HRR achieved during the exercise bouts for each training week. There was a pattern of increas-ing intensity throughout the entire training program, but, in all except 2 participants, it remained below designated intensities.

We identified the AT in 18 participants (82%) of whom 14 had complete training HR data. Most of these participants (71%) trained >75% of the possible time at or above the HR corresponding to their AT (Fig. 4). Participants who attended >75% of possible sessions, all trained >75% of the possible time at or above their AT.

Ratings of perceived exertion during the training sessions were incomplete (data in <80% of the sessions) in 9 participants. In the remaining participants (n=14), the perceived exertion showed an increasing pattern throughout the entire training period (Fig. 5). The percentage of participants who rated at least half of the weekly training sessions as 12 or higher on the Borg Scale increased from 71%, to 91%, to 100% in the 1st, 8th and 16th week of the program, respectively.

Table 1. Participant characteristics.

ET

(n=22)

UC

(n=22)

Demographic data

Mean age (y) 60.1±7.4 56.7±8.9

Female (%) 11 (50%) 13 (59%)

BMI (kg/m2) 26.5±3.4 25.6±4.3


Age at acute polio (y) 3 (1–40) 2 (0–16)

Time since new symptoms (y) 13.2±7.7 14.6±9.5

Present walking distance, n (%)a

Around the houseSeldom further than 1 kmRegularly further than 1km

9 (41%)8 (36%)5 (23%)

6 (27%)11 (50%)5 (23%)

MMT testing sum score legsb 67.8 (41.8–80.0) 69.6 (43.0–80.0)

MMT testing sum score armsc 50.0 (32.0–50.0) 50.0 (16.8–50.0)

Data are mean ± SD, number (%), or median (range).Abbreviations: ET, exercise therapy; UC, usual care; BMI, body mass index; MMT, manual muscle testing.aWalking distance was defined as the daily distance walked and was classified in 4 categories: 1 (indoors only), 2 (around the house), 3 (seldom >1km), and 4 (regularly >1km).bSum score for muscle strength of the legs was calculated by adding 16 muscle groups. Each muscle group had a score between 0 and 5, sum score ranged from 0 to 80.27

cSum score for muscle strength of the arms was calculated by adding 10 muscle groups. Each muscle grouphad a score between 0 and 5, sum score ranged from 0 to 50.27

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Chapter 6

Figure 1. Individual attendance rates in the exercise therapy group.

Figure 2. Total time within the target heart rate range for participants in the exercise therapy group.

Figure 3A. Group mean values (± SD) for training duration achieved during the training sessions for each week of the program. Grey bars indicate designated duration; black bars indicate the actually achieved duration.

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6

Figure 3B. Group mean values (± SD) for intensity sustained during the exercise bouts for each week of the pro-gram. Grey bars indicate designated intensity; black bars indicate the actually achieved intensity.

Figure 4. Total time at or above the heart rate corresponding to the anaerobic threshold for participants in the exercise therapy group.

Figure 5. Group mean values (± SD) for the perceived exertion of training sessions for each week of the training program.

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Chapter 6

Tabl

e 2.

Out

com

e m

easu

res p

re- a

nd p

ost-t

reat

men

t in

the

ET a

nd U

C gr

oup.

ETU

CET

vs U

C

nPr

e-

trea

tmen

t

Post

-

trea

tmen

t

nPr

e-

trea

tmen

t

Post

-

trea

tmen

t

Mea

n di

ffere

nce

in c

hang

e sc

ores

(95%

CI)

Mus

cle

endu

ranc

e an

d st

reng

th

Fatig

ue re

sist

ance

(% re

mai

ning

torq

ue)

346

.3±2

.553

.7±6

.54

40.3

±2.8

46.0

±5.9

1.6

(-10.

6 to

13.

7)

MVT

str

onge

st le

g (N

m)

1610

0.3±

41.6

105.

1±39

.120

81.9

±52.

884

.6±5

0.3

2.0

(-10.

2 to

14.

2)

MVT

wea

kest

leg

(Nm

)11

76.3

±40.

779

.3±4

5.0

1462

.7±3

5.7

65.0

±34.

70.

7 (-1

5.0

to 1

6.5)

Card

iore

spira

tory

fitn

ess

Subm

axim

al H

R (b

pm)

1812

1.0±

14.1

119.

0±12

.021

119.

1±19

.111

7.3±

19.4

-0.3

(-7.

8 to

7.2

)

Resti

ng H

R (b

pm)

1874

.2±8

.077

.1±1

3.2

2173

.0±1

1.3

74.5

±11.

51.

4 (-

4.5

to 7

.3)

AT (m

L/m

in/k

g)13

15.5

±4.4

16.3

±4.3

1115

.4±2

.414

.5±2

.41.

7 (-1

.6 to

4.9

)

Subm

axim

al V̇

o 2 (m

L/m

in/k

g)19

17.1

±4.6

17.0

±4.7

2115

.7±4

.515

.6±4

.90.

1 (-1

.0 to

1.2

)

Subm

axim

al R

ER19

0.94

±0.0

90.

94±0

.06

210.

95±0

.08

0.97

±0.0

8-0

.02

(-0.

06 to

0.0

2)

Subm

axim

al R

PE19

13.5

±2.0

12.9

±2.0

2113

.5±2

.413

.0±2

.1-0

.1 (-

1.5

to 1

.3)

Abbr

evia

tions

: ET,

exe

rcise

the

rapy

; UC,

usu

al c

are;

CI,

confi

denc

e in

terv

al; M

VT, m

axim

al v

olun

tary

torq

ue; H

R, h

eart

rat

e; V̇

o 2 , o

xyge

n co

nsum

ption

; RER

, res

pira

tory

ex

chan

ge ra

tio; R

PE, r

ating

of p

erce

ived

exe

rtion

.

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6

Table 2 shows the outcomes pre- and post-treatment, together with the difference in change scores between ET and UC. We found no significant intervention effect of ET for muscle endurance (1.6%, 95%CI -10.6 to 13.7) and muscle strength (strongest leg 2.0Nm, 95%CI -10.2 to 14.2; weakest leg 0.7Nm, 95%CI -15.0 to 16.5) compared to UC. Also, we found no change in muscle function within both groups, and there were no significant dif-ferences within and between the groups for any of the cardiorespiratory fitness measures.

Figure 6 shows that training dose was not associated with the ∆HRsubmax (R2=0.024, p=0.565).

Three adverse events were reported in the ET group (joint pain of the knee and elbow, and trochanteric bursitis). In 1 patient this led to discontinuation of the intervention. All 3 adverse events were resolved. CK activity levels pre-treatment (median 105.5 U/L, inter-quartile range 71.3–266.3 U/L) were above reference values of healthy individuals in 9 of the 22 participants (41%). Values did not change significantly over time (p=0.552).

Figure 6. Relationship between submaximal heart rate change (∆HRsubmax) and total actual training dose.Abbreviations: bpm, beats per minute.

DISCUSSIONIn the present study, the training dose, in terms of intensity and duration during a high

intensity home-based aerobic training program was quantified in a group of individuals with PPS. Despite the high attendance rate, participants were not able to adhere to the high intensity training program. Nevertheless, participants instead exercised at or little above their AT most of the training period but this did not result in improved muscle function or cardiorespiratory fitness. Our results confirmed that the training program is safe, but not effective in increasing the aerobic capacity of individuals with PPS.

Even though participants attended most training sessions, our results clearly demon-strate that only few of them seem capable of exercising at high intensities (>60 %HRR) for prolonged periods of time. This is surprising, given earlier reports that high intensity train-ing programs are well tolerated by individuals with PPS.7,8,10-13 From these reports, we found only 2 studies describing the mean duration and intensity actually achieved during training sessions. Participants in the 4-month aerobic exercise program of Jones and colleagues,

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for example, were able to adhere to designated intensities of 70–75%HRR; the mean HR during the training period represented 69.2%HRR.12 The higher HRR achieved during their training program may result from the seemingly better exercise capacity pre-treatment and younger age of participants compared to our study group. Comparison is however hampered by the lack of information about demographics and polio characteristics. Fur-thermore, little information was provided about individual variation. Based on the marked individual variations in the actually achieved training dose found in the present study, it may well be that in the Jones study, not all participants could sustain high intensities. This is corroborated by the fact that, as mentioned by the authors, in some participants, duration and intensity had to be adjusted downward. Modifications in exercise intensity were also required in the study by Kriz and colleagues,11 who showed that the mean HR during their arm ergometry training program represented only 50%HRR, while target intensity was set at 70%–75%HRR, a pattern similar to our study. Based on these findings, it may therefore be concluded that, for most individuals with PPS, high exercise intensities seem too exhausting to sustain during training.

While high intensities were difficult to sustain, participants exercised at or above their AT during most of the training period. Participants rated most training sessions as 12 or higher on the Borg Scale, which is in line with findings from a recent study showing that in PPS, the HR attained at the AT corresponds well to a score of 12 on the Borg Scale.24 None-theless, against our expectations, we found no indications of increased cardiorespiratory fitness levels following the aerobic training program.

It may be that our training program resulted in positive muscular adaptations, which, due to the reduced muscle mass of the lower extremities, did not lead to an increased cardiorespiratory fitness. However, as for the cardiorespiratory fitness, we found no indica-tions of an improved muscle function –i.e. neither muscle endurance nor muscle strength significantly improved in the ET group, compared to UC. It is important to realize though that findings regarding muscle function, especially those for endurance, should be inter-preted with caution because they are based on a small number of observations. Possibly, the presence of muscular adaptations could not be detected due to the small sample size.30

When assuming that muscle function was indeed not improved as a consequence of the training program, this indicates that, apparently, the training dose was not sufficient to induce positive training effects. The absence of muscular adaptations in our study is consis-tent with findings from Willén and colleagues who also found no changes in knee extensor muscle function following a 5-month dynamic water exercise program.8 Contrary, Ernstoff and colleagues found an increased muscle strength in some –mainly upper extremity– mus-cle groups, as well as an increased fatigue resistance of the weaker leg, though without any change in aerobic enzyme activity or cross-sectional areas of the muscle fibers.7 A possible explanation for the absence of muscular adaptations in our study is that the involved mus-cles were, apart from the reduced muscle mass, not deconditioned in most individuals. We recently found that fatigue resistance of the knee extensor muscles in PPS was not differ-ent from healthy subjects.26 Possibly, this muscle group, has already adapted considerably in response to the relative higher loading during daily life activities.26,31 This is supported by findings of extensive type I fiber predominance and fiber type hypertrophy.32,33 It may therefore be difficult to improve muscular function and cardiorespiratory fitness through

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exercise that is primarily performed with lower extremities. The increased cardiorespirato-ry fitness found by Willén, Ernstoff, and colleagues could be explained by the fact that their training programs were aimed at whole body exercise, whereas our training program only included training of the lower extremities.

Furthermore, we found that training dose was not associated with the change in car-diorespiratory fitness. This contrasts findings in runners and young soccer players, where explained variance values ranging from 45% to 76% were reported.34,35 A possible expla-nation for this inconsistency relates to the different methods used for calculating the indi-vidual training dose. Had we used a more individualized approach, based on the individual physiological response, this may have resulted in a stronger association.34,35 On the other hand, in healthy persons, the large variability in the way individuals react to training is, besides training dose, also influenced by several other factors such as the subjects’ initial fitness level, psychological factors and genetics.29 It is therefore conceivable that in PPS, other, probably disease specific factors, play a major role as well. One factor that may be of major importance in PPS is the pretraining muscle function and, therewith the potential for trainability of muscles.32,33

Strengths and limitations

A strength of the present study is that we carefully monitored HR of individuals during their home-based training program, enabling us to quantify the actual training dose. The finding that, contrary to earlier reports most individuals with PPS were unable to adhere to a high intensity program emphasizes the necessity to monitor the actually achieved training dose and to reconsider the application of such programs in clinical practice. The fact that we did not select participants based on the presence of deconditioning could be considered a limitation of the present study. Hypothetically, deconditioned participants have more potential to benefit from aerobic training. A more targeted selection, aimed at patients with deconditioned muscles, may have yielded better treatment effects.

Clinical implications

Increasing the aerobic capacity through exercise may be possible in PPS, provided that training programs are highly individualized with respect to the aerobic (muscle) capacity. In some individuals, the muscles that are required for activities in daily life have probably already been largely adapted as a consequence of extensive use, limiting the potential for muscle adaptations. Therefore, for those individuals, increasing the aerobic capacity may be possible by using exercise modes that require the use of other large muscle groups in-stead.

In other individuals, the muscles that are required for daily tasks may be deconditioned due to physical inactivity. In this case, exercise modes should be selected that require the use of those deconditioned muscle groups, in order to improve the aerobic (muscle) capac-ity. Therefore, when prescribing aerobic exercise, one should determine whether function-ally important muscle groups are underloaded during daily life activities. If this is the case, those muscle groups should be involved in the training regime. If not, other exercise modes should be considered.

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Even though it remains uncertain whether there exists a training intensity below which no improvement occurs with training, we now know that, for most individuals with PPS in-tensities of >60%HRR are too exhausting to sustain during training. Instead training intensi-ty prescription based on the AT or alternatively on RPE, rather than on a fixed percentage of the HRR for the entire study group, offers a more individualized target for aerobic training in PPS. Whether this can also be applied to other exercise modes such as arm ergometry or four limb ergometry is uncertain and requires further investigation.

Conclusion

Despite a high attendance rate, individuals with PPS seem unable to adhere to a high intensity home-based aerobic training program on a bicycle ergometer. Although partic-ipants, instead trained around their AT most of the training period, the program did not result in an increased aerobic capacity, as neither cardiorespiratory fitness nor muscle function improved. A possible next step is to study the efficacy of training programs based on exercise modes tailored to the individual’s aerobic (muscle) capacity. This information would facilitate the development of highly individualized training programs that may even-tually alleviate fatigue in individuals with PPS.

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REFERENCES



3. 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;92:899-904.



6. Koopman FS, Voorn EL, Beelen A et al. RCT on exercise therapy and cognitive behavioral thera-py to reduce fatigue in post-polio syndrome. Submitted.



9. Birk TJ. Polio and Post-Polio Syndrome. In: Durstine, J.L., Moore, G.E., editors. Exercise Man-agement for Persons with Chronic Diseases and Disabilities. Human Kinetics, 2009;chapter 43.





14. Kenney WL, Wilmore JH, Costill DL. Physiology of Sport and Exercise. Human Kinetics Publish-ers, 2012.

15. Garber CE, Blissmer B, Deschenes MR et al. American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, mus-culoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing ex-ercise. Medicine and science in sports and exercise 2011;43:1334-1359.


17. Vercoulen JHM, Alberts M, Bleijenberg G. De Checklist Individuele Spankracht (CIS). Gedrags-therapie 1999;32:131-136.

18. Borg G. Perceived exertion as an indicator of somatic stress. Scand J Rehabil Med 1970;2:92-98.

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19. American College of Sports Medicine. Resource manual for guidelines for exercise testing and prescription. Lippincott Williams & Wilkins. Seventh edition, 2012;p 466-482.





24. Voorn EL, Gerrits KH, Koopman FS, Nollet F, Beelen A. Determining the anaerobic threshold in post-polio syndrome: comparison with current guidelines for training intensity prescription. Arch Phys Med Rehabil 2014.

25. Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp BJ. Principles of exercise testing and interpretation; including pathophysiology and clinical applications. Lippincott Williams & Wil-liams, 2005;p. 146-150.


27. Medical Research Council. Aids to examination of the peripheral nervous system. Memoran-dum no. 45. London: Her Majesty’s Stationary Office, 1976.

28. Manfredi TG, Fielding RA, O’Reilly KP, Meredith CN, Lee HY, Evans WJ. Plasma creatine kinase activity and exercise-induced muscle damage in older men. Med Sci Sports Exerc 1991;23:1028-1034.

29. Borresen J, Lambert MI. The quantification of training load, the training response and the effect on performance. Sports Medicine 2009;39:779-795.

30. Voorn EL, Brehm MA, Beelen A, de Haan A, Nollet F, Gerrits KH. Reliability of contractile properties of the knee extensor muscles in individuals with post-polio syndrome. PLoS One 2014;9:e101660.

31. Bickerstaffe A, van Dijk JP, Beelen A, Zwarts MJ, Nollet F. Loss of motor unit size and quadriceps strength over 10 years in post-polio syndrome. Clin Neurophysiol 2014;125:1255-1260.



34. Akubat I, Patel E, Barrett S, Abt G. Methods of monitoring the training and match load and their relationship to changes in fitness in professional youth soccer players. J Sports Sci 2012;30:1473-1480.

35. Manzi V, Iellamo F, Impellizzeri F, D’Ottavio S, Castagna C. Relation between individualized train-ing impulses and performance in distance runners. Med Sci Sports Exerc 2009;41:2090-2096.

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Chapter 7

GENERAL DISCUSSION

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The aim of this thesis was to expand the body of knowledge on the diminished aerobic capacity of individuals with post-polio syndrome (PPS). The studies described in this thesis were based on the assumption that, besides a reduced muscle mass, deconditioning con-tributes to the severely diminished aerobic capacity found in many of these individuals. Deconditioning may result from two factors, the disease process itself and a sedentary lifestyle. While the disease process itself is irreversible, deconditioning as the consequence of a sedentary lifestyle may be reversed by increasing physical activity in daily life or by following exercise programs.

In chapters 2 and 3 of this thesis it was investigated whether altered intrinsic properties of the muscle fibers and peripheral circulation underlie early muscle fatigue, thereby limit-ing the aerobic capacity in PPS. Chapters 4, 5, and 6 focused on aerobic exercise in PPS: in particular on determining the appropriate individual training intensity and evaluating the effectiveness of an intervention aimed at improving the aerobic capacity through lower extremity exercise in a randomized controlled trial, FACTS-2-PPS. In this final chapter, the main findings of these studies are discussed along with their implications for clinical prac-tice. Furthermore, methodological considerations of the studies performed are addressed as well as recommendations for future research.

MAIN FINDINGS

Muscle adaptations and aerobic muscle capacity in post-polio syndrome

The results from the study described in chapter 3 did not support the assumption of deconditioning of the remaining muscle mass in individuals with PPS. The objective of this study was to investigate fatigue resistance of the knee extensor muscles in individuals with PPS during electrically evoked contractions in comparison with healthy subjects in the same age range. The rate of fatigue appeared to be comparable in both groups both in the situation with intact circulation and when the blood flow was occluded. Moreover, there were no differences in favor of the healthy subjects with respect to the recovery of fatigue, which depends to a great extent on the aerobic capacity of the muscle fibers. Contrary to muscle biopsies from individuals with PPS showing a reduced capillary supply and aerobic enzyme activity,1,2 these results argue against an impaired blood flow or reduced aerobic capacity of the fibers in PPS muscles.3

Despite the findings suggesting that aerobic muscle capacity in PPS does not differ from healthy individuals, a marked variability was observed, underscoring the heterogeneity in muscle function between individuals. Hence, aerobic metabolism may be reduced in part of the individuals with PPS as well as in part of the healthy adults. The results of the study described in chapter 2 showed that the assessment of contractile properties, as obtained from electrically evoked contractions, is sufficiently reliable to distinguish individuals with PPS with different fatigue resistance of the knee extensor muscles from each other, and, to evaluate changes over time following interventions. Furthermore, considering the high reliability, it is unlikely that differences between individuals with PPS and healthy subjects could not be detected.

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Aerobic exercise training in post-polio syndrome

The anaerobic threshold (AT) is widely used for setting target intensity for aerobic train-ing4-7 Usually, the AT is assessed through graded maximal exercise testing. In PPS, and other neuromuscular diseases (NMDs), maximal exercise testing is not feasible in all individuals because performance is often symptom-limited. Furthermore, because of the potential risk of muscular overload and excessive fatigue, with a prolonged recovery, maximal exercise testing should be avoided.

In chapter 4 it was shown that submaximal incremental exercise testing can be used for assessment of the AT in most individuals with PPS who can cycle on a bicycle ergometer, enabling physical therapists to better individualize exercise intensity for aerobic training. Furthermore, current guidelines for training intensity prescription based on ratings of per-ceived exertion (RPEs) corresponded better to the AT than prescription based on estimated heart rate reserve (HRR). Considering these findings, it was recommended that, if the AT cannot be identified (e.g. because gas analysis equipment is not available), training pre-scription should preferably be based on RPEs, rather than on a fixed percentage of the estimated HRR for the entire study group, offering a more individualized target for aerobic training in PPS.

Because these new insights regarding the AT were not yet available prior to the start of the FACTS-2-PPS trial, intensity prescription of the aerobic exercise program was still based on the estimated HRR, an easy applicable method. The results of the FACTS-2-PPS trial were described in chapter 5 and failed to show improvements in fatigue through an exercise therapy intervention with a home-based high intensity aerobic exercise program. This was consistent with the absence of an increased cardiorespiratory fitness following the training program.

The process evaluation in which possible causes for the lack of efficacy were explored (chapter 6) revealed that participants attended most training sessions, and that the actu-ally achieved duration of the training sessions increased in accordance with the protocol. Actually sustained exercise intensities, on the other hand, increased throughout the en-tire training program, but remained clearly below designated intensities (60%–70%HRR) in nearly all participants. Other studies investigating high intensity aerobic exercise programs in PPS also showed that, in some participants, duration and intensity had to be adjusted downward.8,9 Based on these findings, it was concluded that, for most individuals with PPS, high exercise intensities are too exhausting to sustain during training on a bicycle ergom-eter.

While high intensities were difficult to sustain, it was shown that participants in the exercise program of the FACTS-2-PPS trial exercised at or above their AT during most of the training period. In addition, participants rated most training sessions as 12 or higher on the Borg Scale, which is in line with findings from a recent study showing that in PPS, the heart rate attained at the AT corresponds well to a score of 12 on the Borg Scale.10 Nonetheless, there were no indications of improved cardiorespiratory fitness levels following the exer-cise program. This is surprising given the extensive use of the AT for setting target intensity for aerobic training, which has shown to be effective in healthy subjects,7 as well as in indi-viduals with chronic disease.4-6

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Subsequently, it was investigated whether the exercise program resulted in positive muscular adaptations, which, due to the limited muscle mass of the lower extremities, did not lead to an increased cardiorespiratory fitness. However, as for the cardiorespiratory fit-ness, there were no indications of an improved muscle function –neither muscle strength, nor muscle endurance improved following the training program (chapter 6). It must be realized though that the findings regarding muscle function, especially those for endur-ance, should be interpreted with caution because they are based on a limited number of observations. Possibly, the presence of muscular adaptations could not be detected due to the small sample size.11

When assuming that muscle function was indeed not improved as a consequence of the training program, this indicates that, apparently, the training dose was insufficient to induce positive training effects. The absence of muscular adaptations following the FACTS-2-PPS exercise program is consistent with findings from Willén and colleagues who also found no changes in knee extensor muscle function following a 5-month dynamic water exercise program.12 Contrary, Ernstoff and colleagues found an increased muscle strength in some –mainly upper extremity– muscle groups, as well as an increased fatigue resistance of the weaker leg, though without any change in aerobic enzyme activity or cross-sectional areas of the muscle fibers.13 Together with the results from chapter 3 this raises the ques-tion whether the muscles of the lower extremities in PPS were, apart from the reduced muscle mass, deconditioned. Hence, as it was shown in older adults that individuals with the lowest aerobic capacity show the greatest response to training it may be possible that the potential for aerobic muscle adaptations induced by the exercise program in the FACTS-2-PPS study group was limited.14

Physical activity, training and aerobic capacity in post-polio syndrome

Several studies have shown that polio survivors are less active than healthy controls using both reported activity and objectively measured activity.15-17 Using activity monitors, Klein, Winberg, and colleagues reported mean values of 6450 and 6212 steps per day, re-spectively,16,17 which is comparable to the values found in the FACTS-2-PPS trial. The mean number of steps recorded in the FACTS-2-PPS trial varied between 6200 and 7050 per day.18 Based on the proposed recommendations of 8000 to 10000 steps per day, most individuals with PPS are therefore considered to be “low active” according to Tudor-Locke and col-leagues.19 These authors suggested that 3000 to 4000 steps are needed for daily activities and consider less than 5000 steps per day indicative of a sedentary lifestyle in healthy adults.

In addition, based on reported activity measures, Winberg and colleagues found that the amount of physical activity varied considerably among individuals with PPS, but on average participants in their study were active almost 3 hours per day. This suggests that individuals with PPS meet the WHO recommendations of 150 minutes of physical activity per week. However, much of the activities in PPS are performed as part of their household activities, which are generally considered as low level physical activities.16 The recommen-dations by the WHO may include household chores, but they have to be at least moder-ate in intensity and performed in bouts of at least 10 minutes in order to be beneficial in

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health.20 Considering that most of the activities performed by individuals with PPS are low level physical activities, whereas the WHO recommends activities that are at least mod-erate in intensity, it was concluded that most of them do not reach the recommended amount of physical activity.16 The question is, however, whether such extrapolation from healthy persons to individuals with PPS is allowed.

It is in this light important to realize that if a person’s capacity is reduced as a conse-quence of muscle paresis from polio, performing activities in daily life will require more of the available capacity. Brehm, Nollet and colleagues found that the energy cost and heart rate were higher in polio survivors compared to healthy subjects for walking and during cycling on an ergometer, mainly in association with the reduced muscle mass.21,22 Activ-ities being characterized as low intensity in healthy adults (such as household activities) may therefore well be of moderate intensity in people with residuals of polio. This may explain why there were, apart from the reduced muscle mass, no signs of deconditioning of the knee extensor muscles found in the FACTS-2-PPS study group.23 Possibly, this muscle group, that is of major importance during locomotion-related activities, has already adapt-ed considerably in response to the relatively higher loading during daily life activities. A recent study showing that the muscle strength declines at a slower rate in PPS compared to healthy age-matched persons supports this hypothesis. The extra loading of the reduced muscle mass during daily tasks could act as a stimulus to help maintain strength.24 That the remaining muscles of polio subjects are adapted as a consequence of the extensive use in daily life is further corroborated by findings of type I fiber predominance and muscle fiber hypertrophy in lower extremity muscles.1,25 Whether these muscular adaptations were also present in participants of the FACTS-2-PPS trial is however not entirely certain because there were no muscle biopsies taken.

The finding that, in most individuals with PPS, the muscles of the lower extremities appear not be deconditioned, does not necessarily imply that exercise is to be considered an ineffective method to improve the aerobic capacity in PPS. There are in fact studies that demonstrated an improved aerobic capacity following aerobic training.12,13 Other studies found an improved peak workload, however, without demonstrating effects on cardiore-spiratory fitness or aerobic muscle capacity.8,26,27 Because it cannot be ruled out that the improved peak workload is the result of habituation rather than an improved aerobic ca-pacity, these studies provide no conclusive evidence on the efficacy of training to improve the aerobic capacity in PPS. Contrary to the FACTS-2-PPS exercise program, the training programs of Willén, Ernstoff, and colleagues aimed at whole body exercise, including the use of muscle groups of the upper extremities.12,13 It is well conceivable that the additional use of other large muscle groups explains why cardiorespiratory fitness levels increased in their study group, while fitness levels remained unchanged following the FACTS-2-PPS exercise program. Despite an increased cardiorespiratory fitness, the studies by Willén, Ernstoff and colleagues found however little or no improvement in lower extremity muscle function. This is in line with findings from the FACTS-2-PPS trial and corroborates the other findings arguing against deconditioning of the lower extremity muscles.

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STRENGTHS AND LIMITATIONS OF THE THESIS

Study population

One could criticize the selection of the population studied in this thesis. Participants had to be able to cycle on an ergometer, and walk, with or without walking aids. Further-more, the FACTS-2-PPS trial was a relatively demanding study with extensive assessments for which participants sometimes had to travel far. Possibly this resulted in a selection of participants with a rather good exercise capacity. Nevertheless, the distance covered during the 2 minute walk test, was somewhat lower in participants of the FACTS-2-PPS trial (mean (SD), 118 (23) meters at baseline in the exercise therapy group), compared to par-ticipants from a previous cohort of polio survivors, the CARPA cohort (136 (28) meters)).28

The CARPA cohort included participants with co-morbidities and is therewith considered a good representation of the general population of polio survivors. Therefore, even though walking capacity is not the sole determinant of exercise capacity, there are no clear indi-cations that our inclusion criteria resulted in a selection bias toward participants with a better physical capacity, thereby restricting generalizability of results to the population of individuals with PPS in general.

Measurements

The measurements for muscle function were performed solely on the knee extensor muscles and not on other muscle groups. Although from literature it is known that the effects are widespread and not necessarily restricted to one muscle group29 this muscle group was investigated, because muscle weakness in PPS often affects the lower limbs, and also measurements can easily be performed on this muscle group that is of major importance for locomotion-related activities.30 Nonetheless, even though it is considered legitimate to perform measurements on the knee extensor muscles, it must be realized that results cannot simply be generalized to other muscles, because muscle function char-acteristics may differ between muscle groups depending on their use in daily life.

A limitation of using electrically evoked contractions to evaluate muscle function is that not all participants tolerate the electrical stimulation. Both, in the cross-sectional study and in the FACTS-2-PPS trial a number of participants did not complete the measurements due to discomfort of the electrical stimulation. In addition, some participants had difficulty in relaxing the muscles during the stimulated contractions. This resulted in fewer observa-tions that could be included in the analyses. Involuntary muscle activation has been report-ed in earlier studies, but the factors responsible for this are unknown.31,32 Especially in the FACTS-2-PPS trial, a substantial number of participants discontinued the muscle endurance measurements. Of the 31 participants performing these measurements at baseline, only 16 participants were willing to perform the measurements after the intervention period. The explanation for this high dropout rate is not fully known to us because the reasons for with-drawal were not explored in detail. Some participants experienced the stimulated mus-cle contractions as uncomfortable. Others found the FACTS-2-PPS trial highly demanding. The muscle function measurements were performed on a separate occasion, which may explain why part of the participants decided not to participate in the follow up measure-

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ments. Therefore, the findings regarding muscle function, especially those for endurance, should be interpreted with caution because they are based on a limited number of obser-vations. This is less the case for the cross-sectional study results. Because of the relatively large sample size included in this study, the withdrawal of some participants probably did not influence the results concerned. For both studies, however, the possibility cannot be excluded that there was a selection bias, possibly toward less severely affected patients, which may have influenced results.

The intervention

A principal strength is that the heart rate of all participants was monitored during the training sessions of the FACTS-2-PPS exercise program. This enabled us to quantify actual training dose in terms of intensity and duration. Even though previous training studies re-ported their designated program,8,12,13,26,27 most of these studies provide incomplete or no insight in the training intensity and duration actually achieved. The process evaluation of the FACTS-2-PPS exercise program showed that training duration increased in accordance with the protocol. More importantly, even though there was a pattern of increasing in-tensity throughout the training program, it remained clearly below designated intensities (60%–70%HRR). Contrary to earlier reports, these findings indicate that high exercise inten-sities are too exhausting to sustain during training in PPS. Moreover, they emphasize the need to monitor the actually achieved training dose and to reconsider the application of such programs in clinical practice.

CLINICAL IMPLICATIONSIncreasing the aerobic capacity through exercise may be possible in PPS, provided that

training programs are highly individualized with respect to the aerobic (muscle) capacity. In part of the individuals, the muscles that are required for activities in daily life have probably already been largely adapted as a consequence of extensive use. During recovery from the acute polio, denervated muscle fibers from permanently lost motor neurons were rein-nervated by means of collateral sprouting from intact axons, leading to the formation of giant motor units.33 Furthermore, the remaining muscle fibers hypertrophied in response to exercise and performing daily life activities. Although the reduced muscle mass is most likely the primary factor responsible for the diminished aerobic capacity in those individu-als, it seems, in the light of these muscular adaptations, undesirable to increase the muscle mass in order to improve the aerobic capacity. Therefore, for those individuals, increasing the aerobic capacity may be possible by using exercise modes that require the use of other large muscle groups instead. One must realize, however, that if the involved muscles are not used during daily life activities, the obtained training effects will probably not sustain and therefore not result in improved physical functioning and perceived health in the long term.

In other individuals with PPS, the muscles required for daily tasks may be deconditioned due to physical inactivity. Obviously, in this case, exercise modes should be selected that require the use of those deconditioned muscle groups, in order to improve the aerobic

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(muscle) capacity. Therefore, when prescribing aerobic exercise, one should determine whether functionally important muscle groups are underloaded during daily life activities. If this is the case, those muscle groups should be involved in the training regime. If not, oth-er exercise modes should be considered. The fatigue resistance measurements that were presented in this thesis can be used to determine the extent to which the knee extensor muscles, a muscle group that is of major importance during locomotion-related activities, are deconditioned. Future research is however required to develop new, preferably less de-manding, methods to accurately determine the degree of deconditioning of independent muscle groups.

In addition, training intensity prescription should also be tailored to the individual pa-tient. The AT enables physical therapists to better individualize intensity prescription for aerobic exercise in PPS and can be assessed from submaximal exercise testing on a bicycle ergometer. If the AT cannot be identified, for example because the gas analysis equipment is not available, intensity prescription should preferably be based on RPEs, rather than on a fixed percentage of the HRR. This offers a more individualized target for aerobic training in PPS. Whether this can also be applied to other exercise modes such as arm ergometry or four limb ergometry is uncertain and requires further investigation.

Besides the positive effects on cardiorespiratory and muscle function, physical activ-ity is known to be essential for good health.20,34 Polio survivors have a high prevalence of co-morbidities, which negatively impact on health and quality of life.35,36 Many of the conditions commonly reported in polio survivors, such as type 2 diabetes, stroke and oth-er cardiovascular diseases, have significantly lifestyle related risk factors.37,38 For example, physical activity will reduce the risk of developing type 2 diabetes by improving insulin sensitivity and assist in diminishing elevated blood glucose levels. Therefore, irrespective of the effects of exercise on the aerobic capacity, staying physically active is essential for individuals with PPS.

FUTURE RESEARCHMore research is required to optimize and further individualize training programs for in-

dividuals with PPS. Even though it remains uncertain whether there exists a training inten-sity below which no improvement of the aerobic exercise capacity occurs with training, it is now known that, for most individuals with PPS intensities of >60%HRR seem too exhausting to sustain during cycle ergometry training. However, the participants in the FACTS-2-PPS were capable of exercising around the AT for prolonged periods of time. The fact that no positive effects of training were found, indicates that the selected exercise mode was not appropriate for this study group. Therefore, the next step should be to study the efficacy of training programs based on exercise modes tailored to the individual’s aerobic (muscle) capacity.

Although it may eventually be possible to increase the individual’s aerobic capacity through individualized exercise programs, the potential benefits in terms of physical func-tioning and perceived health should be assessed. In line with the FACTS-2-PPS trial, some other studies reported the effects of training on such outcome measures. The number of studies is however limited, and, moreover, results are inconsistent.39 Further research in

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this area is therefore necessary. In addition, a study in individuals with PPS and other neu-romuscular diseases revealed that this population experiences difficulties with integrat-ing training programs into their lives.40 One of the research priorities for this population is therefore to find the best ways to tailor training to the individual patient, by finding a balance between staying sufficiently physically active the one hand, and preventing over-burdening on the other hand. For, in the end, it is not the effectiveness of aerobic training programs per se, but the potential benefits in terms of physical functioning and perceived health that is the primary concern for individuals with PPS.

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REFERENCES


2. Grimby G, Kvist H, Grangard U. Reduction in thigh muscle cross-sectional area and strength in a 4-year follow-up in late polio. Arch Phys Med Rehabil 1996;77:1044-1048.

3. Blei ML, Conley KE, Odderson IB, Esselman PC, Kushmerick MJ. Individual variation in contrac-tile cost and recovery in a human skeletal muscle. Proc Natl Acad Sci U S A 1993;90:7396-7400.







10. Voorn EL, Gerrits KH, Koopman FS, Nollet F, Beelen A. Determining the anaerobic threshold in post-polio syndrome: comparison with current guidelines for training intensity prescription. Arch Phys Med Rehabil 2014.

11. Voorn EL, Brehm MA, Beelen A, de Haan A, Nollet F, Gerrits KH. Reliability of contractile properties of the knee extensor muscles in individuals with post-polio syndrome. PLoS One 2014;9:e101660.



14. Vaitkevicius PV, Ebersold C, Shah MS et al. Effects of aerobic exercise training in communi-ty-based subjects aged 80 and older: a pilot study. J Am Geriatr Soc 2002;50:2009-2013.


16. 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;7:302-308.


18. Koopman FS, Voorn EL, Beelen A et al. RCT on exercise therapy and cognitive behavioral thera-py to reduce fatigue in post-polio syndrome. Submitted.

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19. Tudor-Locke C, Hatano Y, Pangrazi RP, Kang M. Revisiting “how many steps are enough?”. Med Sci Sports Exerc 2008;40:S537-S543.

20. World Health Organization (WHO).Global recommendations on physical activity for health. Available at: http://www.who.int/dietphysicalactivity/factsheet_recommendations/en/. Ac-cessed September 25, 2014.

21. Brehm MA, Nollet F, Harlaar J. Energy demands of walking in persons with postpoliomyeli-tis syndrome: relationship with muscle strength and reproducibility. Arch Phys Med Rehabil 2006;87:136-140.



24. Bickerstaffe A, van Dijk JP, Beelen A, Zwarts MJ, Nollet F. Loss of motor unit size and quadriceps strength over 10 years in post-polio syndrome. Clin Neurophysiol 2014;125:1255-1260.




28. Stolwijk-Swuste JM, Beelen A, Lankhorst GJ, Nollet F. SF36 physical functioning scale and 2-min-ute walk test advocated as core qualifiers to evaluate physical functioning in patients with late-onset sequelae of poliomyelitis. J Rehabil Med 2008;40:387-394.



31. Gerrits HL, Hopman MT, Sargeant AJ, de Haan A. Reproducibility of contractile properties of the human paralysed and non-paralysed quadriceps muscle. Clin Physiol 2001;21:105-113.

32. McDonnell MK, Delitto A, Sinacore DR, Rose SJ. Electrically elicited fatigue test of the quadri-ceps femoris muscle. Description and reliability. Phys Ther 1987;67:941-945.

33. Einarsson G, Grimby G, Stalberg E. Electromyographic and morphological functional compensa-tion in late poliomyelitis. Muscle Nerve 1990;13:165-171.

34. Danaei G, Ding EL, Mozaffarian D et al. The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors. PLoS Med 2009;6:e1000058.

35. Stolwijk-Swuste JM, Beelen A, Lankhorst G, Nollet F. Impact of age and co-morbidity on the functioning of patients with sequelae of poliomyelitis: a cross-sectional study. J Rehabil Med 2007;39:56-62.

36. Nielsen NM, Rostgaard K, Askgaard D, Skinhoj P, Aaby P. Life-long morbidity among Danes with poliomyelitis. Arch Phys Med Rehabil 2004;85:385-391.

37. Gawne AC, Wells KR, Wilson KS. Cardiac risk factors in polio survivors. Arch Phys Med Rehabil 2003;84:694-696.

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38. Wu CH, Liou TH, Chen HH, Sun TY, Chen KH, Chang KH. Stroke risk in poliomyelitis survivors: a nationwide population-based study. Arch Phys Med Rehabil 2012;93:2184-2188.

39. Koopman FS, Uegaki K, Gilhus NE, Beelen A, de Visser M, Nollet F. Treatment for postpolio syn-drome. Cochrane Database Syst Rev 2011;CD007818.


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Summary / Samenvatting

ENGLISH SUMMARY & NEDERLANDSE SAMENVATTING

SS

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Sumarry

ENGLISH SUMMARYIndividuals with post-polio syndrome (PPS) report fatigue and a decline in their func-

tional abilities, especially walking outdoors, standing, and climbing stairs, as their major problems. Besides loss of muscle mass, an important factor that is assumed to contribute to the symptoms of fatigue and increased difficulties in performing sustained activities is the severely diminished aerobic capacity found in these patients. Aerobic capacity is de-fined as the (maximum) amount of oxygen the body can use during a specified period of exercise. It is a function both of cardiorespiratory performance and the maximum ability to remove and utilize oxygen from circulating blood in the muscles.

The general aim of this thesis was to expand the body of knowledge on the aerobic capacity of individuals with PPS. The studies described in this thesis were designed based on the assumption that, besides a reduced muscle mass, deconditioning contributes to the severely diminished aerobic capacity found in many of these patients. This deconditioning may result from two factors, the disease process itself and a sedentary lifestyle. While the disease process itself is irreversible, deconditioning as a consequence of a sedentary life-style may well be treated by increasing physical activity in daily life or by following exercise programs.

The first objective was to investigate whether besides the reduced muscle mass, altered intrinsic properties of the muscle fibers and peripheral circulation result in early muscle fa-tigue, thereby contributing to the limited aerobic capacity in these individuals. The second objective was to obtain more knowledge about aerobic exercise in PPS: in particular on determining the appropriate individual training intensity and evaluating the effectiveness of an aerobic exercise intervention in the FACTS-2-PPS trial. These topics were introduced in chapter 1.

Knowledge about the origin of muscle fatigue in PPS is presently limited. Muscle fatigue depends on several factors that may reside in the brain or spinal cord (central fatigue), and/or in the muscles themselves (peripheral fatigue). Based on the muscular adaptations that have been described in PPS, it seems likely that mainly peripheral mechanisms, such as the muscle’s aerobic capacity, fiber type composition and capillary supply, are involved in mus-cle fatigue. Investigation of contractile properties can therefore help to understand the or-igin of fatigue. These can be investigated by electrically evoked muscle contractions; an ex-perimental condition that completely removes central mechanisms. Despite the frequent use of electrically evoked muscle contractions to assess contractile properties only limited information is available about the reliability of these measures. The results described in chapter 2 showed that the assessment of contractile properties, as obtained from elec-trically evoked contractions, is sufficiently reliable to distinguish individuals with PPS with different fatigue resistance of the knee extensor muscles from each other, and, to evaluate changes over time following interventions.

The results from the study described in chapter 3 did not support the assumption of deconditioning of the remaining muscle mass in individuals with PPS. The objective of this study was to investigate fatigue resistance of the knee extensor muscles in individuals with PPS during electrically evoked contractions in comparison with healthy subjects in the same age range. The rate of fatigue appeared to be comparable in both groups, both in the situa-

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tion with intact situation and when the blood flow was occluded. Moreover, there were no differences in favor of the healthy subjects with respect to the recovery of fatigue, which depends to a great extent on the aerobic capacity of the muscle fibers. Contrary to muscle biopsies from individuals with PPS showing a reduced capillary supply and aerobic enzyme activity, these results argue against an impaired blood flow or reduced aerobic capacity of the muscle fibers. Despite the findings suggesting that aerobic muscle capacity in PPS does not differ from healthy individuals, a marked variability was observed, underscoring the heterogeneity in muscle function between individuals. Hence, aerobic metabolism may be reduced in part of the individuals with PPS as well as in part of the healthy adults, and exer-cise programs aimed at reducing muscle fatigue in this subgroup might therefore be useful.

Although the evidence base is limited, physical therapy recommendations for individ-uals with PPS include aerobic exercise. The studies that have been conducted so far show inconsistent results, which may, at least in part, be explained by the limited methodological quality of most studies. Another important factor explaining the inconsistent results may relate to the problems therapists experience when designing training schedules for individ-uals with PPS; exercise levels should be sufficiently intense to stimulate a training effect, yet avoid muscular overload. The anaerobic threshold (AT), a direct indicator of someone’s aerobic capacity, may be useful to overcome this problem. The AT is widely used for set-ting target intensity for aerobic training, and is usually assessed through graded maximal exercise testing. In PPS, maximal exercise testing is not feasible in all individuals because performance is often symptom-limited. Furthermore, maximal exercise may provoke mus-cle complaints and excessive fatigue, with a prolonged recovery, and should therefore be avoided. In chapter 4 it was shown that submaximal incremental exercise testing can be used for assessment of the AT in most individuals with PPS who can cycle on a cycle ergom-eter. Furthermore, current guidelines for training intensity prescription based on ratings of perceived exertion (RPEs) corresponded better to the AT than prescription based on estimated heart rate reserve (HRR). Considering this, if the AT cannot be identified (e.g., because gas analysis equipment is not available), training prescription should preferably be based on RPEs, rather than on a fixed percentage of the estimated HRR for the entire study group, offering a more individualized target for aerobic training in PPS.

Based on the knowledge that current evidence regarding exercise therapy in PPS is re-stricted to studies of limited methodological quality, the FACTS-2-PPS trial was designed. FACTS-2-PPS (Fitness And Cognitive behavioral TherapieS for Fatigue and ACTivitieS in Post-Poliomyelitis Syndrome) is a multicenter randomized controlled trial (RCT), in which the effectiveness of exercise therapy (ET) and cognitive behavioral therapy (CBT) was studied on fatigue, daily activities and health related quality of life in patients with PPS. The results of the trial were described in chapter 5, showing that ET nor CBT is superior to usual care in reducing fatigue in severely fatigued individuals with PPS.

Another important finding of the FACTS-2-PPS trial was that cardiorespiratory fitness did not improve through the high intensity home-based aerobic exercise program. The study described in chapter 6 explored reasons for the lack of efficacy by quantifying training dose and evaluating the effect of the training program on muscle function. Results showed that, despite high attendance rates, individuals with PPS seem unable to adhere to a high intensity home-based aerobic training program on a cycle ergometer. Participants trained

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around the AT most of the time, but the program did not result in an improved aerobic ca-pacity as muscle function nor cardiorespiratory fitness increased. Together with the results from chapter 3 this raises the question whether the muscles of the lower extremities in the studied population were, apart from the reduced muscle mass, deconditioned. Possibly, the involved muscles were already adapted considerably in response to the relative higher loading during daily life activities, limiting the potential for muscular adaptations.

The final chapter, chapter 7, summarized and discussed the most important findings of the thesis, together with some methodological considerations. The results of studies were put into a clinical perspective and recommendations for future research were made.

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NEDERLANDSE SAMENVATTINGMensen met het post-polio syndroom (PPS) rapporteren vermoeidheid en een ach-

teruitgang in functioneren, in het bijzonder (buiten) lopen, staan, en traplopen, als hun belangrijkste problemen. Dit kan voor een groot deel verklaard worden door een vermin-derde spiermassa. Een andere factor die een belangrijke rol lijkt te spelen is de verminder-de aerobe capaciteit. De aerobe capaciteit is gedefinieerd als de (maximale) hoeveelheid zuurstof die het lichaam gedurende een bepaalde periode kan gebruiken. Dit proces wordt bepaald door de capaciteit van het cardiorespiratoire systeem en het vermogen van (spier)cellen om zuurstof aan de bloedcirculatie te onttrekken en te gebruiken.

Het doel van dit proefschrift was om meer inzicht te verkrijgen in de verminderde ae-robe capaciteit die bij veel mensen met PPS wordt gevonden. We weten reeds vanuit de literatuur dat de aerobe capaciteit minder is doordat er bij mensen met PPS (veelal) sprake is van een verminderde spiermassa. De onderzoeken die zijn uitgevoerd in het kader van dit proefschrift zijn gebaseerd op de aanname dat naast een verminderde spiermassa, de-conditionering van de resterende spiermassa ook bijdraagt aan de verslechterde aerobe capaciteit in PPS. Deze deconditionering kan het gevolg zijn van een aantal factoren waar-onder het ziekteproces zelf en een inactieve leefstijl. Daar waar het ziekteproces zelf onom-keerbaar is, kan deconditionering als gevolg van een inactieve leefstijl mogelijk behandeld worden door een toename van fysieke activiteiten in het dagelijks leven of door middel van het volgen van een aeroob trainingsprogramma.

De eerste doelstelling van dit proefschrift was om na te gaan in hoeverre veranderde contractiele eigenschappen van de resterende spiervezels en aanpassingen van de perifere circulatie resulteren in vervroegde spiervermoeidheid en daarmee bijdragen aan de ver-slechterde aerobe capaciteit van mensen met PPS. De tweede doelstelling was om meer kennis te vergaren over aerobe training bij mensen met PPS. In het bijzonder zijn we in-gegaan op het bepalen van de individuele intensiteit voor aerobe training en het evalue-ren van de effectiviteit van een aeroob trainingsprogramma. Dit trainingsprogramma was onderdeel van een grote gerandomiseerde gecontroleerde studie; de FACTS-2-PPS studie. Deze onderwerpen werden geïntroduceerd in hoofdstuk 1.

Er is tot op heden weinig bekend over de oorzaak van spiervermoeidheid bij mensen met PPS. Bekend is dat spiervermoeidheid afhankelijk is van meerdere factoren die hun oorsprong vinden in het brein of zenuwstelsel (centrale vermoeidheid) en/of in de spieren zelf (perifere vermoeidheid). In de literatuur zijn reeds veel aanpassingen op spierniveau beschreven bij mensen met PPS. Op basis hiervan lijkt het aannemelijk dat de oorzaak voor spiervermoeidheid in PPS vooral gezocht moet worden in perifere mechanismen, zoals de aerobe spiercapaciteit, spiervezeltype samenstelling en capillarisatie. Het bestuderen van contractiele eigenschappen kan daarom helpen om meer inzicht te verkrijgen in de oorzaak van spiervermoeidheid. Contractiele eigenschappen kunnen worden bestudeerd d.m.v. elektrisch gestimuleerde spiercontracties, een methode waarbij centrale mecha-nismen van vermoeidheid kunnen worden uitgeschakeld. Ondanks veelvuldig gebruik van elektrisch gestimuleerde contracties om contractiele eigenschappen te bepalen is er nog weinig bekend over de betrouwbaarheid van uitkomstmaten die bepaald worden d.m.v. deze methodiek. De resultaten beschreven in hoofdstuk 2 laten zien dat het bepalen van

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contractiele eigenschappen d.m.v. elektrisch gestimuleerde spiercontracties voldoende betrouwbaar is om mensen met PPS met verschillende contractiele eigenschappen van el-kaar te onderscheiden. Ook veranderingen over de tijd of als gevolg van interventies kun-nen voldoende betrouwbaar worden gemeten.

De resultaten beschreven in hoofdstuk 3 sluiten niet aan bij de aanname dat er sprake zou zijn van deconditionering van de resterende spiermassa in mensen met PPS. Het doel van deze studie was om de weerstand tegen vermoeidheid van de knie extensoren, d.m.v. elektrisch gestimuleerde contracties, te bepalen bij mensen met PPS en deze te vergelijken met gezonde mensen van dezelfde leeftijd. Het verloop van de spiervermoeidheid bleek vergelijkbaar in beide groepen, zowel in de situatie waarin de bloedcirculatie intact was als in de situatie waarin de bloedcirculatie geoccludeerd was. Bovendien herstelden mensen met PPS niet langzamer na vermoeidheid t.o.v. gezonden. Het herstel wordt in grote mate bepaald door de aerobe capaciteit van de spiervezels. In tegenstelling tot eerdere bioptstu-dies bij mensen met PPS waarin een verlaagde capillaire dichtheid en verminderde aerobe enzymactiviteit werden gevonden, zijn er op basis van deze resultaten dus geen duidelijke aanwijzingen voor deconditionering van de resterende spiermassa in PPS. Desondanks was er sprake van een grote variabiliteit, wat de heterogeniteit van de PPS populatie bevestigt. Dit duidt erop dat de aerobe spiercapaciteit wel degelijk verslechterd is in een deel van de mensen met PPS, maar ook in een deel van de gezonde mensen. In deze subgroep zouden interventies gericht op spiervermoeidheid mogelijk tot klachtenvermindering kunnen lei-den.

Er is tot op heden onvoldoende bewijs voor de effectiviteit van aerobe training in PPS. Desondanks maakt aerobe training onderdeel uit van de fysiotherapie richtlijnen. De stu-dies die tot nu toe zijn uitgevoerd laten tegenstrijdige resultaten zien. Dit lijkt in ieder ge-val deels verklaard te kunnen worden door de beperkte methodologische kwaliteit van de meeste studies die tot dusverre zijn uitgevoerd. Verder onderzoek is daarom noodzakelijk om definitieve uitspraken te kunnen doen over de effectiviteit van deze interventie. Een andere verklaring voor de inconsistente resultaten zou kunnen liggen in het feit dat fysio-therapeuten problemen kunnen ervaren bij het opstellen van trainingsprogramma’s voor mensen met PPS: de trainingsintensiteit moet voldoende hoog zijn om een effect te be-werkstelligen, terwijl anderzijds de trainingsintensiteit niet te hoog mag zijn i.v.m. het risico op overbelasting. De anaerobe drempel, een directe indicator van iemands aerobe capaci-teit, biedt mogelijk een oplossing. De anaerobe drempel wordt reeds veelal toegepast voor het bepalen van de trainingsintensiteit bij gezonden en mensen met andere chronische aandoeningen. Een probleem is echter dat de anaerobe drempel normaliter bepaald wordt a.d.h.v. een maximale inspanningstest. Bij mensen met PPS wordt maximale inspanning echter afgeraden i.v.m. het mogelijke risico op overbelasting. In hoofdstuk 4 werd aange-toond dat het, bij de meeste mensen met PPS, mogelijk is de anaerobe drempel te bepalen a.d.h.v. een submaximale inspanningstest op een fietsergometer. Daarnaast bleek dat de aanbevolen intensiteit beter overeenkomt met de anaerobe drempel wanneer deze be-paald wordt op basis van de ervaren mate van inspanning (Borgschaal) dan wanneer deze bepaald wordt op basis van een vast percentage van de geschatte maximale hartslag. Als het niet mogelijk is de anaerobe drempel te bepalen (bijvoorbeeld omdat de ademgasana-lyse apparatuur niet beschikbaar is), dan dient de intensiteit dan ook bij voorkeur voorge-

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schreven te worden op basis van de ervaren mate van inspanning.Gebaseerd op het feit dat het huidige bewijs voor fysieke training bij mensen met PPS

gelimiteerd is tot studies van een beperkte methodologische kwaliteit, is de FACTS-2-PPS studie ontwikkeld. Dit is een multicenter gerandomiseerde gecontroleerde studie waarin de effectiviteit is onderzocht van fysieke training en cognitieve gedragstherapie op ver-moeidheid, dagelijkse activiteiten, en de kwaliteit van leven bij mensen met PPS. De resul-taten van deze studie werden beschreven in hoofdstuk 5 en lieten zien dat fysieke training noch cognitieve gedragstherapie een positief effect had op vermoeidheid, dagelijkse activi-teiten, en de kwaliteit van leven vergeleken met de gebruikelijke zorg bij mensen met PPS.

Een andere belangrijke bevinding van de FACTS-2-PPS studie was dat de cardiorespira-toire fitheid niet verbeterde als gevolg van het trainingsprogramma. In hoofdstuk 6 heb-ben we een studie beschreven waarin we op zoek zijn gegaan naar mogelijke verklaringen voor het uitblijven van trainingseffecten. Dit hebben we gedaan door de daadwerkelijke trainingsbelasting te kwantificeren en de effecten van het trainingsprogramma op de spier-functie te evalueren. De resultaten lieten zien dat, ondanks een hoge therapietrouw, men-sen met PPS niet in staat lijken een hoog intensief trainingsprogramma op een fietsergo-meter te volgen. Deelnemers bleken het grootste deel van de trainingsperiode wel actief te zijn geweest op intensiteiten rond de anaerobe drempel. Desondanks vonden we geen verbetering van de aerobe capaciteit; er bleek geen toename van de cardiorespiratoire fitheid noch verbeterde de (aerobe) spierfunctie. Samen met de resultaten van hoofdstuk 3 werpt dit de vraag op in hoeverre er, binnen de onderzochte populatie, sprake was van deconditionering van de resterende spiermassa. Mogelijk waren de betrokken spieren (van de onderste extremiteiten) reeds optimaal geadapteerd als gevolg van de relatief hoge be-lasting tijdens activiteiten in het dagelijks leven. Dit beperkt wellicht de potentie tot het verbeteren van de aerobe capaciteit d.m.v. een vorm van inspanning die gericht is op de onderste extremiteiten.

In het laatste hoofdstuk, hoofdstuk 7, werden de belangrijkste bevindingen van dit proefschrift samengevat en bediscussieerd, naast de bespreking van enkele methodo-logische overwegingen. De resultaten werden in een klinisch perspectief geplaatst en er werden aanbevelingen gedaan voor verder onderzoek gebaseerd op het werk in dit proef-schrift.

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Het is fijn om na afloop van mijn promotietraject de gelegenheid te hebben om de men-sen te bedanken die, ieder op hun eigen wijze, hebben bijgedragen aan de totstandkoming van dit proefschrift. Een aantal mensen wil ik in het bijzonder benoemen.

Allereerst een woord van dank aan alle patiënten en naasten die hun medewerking hebben verleend aan de onderzoeken. Zonder jullie deelname had dit proefschrift in de huidige vorm niet tot stand kunnen komen. Hoewel met name de 'fysieke metingen' zo nu en dan best intensief waren, waren jullie toch keer op keer bereid naar het AMC of de VU te komen. Ik waardeer de energie en tijd die jullie in het onderzoek hebben gestoken en hoop oprecht dat de bevindingen van dit proefschrift bijdragen aan een betere behandeling van mensen met het post-polio syndroom in de (nabije) toekomst.

Prof. dr. F. Nollet, prof. dr. A. de Haan, dr. A. Beelen en dr. K. Gerrits, Frans, Arnold, Anita en Karin, jullie waren als (co-)promotores onmisbaar voor dit project. Het project betrof een samenwerkingsverband tussen de afdeling Revalidatie van het AMC en de Faculteit der Bewegingswetenschappen van de VU en is een mooi voorbeeld van de koppeling tussen fundamenteel en klinisch bewegingswetenschappelijk onderzoek. De betrokkenheid van 2 promotores alsmede 2 co-promotores vanuit verschillende disciplines is mijns inziens dan ook van absolute meerwaarde geweest voor het slagen van dit zeer interessante, mooie en bovenal uitdagende project.

Beste Frans, één van de belangrijkste lessen die ik van jou heb meegekregen is het belang van oplossingsgericht denken. Daar waar anderen veelal geneigd zijn hun aandacht te blijven richten op het probleem, schakel jij vrijwel direct over naar het nadenken over mogelijke oplossingen. Een constructieve werkwijze, die zonder twijfel heeft bijgedragen aan de (relatief snelle) totstandkoming van dit proefschrift. Beste Arnold, ook jouw betrok-kenheid is van grote waarde geweest voor dit project. Vanuit de VU was je vaak wat meer op de achtergrond aanwezig en wist je, daar waar nodig, sturing te geven aan het proces. Ik waardeer jouw enthousiasme en optimisme en wil je bedanken voor het vertrouwen dat je me hebt gegeven. Beste Anita, met jou heb ik de afgelopen jaren zonder twijfel het meest intensief samengewerkt. Je bent een wetenschapper pur sang en ik voel me verwant met jouw kritische denkwijze. Ik heb genoten van onze inhoudelijke discussies waarbij jij er, als geen ander zorg voor hebt gedragen dat de klinische relevantie van onze bevindingen nooit uit het oog werd verloren. Beste Karin, ook bij jou stond en staat de deur altijd open. Ik heb veel geleerd van onze inhoudelijke discussies en waardeer het enorm dat je naast alle zaken omtrent het promotietraject, oog hebt voor en oprechte interesse toont in andere belangrijke zaken daarbuiten.

Beste Fieke, samen waren wij verantwoordelijk voor de organisatie en uitvoering van het FACTS-2-PPS onderzoek. Ik heb onze samenwerking altijd als zeer prettig ervaren. Het was fijn om een ‘sparringpartner’ te hebben, niet alleen voor de inhoudelijke discussies, maar ook om allerlei andere zaken waar je gedurende een promotietraject tegenaan loopt mee te kunnen bespreken. Bedankt voor de fijne samenwerking en heel veel succes ge-wenst voor de komende (laatste) periode. Ik zie ernaar uit je proefschrift te lezen! Merel, bedankt voor het vele organisatorische werk dat jij hebt verzet in het kader van het FACTS-2-NMD onderzoek. Dit was wellicht niet altijd zichtbaar, maar absoluut noodzakelijk voor het slagen van een dergelijk groot onderzoeksproject.

Mijn dank gaat ook uit naar de revalidatieartsen van de deelnemende ziekenhuizen

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en revalidatiecentra die betrokken waren bij de inclusie van de patiënten: Academisch Medisch Centrum Amsterdam, Universitair Medisch Centrum Utrecht, Radboud Universitair Medisch Centrum Nijmegen, Sint Maartenskliniek Nijmegen, Revalidatiecentrum Roessingh, Enschede, Revalidatiecentrum de Trappenberg, Huizen, Libra Revalidatie, locatie Leijpark, Tilburg en Universitair Medisch Centrum Rotterdam. Ook de bij het FACTS-2-PPS onderzoek betrokken behandelaren waren essentieel. In het bijzonder wil ik Ton en Anne-Carien bedanken. Als fysiotherapeuten van de afdeling Revalidatie van het AMC waren jullie zeer intensief betrokken bij het onderzoek, niet alleen bij de uitvoering, maar ook bij de opzet. Bedankt voor jullie tomeloze inzet en het enthousiasme waarmee jullie je werkzaamheden uitvoer(d)en.

Goede randvoorwaarden zijn van groot belang voor de voortgang van onderzoek. Peter Verdijk, bedankt dat je vrijwel altijd direct klaar stond wanneer zich problemen voordeden met de meetopstelling of met de bijbehorende software.

De leden van de promotiecommissie, prof. dr. R.H.H. Engelbert, prof. dr. A.C.H. Geurts, prof. dr. T.W.J. Janssen, prof. dr. W. van Mechelen, prof. dr. J.H. Ravesloot en prof. dr. M. de Visser wil ik bedanken voor de tijd en aandacht die zij hebben besteed aan het lezen en beoordelen van dit proefschrift.

Een plezierige werkomgeving is van groot belang en mijn (ex-)collega’s van de afdeling Revalidatie hebben hier in hoge mate aan bijgedragen. Bedankt allen voor de lunches, wan-delingen, (inhoudelijke) discussies, staalbuigsessies en gezellige (kerst)borrels.

Vrienden en (‘schoon-’)familie, Manfred & Lianne, Robert & Anneroos, Ruud, Bert & Gerlien, Peter & Özlem, Martin & Jenny, Sander & Janine, veel van jullie zullen waarschijnlijk geen duidelijk beeld hebben van waar ik me de afgelopen jaren precies mee bezig heb ge-houden. Desondanks wil ik jullie bedanken voor alle gezellige activiteiten, etentjes, week-endjes weg, borrels en vakanties, die een aangename afleiding vormden van de werkzaam-heden voor mijn promotie. Super dat jullie bij mijn promotie(feestje) aanwezig zijn! Rianne, voor jou een speciaal woord van dank. Ik kan me nog goed herinneren hoe jij jezelf aan mij voorstelde toen wij elkaar voor het eerst zagen. “Hoi, ik ben de zus van mijn zus.” Vanaf dat moment doe je mij keer op keer beseffen dat je de dingen soms ook niet moeilijker moet maken dan ze zijn. Je bent een kanjer!

Beste Jan, hoewel we elkaar niet vaak (genoeg) zien, heb ik die keren dat het er wel van komt, elke keer opnieuw het gevoel alsof we elkaar gisteren nog zagen. Beiden hadden we denk ik niet voorzien dat onze wegen zo parallel zouden lopen als ze tot nu toe hebben gedaan. Ik geniet intens van het uitwisselen van ervaringen en de inhoudelijke discussies die we hebben, maar bovenal natuurlijk van het slappe ouwehoeren. Het is een genot jouw als vriend te mogen hebben. Beste Tom, eerlijkheid gebiedt mij te zeggen dat ik ergens toch wel enigszins jaloers ben op jouw promotieproject. Laten we vooral proberen ons jaarlijkse etentje erin te houden, zodat je me op de hoogte kunt houden van alle ontwikkelingen.

Manfred en Robert, ik vind het fantastisch dat jullie naast mij staan als paranimfen tij-dens de verdediging van mijn proefschrift. Jullie zijn topvrienden en ik hoop dat er nog vele gezellige uitjes mogen volgen!

Bert en Andrea, als broer(tje) ben ik trots op waar jullie nu staan. Ondanks dat het niet altijd even gemakkelijk is geweest, ben ik dankbaar dat we er voor elkaar waren daar waar nodig en sterkt het mij te weten dat we er voor elkaar zullen zijn daar waar het mogelijk in

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de toekomst nodig zal zijn.Lieve pa en ma, het gezegde “de appel valt niet ver van de boom” is zonder meer op mij

van toepassing. Het kan niet anders dan dat jullie 'sportbloed' ook in mijn aderen terecht is gekomen. Bedankt voor al het moois dat jullie mij hebben gegeven. Jullie hebben mij ge-stimuleerd mijn eigen keuzes te maken en mij daarin altijd onvoorwaardelijk gesteund. Ga vooral door op de weg zoals jullie die nu zijn ingeslagen! Jullie zijn ongetwijfeld trots op mij, maar weet dat ik ook ontzettend trots ben op jullie.

Lieve Marjolein, als geen ander weet jij hoe groot mijn passie is voor de bewegingswe-tenschappen. Je steunt mij altijd onvoorwaardelijk en het vertrouwen dat je mij geeft vind ik geweldig! Ik ben ontzettend dankbaar voor jouw liefde, humor en relativeringsvermogen die eraan bijdragen dat ik alle andere (minstens zo) belangrijke zaken in het leven niet uit het oog verlies. Je bent een levensgenieter en maakt me gelukkig door me hierin mee te nemen. Laten we hopen dat er nog veel moois op ons pad mag komen waar we samen van mogen genieten!

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List of publications

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PEER REVIEWED JOURNALS

1. Voorn EL, Koopman FS, Brehm MA, et al. Aerobic exercise training in post-polio syndrome: process evaluation of the FACTS-2-PPS trial. To be submitted.

2. Koopman FS, Voorn EL, Beelen A, et al. RCT on exercise therapy and cognitive be-havioral therapy to reduce fatigue in post-polio syndrome. Submitted.

3. Voorn EL, Brehm MA, Beelen A, de Haan A, Nollet F, Gerrits KHL. Reliability of con-tractile properties of the knee extensor muscles in individuals with post-polio syn-drome. PloS one 2014; 9: e101660.

4. Voorn EL, Gerrits KHL, Koopman FS, Nollet F, Beelen A. Determining the anaerobic threshold in post-polio syndrome: comparison with current guidelines for training intensity prescription. Arch Phys Med Rehabil 2014; 95: 935–940.

5. Voorn EL, Beelen A, Gerrits KHL, Nollet F, de Haan A. Fatigue resistance of the knee extensor muscles is not reduced in post-polio syndrome. Neuromuscul Disord 2013; 23: 892–898.

Curriculum vitae / Portfolio

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CURRICULUM VITAEEric Lukas Voorn was born in Elburg, the Netherlands, on the 13th of March, 1986. In

2004 he graduated from secondary school at the Lambert Franckens College in Elburg. Between 2004 and 2009 Eric studied Human Movement Sciences at the VU University in Amsterdam, specializing in Systems Physiology and Sports. Next to his Master’s degree Eric attained the postgraduate teaching diploma in 2009. After graduating, Eric started his PhD project ‘Aerobic exercise capacity in post-polio syndrome’ at the department of Reha-bilitation of the Academic Medical Center in Amsterdam. The research was conducted in close corroboration with the Faculty of Human Movement Sciences of the VU University. The project was supervised by Prof. dr. Frans Nollet (AMC), dr. Anita Beelen (AMC), prof. dr. Arnold de Haan (VU) and dr. Karin Gerrits (VU) and resulted in the current doctoral thesis.

Since 2013 Eric has been a teacher and supervisor in several courses at the Faculty of Human Movement Sciences of the VU University in Amsterdam. Besides this, he has been involved in developing and teaching of the course ‘Measurements on the Move’ for the Faculty of Medicine of the University of Amsterdam. After completion of his PhD project Eric will be working as a postdoctoral researcher at the Department of Rehabilitation of the Academic Medical Center in Amsterdam.

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PORTFOLIOPhD student: Eric VoornPhD period: December 2009 – January 2015PhD supervisors: Prof. dr. F. Nollet, Prof. dr. A. de Haan

PHD TRAINING

Year Workload (Hours/ECTS)

General coursesOral presentation in English. AMC Graduate school 2014 22/0.8Scientific writing in English. AMC Graduate school 2013 42/1.5Clinical data management. AMC Graduate school 2013 7.5/0.3Expert management of medical literature. AMC Graduate school

2013 5/0.2

Regression techniques. Department of Epidemiology & Biostatistics

2011 35/1.3

Practical biostatistics. AMC Graduate school 2011 32/1.1Epidemiological research: design and interpretation. De-partment of Epidemiology & Biostatistics

2011 30/1.1

Basic course in legislation and organization for clinical researchers. AMC Graduate school

2010 26/0.9

Specific coursesClinical exercise physiology. Faculty of Human Movement Sciences, VU University

2010 84/3

PresentationsGuidelines for training intensity prescription in PPS ‘Vereniging van Revalidatie Artsen’ annual meeting, Rot-terdam, The Netherlands [oral]

2014 14/0.5

Aerobic exercise capacity in post-polio syndrome. Re-search meeting, AMC, Amsterdam, The Netherlands [oral]

2014 14/0.5

Endurance training in PPS: How to target intensity? PHI’s 11th International Conference, Saint Louis, United States [oral]

2014 14/0.5

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Determining the anaerobic threshold in post-polio syn-drome: comparison with current guidelines for training intensity prescription. 19th European congress of physical and rehabilitation medicine, Marseille, France [oral]

2014 14/0.5

Aerobe training bij NMA: hoe bepaal je de juiste inten-siteit. Refereeravond Revalidatie, AMC, Amsterdam, The Netherlands [oral]

2014 14/0.5

Spiervermoeidheid bij mensen met postpolio. Spierziekte-congres VSN, Veldhoven, The Netherlands [poster]

2013 14/0.5

Lokaal en algeheel uithoudingsvermogen in PPS. Research meeting, AMC, Amsterdam, The Netherlands [oral]

2013 14/0.5

Aerobe training in PPS: hoe bepaal je de juiste intensiteit? Plenary session FACTS-2-NMD study group, Utrecht, The Netherlands [oral]

2013 14/0.5

Trainingsintensiteit bij patiënten met het post-polio syn-droom. Neuroteam, AMC, Amsterdam, The Netherlands [oral]

2013 14/0.5

Determining the anaerobic threshold in patients with post-polio syndrome. Verstoord bewegen, AMC, Amster-dam, The Netherlands [oral]

2012 14/0.5

Fatigue resistance of the knee extensor muscles in post-polio syndrome. ‘Vereniging van Revalidatie Artsen’ annual meeting, Noordwijkerhout, The Netherlands [oral]

2012 14/0.5

Fatigue resistance of the knee extensor muscles in post-polio syndrome. 17th annual congress of the Europe-an college of sport science, Bruges, Belgium [oral]

2012 14/0.5

Ervaringen fietstesten FACTS-2-NMD. Plenary session FACTS-2-NMD study group, Utrecht, The Netherlands [oral]

2012 14/0.5

Fatigue resistance of the knee extensor muscles in post-polio syndrome. Research meeting, AMC, Amster-dam, The Netherlands [oral]

2012 14/0.5

Determining the anaerobic threshold in patients with post-polio syndrome. ‘Vereniging van Revalidatie Artsen’ annual meeting, Ermelo, The Netherlands [oral]

2012 14/0.5

Aerobic (muscle) capacity in post-polio syndrome: first results. Research meeting, Faculty of Human Movement Sciences, Amsterdam, The Netherlands [oral]

2011 14/0.5

How to target aerobic exercise training in polio survivors. 1st European polio conference, Copenhagen, Denmark [oral]

2011 14/0.5

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Aerobic (muscle) capacity in post-polio syndrome: first results. Research meeting, AMC, Amsterdam, The Nether-lands [oral]

2011 14/0.5

Aerobic (muscle) capacity in post-polio syndrome (research proposal). Research meeting, Faculty of Human Movement Sciences, Amsterdam, The Netherlands [oral]

2010 14/0.5

Aerobic (muscle) capacity in post-polio syndrome (research proposal). Plenary session FACTS-2-NMD study group, Utrecht, The Netherlands [oral]

2010 14/0.5

Aerobic (muscle) capacity in post-polio syndrome (research proposal). Research meeting, AMC, Amsterdam, The Neth-erlands [oral]

2010 14/0.5

(Inter)national conferences‘Vereniging van Revalidatie Artsen’ annual meeting, No-vember 6–7 , 2014, Rotterdam, The Netherlands

2014 16/0.6

2nd European polio conference, June 25–27, 2014, Amster-dam, The Netherlands

2014 24/0.9

PHI’s 11th International Conference, June 1–3, 2014, Saint Louis, United States.

2014 24/0.9

19th European congress of physical and rehabilitation medicine, May 26–31, 2014, Marseille, France

2014 16/0.6

4th Symposium Verstoord Bewegen, November 26, 2013, AMC, Amsterdam, The Netherlands

2013 4/0.1

3rd Symposium Verstoord Bewegen, November 22, 2012, AMC, Amsterdam, The Netherlands

2012 4/0.1

‘Vereniging van Revalidatie Artsen’ annual meeting, No-vember 1–2 , 2012, Noordwijkerhout, The Netherlands

2012 16/0.6

17th annual congress of the European college of sport science, July 4–7, 2012, Bruges, Belgium

2012 32/1.1

2nd Symposium Verstoord Bewegen, April 24, 2012, AMC, Amsterdam, The Netherlands

2012 4/0.1

‘Vereniging van Revalidatie Artsen’ annual meeting, No-vember 3–4 , 2011, Ermelo, The Netherlands

2011 16/0.6

1st European polio conference, August 31–September 2, 2011, Copenhagen, Denmark

2011 24/0.9

Other Plenary session FACTS-2-NMD study group, May 2014 2014 4/0.1

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Regionale refereeravonden revalidatiegeneeskunde, AMC, January 2014

2014 4/0.1

Plenary session FACTS-2-NMD study group, April 2013 2013 4/0.1Plenary session FACTS-2-NMD study group, March 2012 2012 4/0.1Regionale refereeravonden revalidatiegeneeskunde, AMC, January 2012

2012 4/0.1

Plenary session FACTS-2-NMD study group, March 2011 2011 4/0.12nd Annual MOVE Research meeting, October 2010 2010 4/0.1Plenary session FACTS-2-NMD study group, March 2010 2010 4/0.1Meeting VVBN interessegroep Revalidatie, February 2010 2010 4/0.1

TEACHING

Year Workload (Hours/ECTS)

Teaching, supervising and tutoringWorkshop. Exercise – from theory to practice. 2nd Europe-an polio conference, Amsterdam, The Netherlands

2014 24/0.9

Developing and teaching of the course “Measurements on the Move”, Faculty of Medicine, University van Amster-dam, Amsterdam, The Netherlands

2013/2014

328/11.7

Tutor in the course “Academic Exploration”, Faculty of Human Movement Sciences, VU University, Amsterdam, The Netherlands

2013 12/0.4

Supervisor in the course “Bachelor Thesis”, Faculty of Hu-man Movement Sciences, VU University, Amsterdam, The Netherlands

2013 43/1.5

Teacher in the course “Exercise Physiology”, Faculty of Human Movement Sciences, VU University, Amsterdam, The Netherlands

2013/2014

16/0.6

Practical supervisor in the course “Applied Exercise Physi-ology”, Faculty of Human Movement Sciences, VU Univer-sity, Amsterdam, The Netherlands

2013 24/0.9

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uva-dare (digital academic repository) aerobic exercise ......chapter 5 rct on exercise therapy and...

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