Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Lower Limb Strength Training for Children with Spastic Diplegic Cerebral Palsy receiving Botulinum Neurotoxin Type-A: Outcome Evaluations at all levels of the International Classification of Functioning, Disability and Health. SÎAN ANDREA WILLIAMS BSc (HONS) THIS THESIS IS PRESENTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY THE UNIVERSITY OF WESTERN AUSTRALIA SCHOOL OF SPORT SCIENCE, EXERCISE AND HEALTH THIS RESEARCH WAS CONDUCTED IN CONJUNCTION WITH THE DEPARTMENT OF PEDIATRIC REHABILITATION, AND THE DEPARTMENT OF DIAGNOSITC IMAGING AT PRINCESS MARGARET HOSPITAL FOR CHILDREN. 2012 i ii DECLARATION FOR THESES CONTAINING PUBLISHED WORK AND/OR WORK PREPARED FOR PUBLICATION This thesis contains published work and/or work prepared for publication, some of which has been co-authored. The bibliographical details of the work are presented for each paper. The work involved in designing the studies described in this thesis was performed primarily by Sîan Williams (candidate). The thesis outline and experimental design was planned and developed by the candidate, in consultation from Dr Siobhan Reid, Dr Catherine Elliott, and Dr Eve Blair (the candidates Academic supervisors), and with contributions from Dr Jane Valentine, Dr Anna Gubbay and Miss Nadine Williams. All participant recruitment and management was carried out by the candidate. In addition, the candidate was responsible for all data analysis. The candidate drafted the original thesis, with Dr Siobhan Reid, Dr Catherine Elliott, Dr Jane Valentine, Dr Eve Blair, Dr Anna Gubbay and Miss Nadine Williams providing feedback on drafts until the examinable version was finalised. Student Signature: Coordinating Supervisor Signature: ii ABSTRACT Cerebral Palsy (CP) is one of the most common childhood physical disabilities in the world1. The associated impairments of CP often encompass all components of functioning. Spasticity and muscle weakness are two major motor impairments associated with CP. Botulinum Neurotoxin Type-A (BoNT-A) is a common treatment for spasticity management with many reported functional benefits; however muscle weakness and muscle atrophy have been linked with BoNT-A treatment. Children with CP are already predisposed to decrements in muscle strength and size, therefore any treatment potentially leading to further weakening and atrophy of the muscle should be well understood. This doctorate is written as a series of papers each adding to the understanding of the effects of BoNT-A and strength training in children with CP. The opening paper presented in this thesis is the first known documentation of the morphological alterations of spastic muscle to BoNT-A, alongside information on alterations in muscle strength and functional ability. Ten boys and five girls with spastic diplegia, aged 5-12 years and classified as Gross Motor Function Classification System (GMFCS) level I-II were recruited from the Cerebral Palsy Mobility Service in Perth, Australia, and were assessed before and (approximately 5weeks) after BoNT-A. Outcome measures included isometric dynamometry assessing muscle strength, Magnetic Resonance Imaging (MRI) to measure muscle volume, and the Timed-Up and Go (TUG) test and the 6-Minute Walk Test (6MWT) to assess functional walking capacity. This paper uncovered documented muscle atrophy in BoNT-A injected muscles and hypertrophy of synergist muscles. However, atrophy of the injected muscle was relatively minor compared to evidence provided in animal studies and appeared to have no negative impact on muscle function. Given that the single treatment of BoNT-A did have an effect on muscle morphology, a logical progression of treatment planning would be to combine both BoNT-A treatment (for spasticity management) and strength training (for muscular weakness) to target both impairments simultaneously. The second, third and fourth paper of this thesis aim to provide a comprehensive overview of the combined effect of BoNT-A treatment and a home based strength training intervention. A secondary aim of this thesis is to determine the best practice in terms of timing of application of a strength training intervention in relation to reception of BoNT-A for children with CP. The International Classification of Functioning, Disability and Health (ICF) is utilised by health professionals as best practice for a holistic approach to the iii management of people with disabilities, and is applied throughout this thesis to assess outcomes of the combined interventions of BoNT-A and strength training. The study design, dictated by current clinical care, utilised a repeated measures crosscomparison design. The fifteen children (aged 5-12 years, GMFCS I-II) recruited in this study completed four assessments over 6months timed around receipt of BoNT-A treatment. Children in the study were block randomised by age, gender and GMFCS level into either a PRE or POST BoNT-A strength training group. The PRE group completed home-based strength training in the 12 weeks prior to injection, and the POST group completed the training following injection. A control group of eight children also completed a 6month preintervention baseline phase, with equivalent assessment time points scheduled around their BoNT-A treatment. Paper two addressed alterations at the level of impairment of the ICF, with assessments including isometric and isokinetic dynamometry for muscle strength, spasticity, selective motor control and muscle volume. It also incorporated the Goal Attainment Scale (GAS) which assessed attainment of individual functional goals. Paper two demonstrated that the combination of BoNT-A and strength training was successful in spasticity reduction, improving strength and achieving functional goals, over and above treatment with BoNT-A alone. Neither training in the PRE or POST group resulted in a superior improvement compared to the other. However, the POST group consistently displayed a greater capacity for changes of strength in the immediate (10 week) response to strength training, whilst the PRE group consistently displayed greater changes at 6months. Paper three addressed further changes at the impairment level and included threedimensional gait analysis to assess outcomes of walking gait (the Gait Deviation Index, GDI, and kinetic joint power profiles). This paper demonstrated that the impact of the combined therapy on walking gait was positive, revealing a resulting gait closer to that of typically developing gait, whilst indicating a more efficient use of muscle energy transfer to drive forward locomotion. The POST group demonstrated greater improvements in the GDI, but there was no difference from timing of strength training on the effect of power generation or absorption at the hip, knee or ankle joints. iv Paper four evaluated the effect of the combined therapy at the activity, participation and quality of life (QoL) dimensions of the ICF. At the activity dimension of the ICF, outcome measures included the TUG and the 6MWT. At the participation dimension of the ICF, The Assessment of Life Habits (LIFE-H), measured difficulties in participation in life habits, and Canadian Occupational Performance Measure (COPM) were included. To assess contextual factors of the ICF, The Cerebral Palsy Quality of Life Questionnaire for Children assessed quality of life (QoL). This paper suggests that the combined therapies had a positive impact on activity, participation and QoL, with improvements in the TUG, and some domains of participation and QoL. There was no differential effect of timing on activity, participation and QoL, with the exception of family health, and emotional well-being and self esteem of the child in favour of the PRE group. Small morphologic alterations were established in injected and synergistic muscles, and indicated the need for BoNT-A treatment to be combined with a muscle strengthening intervention for improved outcomes in children with CP. This research has demonstrated successful outcomes of applying home based strength training in combination with BoNT-A injections at all levels of the ICF. Either delivered PRE or POST BoNT-A treatment, strength training may be individually adapted to suit the needs of the child to improve clinical outcomes. CP management is a lifelong challenge that requires clinicians to consider, and treat, the impairments affecting the child holistically. The outcome of this research has significant implications for the prescription of strength training and BoNT-A therapy in the CP population. REFERENCE 1. Paneth N, Hong T, Korzeniewski S. The descriptive epidemiology of cerebral palsy. Clin Perinatol. 2006;33:251-67. v ACKNOWLEDGEMENTS I have been fortunate enough to have the most amazing support and encouragement from so many people in my life through these past four years. I know that these acknowledgments cannot do my gratitude justice. To my (team) of supervisors, you have been patient teachers and constant cheerleaders over the years, and I am so lucky to have had each of you providing me guidance. Si, I don’t even know where to begin. You have dedicated so much of your time and energy to me and this study, I can’t possibly imagine having done this without you and your support. It has meant so much to be able to work with someone like you who has held my hand the whole way through. Cath, thank you for your time, effort, patience and particularly for the support you gave me through the more challenging aspects of this study. You guided me through this clinical study, a domain of which I had no prior experience in. Jane, I am so grateful for your feedback and persistent interest in my work. Your expertise and support has been a huge motivation, thank you for pushing me and challenging me. Eve, it was a privilege to have you on board, thank you so much for all of your insight, feedback and assistance in the development and writing up of this study. Nadine and Anna, thanks to each of you for your help in the development of this complex study, and sharing your areas of expertise to strengthen it. To those involved at Princess Margaret Hospital, at The Department of Paediatric Rehabilitation and the Department of Diagnostic Imaging. Thank you for your time, support and feedback, particularly throughout the planning and incredibly demanding data collection stage of this study. It took the cooperation and understanding of so many of you to make the complex timing of assessments achievable. Tania Shillington, we made it through some crazy months of data collection, and I thank you so much for everything. You made every one of those sessions possible and enjoyable. To the sixteen children and families involved in this study; I am eternally grateful for you all. I am so thank full for the many hours spent not only throughout assessments but also through the strength programs, participation in this study was a huge undertaking! You literally let me into your homes, and into your lives. It was a true pleasure being able to work with you, and vi getting to know each of you. Particularly to my awesome little participants, you inspired me, and were the biggest motivators anyone could ask for. I dedicate this thesis to you. Mum and Dad, thank you so so so much for your unwavering support, encouragement and for putting up with me, I know it can’t have been easy. I hope you both know how much I appreciate your support and love. The way you both live your lives is an inspiration, you brought me up ready to take on anything and everything, and I thank you for this. To my big sisters Ceinwen and Bronwen (and my very big brother-in-law Andy) you have been the best siblings I could ever ask for. Thank you for helping me survive these last few years, whether it be by listening to my problems, feeding me, distracting me, or lending me clothes for conferences. I love you all to bits. To my friends, thank you for being there for me even when I have not been. You have provided some lovely distractions and have been so understanding of my ventures. To my co-inhabitants of 1.55 (and surrounding offices); thank you for the many hours of conversation, chocolate, laughter and company. Nothing can match the advice and help you have given me, and the distractions you have provided me, whilst at times you may not have helped me complete my work, you definitely kept me sane. Jack, thank you for putting up with me and my thesis (and laptop), allowing me to put you second over all these years, comforting me through the (very frequent) times of distress and celebrating with me over each small triumph. I know you put up with a lot, and you always listened, or at least pretended to listen, to me agonising over each and every detail related to this thesis. Thank you for being there for me. vii PUBLICATIONS AND ABSTRACTS The following is a list of publications and abstracts to which I have contributed during the course of my candidature, arising both directly and indirectly from this thesis. The published manuscript and all abstracts are included in the Appendices section of this Thesis. PEER REVIEWED PUBLICATIONS 1. Williams S, Reid S, Valentine J, Blair E, Smith N, Shillington T, Elliott C. The combination of strength training and Botulinum Neurotoxin Type-A in children with Cerebral Palsy: The effect on activity, participation & quality of life. Disabil Rehabil. 2012. In Review. 2. Williams S, Elliott C, Valentine J, Blair E, Reid S. Improving the gait of children with Cerebral Palsy using the combined interventions of strength training and Botulinum Neurotoxin Type-A. Gait Posture. 2012. In Review 3. Williams S, Reid S, Elliott C, Shipman P, Valentine J. Morphological alterations in spastic muscles immediately following Botulinum Toxin Type-A treatment in children with Cerebral Palsy. Dev Med Child Neurol. In Review 4. Williams S, Elliott C, Valentine J, Gubbay A, Shipman P, Reid S. Combining Strength Training and Botulinum Neurotoxin intervention in children with Cerebral Palsy: The impact on Muscle Morphology and Strength. Disabil Rehabil. 2012. Accepted for publication 5. Pitcher C, Elliott C, Williams S, Licari M, Kuenzel A, Shipman P, Valentine J, Reid S. Childhood muscle morphology and strength: alterations over six months of growth. Muscle Nerve. 2012; In Press. 6. Calley A, Williams S, Reid S, Blair E, Valentine J, Girdler S, Elliott C. A comparison of activity, participation and quality of life in children with and without spastic diplegia cerebral palsy. Disabil Rehabil. 2012; 34(15) 1306-10. Epub 2011 Dec 26. viii ABSTRACTS 1. S Williams, C Elliott, J Valentine, A Gubbay, P Shipman, S Reid. Combining strength training and Botulinum Neurotoxin intervention in children with CP: The impact on muscle morphology and strength. Presented at the AACPDM 66th annual Meeting. 2012 Toronto, ON, Canada. 2. S Williams, C Elliott, J Valentine, N Smith, T Shillington, M Spits, S Reid. Strength training results in stronger but not necessarily bigger muscles for children with Cerebral Palsy. Presented at the AusACPDM 6th Biannual conference. 2012 Brisbane, QLD, Australia. 3. S Williams, C Elliott, J Valentine, A Gubbay, M Spits, S Reid. The immediate effect of Botulinum toxin type-A on muscle morphology and strength in children with Cerebral Palsy. Accepted for presentation at the AusACPDM 6th Biannual conference. 2012 Brisbane, QLD, Australia. 4. Williams S, Elliott C, Valentine J, Gubbay A, Spits M, Shipman S, Reid S. The immediate effect of Botulinum Toxin Type-A on muscle morphology and strength in children with Cerebral Palsy. Presented at the AACPDM 65th annual meeting. 2011 Las Vegas, Nevada, USA. *Received Mac Keith Press Promising Career Award for best paper 5. C Elliott C, Valentine J, Williams S, Shipman P, Kuenzel A, Pitcher C, Reid, S. Does MRIderived muscle size relate to strength in children with and without Cerebral Palsy? Presented at the AACPDM 64th annual Meeting. 2010 Washington, DC, USA. 6. Elliott C, Reid S, Williams S, Pitcher C, Kuenzel A, Shipman P, Valentine J. The relationship between muscle morphology and strength in children with and without Cerebral Palsy. Presented at the AusACPDM Conference, 2010, Christchurch, New Zealand. 7. Williams S, Reid S, Valentine J, Dwyer B, Kuenzel A, Shipman P, Elliott C. The effectiveness of practice to prepare children for MRI Scans. Poster displayed at the ANZSPR conference, 2010, Margaret River, Western Australia. ix TABLE OF CONTENTS ABSTRACT ..................................................................................................................................... iii ACKNOWLEDGEMENTS ................................................................................................................ vi PUBLICATIONS AND ABSTRACTS ............................................................................................... viii TABLE OF CONTENTS ..................................................................................................................... x LIST OF TABLES ........................................................................................................................... xiii LIST OF FIGURES ......................................................................................................................... xiv CHAPTER ONE ................................................................................................................................ 1 INTRODUCTION ............................................................................................................................. 1 1.1 Introduction......................................................................................................................... 1 1.2 Statement of the Problem ................................................................................................... 4 1.3 Thesis Outline ...................................................................................................................... 5 1.4 Definition of Key Terms ..................................................................................................... 10 1.5 Limitations and Delimitations ........................................................................................... 10 1.6 References ......................................................................................................................... 11 CHAPTER TWO ............................................................................................................................. 18 REVIEW OF THE LITERATURE....................................................................................................... 18 2.1 Cerebral Palsy .................................................................................................................... 18 2.2 The International Classification of Functioning, Disability and Health. ............................ 19 2.2.1 Body Function and Structure ...................................................................................... 20 2.2.2 Activity and Participation............................................................................................ 24 2.2.3 Contextual Factors ...................................................................................................... 26 2.3 Therapeutic Interventions ................................................................................................. 27 2.3.1 Botulinum Toxin Type-A ............................................................................................. 28 2.3.2 Functional Outcomes of Botulinum Toxin Type-A ...................................................... 29 2.3.3 Strength training ......................................................................................................... 31 2.3.4 Functional outcomes of Strength Training ................................................................. 33 2.4 The Next Step in Cerebral Palsy Therapy .......................................................................... 36 2.5 Summary ........................................................................................................................... 38 2.6 References ......................................................................................................................... 40 x CHAPTER THREE........................................................................................................................... 58 Morphological Alterations in Spastic Muscles Immediately Following Botulinum Neurotoxin Type-A Treatment in Children with Cerebral Palsy. ..................................................................... 58 Foreword ................................................................................................................................. 59 3.1 Abstract ............................................................................................................................. 60 3.2 Introduction....................................................................................................................... 61 3.3 Methods ............................................................................................................................ 62 3.4 Results ............................................................................................................................... 65 3.5 Discussion .......................................................................................................................... 70 3.6 Clinical Implications ........................................................................................................... 72 3.7 Acknowledgements ........................................................................................................... 73 3.8 References ......................................................................................................................... 74 CHAPTER FOUR ............................................................................................................................ 77 Combining Strength Training and Botulinum Neurotoxin Type-A Intervention in Children with Cerebral Palsy: The Impact on Muscle Morphology and Strength .............................................. 77 Foreword ................................................................................................................................. 78 4.1 Abstract ............................................................................................................................. 79 4.2 Introduction....................................................................................................................... 80 4.3 Methods ............................................................................................................................ 81 4.4 Results ............................................................................................................................... 86 4.5 Discussion .......................................................................................................................... 93 4.6 Clinical Implications ........................................................................................................... 97 4.7 Acknowledgements ........................................................................................................... 97 4.8 References ......................................................................................................................... 98 CHAPTER FIVE ............................................................................................................................ 101 Improving the Gait of Children with Cerebral Palsy using the Combined Interventions of Strength Training and Botulinum Neurotoxin Type-A. .............................................................. 101 Foreword ............................................................................................................................... 102 5.1 Abstract ........................................................................................................................... 103 5.2 Introduction..................................................................................................................... 104 5.3 Methods .......................................................................................................................... 105 5.4 Results ............................................................................................................................. 108 5.5 Discussion ........................................................................................................................ 112 5.6 Conclusion ....................................................................................................................... 114 xi 5.7 Acknowledgements ......................................................................................................... 114 5.8 References ....................................................................................................................... 116 CHAPTER SIX .............................................................................................................................. 119 The Combination of Strength Training and Botulinum Neurotoxin Type-A in Children with Cerebral Palsy: The Effect on Activity, Participation and Quality of Life ................................... 119 Foreword ............................................................................................................................... 120 6.1 Abstract ........................................................................................................................... 121 6.2 Introduction..................................................................................................................... 122 6.3 Methods .......................................................................................................................... 123 6.4 Results ............................................................................................................................. 127 6.5 Discussion ........................................................................................................................ 131 6.6 Conclusion ....................................................................................................................... 134 6.7 Acknowledgements ......................................................................................................... 135 6.8 References ....................................................................................................................... 136 CHAPTER SEVEN ........................................................................................................................ 140 Synthesis of results and Conclusion ........................................................................................... 140 7.1 Summary ......................................................................................................................... 140 7.2 Conclusions...................................................................................................................... 150 7.2.1 Future Research ........................................................................................................ 152 7.2.2 Significance of this Research .................................................................................... 153 7.3 References ....................................................................................................................... 155 APPENDICES ............................................................................................................................... 159 APPENDIX A- Published Manuscript ..................................................................................... 159 APPENDIX B- Accepted Abstracts ......................................................................................... 165 APPENDIX C- Supplementary Data for Chapter Three .......................................................... 179 APPENDIX D- Princess Margaret Hospital Ethical Approval.................................................. 184 APPENDIX E- The University of Western Australia Ethical Approval .................................... 186 APPENDIX F- Parent and Participant Information and Consent forms ................................. 187 APPENDIX G- Selective Control Assessment of the Lower Extremity (SCALE) ...................... 195 APPENDIX H- Canadian Occupational Performance Measure (COPM) ................................ 195 APPENDIX I- Assessment of Life Habits (LIFE-H) ................................................................... 199 APPENDIX J- Cerebral Palsy Quality of Life Questionnaire (CP-QOL) ................................... 206 APPENDIX K - Example of a 10 week Home Based Strength program.................................. 211 xii LIST OF TABLES CHAPTER TWO Table 1 General youth resistance training guidelines as set by the National Strength and Conditioning Association.............................................................................................................33 CHAPTER THREE Table 1 Muscle volumes and strength of the lower leg for 15 children (30 legs) receiving BoNTA to the gastrocnemius muscle group.........................................................................................67 Table 2 PRE and POST group averages, with the grouped average of each individuals percentage change in muscle volumes of the thigh for 10 children (20 legs) receiving BoNT-A to the gastrocnemius muscle group and for 5 children (10 legs) receiving BoNT-A to the medial hamstirngs and gastrocnemius...................................................................................................68 Table 3 PRE and POST average values of knee flexor and knee extensor strength (Isometric peak torque), with the grouped average of individual percentage changes in 10 children (20 legs) receiving BoNT-A to the gastrocnemius muscle group, and 5 children (10 legs) receiving BoNT-A to the medial hamstrings and gastrocnemius................................................................69 CHAPTER FOUR Table 1 Mean change in strength and muscle volume scores for eight children over a 6 month control period of BoNT-A, and over a 6 month intervention period of strength training and BoNT-A........................................................................................................................................87 Table 2 Mean change in strength and muscle volume scores for both PRE and POST groups over their respective 10 weeks of strength training, and 6month intervention of strength training and BoNT-A....................................................................................................................90 CHAPTER FIVE Table 1 Mean within-subject changes of the Gait Deviation Index (GDI), and the Hip, Knee and Ankle joint power generation and absorption over 6 months of the PRE group (training before BoNT-A), of the POST group (training after BoNT-A), and of the entire CP cohort...................110 CHAPTER SIX Table 1 Mean within-subject change of scores for outcome measures of activity, participation and QOL for the control and intervention period (n=8)............................................................128 Table 2 Mean within-subject changes for outcome measures of Activity, Participation and QOL, with changes shown over the 10 weeks of strength training and 6 months............................130 xiii LIST OF FIGURES CHAPTER TWO FIGURE 1 The International Classification of Functioning, Disability and Health Framework.......20 CHAPTER THREE FIGURE 1 Creating a 3 Dimensional model of the leg from an MRI scan using Mimics software to determine muscle volume....................................................................................................64 CHAPTER FOUR Figure 1 Cross-comparison study design, with a pre-intervention baseline assessment for eight participants forming a control and intervention period.............................................................83 Figure 2 Mean scores for the Knee Flexor and Knee Extensor strength, and the Hamstring and Quadriceps muscle volumes for the PRE and POST group over assessment time points. .........92 Figure 3 Mean scores for Gastrocnemius and Tibialis Anterior strength, and the Plantar Flexor and Dorsi Flexor muscle volumes for the PRE and POST group over assessment time points...........................................................................................................................................93 CHAPTER FIVE Figure 1 Cross-comparison study design, with a pre-intervention baseline assessment (B) for 8 participants forming a control period, and 15 children completing the intervention period........................................................................................................................................106 Figure 2 Average power generation (peak), and power absorption (area) at the hip, knee and ankle joints through stance, before and after a control period (of BoNT-A with normal clinical care) for eight children..............................................................................................................109 Figure 3 Average power generation (peak), and average power absorption (area) at the Hip, Knee and Ankle joints through the stance phase of gait for the children in the PRE and POST group, and of all the children in the study grouped together...................................................112 CHAPTER SIX Figure 1 Cross-comparison study design, with a pre-intervention baseline assessment (B) for 8 participants forming a control period, and 15 children completing the intervention period........................................................................................................................................124 xiv CHAPTER ONE INTRODUCTION 1.1 INTRODUCTION Cerebral Palsy (CP) is one of the most common and widely recognised childhood physical disabilities in the world1 with an estimated prevalence of 2.0 to 2.5 for every 1000 live births2. CP was most recently defined as; ‘a group of permanent disorders of the development of movement and posture causing activity limitation that are attributed to non-progressive disturbances that occurred in the developing foetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication, and behaviour, by epilepsy and by secondary musculoskeletal problems.’ 3, 4 This definition highlights the disorder of movement and posture as a neurological disorder with evolving clinical manifestations and musculoskeletal problems as the child matures. With the damage to the developing brain permanent with (presently) no known cure, the aim of current treatment modalities is to manage outward expressions of the disorder5. Health professionals currently utilise the World Health Organisation’s International Classification of Functioning, Disability and Health (ICF) as best practice for a holistic approach to the care, management and rehabilitation of people with disabilities6. The ICF conceptualises an individual’s health as a complex relationship between health-status, the impact this has on body functions, body structures and activity, and how environmental and personal factors can influence the level of participation in everyday settings. In determining the impact of a treatment intervention, the use of the ICF framework guides clinicians in obtaining information on all three dimensions of disablement and functioning (impairment, activity limitations and participation restrictions). This provides a complete and holistic understanding, which in turn may guide future therapeutic interventions. Interventions in CP are commonly targeted towards managing the associated impairments, in an effort to address inefficient movement and limitations in activities of daily living7. Spasticity and muscle weakness are common motor problems associated with CP that are of functional importance, and therefore important to address in clinical management. To date, published research is providing increasing evidence of the value of treating spasticity and muscle weakness in CP, however further research needs to examine the effects of treatments and treatment combinations at all levels of the ICF. 1 Of children with CP, 70% to 80% are classified as having spastic CP8. Spasticity is defined as a velocity-dependant increase in the physiologic resistance of muscle to passive motion9, 10. In CP, spasticity contains neurophysiological components including abnormalities in muscle tone, primitive reflexes and movement and/or postural control response11. Spasticity in CP is also considered to result in musculoskeletal changes including; abnormal changes in connective tissue, muscles and bones and influence the rate of bone growth relative to muscle growth11. Botulinum Neurotoxin type-A (BoNT-A) is widely used for the management of spasticity in children with CP12, 13. Along with an acceptable safety profile14-18, the literature describes many positive outcomes from BoNT-A treatment including; a reduction in muscle tone19-21, increase in joint range of motion19-22, improved gait patterns19, 22, functional improvements23-27 and delayed and reduced requirement for surgical interventions to treat musculoskeletal deformities (when combined with conservative treatments)28, 29. However, generalised muscle weakness16, 17, 30 and weakness in neighbouring non-targeted muscles31, 32 have been reported as undesirable effects of BoNT-A treatment. In addition to this, there have been recent publications raising concern, and calling for more research regarding the effect of BoNT-A on muscle size and morphology, with indications of post BoNT-A atrophy in healthy adults’ muscles33, 34 and in animal studies35, 36. Considering the repetitive nature of BoNT-A treatment for spasticity management in children with CP, it is necessary to understand the impact of this treatment in this population, with regard to all aspects of the ICF. It is well recognised that muscle structure and size are associated with muscle strength in the adult and adolescent population37, 38. Children with CP have been shown to have smaller39,40 and weaker muscles41 than their typically developing peers. Over the last decade, weakness has been increasingly recognised as a significant motor impairment42-45 purportedly affecting the functional ability in children with CP25, 26 . Strength training is now recognised as an effective intervention for improving muscular strength in children with CP46. A growing number of studies confirm that following strength training, people with CP can achieve significant strength improvements that translate to gains in motor function42, 46, 47 such as improvements in walking42, 46, 47, flexibility, posture and balance48. McNee and Colleagues (2009)49 have also reported that alongside improvements in strength, muscles also increase in volume after 5 and 10 weeks of strength training in children with CP. Whilst strength training can be implemented to target muscular weakness (and also increase muscle size49), BoNT-A injections are in common use for spasticity management12 (yet may serve to reduce muscle size33, 34,35,36 ). Spasticity and muscular weakness are two major motor impairments known to negatively impact walking ability in CP50, interventions targeting both these impairments, and their effect on walking gait have only recently received attention in the literature. 2 For people with mild diplegic CP, therapeutic goals are often directed towards improving the ability to walk51. Strength training has demonstrated kinematic changes within gait, with reports of; a more upright posture52, decrease in crouch52-55, improved hip and knee extension through stance56, improved knee extension in late swing54, and trends of improved ankle dorsiflexion at swing and initial contact55. Similarly, BoNT-A treatment is also shown to have a positive impact on gait, with reports of increases in ankle dorsiflexion20, 22, 57, knee extension at initial contact57, and a normalisation of ankle kinetics57, 58 during gait. Impairment of walking ability is significantly associated with reduced participation59. The ability and capacity to walk makes daily life activities and social participation easier for all individuals with CP, and may be especially important for children throughout their years of physical growth and development. It is of concern that research demonstrates that children with CP experience greater activity limitations and to be less physically active than their typically developing peers59-61. In addition to this, compared with typically developing peers, children with CP report difficulties participating in activities across home, school and in the wider community as a result of restrictions in physical functioning and mobility62. Well-being, a ‘broad notion’ used by researchers which considers quality of life63 (QoL), is also generally reported to be lower amongst children with CP63. Information on the effect of BoNT-A and strength training (applied separately or combined) on activity, participation and QoL domains of the ICF is sparse. Whilst the two treatment interventions, of BoNT-A injections and strength training, may already be administered in combination in some clinical settings, very little research has formally applied and reported this combination of therapies within CP, and none have done so and measured outcomes at all levels of the ICF. The concept of applying other forms of therapy management in conjunction with BoNT-A is not new, however it seems that the focus of combined interventions has been to potentiate the effect of the BoNT-A for spasticity reduction64,65 such as stretching, range of motion exercise, serial casting, splinting/orthotics and motor training66. Previous research has called for the need for therapeutic interventions to address more than one impairment of CP if improvements in levels of activity and participation are sought44, and is a logical direction for maximising functional outcomes. A recent pilot study by Bandholm and colleagues(2012)67 included progressive resistance training to their physical rehabilitation program following BoNT-A treatment of the ankle plantar flexors, which resulted in increases in the maximal torque-generating capabilities of the plantar flexors, with a simultaneous reduction in plantar flexor spasticity, and a trend of increased function67. This is the first report formally assessing the combination of BoNT-A and strength training in the 3 lower limb, and highlights the need for a multidimensional approach to assessing the combination of therapies using the ICF. Furthermore, a question remains as to the most effective timing of the strength training in relation to BoNT-A injections. It is unknown if strength training, applied prior to BoNT-A injections will result in superior, equal or inferior outcomes compared to training undertaken following BoNT-A treatment. This is pertinent in a clinical population, where funding structures, family life, and other treatment plans inhibit year-round strength interventions. In addition to this, the possibility of having an option of strength training before or after BoNT-A may expand this as a treatment choice for families. Home based programmes are interventions specifically designed for implementation in the home and in the context of daily life by families68. Home based strength training can be an effective and feasible method of implementing strength training with children69, with potential cost savings and evidence of increased adherence70. For the parents and families, the major advantage of home programs is that they are more time efficient, requiring no travel to gym settings or institutions on their part69. In previous literature, home programs with favourable outcomes tend to involve goal setting, and individualisation of the program42, 68, 70. Further evidence supporting the use of home based strength training, involving goal setting and individualisation of the program will serve to promote this treatment method. Finally, this information will contribute new knowledge and guidance for clinicians worldwide to enhance the overall outcome of current BoNT-A therapy. 1.2 STATEMENT OF THE PROBLEM CP is a physical disability that can significantly impact on an individual’s life and may encompass all components of functioning. Spasticity and muscular weakness are two major motor impairments associated with CP. BoNT-A is a commonly used treatment for spasticity management, however research has linked BoNT-A with muscle weakness and muscle atrophy. For a population already predisposed to weakness and decrements in muscle size, a frequently used treatment that potentially leads to further weakening and atrophy of the muscle should be well understood. In spite of this, the effect of BoNT-A on muscle strength and size in the CP population has not been researched to date. There is strong supportive evidence for the use of strength training to target muscular weakness, and indications of increased muscle size in children with CP. With this in mind, it seems logical to combine both BoNT-A treatment (for spasticity management) and strength 4 training (for muscular weakness) to target both impairments simultaneously. The only published study67 of the combined effect of BoNT-A and strength training in the lower limb reported only kinematic and functional outcomes, the combined effect of BoNT-A and strength training on all other levels of the ICF remains undetermined. Could the combination of therapies address issues other than muscle strength and spasticity at the impairment level? Could this ameliorate the muscle size deficit in CP, avert the potential of post BoNT-A atrophy, and improve outcomes of walking gait? Can an intervention, targeting the impairment level of the ICF, also have ensuing improvements in other domains of activity, participation or quality of life? Finally, can this intervention influence the achievement of functional goals? In answering these questions, it is important to offer guidelines for implementing this intervention, to determine if there is a more effective timing of strength training in relation to BoNT-A, either administrated before or after the injection. This information is needed to guide clinical decision making for children with CP and has the potential to improve clinical outcomes for patients. 1.2.1 STUDY AIMS The overarching aim of this study was to assess the combined effect of a home based, goal directed, and individualised 10 week strength training program with BoNT-A injections for spasticity management for children with CP. Specifically, this combined intervention will be assessed at all levels of the ICF; investigating muscle strength, spasticity, muscle morphology, walking gait, activity, participation, quality of life, and the attainment of functional goals. The outcomes of the combined strength and BoNT-A therapies will be compared, where possible, to changes measured over a control period of BoNT-A injections without the addition of a 10 week strength program (normal care routine). A secondary aim is to determine the best practice in terms of timing of application of a strength training intervention in relation to reception of BoNT-A for children with CP. Specifically if outcomes are most improved if training is undertaken in the weeks preceding the BoNT-A injection, or in the weeks after the injection. 1.2.3 SIGNIFICANCE OF THE STUDY By targeting, what are commonly considered two of the most significant motor impairments of CP, this is the first study to demonstrate the significant implications for the prescription of the two combined therapies, and will do so with a multidimensional assessment at all levels of the ICF. This will allow clinicians to make informed decisions when prescribing strength training programs to children with CP who are also undergoing BoNT-A treatment for spasticity 5 management. Feedback regarding muscle morphological alterations following BoNT-A, in particular, will provide the first look into CP muscle within the literature, and provide important information, and recommendations for clinicians and future research. It is anticipated that the results of this research will be disseminated widely to all medical and therapy staff responsible for treatment and management of CP. 1.3 THESIS OUTLINE The introduction establishes subject matter for this study, and in doing so, communicates the research problem and approaches taken to answer the question. This thesis is presented as a series of individual papers addressing one minor study and one major multidimensional study. The minor study, the first paper, presents the effect of a single injection of BoNT-A on muscle morphology, muscular strength, and function, and provides novel information to clinicians to improve our understanding of the effects of this common treatment for spasticity management in CP. This study also provides background information for the key focus of this thesis. The major study relates to the outcomes of a 10-week home based strength training programme combined with BoNT-A treatment for children with CP. This is presented as three papers addressing the impacts on the major areas of investigation; (i) muscle strength, spasticity, and muscle morphology, (ii) outcomes of walking gait, attainment of functional goals, and (iii) activity, participation and quality of life. At times the presentation of independent papers may seem repetitive; however it is felt that each paper should stand alone for ease of reading, therefore references are provided at the conclusion to each individual paper. The thesis is concluded with a synthesis of results and discussion. This thesis therefore contains four separate but inter-related papers. 1.3.1 CHAPTER TWO- LITERATURE REVIEW The literature review builds the context of the study through a comprehensive overview of previously published research. Opening with a brief introduction to CP, the literature review focuses on functional outcomes of CP, with particular attention to the motor impairments, spasticity and muscular weakness. A review of treatment interventions follows, and focuses on the use of BoNT-A for spasticity management, and strength training for muscle weakness. Available literature pertaining to the effect of both of these interventions is reviewed at all levels of the ICF. This will provide the reader with a greater understanding of the literature presently available to us, and to the ‘gaps’, where further research is needed. 6 1.3.2 CHAPTER THREE- PAPER ONE MORPHOLOGICAL ALTERATIONS IN SPASTIC MUSCLES IMMEDIATELY FOLLOWING BOTULINUM NEUROTOXIN TYPE-A TREATMENT IN CHILDREN WITH CEREBRAL PALSY. The aims of this paper are to: To provide the first known documentation of the morphologic alterations of spastic muscles in response to BoNT-A. To report morphologic response in synergist and antagonist muscle to BoNT-A treatment in spastic muscle To increase understanding of the effect of BoNT-A treatment on muscle strength and functional ability in children with CP. It was hypothesised that Muscles injected with BoNT-A would display a reduction in muscle volume. BoNT-A induced muscle atrophy would also result in a reduced force generating capacity. 1.3.3 CHAPTER FOUR- PAPER TWO COMBINING STRENGTH TRAINING AND BOTULINUM NEUROTOXIN TYPE-A INTERVENTION IN CHILDREN WITH CEREBRAL PALSY: THE IMPACT ON MUSCLE MORPHOLOGY AND STRENGTH. The aims of this paper are to: To combine a 10 week, home based, strength training programme with BoNT-A injections and measure the effects on muscular weakness and spasticity in CP. To determine if the combined interventions would be more successful in improving muscle strength and reducing spasticity than BoNT-A and the current normal care. To determine if changes in muscle strength could be attributed to alterations in muscle morphology. To report if the combination of therapies would successfully improve individual functional goals set by the children in this study compared with BoNT-A and the current normal care. To determine if the timing of strength training, whether it be administered before or after BoNT-A injections, affects outcomes, thereby indicating whether there is an optimal timing of strength training. 7 Provide guidelines for further rehabilitation planning to enhance therapy outcomes for children with CP. It is hypothesised that: The combination for strength training and BoNT-A will result in the simultaneous increase of muscle strength and reductions in muscle spasticity. The 10 week strength intervention will evoke increases in the muscle size of targeted muscles. The combined intervention program, including individual goal-directed strength exercises, will result in functional goal-attainment, as measured by the Goal Attainment Scale (GAS). Children undertaking strength training in the weeks after BoNT-A treatment will have better outcomes of muscle strength, morphology and functional goals than those receiving strength training before BoNT-A treatment. 1.3.4 CHAPTER FIVE- PAPER THREE: IMPROVING THE GAIT OF CHILDREN WITH CEREBRAL PALSY USING THE COMBINED INTERVENTIONS OF STRENGTH TRAINING AND BOTULINUM NEUROTOXIN TYPE-A. The aims of this paper are to: To measure the effects of combining a 10 week, home based, strength training programme with BoNT-A injections (to target both muscular weakness and spasticity) in CP on walking gait evaluated with the Gait Deviation Index (GDI) and kinetic power profiles. To determine if the timing of strength training, whether it be administered before or after BoNT-A injections, affects outcomes, thereby indicating whether there is an optimal timing of strength training. Provide guidelines for further rehabilitation planning to enhance therapy outcomes for children with CP. It is hypothesised that: The combination for strength training and BoNT-A will improve measures of the GDI, indicating children in the study to be walking closer to the style of non-pathological walking gait. 8 The 10 week strength intervention will improve kinetic power profiles at the hip, knee and ankle joints so that they more closely resemble those of typically developing peers. Children undertaking strength training after BoNT-A treatment will have better GDI outcomes (or will have a more normal gait) than children undertaking strength training in the weeks preceding BoNT-A treatment. 1.3.5 CHAPTER SIX- PAPER FOUR THE COMBINATION OF STRENGTH TRAINING AND BOTULINUM NEUROTOXIN TYPEA IN CHILDREN WITH CEREBRAL PALSY: THE EFFECT ON ACTIVITY, PARTICIPATION AND QUALITY OF LIFE. The aims of this paper are to: To determine if a combined 10 week, home based, strength training programme with BoNT-A injections (targeting both muscular weakness and spasticity) in CP at the impairment level of the ICF can evoke changes at the activity, participation or quality of life domains of the ICF, compared with BoNT-A injections and normal care. To determine if the timing of the strength training program, administered around scheduled BoNT-A injections will produce different outcomes on the activity, participation and QoL domains of the ICF. It is hypothesised that: The combined interventions will improve measures of activity, as assessed by the Timed Up and Go (TUG) and the Six-Minute Walk Test (6MWT) Children with CP will have improved outcomes of participation following their involvement in the study (as assessed by the Assessment of Life-Habits, the LIFE-H, for children). Children with CP will have improved outcomes of QoL following their involvement in the study (as assessed by the Cerebral Palsy Quality of Life Questionnaire for Children, CP QOL). 1.3.6 CHAPTER SEVEN SYNTHESIS OF RESULTS AND CONCLUSIONS 9 The final chapter aims to provide an overall synthesis of results presented throughout the thesis, integrating the major findings from each study and provides an overall conclusion of the research programme in its entirety. 1.4 DEFINITION OF KEY TERMS C EREBRAL P ALSY : “Cerebral palsy (CP) describes a group of disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, cognition, communication, perception, and/or behaviour, and/or by a seizure disorder.” pg 572 71 S PASTICITY : A velocity-dependent increase in muscle resistance, in response to a passive stretch9. M USCLE W EAKNESS : a failure or inability to produce or maintain an anticipated level of force72. S TRENGTH TRAINING : A method of improving muscular strength by gradually increasing the ability to resist force through the use of free weights, machines, or the person's own body weight73. F UNCTION : A complex entity that incorporates physical capability and performance, as well as psychological, social and cognitive capability6. B ODY FUNCTIONS AND STRUCTURES : The physiological functioning of the anatomical structures of the organs, limbs and their components6 I MPAIRMENT : Problems with body functions and structures, such as a deviation or loss6. A CTIVITY : The execution of a task or activity by an individual6. P ARTICIPATION : Ones involvement in life situations6. Q UALITY OF L IFE : An individual’s perception of their position in life in the context of the culture and value systems in which they live, and in relation to their goals, expectations, standards, and concerns74. 1.5 LIMITATIONS AND DELIMITATIONS 1.5.1 LIMITATIONS Limitations regarding the individual experience of CP and BoNT-A can lead to difficulties when comparing data, however reflects the clinical reality of this study. CP is a disorder that manifests itself differently in each child, therefore in following with best practice care, each child received individualised variations of the program. The strength training program is based on the child’s individual goals developed with the assistance of an Occupational Therapist and the parent using the Canadian Occupational Performance Measure75. The muscles targeted for 10 inclusion in the training therefore varied between participants, with some children unable to include training of the gastrocnemius muscle due to varying levels of contracture. For example, a child aiming to be able to ‘run faster’ would have the muscle groups that are important for running included in their program, e.g. generally the hip flexors, gluteal, quadriceps, hamstrings and calf muscles (where appropriate). The muscle(s) selected for injection and the total dose of BoNT-A (Botox®, Allergan, Irvine, CA, USA), were determined by the child’s physician based on clinical assessment and functional goal setting, Imposed by limited time and limited number of locally available appropriate participants, a primary limitation of this study is a lack of a control period for each participant (of BoNT-A only). The next best possible option was to allocate children into a control period, and follow with an intervention period, whereby participants were randomly allocated to either PRE or POST BoNT-A training. A random selection of our participants were able to complete the control period, yet we are still limited to the fact that not all of the participants in our study underwent a control period. In addition to this, the lack of a randomised control group, against which the interventions could be directly compared, means that factors such as growth, maturation and time are not well controlled for and therefore is a limitation of this study. Activities undertaken that were not related to the program (i.e. swimming lessons, after school sport etc) were monitored throughout the course of the research period to ensure that they were maintained as a constant throughout control and intervention periods however this could not be controlled. 1.5.2 DELIMITATIONS This study is delimited by the inclusion of children aged 5-12 years as a clinically appropriate age range for children receiving BoNT-A for spasticity management before the need for orthopaedic surgery. Inclusion criteria also include a classification of Spastic Diplegic CP and only children classified as having a Gross Motor Function Classification System76 (GMFCS) level of I-II. In an attempt to minimise the confounding negative effect of immobility on strength, children with a GMFCS classification level of III, IV and V (denoting children with limited selfmobility) were excluded from this study. Precise timing of strength training related to BoNT-A injection meant that each strength training program occurred at the appropriate time in relation to the effect of BoNT-A. This study is also delimited due to the assessment protocols, many of which can only be conducted in a laboratory setting, including; isokinetic and isometric strength assessments, three-dimensional motion analysis, and magnetic resonance imaging for assessment of muscle morphology following set protocols. 11 1.6 REFERENCES 1. Paneth N, Hong T, Korzeniewski S. The descriptive epidemiology of cerebral palsy. Clin Perinatol. 2006;33:251-67. 2. Surveillance of Cerebral Palsy in Europe. Prevalence and characteristics of children with cerebral palsy in Europe. Dev Med Child Neurol. 2002;44:633-40. 3. Rosenbaum P, Paneth N, Levition A, Goldstein M, Bax M. A report: the defintion and classification of cerebral palsy April 2006. Dev Med Child Neurol. 2007;49:9-14. 4. Bax M, Goldstein M, Rosenbaum P, et al. Executive committee for the definition of Cerebral Palsy. (2005) Proposed definition and classification of cerebral palsy, April 2005. Dev Med Child Neurol. 2005;47:571-6. 5. Berker N, Yalçin S. Cerebral Palsy: Orthopedic Aspects and Rehabilitation. Pediatr Clin N Am. 2008;55:1209-25. 6. WHO. International Classification of Functioning, Disability and Health. Geneva: WHO; 2001 [cited 2006 January]; Available from: http://www3.who.int/icf/intros/ICF-Eng-Intor.pdf. 7. Morris C. Definition and classification of cerebral palsy: a historical perspective. Dev Med Child Neurol. 2007;109:3-7. 8. Panteliadis C, Strassburg H. Cerebral palsy: principles and management. Stuttgart (Germany): Thieme; 2004. 9. Lance JW. Spasticity: disordered motor control. Chicago: Year Book Medical Publishers.; 1980. 10. Young R, Delwade P. Drug therapy: Spasticity. . N Engl J Med. 1981;304. 11. Flett P. Rehabilitation of spasticity and related problems in childhood cerebral palsy. J Paediatr Child Health. 2003;39:6-14. 12. Heinen F, Molenaers G, Fairhurst C, et al. European consensus table 2006 on botulinum toxin for children with cerebral palsy. Eur J Paediatr Neurol. 2006;10:215-25. 13. Love S, Novak I, Kentish M, et al. Botulinum toxin assessment, intervention and after- care for lower limb spasticity in children with cerebral palsy: international consensus statement. Eur J Neurol. 2010;17:9-37. 14. Bakheit AM, Severa S, Cosgrove A. Safety profile and efficacy of botulinum toxin in children with muscle spasticity. Dev Med Child Neurol. 2001;43:234-8. 12 15. Langdon K, Blair E, Davidson SA, Valentine J. Adverse events following botulinum toxin type A treatment in children with cerebral palsy. Dev Med Child Neurol. 2010;52:972-3. 16. Naumann M, Albanese A, Heinen F, Molenaers G, Relja M. Safety and efficacy of botulinum toxin type A following long-term use. Eur J Neurol. 2006;13:35-40. 17. O’Flaherty SJ, Janakan V, Morrow AM, Scheinberg AM, Waugh M-CA. Adverse events and health status following botulinum toxin type A injections in children with cerebral palsy. Dev Med Child Neurol. 2011;53:125-30. 18. Naumann M, Jankovic J. Safety of Botulinum toxin: A systematic review and meta- analysis. Curr Med Res Opin. 2004;20:981-90. 19. Koman L, Mooney J, Smith B, Walker F, Leon J. Botulinum toxin type A neuromuscular blockade in the treatment of lower limb spasticity in cerebral palsy: a randomised double-blind placebo controlled trial. J Pediatr Orthop B. 2000;20:108-15. 20. Corry I, Cosgrove A, Duffy C, McNeill S, Taylor T, Graham H. Botulinum Toxin A compared with stretching casts in the treatment of spastic equinus: A randomised prospective trial. J Pediatr Orthop. 1998;18:304-11. 21. Wissel J, Heinen F, Schenkel A, et al. Botulinum toxin A in the management of spastic gait disorders in children and young adults with cerebral palsy: a randomized, double-blind study of ‘‘high-dose’’ versus ‘‘low-dose’’ treatment. Neuropediatrics. 1999;30:120-4. 22. Sutherland DH, Kaufman KR, Wyatt MP, Chambers HG, Mubarak SJ. Double-blind study of botulinum A toxin injections into the gastrocnemius muscle in patients with cerebral palsy. Gait Posture. 1999;10:1-9. 23. Steenbeek D, Meester-Delver A, Becher J, Lankhorst G. The effect of botulinum toxin type A treatment of the lower extremity on the level of functional abilities in children with cerebral palsy: evaluation with goal attainment scaling. Clin Rehabil. 2005;19:274-82. 24. Linder M, Schindler G, Michaelis U, et al. Medium-term functional benefits in children with cerebral palsy treated with botulinum toxin type A: 1-year follow-up using gross motor function measure. Eur J Neurol. 2001;8:120-6. 25. Scholtes VA, Dallmeijer AJ, Knol DL, et al. The combined effect of lower-limb multilevel botulinum toxin type A and comprehensive rehabilitation on mobility in children with cerebral palsy: A randomized clinical trial. Arch Phys Med Rehabil. 2006;87:1551-8. 26. Fehlings D, Rang M, Glazier J, Steele G. An evaluation of botulinum-A toxin injections to improve upper extremity function in children with hemiplegic cerebral palsy. J Pediatr. 2000;137:331-7. 13 27. Mall V, Heinen F, Kirschner J, et al. Evaluation of botulinum toxin A therapy in children with adductor spasm by gross motor function measure. J Child Neurol. 2000;15:214-7. 28. Graham HK. Botulinum toxin type A management of spasticity in the context of orthopaedic surgery for children with spastic cerebral palsy. Eur J Neurol. 2001;8:30-9. 29. Molenaers G, Desloovere K, Farby G, De Cock P. Effects of gait assessment and Botulinum Toxin A on musculoskeletal surgery in cerebral palsy. J Bone Joint Surg Am. 2006;88:161-70. 30. Mohamed KA, Moore AP, Rosenbaum L. Adverse events following repeated injections with botulinum toxin A in children with spasticity. Dev Med Child Neurol. 2001;43:791-2. 31. Yaraskavitch M, Leonard T, Herzog W. Botox produces functional weakness in non- injected muscles adjacent to the target muscle. J Biomech. 2008;41:897-902. 32. Fortuna R, Aurélio Vaz M, Rehan Youssef A, Longino D, Herzog W. Changes in contractile properties of muscles receiving repeat injections of botulinum toxin (Botox). J Biomech. 2011;44:39-44. 33. Gough M, Fairhurst C, Shortland AP. Botulinum toxin and cerebral palsy: time for reflection? Dev Med Child Neurol. 2005;47:709-12. 34. Schroeder A, Ertl-Wagner B, Britsch S, et al. Muscle biopsy substantiates long-term MRI alterations one year after a single dose of botulinum toxin injected into the lateral Gastrocnemius muscle of healthy volunteers. Mov Disord. 2009;24:1494-503. 35. Fortuna R, Aurélio Vaz M, Rehan Youssef A, Longino D, Herzog W. Changes in contractile properties of muscles receiving repeat injections of botulinum toxin. J Biomech. 2011;44:39-44. 36. Ma J, Elsaidi G, Smith T, et al. Time course of recovery of juvenile skeletal muscle after Botoxulinum Toxin A injection. Am J Phys Med Rehabil. 2004;83:774-80. 37. Lieber R, Friden J. Functional and clinical significance of skeletal muscle architecture. Muscle Nerve. 2000;23:1647-66. 38. Enoka RM. Neuromechanics of Human Movement. 3rd ed. Champaign, IL: Human Kinetics; 2002. 39. Barrett RS, Lichtwark GA. Gross muscle morphology and structure in spastic cerebral palsy: a systematic review. Dev Med Child Neurol. 2010;52:794-804. 14 40. Barber L, Hastings-Ison T, Baker R, Barrett R, Lichtwark G. Medial gastrocnemius muscle volume and fascicle length in children aged 2 to 5 years with cerebral palsy. Dev Med Child Neurol. 2011;53:543-8. 41. Pitcher C, Elliott C, Williams S, et al. Childhood muscle morphology and strength: alterations over six months of growth. Muscle Nerve. 2012;In press. 42. Damiano D, Abel M. Functional outcomes of strength training in spastic cerebral palsy. Arch Phys Med Rehabil. 1998;79:119-25. 43. Ross S, Engsberg J. Relationships between spasticity and strength in individuals with spastic diplegic cerebral palsy. Dev Med Child Neurol. 2002;44:148-57. 44. Mockford M, Caulton J. Systematic review of progressive strength training in children and adolescents with cerebral palsy who are ambulatory. Pediatr Phys Ther. 2008;20:318-33. 45. Eaglton M, Iams A, McDowell J, Morrison R, Evans C. The effects of strength training on gait in adolescents with cerebral palsy. Pediatr Phys Ther. 2004;16. 46. Dodd K, Taylor N, Damiano D. A systematic review of the effectiveness of strength- training programs for people with cerebral palsy. Arch Phys Med Rehabil. 2002;83:1157-64. 47. MacPhail A, Kramer J. Effect of isokinetic strength training on functional ability and walking efficiency in adolescents with cerebral palsy. Dev Med Child Neurol. 1995;37:763-75. 48. McBurney H, Taylor N, Dodd K, Graham H. A qualitative analysis of the benefits of strength training for young people with cerebral palsy. Dev Med Child Neurol. 2003;45:658–63. 49. McNee AE, Gough M, Morrissey MC, Shortland AP. Increase in muscle volume after plantarflexor strength training in children with spastic cerebral palsy. Dev Med Child Neurol. 2009:1-7. 50. Love S, Novak I, Kentish M, et al. Botulinum toxin assessment, intervention and after- care for lower limb spasticity in children with cerebral palsy: international consensus statement. Eur J Neurol. 2010;17:9-37. 51. Damiano D, Martellotta T, Sullivan D, Granata K, Abel M. Muscle force production and functional performance in spastic cerebral palsy: Relationship of cocontraction. Arch Phys Med Rehab. 2000;81:895-900. 52. Shepherd R. Cerebral palsy. In: Shepherd R, editor. Physiotherapy in paediatrics. Oxford: Butterworth-Heinemann; 1995. p. 110-4. 53. Unger M, Faure M, Frieg A. Strength training in adolescent learners with cerebral palsy: a randomized controlled trial. Clin Rehabil. 2006;20:469-77. 15 54. Damiano D, Vaughan C, Abel M. Muscle response to heavy resistance exercise in children with spastic cerebral palsy. Dev Med Child Neurol. 1995;37:731-9. 55. Damiano D, Kelly L, Vaughan C. Effects of quadriceps femoris muscle strengthening on crouch gait in children with spastic diplegia. Phys Ther. 1995;75:658-67. 56. Engsberg J, Ross S, Collins D. Increasing ankle strength to improve gait and function in children with cerebral palsy: a pilot study. Pediatr Phys Ther. 2006;18:266-75. 57. Damiano DL, Arnold AS, Steele KM, Delp SL. Can strength training predictably improve gait kinematics? A pilot study on the effects of hip and knee extensor strengthening on lowerextremity alignment in cerebral palsy. Phys Ther. 2010 Feb;90:269-79. 58. Zurcher A, Molenaers G, Desloovere K, Fabry G. Kinematic and kinetic evaluation of the ankle after intramuscular injection of botulinum toxin A in children with cerebral palsy. Acta Orthopædica Belgica. 2001;67:475-80. 59. Fauconnier J, Dickinson H, Beckung E, et al. Participation in life situations of 8-12 year old children with cerebral palsy: cross sectional European study. BMJ. 2009;338:b1458. 60. Maher C, Williams M, Olds T, Lane A. Physical and sedentary activity in adolescents with cerebral palsy. Dev Med Child Neurol. 2007;49:450-7. 61. Bjornson K, Belza B, Kartin D, Logsdon R, McLaughlin J. Self-reported health status and quality of life in youth with cerebral palsy and typically developing youth. Arch Phys Med Rehab. 2008;89:121-7. 62. Van Zelst B, Miller M, Russo R, Murchland S, Crotty M. Activities of daily living in children with hemiplegic cerebral palsy: a cross- sectional evaluation using the assessment of motor and process skills. Dev Med Child Neurol. 2006;48:723-7. 63. Calley A, Williams S, Reid S, et al. A Comparison of Activity, Participation and Quality of Life in Children with and without Spastic Diplegia Cerebral Palsy. Disabil Rehabil. 2012;34:130610. 64. Livingston M, Rosenbaum P, Russell D, Palisano R. Quality of life among adolescents with cerebral palsy: what does the literature tell us? Dev Med Child Neurol. 2007;49:225-31. 65. Boyd R, Graham H. Botulinum toxin A in the management of children with cerebral palsy: indications and outcome. Eur J Neurol. 1997;4:15-22. 66. Graham H, Aoki K, Autti-Ramo I, et al. Recommendations for the use of botulinum toxin type A in the management of cerebral palsy. Gait Posture. 2000;11:67-79. 67. Goldstein E. Spasticity management: an overview. J Child Neurol. 2001;16:16-23. 16 68. Bandholm T, Jensen B, Nielsen L, et al. Neurorehabilitation with versus without resistance training after botulinum toxin treatment in children with cerebral palsy: A randomized pilot study. NeuroRehabilitation. 2012;30:277-86. 69. Novak I, Cuisick A. Home programmes in paediatric occupational therapy for children with cerebral palsy: Where to start? Aust Occup Ther J. 2006;53:251-64. 70. Dodd K, Taylor N, Graham H. A randomized clinical trial of strength training in young people with cerebral palsy. Dev Med Child Neurol. 2003;45:652–7. 71. Novak I. Effective home programme intervention for adults: a systematic review. Clin Rehabil. 2011 August 10, 2011. 72. Bax M, Goldstein M, Rosenbaum P, Leviton A, Paneth N. Proposed definition and classification of cerebral palsy, April 2005. Dev Med Child Neurol. 2005;47:571-6. 73. Edwards R. Physiological analysis of skeletal muscle weakness and fatigue. Clin Sci Mol Med. 1978;54:463-70. 74. Mosby's Medical Dictionary. 8th ed: Elsevier; 2008. 75. WHOQOL. Development of the WHOQOL: rationale and current status. Int J Mental Health webcite. 1994;23:24-56. 76. Palisano R, Rosenbaum P, Walter S, et al. Development and Reliability of a System to Classify Gross Motor Function in Children with Cerebral Palsy Developmental Medicine and Child Neurology. 1997;39:214. 77. Law M, Baptise S, Carswell A, McColl M, Polatajko H, Pollock N. Canadian Occupational Performance Measure. Third ed. Ottawa: CAOT Publications ACE; 1998. 17 CHAPTER TWO REVIEW OF THE LITERATURE This literature review will open with a brief introduction to Cerebral Palsy (CP), with a focus on spastic diplegia, the target population of this thesis. The review then introduces The International Classification of Functioning Disability and Health (ICF) and explores the impact of CP at the level of body functions and structures, activity and participation and the impact on an individual’s quality of life. There are numerous impairments to body function and structures associated with CP. Spasticity and muscle weakness are the focus of this research, and special attention is given in this review to the impact of both motor impairments. Followed by discussion of Botulinum Neurotoxin Type-A (BoNT-A) and strength training as treatment options to counteract spasticity and muscle weakness. This discussion will encompass research pertaining to outcomes across the levels of body structures and function, activity, participation and quality of life of children with CP. The final objective of this review is to investigate the combination of strength training and BoNT-A therapy in children with CP. 2.1 CEREBRAL PALSY Cerebral Palsy (CP) is one of the most common and widely recognised childhood physical disabilities in the world with an estimated prevalence of 2.0 to 2.5 for every 1000 live births1. The term ‘Cerebral Palsy’ describes a group of disorders of the development of movement and posture due to non-progressive disturbances in the immature brain2. Although the lesion is static, the disorder of movement or posture is usually not unchanging and has a wide variety of musculoskeletal problems and other associated conditions that manifest as the child matures and develops. Some of the frequent motor impairments resultant from the neural deficits include spasticity, dystonia, muscle contractures, in-coordination, loss of selective motor control, and muscle weakness3. Spasticity is the most common motor impairment in children with CP, with 70% to 80% of CP children classified as spastic4. Up to 50% of children with spastic CP have diplegia, the most common subtype of CP5, 6. Diplegia is characterised by a greater involvement in the lower extremities than the upper extremities2. Children with spastic diplegic CP generally require various interventions to be able to walk independently, with many using walking aids and eventually requiring surgery for contractures and deformities6, 7. The Gross Motor Function 18 Classification System8 (GMFCS) was developed to provide an objective classification of the patterns of motor disability in children with CP. Functional mobility is divided into five levels: children in Level I have the most independent motor function and children in Level V have the least, with clinically meaningful distinctions between the levels based on functional abilities and limitations8. The most common classifications for children with CP are GMFCS I (32-52%) and GMFCS II (17-21%) these children can be described as having the ability to walk independently, without the need for assistive mobility aids8. Children who are classified as spastic diplegic, GMFCS I and II therefore comprise a large portion of those with CP, though are considered as being on the higher end of the functional scale. With the motor impairments of CP affecting many aspects of an individual’s life, the aim of many current treatment modalities is to manage outward expressions of the disorder9. Therefore a multidimensional approach to treatment and the evaluation of treatment interventions is of high relevance. 2.2 THE INTERNATIONAL CLASSIFICATION OF FUNCTIONING, DISABILITY AND HEALTH. The World Health Organisation (WHO) recognises that functioning is more than just one’s ability to move10. Functioning is defined as a complex entity that incorporates physical capability and performance, as well as psychological, social and cognitive capability10. The International Classification of Functioning Disability and Health (ICF)11 is a theoretical classification scheme devised by the WHO, that incorporates all of these aspects of functioning. It offers a scientific tool for understanding human function and disability for clinical, research and other public health purposes11. “Functioning” and “disability” are umbrella terms that are conceived as a dynamic interaction between health conditions (e.g., disorders, diseases, injuries) and contextual factors (environmental, personal factors)12. The ICF provides a generalised framework for understanding the dimensions of disability and functioning with respect to the body, the whole person, and the whole person in a social context. The ICF is composed of two parts; (i) functioning and disability; which comprise body functions, body structures, activity and participation and (ii) contextual factors which are made up of environmental factors and personal factors (Figure 1)10. Whilst domains of the ICF are separately defined, each is interrelated to encompass overall function of a health condition. 19 Figure 1 The International Classification of Functioning, Disability and Health (ICF) Framework10 The ICF is a framework that captures the breadth of difficulties experienced by those with CP and the many areas of impact13. It promotes a broad application of outcome measures that ensures interventions and rehabilitation programs are being evaluated, not only at the level of the organ system (impairments), but also at the individual (activity limitations) and societal levels (participation restrictions)14. For example, whilst an intervention may result in improvement at the level of body function and activity, this does not necessarily mean there will be improvements in participation or family satisfaction15. The philosophy behind the ICF has resulted in a shift of therapeutic focus from impairment prevention to maximising overall health status16. The ICF has been shown to be valuable in assessing the efficacy of rehabilitation services in the CP population17, 18, and will be utilised in this literature review to describe functional limitations for children with CP and the impact of interventions at each level of the ICF. 2.2.1 BODY FUNCTION AND STRUCTURE The first component of the ICF ‘functioning and disability’ includes body functions and structures which refer to the physiological functioning of the anatomical structures of the organs, limbs and their components. Problems, such as deviation or loss, are referred to as impairments10. Spasticity, weakness, dystonia, muscle contractures, bony deformities, in-coordination and loss of selective motor control are amongst the list of possible motor impairments associated with CP; with sensory deficits also adversely impact a child’s functioning3. However, for the scope of 20 this literature review, spasticity and muscle weakness will be the focus for investigation, as two common impairments of CP that may co-exist in the same muscle19, 20. 2.2.1.1 SPASTICITY Spasticity is defined as a velocity-dependant increase in the physiologic resistance of muscle to passive motion21, 22. The motor impairment is often associated with overactive stretch reflexes, loss of dexterity, and weakness23. It is thought that by inhibiting the muscles ability to stretch, spasticity can also inhibit growth in the length of the muscle, resulting in a decreasing range of joint motion24 and culminating in the development of muscle contracture25. As a consequence of spasticity, individuals often report muscle stiffness, pain or discomfort, loss of function in the extremities, and difficulties in maintain standing and/or sitting posture26. The effect of spasticity on locomotive and gross motor patterns is evident, although variable in children with CP27, 28. Ambulant children with spastic diplegic CP are reported to adopt a range of gait patterns observable in the sagittal plane24, 29. Described by Sutherland and Davids (1993)30, and further classified by Rodda and Colleagues (2004)29 typical gait patterns of CP include crouch gait, jump knee, stiff knee, and recurvatum knee; with equinus or equinovalgus foot and an internally rotated hip also commonly reported24, 29-31 . Collectively referred to as `lever arm disease', torsional deformities of the long bones and foot deformities frequently contribute to gait alterations observable in the transverse plane31. The differing characteristics of gait may be explained by the presence of spasticity within different muscles groups; the flexors of the hip and the knee and plantar flexors of the ankle are the key muscle groups, displaying spasticity and contracture, affecting the pattern of gait29. Crouch gait, for example, may a result of overactivity or shortening of the hamstrings32, and can be identified by excessive flexion at the hip and knee, and excessive dorsi flexion at the ankle, whilst equinus walking is related to plantarflexor spasticity33. However, it is important to note that whilst spasticity is a significant impacting factor of these gait patterns, other factors are also influential; co-contractions may interact with torsional deformities of the femur and tibia, in addition to poor selective motor control and muscular weakness29. 2.2.1.2 MUSCLE WEAKNESS As indicated by the nomenclature ‘cerebral palsy’, meaning weakness originating at the brain, muscular weakness has long been recognised as a primary clinical feature of CP34. The term 21 ‘weakness’ implies a failure or inability to produce or maintain an anticipated level of force 35. Over the last decade, weakness has been increasingly recognised as a significant motor impairment36-39, purportedly affecting the functional ability in children with CP40, 41. Muscular weakness is a pervasive symptom in CP; Wiley and Damiano (1998)38 demonstrated that children with diplegic CP were weaker than typically developing children in all major muscle groups of the lower extremities, even the highly functional ambulatory children with spastic diplegic CP38. Literature demonstrates muscle weakness to be most pronounced in the plantar flexors, knee flexors and hip abductors and extensors37, 38, 42-44 in children and adolescents with CP. Additionally, a number of reports have also identified concentric and eccentric weaknesses in individuals with CP38, 45-47. The past assumption that deficient performance of the agonist muscle was due to antagonist spastic restraint, has been superseded by the contention that the major cause of muscle weakness is now primarily due to agonist deficiency48. In fact the literature suggests that the extent of muscular weakness is independent of the presence of spasticity38, 39, 49, 50. Ross and Engsberg (2002)39 suggest that spasticity is not related to strength in individuals with CP, revealing that whilst spasticity was not always present in muscles with CP, muscular weakness almost always was39. The weakness found in children with CP can be attributable to both altered neural mechanisms and muscle tissue changes36. Many believe low force production is due to either inability to maximally activate muscle or a decrease in motor unit discharge rate38, 47, 51, 52 . Decreased central drive, incomplete motor unit recruitment, and increased agonist/antagonist coactivation are all neurological factors of muscular weakness suggested to exacerbate the inability of the child with CP to produce high levels of muscle force, work and power, consequently affecting motor performance34, 38, 46, 48, 52. It is likely that these factors are not mutually exclusive, but integrally related to contribute to muscle weakness. Changes in the mechanical properties of the muscles observed in CP may, in part, account for decreased muscle force production53. There is increasing evidence to confirm that spastic muscles show differences in structural morphology that may affect force generation capabilities53-55. Muscle structure and size is associated with muscle strength in the adult and adolescent population55, 56, and Pitcher and Colleagues (2012)57 reported strong associations between muscle size and strength in typically developing children57. This factor is particularly 22 relevant when we consider that children with CP are shown to have smaller muscles then their typically developing peers57. A recent review of the literature in spastic CP found consistent evidence for small muscle size as indicated by reduced muscle volume, cross sectional area, thickness and belly length in comparisons of paretic muscles with non-paretic and typically developing muscles58. Barber and Colleagues (2009)59 have described volumetric deficits in the medial gastrocnemii of young children (2–5y) with spastic CP of 22% compared with typically developing children59. Elder and Colleagues (2003) 52 demonstrated the calf musculature of the paretic limbs of children with spastic hemiplegic CP to be on average 73% of the volume of the non-paretic limb52. Similarly Malaiya and Colleagues (2007) 60 reported the medial gastrocnemius in the paretic limb to be approximately two-thirds of the volume of the muscle in the non-paretic or in typically developing limbs60. Whilst in a group of young adults with spastic hemiplegic CP, Lampe and Colleagues (2006)61 reported all the muscles in the affected lower limb to be smaller than those in the unaffected limb61. It is clear that both neural and structural mechanisms may impair the muscle of children with CP to work to its true functional capacity. Functional limitations of both the upper and lower extremities are a consequence of a plethora of neural and muscular impairments present in the CP population; muscular impairments include abnormal muscle tone, muscular weakness, a variety of muscle synergies, muscular tendon contracture, patterns of co-activation, decreased inhibition of reflexes, altered biomechanics and inadequate muscle force production46, 51, 62, 63. Whilst many of the muscular impairments are related to movement deficits44, 49, 64, lower extremity muscle weakness has shown a stronger association with walking parameters than other motor impairments in CP 39, 65, 72 . Using the Gross Motor Function Measure (GMFM)66, Ross & Engsberg (2007) reported muscle strength to correlate significantly with 11 of the 15 variables tested42. In particular, across the GMFM dimension of walking, running and jumping, where gait speed, stride length, knee flexion at initial contact, pelvic tilt and range of motion during gait were all associated with increased weakness42. Muscular strength is positively associated with walking ability43 and temporal gait parameters such as walking speed, stride length and cadence65, 67, with this, weakness appears to be a key contributing factor to gait deviations observed in CP. Similar to typically developing children68, muscles at the ankle (ankle plantar flexors) and the hip (including the hip flexors) joints provide approximately 90% of the mechanical power generated for forward propulsion throughout gait in individuals with CP64. However, the literature has observed a general shift in power generation from the ankle to the hip joint 23 during gait, with children with CP adopting a more ‘hip’ driven pattern of locomotion rather than an ankle driven pattern64, 69, 70 . Numerous studies have displayed inadequate power production in the affected lower extremities of children with CP, particularly in the ankle plantar-flexor and knee extensor muscles50, 64, 71. Dallmeijer and Colleagues (2011)71 reported that peak ankle power to be reduced by more than 40% in CP compared to normative values for typically developing children71, whilst Rose and McGill (1998)50 reported individuals with CP to have 50% less ankle power during push-off when compared with age-matched controls50. This is supported with Engsberg and Colleagues (2000)37 finding that children with CP were significantly weaker in both dorsi flexors and plantar flexors37. With inadequate muscular power50, 64, 71, children with CP are likely to experience difficulties in functional tasks. 2.2.2 ACTIVITY AND PARTICIPATION The ‘functioning and disability’ component of the ICF also comprises activity and participation, where activity refers to the execution of a task or activity by an individual and participation refers to ones involvement in life situations10. As well as motor disturbances, children with CP are at risk of experiencing participation restrictions67, reduced participation in active-physical activities72-74, greater activity limitations and are considered to be less physically active then their typically developing peers74, 75. 2.2.2.1 ACTIVITY Literature consistently reports lower levels of activity for children with CP74-78. Maher and Colleagues (2007)74 using the Physical Activity Questionnaire found that the level of selfreported physical activity was lower for adolescents with CP when compared to their typically developing peers74. Bjornson and Colleagues (2007)76 reported that children with CP to be active only 40.2% of the time, compared with 49.6% displayed in typically developing children76. Similar to this, Van Zelst and Colleagues (2006)75 reported children with hemiplegic CP experience significantly lower motor and process skills, using the Assessment of Motor and Process Skills which may impact on their levels of physical activity75. It has been shown that as the level of functional walking declines (as the GMFCS level increases), daily walking activity and percentage of time the child is active also decreases76. As assessed by the Six Minute Walk Test (6MWT); Calley and Colleagues (2012)78 found children with CP to experience more limitations across longer distances when compared to their typically developing peers78. Although the two concepts are closely linked, it is important to recognize them as separate 24 constructs that together with body structures and function and environmental factors all impact upon an individuals’ quality of life10. 2.2.2.2 PARTICIPATION Having a positive influence on the development of skills and competence, social relationships, and long-term mental and physical health, participation in day-to-day formal and informal activities is vital for children79, 80. Children and youth with physical disabilities are at risk of limited participation81. Numerous studies have shown that compared with typically developing peers, children with CP have difficulties participating in activities across home, school and in the wider community as a result of restrictions in physical functioning and mobility78, 82-84. Research comparing the differences in participation at school (using the School Function Assessment85) reported that children with CP experienced lower levels of participation across all domains, with the largest difference to be found in the environment of playground/recess, compared with typically developing children86. Outside of school, as assessed via the Children’s Assessment of Participation and Enjoyment (CAPE)87, children with CP are reported to participate less frequently, and in a lower range of activities88. Children with CP also spend more time using a computer than their typically developing peers, as assessed by the Frequency of Participation Questionnaire (FPQ)89, 90. The Assessment of Life Habits (LIFE-H) assesses the way in which the young person accomplishes their life habits at home, at school and in the wider community, and covers 12 domains of participation; nutrition, fitness, personal care, communication, housing, mobility, responsibilities, interpersonal relationships, community life, education, work and recreation. Comparing responses of children with CP and typically developing children, research by Calley and Colleagues (2012)78 indicated children with CP experience restrictions in their participation across all domains with the exception of relationships and work78. This was similar to work by Lepage and Colleagues (1999)91, reporting significant limitations within the recreation, community and personal care domains91. The cause of the reported limitations in participation and activities, like most aspects of CP, are likely to stem from a multitude of factors. As children approach adolescence, with growth, there appears to be an increased tendency towards muscle tightness, bony mal-alignment and weakness in the antigravity muscles92. This is followed by the appearance of muscular contractures and an increasing disuse of affected limbs that in turn exacerbates weakness. Since many children with CP are considered to be less 25 actively mobile than typically developing children, it is reasonable to assume that the disused muscles become atrophic compared with normal musculature50, further disadvantaging the force generating capability of muscle. Maruishi and Colleagues (2001) proposed that activities of daily living to be independently affected by both muscle strength and spasticity in adults with CP93. Ferland and Collegues (2011) evaluated the relationship between lower limb muscle strength and measures of locomotor capacity; they reported hip flexor muscle strength and ankle plantar flexor concentric muscle strength to be independently and significantly associated with level ground walking (6MWT94) and stair locomotion capacities95. It can be said that impairments in body structure and function (muscle strength and spasticity) may be contributing factors to limitations in activities and social participation experienced by children with CP26. 2.2.3 CONTEXTUAL FACTORS The second component of the ICF ‘contextual factors’ is made up of environmental factors and personal factors. Environmental factors refer to the physical, social and attitudinal environment in which people conduct their lives, while personal factors refer to one’s attributes as a person10. Quality of life (QoL) is defined as; an individual’s subjective perception of their satisfaction across various domains in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns96. A multidimensional notion, QoL is considered in terms of different domains of an individual’s life. A variety of measures have been developed to assess QoL, either from a health or a disorder related focus. For example, the disorder specific measure, The Cerebral Palsy Quality of Life Questionnaire for Children (CP-QoL)97, assesses seven domains of QoL including social well-being and acceptance, feelings about functioning, participation, and physical health, emotional wellbeing, access to services, pain and feeling about disability and family health97. Literature has reported children with CP to experience a lower QoL than children who are typically developing78, 98-100 across all domains, in particular physical and emotional wellbeing98, 99. Russo and Colleagues (2008)101 found significantly lower scores for children with CP across all domains of the Pediatric Quality of Life Inventory (PedsQoL)102 except for emotional functioning, which was reported as equal between the two groups101. This was in contrast to findings by Bjornson and Colleagues (2008)103 who reported a difference between CP and 26 typically developing children in self reported emotional health using the Child Health Questionnaire (CHQ104)103. With the exception of reporting a lower QoL in terms of physical pursuits, Calley and Colleagues (2012)78 also reported children with CP to experience a QoL similar to their typically developing peers78, however it should be noted that the sample of children (GMFCS I-II) were highly functional. Interestingly, at the milder end of the motor spectrum (GMFCS I) children with CP are reported to show a lower emotional QoL than children with more severe levels of motor impairment (GMFCS II and III)100. This is consistent with the ‘disability paradox’ whereby children with milder limitations, who are more likely to attend mainstream schools and spend more time around children without impairment, may be more aware of the physical differences between themselves and their typically developing peers105. The ICF provides a holistic framework, considering activity, participation, and body structures and functions. Enhancing any one of these components through therapeutic intervention can be viewed as a positive rehabilitation outcome with the ultimate goal to increase an individual’s overall QoL and life satisfaction106. 2.3 THERAPEUTIC INTERVENTIONS For the various neuromuscular and musculoskeletal problems associated with CP, it is considered that most children can benefit from a multitude of different treatments and not just a single treatment modality3. Because of the complexities in treating a child with CP, treatment should be determined using a multidisciplinary team approach with clearly outlined goals3. Gormely (2001) discussed that treatment for impairments present in a child should be treated not because of their presence, but if they are interfering with some level of functioning3. As stated previously, spasticity and muscular weakness, two motor impairments known to impact function, will be the focus of this literature review. In the broadest terms, the goals of any spasticity treatment plan are to maximise active function, ease care, and prevent secondary problems such as pain, subluxation, and contracture107. The range of treatments for spasticity is large, from simple stretching exercises, to oral and injectable therapies, to surgeries such as, tendon lengthening procedures108, intrathecal baclofen pumps109 and selective dorsal rhizotomies110. In determining the best treatment plan, each case is unique. Treatments likely to maximally improve function should be used, balanced against the risks and cost effectiveness3. BoNT-A has been shown to be 27 effective in reducing spasticity in children with CP111, 112 and will be discussed in further detail below. In recent years, the management of muscular weakness has received substantial interest; with strength training recognised as a key therapeutic intervention113-115. Strength training and its functional outcomes in the CP population will also be discussed in further detail in this review. 2.3.1 BOTULINUM TOXIN T YPE-A Botulinum Neurotoxin (BoNT) is a product of the synthesis of the bacterium Clostridium Botulinum116. It is a potent neurotoxin known to have seven different serotypes with names assigned as type A through to type G. BoNT-Type A (BoNT-A) is the most commonly utilised serotype for therapeutic purposes as it has the longest duration of effect117. Following its injection into muscular tissue BoNT-A acts to inhibit the release of acetylcholine in the neuromuscular junction, causing partial chemodenervation and muscle relaxation of the injected muscle118. This effectively acts to paralyse the overactive muscle, a pharmacological affect that takes peak affect 2 weeks post injection119, 120. However, paralysis of the muscle is only temporary with re-innervation beginning to take place at three months post injection and neuronal activity completely returning to normal by six months121-123. The application of BoNT-A in the management for spasticity is widely accepted and utilised as a treatment option for individuals with spastic CP124-128. Numerous studies report positive results of its effectiveness in temporarily treating spasticity112, 123-127, 129-132 and importantly, it is shown to have an acceptable safety profile129, 133-137 . Muscular injections of BoNT-A for spasticity presents no hazard for patients, with careful administration and close monitoring of dose levels that are determined based on body weight, muscle mass and degree of spasticity as per established guidelines112, 117, 123, 138, 139. The adverse effects of injection are uncommon, mild and transient140, consisting of the possibility of skin rash, pain on injection, occasionally mild flu-like symptoms, anaphylaxis, excessive fatigue, and the most common, excessive weakness122, 129, 141 . Due to the nature of the action of BoNT-A, muscle weakness in the targeted muscle is to be expected142, 143. In an animal study, Longino and Colleagues(2005)142, demonstrated that BoNT-A induced muscle weakness in the long term is frequency and muscle length dependent, with muscle weakness being greater in short compared with long muscles142. However, muscle weakness in non-targeted neighbouring muscles and antagonist muscles have also been reported following BoNT-A in animal studies, postulated to be a result 28 of functional limb disuse or the diffusion of BoNT143, 144 . It has also been noted that when BoNT-A is injected into the hyperactive muscle the induced paresis will produce a reduction of the diameter of the target muscle and that, if given over a long period of time, may result in real muscle atrophy116. Recent publications have raised concern regarding the effect of BoNT-A on muscle size and morphology145, 146 . Schroeder and Colleagues (2009)146 measured neurogenic atrophy in the injected medial gastrocnemius in two healthy adults post BoNT-A; with a reduction of 14-19% in cross sectional area after 3 months, and reductions still seen at 6, 9 and 12 months post BoNT-A, whilst there were no changes in the contralateral placebo injected muscle. Dunn and Colleagues (2010)147 supplemented this finding with reports of prolonged denervation of BoNT-A injected muscles up to 5 months post injection. Rare reports in the cosmetic industry provides us with some observable examples for BoNT-A related atrophy, with its use in facial contouring for reducing masseter muscle thickness148, 149, and its use in reduction of muscle size in women’s legs in the desire to appear more aesthetically appealing150. Animal studies have also revealed BoNT-A’s effect on muscle; Fortuna and Colleagues (2011) 151 compared the injected limbs to non-injected limbs of rabbits to find reductions in muscle mass of up to 50% injected muscles 1month after injection, Ma and Colleagues (2004)152, found muscle mass in injected limbs in rats to be reduced by 32% of the control side 2 weeks after the injection, with reduction of 24% still evident at 3months post. Despite these reports, the potential effect of atrophy as a muscular response to BoNT-A treatment is yet to be investigated in abnormal muscles such as that of CP. Despite this concern, functional outcomes of BoNT-A remain positive. Molenaers and Colleagues (2010)153 concluded that, when applied according to an integrated approach and started at a young age, BoNT-A treatment has the potential to improve the overall function of children with CP153. 2.3.2 FUNCTIONAL OUTCOMES OF BONT-A 2.3.2.1 AT THE LEVEL OF BODY FUNCTION AND STRUCTURE Along with the benefits of reduced muscle tone154, BoNT-A therapy also provides pain relief116 and improvements in range of joint motion154, 155. With the spasticity treatment often allowing the child the opportunity to learn specific targeted movement patterns otherwise restricted to them, improvements are also reported in functional measures156-160, in motor skill abilities161, 162 and in gait154. Also a result of the reduction of spasticity, improvements in walking gait following BoNT-A are reported in both kinematics (dynamic range of joint) and kinetics (joint 29 moments and power generation)15, dorsiflexion166, 168, 169 123, 163-167 . More specifically, increases in ankle , knee extension at initial contact166, and a normalisation of ankle kinetics166 during gait can be expected. Zurcher and Colleagues (2001)166 evaluated kinetics at the ankle during gait and reported an increase in power after BoNT-A injections in children with CP. In contrast with these reports, Maanum and Colleagues (2011)170 did not find any clinically relevant effects of BoNT-A on predefined kinematic variables in a population of adults with spastic CP170. However, they concluded their results to reflect relatively fixed gait strategies in adults with spastic CP, with co-existing other impairments, such as contractures, muscle weakness and reduced motor control and balance170. With this in mind, reducing muscle tone alone may not be enough to change joint angles during gait170-173. In treating dynamic equinus, BoNT-A works to prevent gastrocnemius shortening, and acts to avert fixed deformities, from a long term perspective, this can defer the need for orthopaedic surgery127, 154 . The use of BoNT-A in the CP population results in improvements in body structures and functions156, 157, 163, 174, 175. A recent systematic review of the literature uncovered a focus on the effects of BoNT-A on body structure and function measures, as well as gait analysis parameters, in the studies of BoNT-A use in CP176. Baird and Colleagues (2010)176 explained that measures for this domain are most proximate to the intervention, therefore are most likely to manifest changes176, however it is still important to understand the effect of BoNT-A treatment at the levels of activity and participation. 2.3.2.2 AT THE LEVEL OF ACTIVITY AND PARTICIPATION It is considered that the positive effect of BoNT-A therapy on gross motor function or gait may extend to concomitant improvements in activity and participation. However, despite the wealth of research investigating the effect of BoNT-A on the body structures and function, very few studies have evaluated its effectiveness on functionality with respect to activity and participation measures. In an adult population with spastic CP, activity was demonstrated to improve following BoNT-A, assessed by the Timed Up and Go (TUG), compared with a placebo group170. Within children, a study by Bjornson and Colleagues (2007), reported differences in activity domains (GMFM-66 and GMFM-88, COPM) but demonstrated no differences on the effect of BoNT-A in the participation domain using the COPM satisfaction scores and the Goal Attainment Scale15. Wright and Colleagues (2008)163 also indicated improvements in measures of activity (assessed by the GMFM and the Pediatric Evaluation of disability inventory), as well as in participation (the Pediatric Outcomes Data Collection Instrument) alongside reductions in 30 measures of body functions and structures163. These reports indicate that BoNT-A treatment can have an effect on daily activities130, however information is sparse on the effect on participation177, 178 . Outcomes within the activity and participation domains are of great interest, however they may represent secondary and tertiary effects of BoNT-A176, this may explain the paucity of research in this area. 2.3.2.3 AT THE LEVEL OF CONTEXTUAL FACTORS Of the effect of BoNT-A on a child’s QoL, literature is sparse. Research investigating the healthrelated quality of life (HRQoL, using the Short Form-36) found no change following BoNT-A in the lower limbs of adults with spastic CP170 or in the upper limbs of children with hemiplegic CP179. In contrast to this, a population of adults with upper motor neuron lesions (e.g. stroke or CP) did report improvements in perceived health-related QoL following BoNT-A treatment and physical intervention (physical therapies, orthoses, orthopaedic shoes and footwear correction)180. A study by Coutinho dos Santos and Colleagues (2011)181 utilised two measures, the Pediatric Outcomes Data Collection Instrument (PODCI) and the Child Caregiver Questionnaire (CCQ) to show improvements in QoL in children with CP a year after BoNT-A, however no inclusion of a control group limits these results181. In the hemiplegic CP population, Russo and Colleagues (2007)182 reported improvements in self worth, but not in QoL (using the Pediatric Quality of Life Inventory)182. QoL may depend on multiple factors that may or may not necessarily be influenced by the intervention182; as for activity and participation, more research is needed to improve our understanding of the complete functional effect of BoNT-A on CP. 2.3.3 STRENGTH TRAINING Strength training is defined as a method of improving muscular strength by gradually increasing the ability to resist force through the use of free weights, machines, or the person's own body weight183. The terms strength training and resistance training are often used synonymously, with resistance training generally a broader term, defined as a specialised method of conditioning, which involves the progressive use of a wide range of resistive loads and a variety of training modalities designed to enhance health, fitness, and sports performance”184. With the major focus on spasticity management in CP, early concerns that any excessive force would lead to an increase in spasticity meant that resistance training was avoided for children 31 with spastic CP185. However, with weakness gaining more recognition as a significant impairment in CP, recent literature has turned its interest towards strengthening the muscles113-115. Ross and Engsberg (2002)39 stated that strengthening muscles in individuals with CP should become a treatment priority, after reporting that muscle weakness was consistent in CP whereas spasticity was not39. A further endorsement is that to date there is no empirical evidence of strength-training increasing spasticity or contractures in people with CP46, 177, 186-190. A growing number of studies have confirmed that individuals with CP can have significant strength improvements following effective strength-training programs44-46, 65, 187-196. However contrary to previous systematic reviews114, 115, 197-199 , Scianni and Colleagues (2009)200 controversially suggested strength training to be neither effective nor worthwhile in children and adolescents with the CP. This review brought into question, again, the future of strength training in the CP population201-203. However responders were quick to critique areas of concern within this review. Scianni restricted the reviewed research to randomised controlled trials (RCT’s); whilst it is agreed upon that more rigorously conducted studies are needed201, by only including RCT’s it was felt that this review excluded important evidence from uncontrolled trials while including evidence from randomised controlled trials of poor quality201. The unusual mixture of interventions in the review by Scianni is also queried, with the analysis of three different modes of intervention (electrical stimulation, progressive resistance exercise training, endurance training) within one meta-analysis202, 203 . Questions were raised about whether the interventions were applied with sufficient intensity to increase muscle strength203, in particular, the inclusion of two studies that used electrical stimulation as the sole intervention 204, 205 and a loaded sit-to-stand study192. However, this review is in agreement that there is a concerning lack of appropriate intervention protocols for strength training in children with CP200, 201, 203, 206. Verschuren and Colleagues (2011)206 stated that research is yet to determine the most effective protocol for improving strength in the CP population206. As a guide, the key elements that should be included in a strength training program are: i) sufficient resistance so that only a relatively small number of repetitions (usually less than 12) can be completed before fatigue; ii) resistance is progressed as strength increases, and iii) the program runs for a sufficient time (usually a minimum of six weeks) for the benefits to accrue115, 207. However, amongst research investigating the effects of strength training in the CP population, there is noticeable variability in the parameters of training programs being administered; differing in the type of equipment, the exercise details, the duration and intensity of the program115. Strength programs include the use of body weighted exercises, 32 free weights, and strength training machines. Programs have varied in duration from four190, six44, 65, 187, 188, 208, 209, eight46, 210, ten189, 211, 212 and 12 weeks191, 195, but typically each frequented three times per week. With strength-training interventions involving effort against progressive resistance, the amount of resistance has varied throughout research from 65%44, 65, 188, 213, 214 , 70%189 and 80%193, 208 of one repetition maximum, (i.e. the maximum weight the participant could lift in one repetition), to using the maximum load that the child could manage for the required number of repetitions before fatiguing187, 195, 196, 212, 215. However despite the variability in the loading, each study incorporated an element of progression throughout their programs, in either the load weight or in the number of repetitions. At this stage more research is needed to specifically determine the type, intensity, duration and the intervals of rest206 for training muscle strength in children with CP. However until specific guidelines have been set for the CP population, Verschuren and Colleagues (2011)206 encourage clinicians to refer to the National Strength and Conditioning Association (NSCA) guidelines for resistance training for children who are developing typically184 (Table 1). Table 1 General youth resistance training guidelines as set by the National Strength and Conditioning Association184. * 1 RM= 1 Repetition Maximum. Variables of resistance training NSCA guidelines Warm up Intensity/volume 5–10 minutes of dynamic activities Single-joint and multi-joint exercises utilizing concentric and eccentric contractions 1–3 sets of 6–15 repetitions of 50%–85% of 1 RM* Rest intervals 1–3 minutes Frequency 2–4 times a week on non-consecutive days Duration 8–20 weeks Progression Increase resistance gradually (5%–10%) as strength improves Age Age 7 years and older Type 2.3.4 FUNCTIONAL OUTCOMES OF STRENGTH TRAINING 2.3.4.1 AT THE LEVEL OF BODY STRUCTURES AND FUNCTION There is strong evidence supporting the view that strength training can increase the ability to generate muscle force in people with CP44-46, 65, 187-196. Adding value to this is that the strength gains are reported to be similar to those experienced by the non- CP population following 33 training45, 46 and can be maintained over a period of time following the cessation of strength training 46, 188, 190, 212, 216. Research has documented that following strength training people with CP can achieve significant strength improvements that are translatable to gains in motor function46, 65, 115. Such gains have included flexibility, posture and balance177, with stable194, 217, 211 or increased ROM at the knee194, 217, improvements relating to walking46, 65, 115, 193, 210, 213, with increase in muscle strength considered one of the major factors of gait function196. Using three dimensional gait analysis (3DGA), literature has measured improvements in some gait parameters, although this was not always statistically significant44, 65, 193, 210, 213. Following strengthening, changes in kinematics have been demonstrated including; a more upright posture210, decrease in crouch210, 213, 193, improved hip and knee extension through stance193, 215, improved knee extension in late swing213, and trends of improved ankle dorsi-flexion at swing and initial contact193. These are particularly pertinent outcomes, with excessive hip and knee flexion common features observed in CP that will only worsen without intervention218. During typical gait, the ankle plantar-flexors act as the greatest contributors to forward propulsion, vital for a normal gait pattern219. Eek and Colleagues (2011)69 reported a relationship between muscle strength (weakness) and gait pattern, seen in particular in kinetic variables at the ankle, but also surmised that adequate strength around the hip and knee joints are needed for stability to allow plantar-flexor power generation at push off69. However, few studies that implemented 3DGA have reported kinetic alterations following strengthening. Engsberg and Colleagues (2006)193 report inconclusive kinetic alterations following strength training and suggested that future research should include the calculation of power. Power is defined as the work performed per unit of time and may be used to document the net energy generation or absorption of the muscles during activity31. Strengthening of the muscles is more likely to result in changes in the muscles force generating capacity than to alter kinematic profiles, therefore, investigating power throughout the gait cycle may be a more revealing method of evaluating the effect of strength training on gait. Improvements in recruitment and muscle activation are possible contributors to the improved gait patterns following strength training193, 210, 213 , however, with muscle strength associated with hypertrophy212, improvements in muscle morphology may also be a potential factor. Hypertrophy is thought to result from the increase in individual muscle fibre size – which can contribute to increases in muscle mass, cross sectional area and volume, with associated 34 increases in muscle strength220. In the typically developing population, research has shown increase in muscle volume up to 14% in the knee extensors of adult’s males, and up to 11% in the elderly following strengthening221, 222. It is thought that within the first 3 to 5 weeks of progressive strength training improved neural activation is responsible for the major portion of strength gained, however after this time, increases in muscle strength are primarily due to hypetrophy223. Therefore, to increase the size of healthy muscle, a prolonged period of progressive strength training is required. To date, the effect of strength training on muscle volume in children with spastic CP has only been investigated in one study; McNee and Colleagues (2009)212 reported that alongside improvements in plantar flexor strength, gastrocnemius muscles also increased in volume up to 17% after 5 weeks and up to 23% after 10 weeks of strength training in children with CP. McNee’s research indicates that strength training could amend the pre-existing muscle size and muscle strength deficit that is commonly present in CP212. Literature reporting functional outcomes such as walking ability has mixed results. The GMFM is a common measure used in studies reporting the effect of strength training on functional changes; following strength-training programs targeting muscles of the lower limb improvements have been significant in Dimension E65,188,192, 193, 224, relating to walking, running and jumping. However this did not reach statistical significance for some studies187, 225 . Similarly, whilst some studies show significant improvements in walking velocity65, 193, 208, 224, others do not44, 46, 190, 210, 213 . Whilst the effect of strength training on body structure and functions is generally positive, it remains undecided whether strength training is effective in improving activity or participation. 2.3.4.2 AT THE LEVEL OF ACTIVITY AND PARTICIPATION Little information is available on the effects of strength training on the participation dimension of functioning and disability115. McBurney and Collegues (2003)177 demonstrated qualitative examples of children increasing participation in school, leisure, social and family events after undertaking a home based strength program, in agreement, Darrah and Colleagues (1999)211 provided anecdotal support for increased participation in children with CP after completing a community fitness program of aerobics, strength training, and stretching211. Quantitative measures of participation as an outcome of strength training are rare115. Scholtes and Colleagues (2012)226 utilised the Children’s Assessment of Participation and Enjoyment (CAPE) questionnaire to measure participation following a 12 week strength training program in children with CP, and subsequently found no effect226. 35 Possible explanations for this mixture of results are; the relatively short training periods administered in the studies (i.e., 4–8 weeks), the diversity in the type of training (e.g., home or school-based, and functional or non-functional training regimes), and insufficient training resistance or progressions226. Scholtes and Colleagues (2012)191 responded to these reports with a 12-week functional progressive resistance training program which followed appropriate guidelines184 and despite resulting in significant increases in muscle strength (by up to 14%)191, there was no carry over effect to walking ability (as assessed by the Timed 10-Meter Walk Test, 1Minute Fast Walk Test, and the Timed Stair Test) or participation226. The conclusion was in agreement with Antilla and Colleagues (2008)199 systematic review that stated strength training does not improve walking speed and stride length in children with CP199, with the contention that in order for a domain such as walking ability to be improved, task specific interventions, such as a specific ambulation programs are recommended226 rather than a strength program. 2.3.4.3 AT THE LEVEL OF CONTEXTUAL FACTORS To our knowledge, only two studies have examined the effect of strength training on QoL in children with CP. Engsberg and Colleagues (2006)193 reported significant improvements in QoL193, whilst Verschuren and Colleagues’ (2007)178 results also demonstrated a positive impact of strength training on QoL178. However, neither measure used for assessing QoL were condition specific (the Pediatric Quality of Life Inventory and the Children’s Health-Related Quality of Life)178, 193, and therefore may not be as relevant to a child with CP and the issues pertinent to their QoL. Despite the paucity of research in this area, contextual factors are an important aspect to consider in the assessment of strength training. However, Tsoi and Colleagues (2012)227 suggested that if improvements in QoL are to be expected in the management of CP, there is a need for comprehensive treatment approaches, targeted not just the impairment but the loss of function227. 2.4 THE NEXT STEP IN CP THERAPY CP is a disability that by its very definition, involves an extensive range and combination of neuromotor and musculoskeletal problems and associated conditions2. In the clinical setting, it is inconceivable to treat just one motor impairment and expect remarkable improvements in overall function. Therapeutic interventions need to consider more than one impairment of CP 36 if improvements in levels of activity and participation are sought114, and is a logical direction for maximising functional outcomes. The combination of therapies is already somewhat in practice for the CP population; however only recently does the literature appear to formally investigate this. Clinicians need practical evidence, and guidelines to direct evidence based care. Spasticity management with BoNT-A is a commonly used treatment option for children with CP; it is suggested that the reduction in spasticity through BoNT-A treatment may ease the ability to move, and clinicians frequently utilise this time period (of reduced spasticity) to administer complimentary interventions to potentiate the effect of the BoNT-A for spasticity reduction127,228 such as stretching, range of motion exercise, serial casting, splinting/orthotics and motor training229. Literature has consistently emphasised the importance of physical therapy combined with BoNT-A treatment34, 154, 157, 172, 230 and functional outcomes have been positive. For example, Scholtes and Colleagues (2007)172 demonstrated that comprehensive rehabilitation, administered in combination with multilevel BoNT-A successfully improved knee extension during gait, increased muscle length, and decreased spasticity172. A systematic review indicated that trials favoured BoNT-A with usual care or physiotherapy over usual care or physiotherapy alone, however due to modest methodological quality neither treatment method could be definitively recommended231. Occupational therapy has also been administered in combination with upper limb BoNT-A therapy, and has successfully demonstrated a significant reduction in muscle tone, whilst at the same time achieving an accelerated attainment of functional goals232, improvements in body structure, activity participation, and self-perception in children with CP182. Muscular weakness and spasticity are concurrent impairments of a CP, with neither the only cause of the motor dysfunction in CP, therefore, it is reasonable to state that alleviating only one of the symptoms will have only partial effect on the improvement of motor function233. With this in mind, it seems a logical step to target both spasticity and muscular weakness in combination.A recent pilot study by Elvrum and Colleagues (2012)234 investigated the combination of resistance training and BoNT-A in the hand234. Their results demonstrated that the addition of eight weeks resistance training strengthened non injected muscles temporarily without a concomitant systematic increase in muscle tone234. Furthermore, the resistance training may have reduced the short-term strength loss that results from BoNT-A injections in the spastic muscles, and it was suggested that additional resistance training may have also increased active range of motion to a larger extent than BoNT-A alone234. However, the 37 combination of therapies was not successful in improving hand and arm use over and above BoNT-A treatment alone; and it was concluded that more task-related resistance training may be required234. In addition to this, a pilot study by Bandholm and Colleagues (2012)195 included progressive resistance training to their physical rehabilitation program following BoNT-A treatment of the ankle plantar flexors195. This study resulted in increases in the maximal torque-generating capabilities of the plantar flexors, with a simultaneous reduction in plantar flexor spasticity, and a trend of increased function195. These two pilot studies are the first indications of a formal combination of BoNT-A and strength training within the literature, and highlights the potential for future therapy. 2.5 SUMMARY CP describes a group of disorders that encompass a wide variety of musculoskeletal problems, and secondary conditions2. Spasticity, weakness, dystonia, muscle contractures, bony deformities, in-coordination and loss of selective motor control are amongst the list of possible motor impairments associated with CP, affecting function3. The ICF promotes a broad application of outcome measures that ensures a multidimensional evaluation of functioning, and of therapeutic interventions11, 14, and is the ideal tool to further understand the effects of interventions in the lives of children with CP. Spasticity26 and muscular weakness36, 37-39, 236 are two key motor impairments of CP; both significantly affecting function27, 28. Particular attention throughout the literature pertains to walking, with the presence of spasticity typified by different alterations of gait29. However, whilst it is important to note spasticity is a significant impacting factor on deviations of gait frequently associated with CP, other factors are also influential; such as the development of contractions, poor selective motor control and muscular weakness29. Muscular weakness is increasingly considered as a significant motor impairment of CP36, 37-39, 236. Attributable to both neural mechanisms and muscle tissue changes36, the literature has demonstrated that children with CP have smaller muscles then their typically developing peers52, 57-60. Muscle strength is positively associated with walking ability43, with muscle weakness potentially linked with gait deviations50, 64, 71. Children with CP are reported to experience lower levels of activity74-78, are 38 at a higher risk of limited participation81, and experience a lower QoL than children who are typically developing78, 98-100. The application of BoNT-A in the management for spasticity is widely accepted and utilised as a treatment option for spasticity for individuals with CP124-128. Numerous studies report positive results of its effectiveness in temporarily treating spasticity112, 123, 126, 127, 129, 130, 160. However, recent literature has reported a potential for post BoNT-A weakness122, 129, 141 and atrophy146, 147 . This is of particular concern for a population of children already predisposed to muscular weakness38, and smaller muscles57. Despite the concern, there is a paucity of research investigating the effect of BoNT-A on the muscle morphology and strength of children with CP. Of the ICF, at the level of body structures and functions, the use of BoNT-A in the CP population is encouraging156, 157, 163, 174, 175. As well as indications of functional improvement156160 , literature indicates a positive effect of BoNT-A on gait patterns154, 166. The effect of BoNT-A, however has not been researched to a large extent at other levels of the ICF; reports indicate that BoNT-A treatment can have a positive effect on daily activities130, however information is sparse and inconclusive on the effect on participation177, 178 and QoL170, 179. Targeting muscular weakness, a growing number of studies have confirmed that individuals with CP can achieve significant strength improvements following effective strength-training programs44-46, 65, 187-196. In addition to strength gains, literature suggests improvements relating to walking46, 65, 115, 193, 210, 213 . Whilst only one study has investigated the potential for hypertrophy in the CP population212, this evidence is positive, indicating that strength training could amend the pre-existing muscle size and muscle strength deficit common in CP212. Whilst the effect of strength training on body structure and functions is generally positive, it remains to be determined whether strength training is effective in improving activity or participation. In addition to this, there is also a paucity of research pertaining to QoL in relation to strength training in the CP population. The application of outcome measures at all levels of the ICF is recommended for comprehensive evaluations of therapeutic treatments. In this regard, current research is limited on the comprehensive effects of two common interventions for children with CP, BoNT-A and strength training, hence more research is needed. In terms of the body structures and function dimension of the ICF, the effectiveness of BoNT-A for spasticity management and strength training for muscular weakness is evident throughout the literature. The next, logical progression is to combine both therapy options, in an aim to achieve optimal functional outcomes for children with CP, which may impact across all levels of the ICF. 39 2.6 REFERENCES 1. Paneth N, Hong T, Korzeniewski S. The descriptive epidemiology of cerebral palsy. Clin Perinatol. 2006;33:251-67. 2. Bax M. Terminology and classification of cerebral palsy. Dev Med Child Neurol. 1964;6:295-307. 3. Gormley MT. Treatment of neuromuscular and musculoskeletal problems in cerebral palsy. Pediatr Rehabil. 2001;4:5-16. 4. Panteliadis C, Strassburg H. Cerebral palsy: principles and management. Stuttgart (Germany): Thieme; 2004. 5. Watt J, Robertson C, Grace M. Early prognosis for ambulating of neonatal survivors with cerebral palsy. Dev Med Child Neurol. 1989;31:766-73. 6. Aiona M, Sussman M. Treatment of spastic diplegia in patients with cerebral palsy: part II. Journal of Pediatric Orthopaedics. 2004;13:13-38. 7. Rodda J, Graham H. Classification of gait patterns in spastic hemiplegia and spastic diplegia: a basis for a management algorithm. Eur J Neurol. 2001;8:98-108. 8. Palisano R, Rosenbaum P, Walter S, et al. Development and Reliability of a System to Classify Gross Motor Function in Children with Cerebral Palsy Developmental Medicine and Child Neurology. 1997;39:214. 9. Berker N, Yalçin S. Cerebral Palsy: Orthopedic Aspects and Rehabilitation. Pediatr Clin N Am. 2008;55:1209-25. 10. WHO. International Classification of Functioning, Disability and Health. Geneva: WHO; 2001 [cited 2006 January]; Available from: http://www3.who.int/icf/intros/ICF-Eng-Intor.pdf. 11. Üstün T, Chatterji S, Bickenbach J, Kostanjsek N, Schneider M. The International Classification of Functioning, Disability and Health: a new tool for understanding disability and health. Disabil Rehabil. 2003;25:565-71. 12. Rosenbaum L, Steward D. The World Health Organization International Classification of Functioning, Disability, and Health: A Model to Guide Clinical Thinking, Practice and Research in the Field of Cerebral Palsy. Semin Pediatr Neurol. 2004;11:5-10. 13. Vargus-Adams J. Understanding function and other outcomes in cerebral palsy. Phys Med Rehabil Clin N Am. 2009;20:567-75. 40 14. Majnemer A, Mazer B. New directions in the outcome evaluation of children with cerebral palsy. Semin Pediatric Neurology. 2004;11:11-7. 15. Bjornson K, Hays R, Graubert C, et al. Botulinum toxin for spasticity in children with cerebral palsy: A comprehensive evaluation. Pediatrics. 2007;120:49-58. 16. Kelly M, Darrah J. Aquatic exercise for children with cerebral palsy. Dev Med Child Neurol. 2005;47:383-42. 17. Johnston TE, Wainwright SF. Cycling with functional electrical stimulation in an adult with spastic diplegic Cerebral Palsy. Phys Ther. 2011;91:970-82. 18. Ramstad K, Jahnsen R, Lofterod B, Skjeldal OH. Continuous intrathecal baclofen therapy in children with cerebral palsy - when does improvement emerge? Acta Paediatrica. 2010;99:1661-5. 19. Pandyan A, Gregoric M, Barnes M, et al. Spasticity: clinical perceptions, neurological realities and meaningful measurement. Disabil Rehabil. 2005;27:2-6. 20. Mayston M. Strength-training for children with cerebral palsy. Assoc Paediatr Chartered Physiother. 2003;107:14-8. 21. Lance JW. Spasticity: disordered motor control. Chicago: Year Book Medical Publishers.; 1980. 22. Young R. Spasticity: a review. Neurology. 1994;44:12-20. 23. Lance J. Pyramidal and extrapyramidal disorders, in Central EMG: Electromyography in CNS Disorders. Boston, MA: Butterworth; 1984. p. 1-19. 24. Rang M, Silver R, de la Garza J. Cerebral palsy, In: Pediatric Orthopaedics. 2nd ed. Lovell WW, Winter RB, editors. Philadelphia: J B Lippincott; 1986. 25. Hägglund G, Wagner P. Spasticity of the gastrosoleus muscle is related to the development of reduced passive dorsiflexion of the ankle in children with cerebral palsy. Acta Orthop. 2011;82:744-8. 26. Bethoux F. Spasticity patients: Special considerations. Seminars in Pain Medicine. 2004;2:36-42. 27. Badell-Ribera A. Cerebral palsy: postural-locomotor prognosis in spastic diplegia. Arch Phys Med Rehabil. 1985;66:614-9. 28. Yokochi K, Hosoe A, Shimabukuro S, Kodama K. Gross motor patterns in children with cerebral palsy and spastic diplegia. Pediatr Neurol. 1990;6:245-50. 41 29. Rodda JM, Graham HK, Carson L, Galea MP, Wolfe R. Sagittal gait patterns in spastic diplegia. J Bone Joint Surg Br. 2004;86:251-8. 30. Sutherland D, Davids J. Common gait abnormalities of the knee in cerebral palsy. Clin Orthop. 1993;288:139-47. 31. Gage J. Gait Analysis in Cerebral Palsy. Oxford: MacKeith Press; 1991. 32. Sutherland D, Cooper L. The pathomechanics of progressive crouch gait in spastic diplegia. Orthop Clin North Am. 1978;9:143-54. 33. Yokochi K. Gait patterns in children with spastic diplegia and periventricular leukomalacia. Brain Dev. 2001;23:34-7. 34. Damiano D, Quinlivan J, Owen B, Shaffrey M, Abel M. Spasticity versus strength in cerebral palsy: relationships among involuntary resistance, voluntary torque, and motor function. Eur J Neurol. 2001;8:40-9. 35. Edwards R. Physiological analysis of skeletal muscle weakness and fatigue. Clin Sci Mol Med. 1978;54:463-70. 36. Mockford M, Caulton J. The pathophysiological basis of weakness in children with cerebral palsy. Pediatr Phys Ther. 2010;22:222-33. 37. Engsberg J, Ross S, Olree K, Park T. Ankle spasticity and strength in children with spastic diplegic cerebral palsy. Dev Med Child Neurol. 2000;42:42-4. 38. Wiley ME, Damiano DL. Lower-Extremity strength profiles in spastic cerebral palsy. Dev Med Child Neurol. 1998;40:100-7. 39. Ross S, Engsberg J. Relationships between spasticity and strength in individuals with spastic diplegic cerebral palsy. Dev Med Child Neurol. 2002;44:148-57. 40. Damiano D, Dodd K, Taylor N. Should we be testing and training muscle strength in cerebral palsy? Dev Med Child Neurol. 2002;44:68–72. 41. Goh H, Thompson M, Huang W, Schafer S. Relationships among measures of knee musculoskeletal impairments, gross motor function, and walking efficiency in children with cerebral palsy. Pediatr Phys Ther. 2006;18:253-61. 42. Ross SA, Engsberg JR. Relationships between spasticity, strength, gait, and the GMFM- 66 in persons with spastic diplegia Cerebral Palsy. Arch Phys Med Rehabil. 2007;88:1114-20. 43. Eek M, Beckung E. Walking ability is related to muscle strength in children with cerebral palsy. Gait Posture. 2008;28:366-71. 42 44. Damiano D, Vaughan C, Abel M. Muscle response to heavy resistance exercise in children with spastic cerebral palsy. Dev Med Child Neurol. 1995;37:731-9. 45. McCubbin J, Shasby G. Effects of isokinetic exercise on adolescents with cerebral palsy. Adapt Phys Activ Q. 1985;2:56-64. 46. MacPhail A, Kramer J. Effect of isokinetic strength training on functional ability and walking efficiency in adolescents with cerebral palsy. Dev Med Child Neurol. 1995;37:763-75. 47. Damiano D, Martellotta T, Quinlivan J, Abel M. Deficits in eccentric versus concentric torque in children with spastic cerebral palsy. Med Sci Sports Exerc. 2001;33:117-22. 48. Leonard C, Moritani T, Hirschfeld H, Forssberg H. Deficits in reciprocal inhibition of children with cerebral palsy as revealed by H reflex testing. Dev Med Child Neurol. 1990;32:974-84. 49. Brown JK, Rodda J, Walsh EG, Wright GW. Neurophysiology of lower-limb function in hemiplegic children. Dev Med Child Neurol. 1991;33:1037-47. 50. Rose J, McGill K. The motor unit in cerebral palsy. Dev Med Child Neurol. 1998;40:270- 7. 51. Berger W, Quintern J, Dietz V. Pathophysiology of gait in adolescents with cerebral palsy. Electroencephalogr Clin Neurophysiol. 1982;53:538-48. 52. Elder G, Kirk J, Stewart G, et al. Contributing factors to muscle weakness in children with cerebral palsy. Dev Med Child Neurol. 2003;45. 53. Dietz V, Berger W. Cerebral palsy and muscle transformation. Dev Med Child Neurol. 1995;37:180-4. 54. Booth CM, Cortina Borja MJ, Theologis TN. Collagen accumulation in muscles of children with cerebral palsy and correlation with severity of spasticity. Dev Med Child Neurol. 2001;43:314-20. 55. Lieber R, Friden J. Functional and clinical significance of skeletal muscle architecture. Muscle Nerve. 2000;23:1647-66. 56. Enoka RM. Neuromechanics of Human Movement. 3rd ed. Champaign, IL: Human Kinetics; 2002. 57. Pitcher C, Elliott C, Williams S, et al. Childhood muscle morphology and strength: alterations over six months of growth. Muscle Nerve. 2012;In press. 58. Barrett RS, Lichtwark GA. Gross muscle morphology and structure in spastic cerebral palsy: a systematic review. Dev Med Child Neurol. 2010;52:794-804. 43 59. Barber L, Hastings-Ison T, Baker R, Barrett R, Lichtwark G. Medial gastrocnemius muscle volume and fascicle length in children aged 2 to 5 years with cerebral palsy. Dev Med Child Neurol. 2011;53:543-8. 60. Malaiya R, McNee AE, Fry NR, Eve LC, Gough M, Shortland AP. The morphology of the medial gastrocnemius in typically developing children and children with spastic hemiplegic cerebral palsy. J Electromyogr Kinesiol. 2007;17:657-63. 61. Lampe R, Grassl S, Mitternacht J, Gerdesmeyer L, Gradinger R. MRT-measurements of muscle volumes of the lower extremities of youths with spastic hemiplegia caused by cerebral palsy. Brain Dev. 2006;28:500-6. 62. Graves P. Therapy methods for cerebral palsy. J Paediatr Child Health. 1995;31:24-8. 63. Mayston M. People with cerebral palsy: Effects of and perspectives for therapy. Neural Plast. 2001;8:122-8. 64. Olney SJ, MacPhail A, Hedden D, Boyce WF. Work and power in hemiplegic cerebral palsy. Phys Ther. 1990;70:431-8. 65. Damiano D, Abel M. Functional outcomes of strength training in spastic cerebral palsy. Arch Phys Med Rehabil. 1998;79:119-25. 66. Russell D, Rosenbaum P, Gowland C, et al. Gross motor function measure manual. 2nd ed. Hamilton: McMaster Univ; 1993. 67. Shelly A, Davis E, Waters E, et al. The relationship between quality of life and functioning for children with cerebral palsy. Dev Med Child Neurol. 2008;50:199-203. 68. Ounpuu S, Gage JR, Davis RB. Three-dimensional lower extremity joint kineticsbin normal pediatric gait. J Pediatr Orthop. 1991;11:341-9. 69. Eek MN, Tranberg R, Beckung E. Muscle strength and kinetic gait pattern in children with bilateral spastic CP. Gait Posture. 2011;33:333-7. 70. Riad J, Haglund-Akerlind Y, Miller F. Power generation in children with spastic hemiplegic cerebral palsy. Gait Posture. 2008;27:641-7. 71. Dallmeijer AJ, Baker R, Dodd KJ, Taylor NF. Association between isometric muscle strength and gait joint kinetics in adolescents and young adults with cerebral palsy. Gait Posture. 2011;33:326-32. 72. Imms C, Reilly S, Carlin J, Dodd K. Diversity of participation in children with cerebral palsy. Dev Med Child Neurol. 2008;50:363-9. 44 73. Law M, King G, King S, et al. Patterns of participation in recreational and leisure activities among children with complex physical disabilities. Dev Med Child Neurol. 2006;48:337-42 74. Maher C, Williams M, Olds T, Lane A. Physical and sedentary activity in adolescents with cerebral palsy. Dev Med Child Neurol. 2007;49:450-7. 75. Van Zelst B, Miller M, Russo R, Murchland S, Crotty M. Activities of daily living in children with hemiplegic cerebral palsy: a cross- sectional evaluation using the assessment of motor and process skills. Dev Med Child Neurol. 2006;48:723-7. 76. Bjornson K, Belza B, Kartin D, Logsdon R, McLaughlin J. Ambulatory physical activity performance in youth with cerebral palsy and youth who are developing typically. Phys Ther. 2007;87:248-57. 77. Van den Berg-Emons H, Saris W, De Barbanson D, Westerterp K, Huson A, van Baak M. Daily physical activity of schoolchildren with spastic diplegia and of healthy control subjects. J Pediatr. 1995;127:578-84. 78. Calley A, Williams S, Reid S, et al. A Comparison of activity, participation and quality of life in children with and without spastic diplegia Cerebral Palsy. Disabil Rehabil. 2012;34:130610. 79. Forsyth R, Jarvis S. Participation in childhood. Child Care Health Dev. 2002;28:277-9. 80. Caldwell L, Gilbert A. Leisure, health, and disability: a review and discussion. Can J Commun Ment Health. 1990;9:111-22. 81. Brown M, Gordon W. Impact of impairment on activity patterns of children. Arch Phys Med Rehabil. 1987;68. 82. Tuzun E, Eker L, Daskapan A. An assessment of the impact of cerebral palsy on children's quality of life. WFizyoterapi Rehabilitasyon 2004;15:3-8. 83. Vargus-Adams J. Health-related quality of life in childhood cerebral palsy. Arch Phys Med Rehab. 2005;86:940-5. 84. Varni J, Burwinkle T, Sherman S, et al. Health related quality of life of children and adolescents with cerebral palsy: Hearing the voices of the children. Dev Med Child Neurol. 2005;47:592-7. 85. Coster W, Deeney T, Haltiwanger J, Haley S. School function assessment, user’s manual. San Antonio, TX: Therapy Skill Builders; 1998. 45 86. Schenker R, Coster W, Parush S. Participation and activity performance of students with cerebral palsy within the school environment. Disabil Rehabil. 2005;27:539-52. 87. King G, Law M, King S, et al. Measuring children’s participation in recreation and leisure activities: Construct validation of the CAPE and PAC. Child Care Health Dev. 2006;33:2839. 88. Engel-Yeger B, Jarus T, Anaby D, Law M. Differences in patterns of participation between youths with cerebral palsy and typically developing peers. Am J Occup Ther. 2009;63:96-104. 89. Michelsen SI, Flachs EM, Uldall P, et al. Frequency of participation of 8-12-year-old children with cerebral palsy: a multi-centre cross-sectional European study. Eur J Paediatr Neurol 2009;13:165-77. 90. Mc Manus V, Corcoran P, Perry I. Participation in everyday activities and quality of life in pre-teenage children living with cerebral palsy in South West Ireland. BMC Pediatrics. 2008;8:50. 91. Lepage C, Noreau L, Bernard P, Fougeyrollas P. Profile of handicap situations in children with cerebral palsy. Scand J Rehabil Med. 1998;30:263-72. 92. Boyd R. A physiotherapy perspective on assesment and outcome measurement of children with Cerebral Palsy. In: Scrutton D, Damiano D, Mayston M, editors. Management of the Motor disorders of children with Cerebral Palsy. London: Mac Keith Press; 2004. p. 52-66. 93. Maruishi M, Mano Y, Sasaki T, Shinmyo N, Sato H, Ogawa T. Cerebral palsy in adults: Independent effects of muscle strength and muscle tone. Arch Phys Med Rehabil. 2001;82:637-41. 94. American Thoracic Society. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111-7. 95. Ferland C, Lepage C, Moffet H, Maltais D. Relationships between lower limb muscle strength and locomotor capacity in children and adolescents with cerebral palsy who walk independently. Phys Occup Ther Pediatr 2011;32:320-32. 96. WHOQOL. Development of the WHOQOL: rationale and current status. Int J Mental Health. 1994;23:24-56. 97. Waters E, Davis E, Boyd R, et al. Cerebral Palsy Quality of Life Questionnaire for Children (CP QOL-Child) Manual. Melbourne: Deakin University 2006. 46 98. Liptak GS, O’Donnell M, Conaway M, et al. Health status of children with moderate to severe cerebral palsy. Dev Med Child Neurol. 2001;43:364-70. 99. Dickinson H, Parkinson K, Ravens-Sieberer U, et al. Self-reported quality of life of 8–12 year-old children with cerebral palsy: a cross-sectional European study. Lancet. 2007;369:2171–8. 100. Bjornson K, Belza B, Kartin D, Logsdon R, McLaughlin J. Self-reported health status and quality of life in youth with cerebral palsy and typically developing youth. Arch Phys Med Rehab. 2008;89:121-7. 101. Russo RM, Goodwin EB, Miller M, Haan E, Connell TM, Crotty M. Self-esteem, self- concept, and quality of life in children with hemiplegic cerebral palsy. J Pediatr. 2008;153:4737. 102. Varni J, Burwinkle T, Seid M. The PedsQL 4.0 as a school population health measure: feasibility, reliability, and validity. Qual Life Res. 2006;15:203-15. 103. Bjornson K, Belza B, Kartin D, Logsdon R, McLaughlin J, Thompson E. The relationship of physical activity to health status and quality of life in cerebral palsy. Pediatr Phys Ther. 2008;20:247-53. 104. Edwards T, Heubner C, Connell F, Patrick D. Adolescent quality of life. Part I: conceptual and measurement model. J Adolesc. 2002;25:275-86. 105. Albrecht GL, Devlieger PJ. The disability paradox: high quality of life against all odds. Soc Sci Med. 1982;48:977-88. 106. Sakzewaki L, Boyd R, Ziviani J. Clinimetric properties of participation measures for 5 to 13 year old children with cerebral palsy: a systematic review. Dev Med Child Neurol. 2007;49:232- 40. 107. Tilton A. Management of spasticity in children with cerebral palsy. Semin Pediatr Neurol. 2009;16:82-9. 108. Chambers H. The surgical treatment of spasticity. Muscle Nerve. 1997;6:121-8. 109. Albright A, Barron W, Fasick M, Polinko P, Janosky J. Continuous intrathecal baclofen infusion for spasticity of cerebral origin. JAMA. 1993;270:2475-7. 110. Peacock W, Staudt L. Spasticity in cerebral palsy and the selective posterior rhizotomy procedures. J Child Neurol. 1990;5:179-85. 111. Koman L, Mooney J, Smith B, Goodman A, Mulvaney T. Management of cerebral palsy with botulinum-A toxin : preliminary investigation. J Pediatr Orthop B. 1993;13:489-95. 47 112. Cosgrove A, Corry I, Graham H. Botulinum toxin in the management of the lower limb in cerebral palsy. Dev Med Child Neurol. 1994;36:386-96. 113. Darrah J, Fan JSW, Chen LC, Nunweiler J, Watkins B. Review of the effects of progressive resisted muscle strengthening in children with Cerebral Palsy: A clinical consensus exercise. Pediatr Phys Ther. 1997;9:12-7. 114. Mockford M, Caulton J. Systematic review of progressive strength training in children and adolescents with cerebral palsy who are ambulatory. Pediatr Phys Ther. 2008;20:318-33. 115. Dodd K, Taylor N, Damiano D. A systematic review of the effectiveness of strength- training programs for people with cerebral palsy. Arch Phys Med Rehabil. 2002;83:1157-64. 116. Dressler D, Adib Saberi F. Botulinum Toxin: Mechanisms of Action. Arq Neuropsiquiatr. 2005;53:3-9. 117. Dressler D. Botulinum Toxin Therapy. New York: Thieme; 2000. 118. Simpson L. The origin, structure, and pharmacological activity of botulinum toxin. Pharmacol Rev. 1981;33:155-88. 119. Bhidayasiri R, Truong D. Expanding use of botulinum toxin. J Neurol Sci. 2005;235:1-9. 120. Verrotti A, Greco R, Spalice A, Chiarelli F, Iannetti P. Pharmacotherapy of spasticity in children with cerebral palsy. Pediatr Neurol. 2006;34:1-6. 121. De Paiva A, Meunier F, Molgo J, Aoki K, Dolly J. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci U S A. 1999;96: 3200–5. 122. Brin M. Botulinum toxin: chemistry, pharmacology, toxicity, and immunology. Muscle Nerve. 1997;6:146-68. 123. Wong V. Use of Botulinum Toxin Injection in 17 Children with Spastic Cerebral Palsy. Pediatr Neurol. 1998;18:124-31. 124. Boyd RN, Graham HK. Objective measurement of clinical findings in the use of botulinum toxin type A for the management of children with cerebral palsy. Eur J Neurol. 1999;6:23-35. 125. Jefferson RJ. Botulinum toxin in the management of cerebral palsy. Dev Med Child Neurol. 2004;46:491-9. 126. Carr L, Cosgrove A, Gringras P, Neville B. Position paper on the use of botulinum toxin in cerebral palsy. UK Botulinum Toxin and Cerebral Palsy Working Party. Arch Dis Child 1998;79:271-3. 48 127. Graham H, Aoki K, Autti-Ramo I, et al. Recommendations for the use of botulinum toxin type A in the management of cerebral palsy. Gait Posture. 2000;11:67-79. 128. Morton RE, Hankinson J, Nicholson J. Botulinum toxin for cerebral palsy; where are we now? Arch Dis Child. 2004;89:1133-7. 129. Delgado MR, Hirtz D, Aisen M, et al. Practice Parameter: Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review). Neurology. 2010;74:336-43. 130. Boyd R, Hays RM. Current evidence for the use of botulinum toxin type A in the management of children with cerebral palsy: A systematic review. Eur J Neurol. 2001;8:1-20. 131. Fehlings D, Rang M, Glazier J, Steele G. An evaluation of botulinum-A toxin injections to improve upper extremity function in children with hemiplegic cerebral palsy. J Pediatr. 2000;137:331-7. 132. Love S, Novak I, Kentish M, et al. Botulinum toxin assessment, intervention and after- care for lower limb spasticity in children with cerebral palsy: international consensus statement. Eur J Neurol. 2010;17:9-37. 133. Bakheit AM, Severa S, Cosgrove A. Safety profile and efficacy of botulinum toxin in children with muscle spasticity. Dev Med Child Neurol. 2001;43:234-8. 134. Langdon K, Blair E, Davidson SA, Valentine J. Adverse events following botulinum toxin type A treatment in children with cerebral palsy. Dev Med Child Neurol. 2010;52:972-3. 135. Naumann M, Albanese A, Heinen F, Molenaers G, Relja M. Safety and efficacy of botulinum toxin type A following long-term use. Eur J Neurol. 2006;13:35-40. 136. O’Flaherty SJ, Janakan V, Morrow AM, Scheinberg AM, Waugh M-CA. Adverse events and health status following botulinum toxin type A injections in children with cerebral palsy. Dev Med Child Neurol. 2011;53:125-30. 137. Naumann M, Jankovic J. Safety of Botulinum toxin: A systematic review and meta- analysis. Curr Med Res Opin. 2004;20:981-90. 138. Heinen F, Desloovere K, Schroeder A, et al. The updated European Consensus 2009 on the use of botulinum toxin for children with cerebral palsy. Eur J Paediatr Neurol. 2010;14:4566. 139. Fehlings D, Novak I, Berweck S, et al. Botulinum toxin assessment, intervention and follow-up for paediatric upper limb hypertonicity: international consensus statement. Eur J Neurol. 2010;2:38-56. 49 140. Boyd R, Graham J, Nattrass G, Graham H. Medium term outcome-response characterisation and risk factor analysis of Botulinum Toxin type A in the management of spasticity in children with cerebral palsy. Eur J Neurol. 1999;6:37-45. 141. Davis E, Barnes M. Botulinum toxin and spasticity. J Neurol Neurosurg Psychiatry. 2000;69:143-7. 142. Longino D, Butterfield T, Herzog W. Frequency and length-dependent effects of botulinum toxin-induced muscle weakness. Journal of Biomechanics. 2005;38:609-13. 143. Yaraskavitch M, Leonard T, Herzog W. Botox produces functional weakness in non- injected muscles adjacent to the target muscle. Journal of Biomechanics. 2008;41:897-901. 144. Shaari C, Sanders I. Quantifying how location and dose of botulinum toxin injections affect muscle paralysis. Muscle Nerve. 1993;16. 145. Gough M, Fairhurst C, Shortland AP. Botulinum toxin and cerebral palsy: time for reflection? Dev Med Child Neurol. 2005;47:709-12. 146. Schroeder A, Ertl-Wagner B, Britsch S, et al. Muscle biopsy substantiates long-term MRI alterations one year after a single dose of botulinum toxin injected into the lateral Gastrocnemius muscle of healthy volunteers. Mov Disord. 2009;24:1494-503. 147. Dunne J, Singer BJ, Silbert PL, Singer KP. Prolonged vastus lateralis denervation after botulinum toxin type A injection. Mov Disord. 2010;25:397-401. 148. Kim J, Shin J, Kim S, Kim C. Effects of two different units of Botulinum Toxin Type A evaluated by computed tomography and electromyographic measurements of human masseter muscle. Plast Reconstr Surg. 2007;119:711-7. 149. Kim N, Chung J, Park R, Park J. The use of Botulinum Toxin Type A in aesthetic mandibular contouring. Plast Reconstr Surg. 2005;115:919-30. 150. Han KH, Joo YH, Moon SE, Kim KH. Botulinum toxin A treatment for contouring of the lower leg. J Dermatolog Treat. 2006;17:250-4. 151. Fortuna R, Aurélio Vaz M, Rehan Youssef A, Longino D, Herzog W. Changes in contractile properties of muscles receiving repeat injections of botulinum toxin. J Biomech. 2011;44:39-44. 152. Ma J, Elsaidi G, Smith T, et al. Time course of recovery of juvenile skeletal muscle after Botoxulinum Toxin A injection. Am J Phys Med Rehabil. 2004;83:774-80. 50 153. Molenaers G, Van Campenhout A, Fagard F, De Cat J, Desloovere K. The use of botulinum toxin A in children with cerebral palsy, with a focus on the lower limb. J Child Orthop. 2010;4:183-95. 154. Koman L, Mooney J, Smith B, Walker F, Leon J. Botulinum toxin type A neuromuscular blockade in the treatment of lower limb spasticity in cerebral palsy: a randomised double-blind placebo controlled trial. J Pediatr Orthop B. 2000;20:108-15. 155. Hawamdeh ZM, Ibrahim A, Al-Qudah AA. Long-term effect of botulinum toxin (A) in the management of calf spasticity in children with diplegic cerebral palsy. Europa Medicophysica. 2007;43:311 -8. 156. Flett P, Stern LM, Waddy H, Connell T, Seeger JD, Gibson SK. Botulinum toxin A verus fixed cast stretching for dynamic calf tightness in cerebral palsy. J Paediatr Child Health. 1999;35:71-7. 157. Love S, Valentine J, Blair E, Price C, Cole J, Chauve lP. The effect of botulinum toxin type A on the functional ability of the child with spastic hemiplegia: a randomized controlled trial. Eur J Neurol. 2001;8:50-8. 158. Steenbeek D, Meester-Delver A, Becher J, Lankhorst G. The effect of botulinum toxin type A treatment of the lower extremity on the level of functional abilities in children with cerebral palsy: evaluation with goal attainment scaling. Clin Rehabil. 2005;19:274-82. 159. Linder M, Schindler G, Michaelis U, et al. Medium-term functional benefits in children with cerebral palsy treated with botulinum toxin type A: 1-year follow-up using gross motor function measure. Eur J Neurol. 2001;8:120-6. 160. Fehlings D, Rang M, Glazier J, Steele C. An evaluation of botulinum-A toxin injections to improve upper extremity function in children with hemiplegic cerebral palsy. J Pediatr. 2000;137:331-7. 161. Park E, Park C, Chang H, Park C, Lee D. The effect of botulinum toxin type A injection into the gastrocnemius muscle on sit-to-stand transfer in children with spastic diplegic cerebral palsy. Clin Rehabil. 2006;20:668-74. 162. Fragala M, O’Neil M, Russo K, Dumas H. Impairment, disability, and satisfaction outcomes after lower- extremity Botulinum toxin A injections for children with cerebral palsy. Pediatr Phys Ther. 2002;14:132-44. 163. Wright FV, Rosenbaum PL, Goldsmith CH, Law M, Fehlings DL. How do changes in body functions and structures, activity, and participation relate in children with cerebral palsy? Dev Med Child Neurol. 2008;50:283-9. 51 164. Sarioglu B, Serdaroglu. G, Tutuncuoglu. S, Ozer E. The use of Botulinum Toxin Type A treatment in children with spasticity. Pediatr Neurol. 2003;29:299-301. 165. Sutherland D, Kaufman K, Wyatt M, Chambers H. Injection of botulinum A toxin into the gastrocnemius muscle of patients with cerebral palsy: a 3-D motion analysis study. Gait Posture. 1995;4:269–79. 166. Zurcher A, Molenaers G, Desloovere K, Fabry G. Kinematic and kinetic evaluation of the ankle after intramuscular injection of botulinum toxin A in children with cerebral palsy. Acta Orthopædica Belgica. 2001;67:475-80. 167. Boyd R, Pliatsios V, Starr R, Wolfe R, Graham H. Biomechanical transformation of the gastroc-soleus muscle with botulinum toxin A in children with cerebral palsy. Dev Med Child Neurol. 2000;42:31-41. 168. Sutherland DH, Kaufman KR, Wyatt MP, Chambers HG, Mubarak SJ. Double-blind study of botulinum A toxin injections into the gastrocnemius muscle in patients with cerebral palsy. Gait Posture. 1999;10:1-9. 169. Corry I, Cosgrove A, Duffy C, McNeill S, Taylor T, Graham H. Botulinum Toxin A compared with stretching casts in the treatment of spastic equinus: A randomised prospective trial. J Pediatr Orthop. 1998;18:304-11. 170. Maanum G, Jahnsen R, Stanghelle J, Sandvik L, Keller A. Effects of botulinum toxin A in ambulant adults with spastic cerebral palsy: A randomized double-blind placebo controlledtrial. J Rehabil Med. 2011;43:338-47. 171. Gage JR, Schwartz MH, Koop SE, Novacheck TF. Identification and treatment of gait problems in cerebral palsy. Clinics in Developmental Medicine 2nd ed. London: Mac Keith Press; 2009. p. 180-1. 172. Scholtes VA, Dallmeijer AJ, Knol DL, et al. Effect of multilevel botulinum toxin A and comprehensive rehabilitation on gait in cerebral palsy. Pediatr Neurol. 2007;36:30-9. 173. Olver J, Esquenazi A, Fung VS, Singer BJ, Ward A. Botulinum toxin assessment, intervention and aftercare for lower limb disorders of movement and muscle tone in adults: international consensus statement. Eur J Neurol. 2010;17:57-73. 174. Slawek J, Klimont L. Functional improvements in cerebral palsy patients treated with botulinum toxin A injections - preliminary results. Eur J Neurol. 2003;10:313-17. 175. Ade-Hall RA, Moore AP. Botulinum toxin type A in the treatment of lower limb spasticity in cerebral pasly. Cochrane Database Syst Rev. 2004;CD001408. 52 176. Baird MW, Vargus-Adams J. Outcome measures used in studies of botulinum toxin in childhood cerebral palsy: A systematic review. J Child Neurol. 2010, 2010;25:721-7. 177. McBurney H, Taylor N, Dodd K, Graham H. A qualitative analysis of the benefits of strength training for young people with cerebral palsy. Dev Med Child Neurol. 2003;45:658–63. 178. Verschuren O, Ketelaar M, Gorter J, Helders PJM, Uitervaal CSPM, Takken T. Exercise training program in children and adolescents with cerebral palsy. A randomised controlled trial. Arch Pediatr Adolesc Med. 2007;161:1075-81. 179. Redman T, Finn J, Bremner A, Valentine J. Effect of upper limb botulinum toxin-A therapy on health-related quality of life in children with hemiplegic cerebral palsy. J Paediatr Child Health. 2008;44:409-14. 180. Bergfeldt U, Skold C, Julin P. Short Form 36 assessed health-related quality of life after focal spasticity therapy. J Rehabil Med. 2009;41:279 -81. 181. Coutinho dos Santos LH, Bufara Rodrigues DC, Simoes de Assis TR, Bruck I. Effective results with botulinum toxin in cerebral palsy. Pediatr Neurol. 2011;44. 182. Russo R, Crotty M, Miller M, Murchland S, Flett P, Haan E. Upper-limb botulinum toxin A injection and occupational therapy in children with hemiplegic cerebral palsy identified from a population register: a single-blinded, randomized, controlled trial. Pediatrics. 2007;119:114958. 183. Mosby's Medical Dictionary. 8th ed: Elsevier; 2008. 184. Faigenbaum AD, Kraemer WJ, Blimkie CJR, et al. Youth resistance training: Updated position statement paper from the national strength and conditioning association. J Strength Cond Res. 2009;23. 185. Bobath B. Motor development, its effect on general development, and application to the treatment of cerebral palsy. Physiotherapy. 1971;57. 186. Fowler E, Ho T, Nwigwe A, Dorey F. The effect of quadriceps femoris muscle strengthening exercises on spasticity in children with cerebral palsy. Phys Ther. 2001;81:1215– 23. 187. Dodd K, Taylor N, Graham H. A randomized clinical trial of strength training in young people with cerebral palsy. Dev Med Child Neurol. 2003;45:652–7. 188. Morton J, Brownlee M, McFadyen A. The effects of progressive resistance training for children with cerebral palsy. Clin Rehabil. 2005;19:283 - 9. 53 189. Andersson C, Grooten W, Hellsten M, Kaping K, Mattsson E. Adults with cerebral palsy: walking ability after progressive strength training. Dev Med Child Neurol. 2003;45:220-8. 190. Blundell S, Shepherd R, Dean C, Cahill B. Functional strength training in cerebral palsy: a pilot study of a group circuit training class for children aged 4–8 years. Clin Rehabil. 2003;17:48-57. 191. Scholtes VA, Becher JG, Comuth A, Dekkers H, Van Dijk L, Dallmeijer AJ. Effectiveness of functional progressive resistance exercise strength training on muscle strength and mobility in children with cerebral palsy: A randomized controlled trial. Dev Med Child Neurol. 2010;52:107-13. 192. Liao H, Liu Y, Liu W, Lin Y. Effectiveness of loaded Sit-to-Stand resistance exercise for children with mild spastic diplegia: A randomized clinical trial. Arch Phys Med Rehab. 2007;88:25-31. 193. Engsberg J, Ross S, Collins D. Increasing ankle strength to improve gait and function in children with cerebral palsy: a pilot study. Pediatr Phys Ther. 2006;18:266-75. 194. Tweedy S. Evaluation of strength and flexibility training for adolescent athletes with cerebral palsy: full report: Belconnen (Aust): Australian Sports Commission.1997. 195. Bandholm T, Jensen B, Nielsen L, et al. Neurorehabilitation with versus without resistance training after botulinum toxin treatment in children with cerebral palsy: A randomized pilot study. NeuroRehabilitation. 2012;30:277-86. 196. Eek M, Tranberg R, Zügner R, Alkema K, Beckung E. Muscle strength training to improve gait function in children with cerebral palsy. Dev Med Child Neurol. 2008;50:759- 64. 197. Taylor N, Dodd K, Damiano D. Progressive resistance exercise in physical therapy: a summary of systematic reviews. Phys Ther. 2005;85:1208-23. 198. Verschuren O, Ketelaar M, Takken T, Helders P, Gorter J. Exercise programs for children with cerebral palsy: a systematic review of the literature. Am J Phys Med Rehabil. 2008;87:404–17. 199. Antilla H, Autti-Ramo I, Suoranta J, Makela M, Malmivaara A. Effectiveness of physical therapy interventions for children with cerebral palsy: A systematic review. BMC Pediatrics. 2008;8:14. 200. Scianni, A., Butler J, Ada L, Teixeira-Salmela L. Muscle strengthening is not effective in children and adolescents with cerebral palsy: a systematic review. Aust J Physiother. 2009;55:81-7. 54 201. Lancaster A, Mudge A, Wu J, Lewis J, Bau K. Should we change practice? Aust J Physiother. 2009;55:291. 202. Graham HK, Thomason P. Is there sufficient evidence? Aust J Physiother. 2009;55:223. 203. Taylor N. Is progressive resistance exercise ineffective in increasing muscle strength in young people with cerebral palsy? Aust J Physiother 2009;55:222. 204. Kerr C, McDowell B, Cosgrove A, Walsh D, Bradbury I, McDonough S. Electrical stimulation in cerebral palsy: a randomized controlled trial. Dev Med Child Neurol. 2006;48:870-6. 205. Van der Linden M, Hazlewood M, Aitchison A, Hillman S, Robbb J. Electrical stimulation of gluteus maximus in children with cerebral palsy: effects on gait characteristics and muscle strength. Dev Med Child Neurol. 2003;45:385-90. 206. Verschuren O, Ada L, Maltais DB, Gorter JW, Scianni A, Ketelaar M. Muscle strengthening in children and adolescents with spastic Cerebral Palsy: Considerations for future resistance training protocols. Phys Ther. 2011;91:1130-9. 207. Faigenbaum A. Strength training for children and adolescents. Clin Sports Med. 2000;19:593-619. 208. Eaglton M, Iams A, McDowell J, Morrison R, Evans C. The effects of strength training on gait in adolescents with cerebral palsy. Pediatr Phys Ther. 2004;16:22-30. 209. Damiano D, Vaughan C, Abel M. Muscle response to heavy resistance exercise in children with spastic cerebral palsy. Developmental Medicine & Child Neurology. 1995;37:7319. 210. Unger M, Faure M, Frieg A. Strength training in adolescent learners with cerebral palsy: a randomized controlled trial. Clin Rehabil. 2006;20:469-77. 211. Darrah J, Wessel J, Nearingburg P, O'Connor M. Evaluation of a community fitness program for adolescents with cerebral palsy. Pediatr Phys Ther. 1999;11:18-23. 212. McNee AE, Gough M, Morrissey MC, Shortland AP. Increase in muscle volume after plantarflexor strength training in children with spastic cerebral palsy. Dev Med Child Neurol. 2009:1-7. 213. Damiano D, Kelly L, Vaughan C. Effects of quadriceps femoris muscle strengthening on crouch gait in children with spastic diplegia. Phys Ther. 1995;75:658-67. 214. DiIenno M, Atkinson H. Quality of life, strength and function following an intensive strengthening program in a 17 year old with cerebral palsy. Pediatr Phys Ther. 2006;18:73-4. 55 215. Damiano DL, Arnold AS, Steele KM, Delp SL. Can strength training predictably improve gait kinematics? A pilot study on the effects of hip and knee extensor strengthening on lowerextremity alignment in cerebral palsy. Phys Ther. 2010, 90:269-79. 216. Dodd K, Taylor N, Graham H. A randomized clinical trial of strength training in young people with cerebral palsy. Dev Med Child Neurol. 2003;45:652–7. 217. Healy A. Two methods of weight training for children with spastic type of cerebral palsy. Res Q. 1958;29:389-95. 218. Arnold A, Anderson F, Pandy M, Delp S. Muscular contributions to hip and knee extension during the single limb stance phase of normal gait: a framework for investigating the causes of crouch gait. J Biomech. 2005;38:2181-9. 219. Gage J. A qualitative description of normal gait: The treatment of gait problems in cerebral palsy. Gage J, editor. London: Mac Keith Press; 2004. 220. Fluckey JD, Dupont-Versteegden EE, Montague DC, et al. A rat resistance exercise regimen attenuates losses of musculoskeletal mass during hindlimb suspension. Acta Physiol Scand. 2002;176:293-300. 221. Aagaard P, Andersen JL, Dyhre-Poulsen P, et al. A mechanism for increased contractile strength of human pennate muscle in response to strength training: changes in muscle architecture. J Physiol. 2001;534:613-23. 222. Harridge S, Kryger A, Stensgaard A. Knee extensor strength, activation, and size in very elderly people following strength training. Muscle Nerve. 1999;22:831-39. 223. Moritani T, deVries H. Neural factors versus hypertrophy in the time course of muscle strength gain. Am J Phys Med. 1979;58:115-30. 224. Jiang Q, Liu P, Wang C. The effect of functional strength training in spastic cerebral palsy. Chin J Rehabil Med 2006;21:896–8. 225. Patikas D, Wolf S, Mund K, Armbrust P, Schuster W, Döderlein L. Effects of a postoperative strength-training program on the walking ability of children with cerebral palsy: A randomized controlled trial. Arch Phys Med Rehab. 2006;87:619-26. 226. Scholtes VA, Becher JG, Janssen-Potten YJ, Dekkers H, Smallenbroek L, Dallmeijer AJ. Effectiveness of functional progressive resistance exercise training on walking ability in children with cerebral palsy: A randomized controlled trial. Res Dev Disabil. 2012;33:181-8. 227. Tsoi WSE, Zhang LA, Wang WY, Tsang KL, Lo SK. Improving quality of life of children with cerebral palsy: a systematic review of clinical trials. Child Care Health Dev. 2012;38:21-31. 56 228. Boyd R, Graham H. Botulinum toxin A in the management of children with cerebral palsy: indications and outcome. Eur J Neurol. 1997;4:15-22. 229. Goldstein E. Spasticity management: an overview. J Child Neurol. 2001;16:16-23. 230. Leach J. Children undergoing treatment with Botulinum toxin: the role of the physical therapist. Muscle Nerve. 1997;6:194-207. 231. Ryll U, Bastiaenen C, De Bie R, Staal B. Effects of leg muscle botulinum toxin A injections on walking in children with spasticity-related cerebral palsy: a systematic review. Dev Med Child Neurol. 2011;53:210-06. 232. Wallen M, O'Flaherty S, Waugh M. Functional outcomes of intramuscular botulinum toxin type A and occupational therapy in the upper limbs of children with cerebral palsy: a randomised controlled trial. Arch Phys Med Rehab. 2007;8:1-10. 233. Fowler E, Kolobe T, Damiano D, et al. Promotion of physical fitness and prevention of secondary conditions for children with Cerebral Palsy: section on pediatrics research summit proceedings. Phys Ther. 2007;87:1495-510. 234. Elvrum A-K, Braendvik S, Saether R, Lamvik T, Vereijken B, Roeleveld K. Effectiveness of resistance training in combination with botulinum toxin-A on hand and arm use in children with cerebral palsy: A pre-post intervention study. BMC Pediatrics. 2012;12:Epub ahead of print. 235. Engsberg J, Ross SA, Collins D, Sung Park T. Effect of selective dorsal rhizotomy in the treatment of children with cerebral palsy. J Neurosurg. 2006;105:8-15. 57 CHAPTER THREE MORPHOLOGICAL ALTERATIONS IN SPASTIC MUSCLES IMMEDIATELY FOLLOWING BOTULINUM NEUROTOXIN TYPE-A TREATMENT IN CHILDREN WITH CEREBRAL PALSY. This manuscript was submitted for publication into Muscle and Nerve in December, 2012 and is currently under review. Williams SA, Reid SL, Elliott CM, Shipman P, Valentine J. Morphological alterations in spastic muscles immediately following Botulinum Toxin Type-A treatment in children with Cerebral Palsy. Muscle and Nerve. 2012 (In Review) The PhD candidate, Sîan A Williams, accounted for 80% of the intellectual property associated with the final manuscript. Collectively, the remaining authors contributed 20%. 58 FOREWORD BoNT-A is widely accepted and utilised as an established treatment option for spasticity management for individuals with CP. There are some concerns that whilst children appear to do well functionally with the use of BoNT-A, there is evidence for an atrophic effect of BoNT-A documented in typically developing muscles in human and animal research. To the authors knowledge this has not yet been investigated in pathological muscles. This first paper presented in this thesis has investigated the effect of BoNT-A on muscle morphology, muscle strength and functional ability in children with CP, and in doing so presents the first known documentation of the morphologic alterations of pathological muscles in response to BoNT-A. This new information presents implications for future research, which in turn may guide future treatment plans for the use of BoNT-A in spasticity management. 59 3.1 ABSTRACT Aim: To investigate the morphological alterations of muscles of the lower limbs in children with CP following Botulinum Toxin Type-A (BoNT-A) treatment. Method: Fifteen children, aged 5-12 years (x=8years 5mo, SD 1yr 10mo) with CP receiving BoNT-A for spasticity management were included. Muscle morphology was assessed using Magnetic Resonance Imaging and Mimics software. Strength was assessed using dynamometry and functional measures included the Timed-Up-and-Go and the 6-Minute Walk Test. Assessments were timed 2weeks prior to and 5 weeks post injection. Results: Whilst total muscle group morphology of the injected muscle group remained unchanged, individual muscle alterations were evident. A 4.47% decrease in the injected gastrocnemius muscle volume (MV) was statistically significant, (p=0.006) as was a 3.96% increase in soleus MV (p=0.020) following BoNT-A. Injected medial hamstrings MV decreased by 5.85%, approaching statistical significance (p=.076).There were no statistically significant changes in strength or function (p<.05). Interpretation: MV decreases were observed in the injected muscle, with synergistic muscle hypertrophy that appeared to compensate for this decrement. The 4-5% decreases in BoNT-A injected muscles are not dramatic comparative to reports in recent animal studies. This is a positive indication for BoNT-A, particularly as it also did not negatively alter function. 60 3.2 INTRODUCTION Spasticity, muscle weakness and muscle co-contraction are common motor problems associated with Cerebral Palsy (CP). Botulinum toxin (BoNT-A) is widely used for the management of spasticity in children with CP1, 2. As well as its respectable safety profile3-5, the literature describes many positive outcomes from BoNT-A treatment including; a reduction in muscle tone6, increase in joint range of motion6, improved gait patterns6, functional improvements7, 8 and delayed and reduced requirement for surgical interventions to treat musculoskeletal deformities when combined with conservative treatments9. However, generalised muscle weakness5, 10, 11 and weakness in neighbouring non-targeted muscles12, 13 have been reported as undesirable effects of BoNT-A. There have been recent publications raising concern regarding the effect of BoNT-A on muscle size and morphology14, 15 . Schroeder et al.,(2009)15 measured neurogenic atrophy in the injected lateral gastrocnemius in two healthy adults post BoNT-A; with a reduction of 14-19% in cross sectional area after 3months, and reductions still seen at 6,9 and 12 months post BoNT-A, there were no changes in the contralateral placebo injected muscle. Dunne et al., (2010)16 supplemented this finding with reports of prolonged denervation of BoNT-A injected muscles up to 5months post injection. Rare reports in the cosmetic industry provides us with some observable examples for BoNT-A related atrophy, with its use in facial contouring for reducing masseter muscle thickness17, 18, and its use in reduction of muscle size in women’s legs in the desire to appear more aesthetically appealing19. Animal studies have also revealed BoNT-A’s effect on muscle; Fortuna et al.,(2011) 13 compared the injected limbs to non-injected limbs of rabbits to find reductions in muscle mass of up to 50% injected muscles 1month after injection, Ma et al.(2004)20, found muscle mass in injected limb in rats to reduced by 32% of the control side 2 weeks after the injection, and still to be reduced by 24% at 3months post. Considering the repeated use of BoNT-A to treat spasticity in children with CP, it is necessary to understand the impact of this treatment in this population, particularly with regard to muscle function and structure. It is well recognised that muscle structure and size is associated with muscle strength in the adult and adolescent population21, 22. Children with CP have also been shown to have smaller and weaker muscles23. Over the last decade weakness has been increasingly recognised as a significant motor impairment22-24 purportedly affecting the functional ability in children with CP25, 26. A recent review of the literature in spastic CP found consistent evidence for small 61 muscle size as indicated by reduced muscle volume, cross sectional area, thickness and belly length in comparisons of paretic muscles with non-paretic and typically developing muscles24. Barber et al.(2009)25 has described volumetric deficits in the medial gastrocnemii of young children (2–5y) with spastic CP of 22% compared with typically developing children. For a population already predisposed to decrements in muscle size and strength, a treatment that potentially leads to further atrophy and weakening of the muscle should be well understood. The concern is that whilst children appear to do functionally well with the use of BoNT-A, there is evidence for an atrophic effect of BoNT-A documented in typically developing muscles in human and animal research that, to the authors knowledge, has not yet been investigated in pathological muscles. This research is the first to investigate the immediate morphological alterations in muscles of the lower limbs of children with CP following BoNT-A treatment for spasticity management. To report the comprehensive effect if the neurotoxin, we report the alterations of the injected, synergist and antagonist muscles to the BoNT-A, and include measures of strength and functional ability. It was hypothesised that the injected muscle would display a reduction in muscle morphology (volume) which could also result in a reduced strength capacity. 3.3 METHODS 3.3.1 PARTICIPANTS Ten boys and five girls with spastic diplegic CP classified as Gross Motor Function Classification System (GMFCS) level of I-II were recruited via the spasticity management service at Princess Margaret Hospital (PMH) in Perth, Australia. The children ranged from 5-12years, mean age of 8years 5mo (SD 1yr 10 mo, range 5-11yrs), an average height of 129.87cm (SD 10.92cm), weight of 27.97kg (SD 7.43kg) and BMI of 16.34 (SD 2.4). No child had undergone serial casting in the previous six months and no child a history of lower limb surgery. Informed written consent was obtained from the parents of all the participants. Ethical approval for the study was obtained from the Ethics Committee of PMH (1766), and from the University of Western Australia. Spasticity was assessed bilaterally using the Modified Ashworth Scale (MAS)26 by the same assessor, blinded to timing of BoNT-A . All 15 children were receiving BoNT-A treatment for spasticity management bilaterally in their lower limbs, and had already received a minimum of 62 two series of BoNT-A prior to the injection series included in the study (maximum series=15, mean series=8.93). The muscle(s) selected for injection were determined by clinical assessment and functional goals, the total dose of BoNT-A (Botox®, Allergan, Irvine, CA, USA) was empirically selected for each muscle, and injections were guided by ultrasound. All participants received BoNT-A to bilateral gastrocnemius' (30 legs injected; 2-6U/kg), and five participants also received BoNT-A to bilateral medial hamstrings (10 legs; 2-4U/kg). Other muscles injected included the soleus (4legs; 1-2U/kg) adductors (2 legs; 1U/Kg), rectus femoris (2 legs; 1U/Kg), and tibialis posterior (1 leg; 1U/Kg). No child had more than three muscles injected per leg. Of the five children who received BoNT-A to both the medial hamstrings and the gastrocnemius, the mean age was 7yrs, 10mo (SD 2yrs, 7mo), three were classified as GMFCS I and two GMFCS II. 3.3.2 PROCEDURES The study was a single group repeated measures design. Children completed two assessments; 1) timed approximately 2 weeks prior to their scheduled BoNT-A (PRE) & 2) on average 5 weeks (SD 1week, range 3-6weeks) post injection (POST). 3.3.2.1 MUSCLE MORPHOLOGY Muscle Morphology (muscle volume (MV)) of the lower limbs was assessed using Magnetic Resonance Imaging (MRI). Efforts were made to standardise the time of day that each participant completed their scan. Axial spin-echoT1-weighted MR images were acquired bilaterally from the level of the ankle malleoli to the iliac crest while subjects lay prone in a 1.5T whole body MR unit (Magnetom Sonata Maestro Class, Siemens Medical Solutions, Erlangen, Germany). Subjects were positioned in neutral hip rotation, maintained passively using standard patient positioning with foam pads. Images of the thigh and lower leg were collected using a repetition time of 572ms, echo time of 13ms, slice thickness of 5mm, and mean inter-slice gap between 5-7mm. A matrix size of 256×160mm was used for all thigh scans, and 256x144 for lower leg, and the field of view (280-300mm) was varied to maximize in-plane resolution for each scan. The mean number of axial slices for the thigh was 30.27 (SD 1.53), and for the lower leg were 28.60 (SD 1.99). 63 Figure 1 Creating a 3 Dimensional model of the leg from an MRI scan using Mimics software (Version 9.0, Materialise, Leuven) to determine muscle volume. MR images were transferred to an independent workstation for digital reconstruction. Isotropic voxel size was obtained using a trilinear interpolation routine. Muscles were manually traced (see figure 1) and segmented for all subjects using a digitisation tablet (Intuos2, Wacom Technology Corp., Vancouver, WA) and Mimics software (Version 9.0, Materialise, Leuven). The segmented muscles included the semitendinosis, semimembranosis, biceps femoris, rectus femoris, vastus lateralis and medialis, medial gastrocnemius, lateral gastrocnemius, soleus, and the tibialis anterior. MV was calculated by summing the number of voxels contained within each muscle and multiplying by the voxel dimension (1mm3). To account for the large variation of age and height, and to account for confounding effects of skeletal growth, MV was normalised to femur and tibia length as determined from MR images with Mimics Software. MV was then presented as a percentage of MV (cm3) per femur (for thigh (cm)) or tibial length (for shank (cm)). We have previously reported the intraclass correlation coefficient (ICC) of MV using this method23, reporting that both intra- and inter-rater reliability were high with ICC values consistently greater than 0.92 and 0.94 (95% CI), respectively for quadriceps and hamstring muscle volume23. In the present study, intra-rater reliability was high with an ICC value of 0.97, tested in a random selection of five MRI scans of the hamstrings PRE and POST, whereby the investigator was blinded to the scan time point and was. In this study, all data was processed and analysed by one investigator (SW). 64 3.3.2.2 MUSCLE STRENGTH A Biodex System-3 dynamometer (Biodex Medical Systems, Inc. Shirley, NY) was employed to assess isometric strength of the knee flexors (KF) and knee extensors (KE). Children performed three maximum isometric contractions of the KF and KE bilaterally, with the order of sidetested randomised. Trials evaluated muscle peak torque normalised to body weight (PT/BW) in a static posture with the knee flexed at 90°. Standard straps constrained the upper body and pelvis to avoid the contribution of other muscles in the assessment. The lower limb segment was attached to the Biodex arm using the standard Velcro straps, leaving the ankle joint unconstrained during the knee flexion/extension tasks. Continual verbal encouragement was provided throughout the assessment with adequate rest and recovery in between contractions to minimise muscle fatigue. A hand held dynamometer (HHD) (Model 01163, Lafayette Instrument Company) was used to determine maximal isometric strength for plantar flexion (PF) and Dorsi Flexion (DF) by a trained and experienced physiotherapist. For PF, the child lay supine with straight legs, the HHD was placed under the padding of the foot with the foot in as close to 90° as achievable. The child was instructed to ‘point to toes down’, pushing against the HHD, whilst another tester constrained the child at the knee and the hip. DF was measured with the child seated upright, knee’s flexed at 90° and the HHD positioned on top of the foot. The child was constrained at the knee, hips and torso, with arms crossed over the chest. For consistency of results, the same assessor recorded all measurements for both assessment time points. 3.3.2.3 FUNCTIONAL ABILITY The 6-minute walk test (6-MWT) was used to measure functional walking capacity27. In addition to this children performed the Timed Up and Go (TUG) assessment from an adjustable-height chair in accordance with the test protocol28. 3.3.3 STATISTICAL ANALYSIS To estimate the effect of BoNT-A, we determined whether the difference in measures of muscle volume and strength was significantly different from zero, accounting for possible within-person correlations by using a mixed model with a random intercept. For functional ability measures, a comparison of the pre and post BoNT-A group means were analysed using repeated measures, two-tailed t-tests with a confidence interval of 95%, level=.05. Effect 65 sizes were determined using Cohen’s d equation using the mean standard deviation of the two scores beings compared. Each individual’s percentage change was grouped and averaged to provide a mean percentage change for measures presented in the included tables. A post hoc power analysis using the sample size of 15 revealed a power of 0.64. 3.4 RESULTS 3.4.1 SPASTICITY All of the children in this study had a clinically appropriate response to BoNT-A treatment, demonstrating improvements in spasticity. Total scores from the MAS were summated to provide a representation of spasticity, with a lower score indicating less spasticity in the lower limbs. Spasticity scores for the entire sample significantly decreased immediately following BoNT-A injection, from a mean score of 10.07 (SD 3.94) to 8.27 (SD 2.12), (t(14)=2.358, p=.033, ES=1.17). 3.4.2 PLANTAR/DORSI FLEXORS This section on plantar/dorsi flexor muscle morphology and strength changes relates to all 15 children in the study as they all received BoNT-A to the gastrocnemius. 3.4.2.1 MUSCLE MORPHOLOGY There were no significant changes in the MV for the total PF muscle group (the combination of the soleus, and lateral and medial gastrocnemius) across the two time points (t(14)=-0.195, p=0.848, ES=0.01). The combined volumes of the lateral and medial gastrocnemius showed a significant decrease in gastrocnemius volume (t(14)=-2.42, p=.030, ES=0.17) of 4.47% (SD 8.57%), whilst the soleus volume had a significant increase of 3.96% (SD 8.05%), (t(14)=2.205, p=.045, ES=0.10). The prime antagonist muscle of the DF group, the tibialis anterior, remained constant with no significant change in MV (t(14)=0.645, p=.529, ES=0.05) (table 1). 3.4.2.2 MUSCLE STRENGTH There were no significant differences reflected in the measures of strength as measured by the HHD for the plantar flexors or dorsi flexors (table 1). 66 Table 1 Muscle volumes and strength of the lower leg for 15 children (30 legs) receiving BoNT-A to the gastrocnemius muscle group. All values for muscle volume (MV) are expressed as % of muscle volume (cm3) divided by tibia length (cm). Strength values are in kilograms. PRE and POST group averages and the average of each individuals percentage change are presented. *significance at p<0.05 Pre Post Mean individual % change P value ES Gastrocnemius MV 3.00 SD 0.93 2.84 SD 0.85 -4.47 SD 8.57 p=.003* ES=0.17 Soleus MV 4.32 SD 1.42 4.46 SD 1.38 3.96 SD 8.05 p=.045* ES= 0.10 Total PF MV 7.32 SD 2.25 7.30 SD 2.12 0.45 SD 7.15 p=.848 ES= 0.01 Total DF MV 1.27 SD 0.34 1.29 SD 0.32 2.64 SD 12.02 p=.529 ES= 0.05 PF strength 29.80 SD 7.62 30.46 SD 8.71 2.45 (SD 17.92 p=.277 ES=0.24 DF strength 12.04 SD 4.73 12.23 SD 3.85 1.23 SD 20.97 p=.788 ES=0.25 3.4.3 KNEE FLEXORS/EXTENSORS In reporting the measured morphological response of the hamstring (KF) and quadriceps (KE) muscle, the results of the 10 children (20 legs) that received BoNT-A to the gastrocnemius are reported separately from the five children (10 legs) who received medial hamstring injections in addition to the gastrocnemius. 3.4.3.1 MUSCLE MORPHOLOGY 3.4.3.1.1 BONT-A TREATMENT IN THE GASTROCNEMIUS (N=10 CHILDREN, 20 LEGS) There was a non-significant change of 2.85% (SD 6.17%) in the MV of the total hamstring muscle group (t(9)=1.788, p=.107, ES=0.10) in the 10 children who received BoNT-A in the gastrocnemius. When considering the individual muscles of the hamstring group, we found that whilst the biceps femoris approached a significant increase by 4.67% (SD 8.54%), (t(9)=2.221, p=0.053, ES= 0.19), the MV of the medial hamstrings (semitendinosis and semimembranosis) remained relatively constant (t(9)=0.535, p=.606, ES= 0.04). The antagonist to the hamstring, the quadriceps muscle (KE) group increased its total MV significantly by 4.23% (SD 5.84%), (t(9)=2.658, p=.026, ES=0.17). 67 3.4.3.1.2 BONT-A TREATMENT IN THE GASTROCNEMIUS AND MEDIAL HAMSTRINGS (N=5 CHILDREN, 10 LEGS) In the group of five children (10 legs) who had BoNT-A injections in both the gastrocnemius muscle group and the medial hamstring there was no significant change in total hamstring (KF) muscle volume (t(4)=-1.455, p=.219, ES=0.29). However the medial hamstrings did show a decrease of 5.89% (SD 9.23%) in MV but was not statistically significant (t(4)=-2.007, p=.076, ES=0.45). The prime antagonists, the quadriceps muscle group (KE) displayed no significant change in morphology (t(9)=0.190, p=.859, ES=0.01) (table 2). Table 2 PRE and POST group averages, with the grouped average of each individuals percentage change in muscle volumes of the thigh for 10 children (20 legs) receiving BoNT-A to the gastrocnemius muscle group and for 5 children (10 legs) receiving BoNT-A to the medial hamstirngs and gastrocnemius. All values are expressed as % of muscle volume (cm3) /femur length (cm). *significance at p<0.05 BoNT-a treatment Gastroc only (N=10 children, 20 legs) Muscle group MV Medial Hamstring Biceps Femoris Total Hamstring Total Quadriceps BoNT-A treatment Gastroc + Hamstring (N=5 children,10 legs) Pre Post Mean individual % change P value ES Pre Post Mean individual % change P value ES 3.52 3.56 1.80 p=.606 2.87 2.68 -5.89 p=.076 SD 0.94 SD 0.84 SD 6.86 ES= 0.04 SD 0.47 SD 0.38 SD 9.23 ES=0.45 2.60 2.71 4.67 p=.053* 2.34 2.31 -1.14 p=.674 SD 0.56 SD 0.55 SD 8.54 ES= 0.19 SD 0.39 SD 0.40 SD 8.34 ES=0.08 6.12 6.26 2.85 p=.107 5.21 4.99 -3.84 p=.219 SD 1.43 SD1.34 SD 6.17 ES= 0.10 SD 0.82 SD 0.74 SD 8.07 ES=0.29 12.51 12.96 4.23 p=.026* 12.41 12.44 -0.14 p=.859 SD 2.79 SD 2.57 SD 5.84 ES= 0.17 SD 2.21 SD 2.49 SD 2.71 ES= 0.01 3.4.3.2 MUSCLE STRENGTH AND FUNCTION 3.4.3.2.1 BONT-A TREATMENT IN THE GASTROCNEMIUS (N=10 CHILDREN, 20 LEGS) From the 10 children (20 legs) receiving BoNT-A injections in the gastrocnemius muscles only, there was no statistical change in the KF muscles (-2.19% SD 42.34%, t(9)=-1.155, p=.277, ES=0.26), or the the KE muscles (11.70%, SD 33.72%, t(9)=0.389, p=.706, ES=0.05) (table 3). 68 In the 10 children having BoNT-A to the gastrocnemius muscles only, there were no statistically significant changes after BoNT-A in function as assessed by the TUG, completing the task in 4.50 sec (SD 0.95) before BoNT-A compared with 4.66 sec (SD 0.98) after BoNT-A, a 3.94% increase in time (SD 12.54%),(t(9)=-0.925, p=.379, ES=0.16). There was also no statistically significant change in the distance covered in the 6-MWT; 577.49m (SD 73.53) to 559.89m (SD 72.14), a 2.89% decrease in distance (SD 6.45%),(t(9)=1.442, p=.183, ES=0.24). 3.4.3.2.2 BONT-A TREATMENT IN THE GASTROCNEMIUS AND MEDIAL HAMSTRINGS (N=5 CHILDREN, 10 LEGS) In the measures of muscle strength, isometric peak torque showed no statistically significant change in the KF (t(4)=-1.088, p=.338, ES=0.57) or KE muscles (t(4)=-0.453, p=.674, ES=0.38) (table 3). In the five children who had gastrocnemius and hamstring injected, there were no statistically significant changes in the TUG after BoNT-A, completing the task in 4.76 sec (SD 0.91) before and 4.68 sec (SD 0.91) after BoNT-A, a 0.89% decrease in time (SD 11.79%), (t(4)=0.356, p=.740, ES=0.09). Distance covered in the 6-MWT also did not statistically change after BoNTA, from 512.82 m (SD 103.65) to 517.55m (SD 99.77), A 1.34% increase (SD 8.78%) (t(4)=-0.234, p=.826, ES=0.05). Table 3 PRE and POST average values of knee flexor and knee extensor strength (Isometric peak torque), with the grouped average of individual percentage changes in 10 children (20 legs) receiving BoNT-A to the gastrocnemius muscle group, and 5 children (10 legs) receiving BoNT-A to the medial hamstrings and gastrocnemius. Values are normalised to body weight.*significance at p<0.05 Gastroc n=10 children (20 legs) Isometric Pk Torque (Nm/Kg) Pre Knee Flexion Knee Extension Gastroc & HS n=5 children (10 legs) Post Mean individual % change P value ES Post Mean individual % change Pre P value ES 83.86 SD 47.79 72.36 SD 40.20 -2.19 SD 42.34 p=.277 ES=0.26 62.68 SD 7.94 56.09 SD 15.12 -9.75 SD 25.46 p=.338 ES= 0.57 205.86 SD112.74 211.85 SD108.44 11.70 SD 33.72 p=.706 ES= 0.05 207.10 SD 35.13 222.24 SD 44.17 8.70 SD 18.27 p=.674 ES= 0.38 69 3.5 DISCUSSION This study has for the first time provided an in depth investigation into the immediate morphological responses to BoNT-A injections of muscles of the lower limbs of children with CP. In agreement with Schroeder et al’s., (2009)15 research on BoNT-A in the healthy muscle, reports from the cosmetic industry17-19, and animal research13, 20, we also found evidence of muscular atrophy in BoNT-A injected muscles. An average reduction of 4.5% was measured in the gastrocnemius muscle of 15 children undergoing BoNT-A for spasticity management, whilst five of those children who also had the medial hamstrings injected had an average decrease of 5.9% in the medial hamstring MV. These results are reassuring, in that whilst we did measure atrophy, they appear to be much smaller than the concerning reports of almost 20% reduction as seen in healthy adult muscles of the gastrocnmeius15, the 22-25% reduction in masseter muscle thickness17, 18, and the changes seen in animal research of 32-50% decreases13,20. These responses however should be viewed with perspective and compared with caution. Previous reports of muscle atrophy use a variety of methods to measure muscle morphology, making it difficult to draw true comparisons of results. In addition to this, the research in healthy muscles reports the response of muscles to the first series BoNT-A injection. In our study in pathological muscles, children had already received a minimum of 2 series of BoNT-A; the responses reported here are likely to not be as strong as they may have been if it were to their first injection of BoNT-A. Fortuna et al.,(2011)13 animal study on repeat injections of BoNT-A reported that the greatest amount of atrophy occurred as the muscles first response to BoNTA. The animal studies have also indicated that muscle atrophy was not homogenous within a muscle group exposed to BoNT-A, and could be affected by the muscle fibre type13, a factor that could be highly variant in individuals with spastic muscle. The reality is that muscles in children with CP are variable, and the use of BoNT-A for spasticity management is repeated over many years. This study provides the first snapshot into morphology alterations of this population. From here research needs to look at alterations after the muscles first BoNT-A injection, and delve further into the muscles response following sequential series’ of BoNT-A. In exploring the alterations of each of the injected, synergist and antagonist muscle to BoNT-A, an interesting outcome emerged. Whilst the volume of the injected gastrocnemius muscle decreased by 4.5%, the soleus muscle matched the decrease with nearly a 4% increase in volume, with a consequential total volume for the PF muscle group that is relatively stable after the BoNT-A. This is a potential indication of a compensatory reaction with synergist hypertrophy. The prime antagonist muscle, the tibialis anterior, also did not show any changes 70 in MV, whilst increases were also measured in the hamstring and quadriceps MV (out of the ten children not receiving BoNT-A in the hamstrings). The quadriceps MV increase was complimented with an 11.7% increase in KE strength, in accordance with evidence that muscle size is related to muscle strength21, 22. The KF strength however, indicated more of a decreasing trend, possibly in part a result of the contribution of the gastrocnemius in knee flexion, weakened as a response to BoNT-A. However with no statistical significance, and small effect sizes, we cannot extrapolate our observations of strength but merely speculate. The HHD measures strength for the PF and DF also showed no significant changes, and large variations in scores. Indeed a slight increase in isometric strength was measured in the PF and DF following the BoNT-A, possibly attributed to the participants ease in achieving range following the BoNT-A treatment. Unfortunately, our measures of strength are limiting in that they cannot separate out the individual contributions of each muscle, but instead provide us with a more holistic assessment of the torque about a joint. It was a slightly different story for the five children who had BoNT-A injected to both the medial hamstring and gastrocnemius. As previously mentioned, there was a decreasing trend in medial hamstring volume that approached significance; the synergist biceps femoris muscle did not increase in response, but rather showed a small decrease in MV. This resulted in an overall decrease of 3.8% for the total hamstring group MV that corresponded with a decrease in KF strength, that although, was not statistically significant, had a moderate effect size of 0.57. The antagonist quadriceps MV showed no notable change, whilst the strength of the KE showed an increasing trend but also did not reach statistical significance. Whilst these minor alterations may be explained by the muscle strength–size relationship21, 22, we cannot rule out the possibility of any neurological alterations as a result of BoNT-A altering innervation patterns. A possible confounding limitation in our study was that four other muscles in the leg in addition to the gastrocnemius or hamstrings were targeted for injection for five of the children included in this study which may have compromised results. This was determined by clinical decision and was out of the researcher’s control. However, doses were minimal and only two children received injections into an additional muscle in the gastrocnemius and hamstring injected group. The soleus muscle, as well as the gastrocnemius muscle, was injected in two of the children in this study; when we removed their results the increase of the soleus muscle 71 was even greater at 4.4% (with the gastrocnemius MV decrease changing to 5.4%), which supports our premise of synergist hypertrophy of the soleus. Instituting MRI analysis in research designs is costly and time consuming; unfortunately the addition of a control group (no treatment or saline injected) was not feasible for this study. Our measurements of change could be queried as many of our statistics include small effect sizes, for example the gastrocnemius decrease in MV was significant but had a small effect size, whilst the drop in the injected hamstring muscle approached significance yet had a moderate effect size. In addition to this, interpretations of our results are limited by our small sample size. With this in mind, it is important that findings within this study be viewed with some caution. Nonetheless, we believe the new information presented in this study to be clinically important. The morphological alterations in spastic muscle in our sample of children with CP did not show atrophy as severe as that shown in animal studies and healthy muscle13. This is certainly optimistic for the continued future of BoNT-A use, however as mentioned, the initial response to BoNT-A in spastic muscle may be different. Despite this, this study also appeared to uncover the possibility of compensatory hypertrophy in synergist muscles as a response to atrophy of the injected muscles. With this in mind for the future application of BoNT-A, the morphological response of muscle to BoNT-a treatment may not be limited to the injected muscle alone. The hypertrophy is likely a product of an increased physiological demand on the synergist muscle, the increasing work and load of the synergist muscle, leading to work-induced hypertrophy29. In terms of muscle strength, our results showed no significant changes from BoNT-A but may indicate potential changes, in particular in children who are having multiple muscles injected. It is also important to note that the morphological alterations following BoNT-A did not have any significant detrimental effects on the children’s functional performance. In the present study the effects of BoNT-A injections where measured to correspond with the BoNT-A taking peak effect; to get a deeper understanding, follow up assessments would provide us with a clearer picture as to how the muscles are responding to the BoNT-A in the longer term. 3.6 CLINICAL IMPLICATIONS This is the first study, to our knowledge, to report upon the immediate morphological alterations in spastic muscles following BoNT-A treatment. It has demonstrated reductions in muscle volume in the injected muscle, and hypertrophy in a synergist muscle as a compensatory reaction in children with CP. This potentially has a role in explaining the good clinical and functional response in children after BoNT-A injections. The atrophy measured in 72 our sample of children with CP was not as large as that reported in animal and healthy muscle research. Whilst strength deficits were not seen following a single site injection in this study, attention should be paid to muscle alterations of children undergoing treatment to multiple sites on repeated occasions. 3.7 ACKNOWLEDGEMENTS This project was supported by the Princess Margaret Hospital (PMH) Foundation Grant as well as by the University of Western Australia’s Research and Development Awards. The authors would like to thank the Department of Paediatric Rehabilitation, PMH for their support and assistance with recruitment, the Department of Diagnostic Imaging, PMH for their assistance and knowledge in data collection and the contribution of the School of Sport Science, Exercise & Health at UWA for the use of equipment and facilities. They would also like to thank Tania Shillington, Bree Dwyer and Martin Spits for their role with the data collection, and Associate Professor Eve Blair (Telethon Institute for child health research) for her statistical advice in the preparation of this manuscript. 73 3.8 REFERENCES 1. Heinen F, Molenaers G, Fairhurst C, et al. European consensus table 2006 on botulinum toxin for children with cerebral palsy. Eur J Paediatr Neurol. 2006;10:215-25. 2. Love S, Novak I, Kentish M, et al. Botulinum toxin assessment, intervention and after- care for lower limb spasticity in children with cerebral palsy: international consensus statement. Eur J Neurol. 2010;17:9-37. 3. Bakheit AM, Severa S, Cosgrove A. Safety profile and efficacy of botulinum toxin in children with muscle spasticity. Dev Med Child Neurol. 2001;43:234-8. 4. Langdon K, Blair E, Davidson SA, Valentine J. Adverse events following botulinum toxin type A treatment in children with cerebral palsy. Dev Med Child Neurol. 2010;52:972-3. 5. Naumann M, Albanese A, Heinen F, Molenaers G, Relja M. Safety and efficacy of botulinum toxin type A following long-term use. Eur J Neurol. 2006;13:35-40. 6. Koman L, Mooney J, Smith B, Walker F, Leon J. Botulinum toxin type A neuromuscular blockade in the treatment of lower limb spasticity in cerebral palsy: a randomised double-blind placebo controlled trial. J Pediatr Orthop B. 2000;20:108-15. 7. Steenbeek D, Meester-Delver A, Becher J, Lankhorst G. The effect of botulinum toxin type A treatment of the lower extremity on the level of functional abilities in children with cerebral palsy: evaluation with goal attainment scaling. Clin Rehabil. 2005;19:274-82. 8. Linder M, Schindler G, Michaelis U, et al. Medium-term functional benefits in children with cerebral palsy treated with botulinum toxin type A: 1-year follow-up using gross motor function measure. Eur J Neurol. 2001;8:120-6. 9. Graham HK. Botulinum toxin type A management of spasticity in the context of orthopaedic surgery for children with spastic cerebral palsy. Eur J Neurol. 2001;8:30-9. 10. O’Flaherty SJ, Janakan V, Morrow AM, Scheinberg AM, Waugh M-CA. Adverse events and health status following botulinum toxin type A injections in children with cerebral palsy. Dev Med Child Neurol. 2011;53:125-30. 11. Mohamed KA, Moore AP, Rosenbaum L. Adverse events following repeated injections with botulinum toxin A in children with spasticity. Dev Med Child Neurol. 2001;43:791-2. 12. Yaraskavitch M, Leonard T, Herzog W. Botox produces functional weakness in non- injected muscles adjacent to the target muscle. J Biomech. 2008;41:897-902. 74 13. Fortuna R, Aurélio Vaz M, Rehan Youssef A, Longino D, Herzog W. Changes in contractile properties of muscles receiving repeat injections of botulinum toxin. J Biomech. 2011;44:39-44. 14. Gough M, Fairhurst C, Shortland AP. Botulinum toxin and cerebral palsy: time for reflection? Dev Med Child Neurol. 2005;47:709-12. 15. Schroeder A, Ertl-Wagner B, Britsch S, et al. Muscle biopsy substantiates long-term MRI alterations one year after a single dose of botulinum toxin injected into the lateral Gastrocnemius muscle of healthy volunteers. Mov Disord. 2009;24:1494-503. 16. Dunne J, Singer BJ, Silbert PL, Singer KP. Prolonged vastus lateralis denervation after botulinum toxin type A injection. Mov Disord. 2010;25:397-401. 17. Kim J, Shin J, Kim S, Kim C. Effects of two different units of Botulinum Toxin Type A evaluated by computed tomography and electromyographic measurements of human masseter muscle. Plast Reconstr Surg. 2007;119:711-7. 18. Kim N, Chung J, Park R, Park J. The use of Botulinum Toxin Type A in aesthetic mandibular contouring. Plast Reconstr Surg. 2005;115:919-30. 19. Han KH, Joo YH, Moon SE, Kim KH. Botulinum toxin A treatment for contouring of the lower leg. J Dermatolog Treat. 2006;17:250-4. 20. Ma J, Elsaidi G, Smith T, et al. Time course of recovery of juvenile skeletal muscle after Botoxulinum Toxin A injection. Am J Phys Med Rehabil. 2004;83:774-80. 21. Lieber R, Friden J. Functional and clinical significance of skeletal muscle architecture. Muscle Nerve. 2000;23:1647-66. 22. Enoka RM. Neuromechanics of Human Movement. 3rd ed. Champaign, IL: Human Kinetics; 2002. 23. Pitcher C, Elliott C, Williams S, et al. Childhood muscle morphology and strength: alterations over six months of growth. Muscle Nerve. 2012;46:360-6. 24. Barrett RS, Lichtwark GA. Gross muscle morphology and structure in spastic cerebral palsy: a systematic review. Dev Med Child Neurol. 2010;52:794-804. 25. Barber L, Hastings-Ison T, Baker R, Barrett R, Lichtwark G. Medial gastrocnemius muscle volume and fascicle length in children aged 2 to 5 years with cerebral palsy. Dev Med Child Neurol. 2011;53:543-8. 26. Bohannon R, Smith M. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther. 1987;67:206-7. 75 27. American Thoracic Society. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111-7. 28. Williams E, Carroll S, Reddihough D, Phillips B, Galea M. Investigation of the Timed ‘Up & Go’ Test in children. Dev Med Child Neurol. 2005;47:518-24. 29. Goldberg AL. Work-induced growth in skeletal muscle of normal and hypophysectomized rats. Am J Physiol. 1967;213:1193-8. 76 CHAPTER FOUR COMBINING STRENGTH TRAINING AND BOTULINUM NEUROTOXIN TYPE-A INTERVENTION IN CHILDREN WITH CEREBRAL PALSY: THE IMPACT ON MUSCLE MORPHOLOGY AND STRENGTH This manuscript was accepted for publication into Disability and Rehabilitation in July 2012. Williams SA, Elliott CM, Valentine J, Gubbay A, Shipman P, Reid SL. Combining Strength Training and Botulinum Neurotoxin intervention in children with Cerebral Palsy: The impact on Muscle Morphology and Strength. Disabil Rehabi. 2012 (Accepted for publication) The PhD candidate, Sîan A Williams, accounted for 80% of the intellectual property associated with the final manuscript. Collectively, the remaining authors contributed 20%. 77 FOREWORD The first paper confirmed the presence of localised muscle atrophy following BoNT-A to the gastrocnemius and medial hamstring muscles, but this did not significantly influence the force output of the muscle groups. Children with CP are known to have smaller and weaker muscles then their typically developing peers. This paper investigates the effect of a home based strength training, added in combination with BoNT-A injections to simultaneously target muscle weakness and spasticity. Specifically, it demonstrates the outcomes of muscle strength, morphology and functional goal attainment. It also questions the most effective timing of the strength training in relation to the BoNT-A, to guide clinicians in the application of this treatment concept. 78 4.1 ABSTRACT Purpose: Investigate the combination effects of strength training and Botulinum Toxin Type-A (BoNT-A) on muscle strength and morphology in children with Cerebral Palsy (CP). Methods: Fifteen children receiving BoNT-A, classified as Spastic Diplegic CP, GMFCS I-II, and aged 5-12years were recruited for this study. Randomly allocated to 10 weeks of strength training either before or after BoNT-A, children were assessed over 6 months. Eight of the 15 children also completed a control period. The Modified Ashworth Scale measured spasticity. The Goal Attainment Scale (GAS) assessed achievement of functional goals. Magnetic Resonance Imaging assessed muscle volume (MV). Instrumented dynamometry assessed strength. Results: Spasticity was significantly reduced following BoNT-A injection (p=.033). Children made significant isokinetic strength gains (mean p=.022, ES=0.57) in the intervention period compared to the control period (mean p=.15, ES=0.56). Irrespective of timing, significant strength improvements were seen immediately (10 weeks) and over 6 months for all children. This was also the case for improvements in the GAS (immediately: mean p=.007, ES=4.17, 6months: mean p=.029, ES=0.99), and improvements in MV in all assessed muscles. Conclusion: The simultaneous use of BoNT-A and strength training was successful in spasticity reduction, improving strength and achieving functional goals, over and above treatment with BoNT-A alone. Muscles targeted for BoNT-A injection should be included in strength training. 79 4.2 INTRODUCTION Children with Cerebral Palsy (CP), have been shown to have significantly weaker muscles than their typically developing peers3, 4 which can contribute to significant motor impairment5. Muscle weakness is linked with limitations in functional activities and can make activities of daily living such as walking5,6 difficult to accomplish. The cause of muscle weakness in CP may be attributed to a combination of abnormal muscle structure and/or altered neural mechanisms6. The morphological and structural properties of a muscle influence its ability to generate force7 such that a decrease in muscle volume can reasonably be associated with a diminished ability of the muscle to produce torque and power8. A recent review in spastic CP found consistent evidence for reduced muscle size in the lower limb8. The affected muscles of children with CP display reduced muscle volume, cross-sectional area, thickness and muscle belly length compared to their non-paretic limb and the muscles of typically developing children8. In addition to these anatomical factors, individuals with CP have greater amounts of cocontraction9 and are less able to activate their muscles maximially10. Spasticity is a very common clinical sign in children with CP and is considered the main cause of the secondary musculoskeletal complications that arise11. Spasticity is associated with abnormalities in muscle tone, overactive stretch reflexes and movement and/or postural control responses, and has been suggested to contribute both to the impairment of function and reduced longitudinal muscle growth in children with CP12. With both muscular weakness and spasticity considered to be significantly detrimental to function in children with CP5 there is a call for research to determine the efficacy of treatment for these motor impairments. Strength training is now recognised as an effective intervention for improving muscular strength in children with CP13. A growing number of studies confirm that following strength training, people with CP can achieve significant strength improvements that are translatable to gains in motor function13-15. Contrary to this evidence and to previous systematic reviews6, 13, 1617 , one systematic review18 suggested strength training to be neither effective nor worthwhile in children and adolescents with the CP, however this review evaluated only (six) randomized controlled trials, and did not suggest strength training to be harmful or that it should no longer be administered in clinical practice for children with CP. The outcomes of this review have been questioned, Verschuren and Colleagues (2011)17 reasoned that the conclusions of Scianni be viewed with caution given that the training protocols of the included papers were 80 inconsistent with guidelines set for resistance training in children. Despite this particular review, strength gains have been associated with improvements relating to walking13-15, flexibility, posture and balance19. McNee and Colleagues (2009)20 have also reported that alongside improvements in strength, muscles also increase in volume after 5 and 10 weeks of strength training in children with CP. McNee’s research indicates that strength training could amend the pre-existing muscle size and muscle strength deficit that is common with CP20. Whilst strength training targets muscular weakness, Botulinum Toxin Type-A (BoNT-A) is an established treatment option for spasticity management for children with CP21. The benefits of BoNT-A treatment include a reduction in muscle tone22, increased joint range of motion22, improved gait patterns22, and functional improvements23. However, there is a known association between the use of BoNT-A and muscle weakness, with reports of generalised muscle weakness24 and weakness in neighbouring non-targeted muscles24, 25 . Recent publications have also raised concern regarding the effect of BoNT-A on muscle size and morphology26, 27. Schroeder and Colleagues (2009)27 identified neurogenic atrophy up to 12 months following BoNT-A in healthy adults. Knowing that muscle structure and size is associated with muscle strength5, muscle atrophy could therefore affect its ability to generate force. In children with CP who have pre-existing weakness, added weakening could be particularly detrimental. With strong supportive evidence for the use of strength training to target muscular weakness, and similarly, the use of BoNT-A for spasticity management and improved function, should we be applying strength training concurrently with BoNT-A treatment to further improve clinical outcome for patients? We hypothesize that with the combination of both BoNT-A and strength training, children with CP can have improvements in muscle size and muscle strength simultaneous with a reduction in spasticity. Furthermore we aim to determine when strength training should occur in relation to BoNT-A treatment to optimise functional outcomes for the patients. 4.3 METHODS 4.3.1 PARTICIPANTS Ten boys and five girls with spastic diplegia, classified as Gross Motor Function Classification System (GMFCS) level I-II were recruited from the Cerebral Palsy Mobility Service at Princess Margaret Hospital (PMH) in Perth, Australia. The fifteen participating children had a mean age 81 of 8years 5mo (SD 1yr 10 mo, range 5-11yrs), an average height of 129.87cm (SD 10.92cm) average weight of 27.97kg (SD 7.43kg) and Body Mass Index of 16.34 (SD 2.4). No child had undergone serial casting in the previous six months and no child had a history of lower limb surgery. Ethical approval for the study was obtained from the Ethics Committee of PMH (1766/EP), and from the University of Western Australia. Written consent was obtained from the parents of all the participants. All 15 children were receiving BoNT-A treatment for spasticity management bilaterally in their lower limbs, and had already received a minimum of two series of BoNT-A prior to the injection series included in the study (maximum series=15, mean series=8.93). The muscle(s) selected for injection were determined by the child’s physician based on clinical assessment and functional goal setting, the total dose of BoNT-A (Botox®, Allergan, Irvine, CA, USA) was empirically selected for each muscle. All participants received BoNT-A to bilateral medial gastrocnemius' (30 legs injected; 2-6U/kg), and five participants also received BoNT-A to bilateral medial hamstrings (10 legs; 2-4U/kg). Other muscles injected included the soleus (4legs; 1-2U/kg) adductors (2 legs; 1U/Kg), rectus femoris (2 legs; 1U/Kg), and tibialis posterior (1 leg; 1U/Kg). No child had more than three muscles injected per leg. 4.3.2 DESIGN AND PROCEDURES The study design, dictated by current clinical care, utilised a repeated measures crosscomparison design with a 6month pre-intervention baseline phase serving as a control period (Figure 1). Children in the study were block randomised by age, gender and GMFCS level into either a PRE or POST BoNT-A strength training group. Children completed four assessments; Assessment 1 (A1) timed approximately 12 weeks prior to their scheduled BoNT-A, Assessment 2 (A2) approximately 2 weeks prior to their scheduled BoNT-A, Assessment 3 (A3) on average 5 weeks (SD 1week, range 3-6weeks) post injection and Assessment 4 (A4) approximately 14 weeks post injection. The PRE group completed strength training in the weeks between A1-A2 and the POST group completed the training between A3-A4. In the weeks where the children were not allocated strength training, they continued with their normal care routine, which included their standard clinical care. Eight children completed assessments at the same time points as A1 and A4 scheduled around their BoNT-A for a control period assessment. 82 BoNT-A Normal Care Routine BoNT-A A2 A3 A1 B Normal Care Routine PRE strength training Normal Care Routine Normal Care Routine POST strength training Control Period n=8 W-26 W-12 A4 W0 Intervention period n=15 W12 W26 Figure 1 Cross-comparison study design, with a pre-intervention baseline assessment for eight participants forming a control (Week-26 to Week0) and intervention (Week0 to Week 26) period. The dashed lines represent BoNT-A injection. In the intervention, children were allocated to either PRE or POST BoNT-A strength training. 4.3.2.1 ASSESSMENTS All assessments were conducted by the same assessor who was blinded to group allocation. 4.3.2.1.1 GOALS For each child, individual goals were defined and translated into assessable tests so that quantitative scores could be obtained. To assess each child’s outcome over the research time points, scores were input and rated into the Goal Attainment Scale (GAS) by an independent Occupational Therapist who was blinded to group allocation. The GAS is an individualised criterion referenced measure that can be used to assess qualitative changes and small but clinically significant improvements in motor development and function over time28. The scores of all individual goals were summed and converted into a standard T-score with an equal weight for each goal28. Converted GAS scores of 50 or more are representative of a successful treatment outcome. 4.3.2.1.2 SPASTICITY AND SELECTIVE MOTOR CONTROL Spasticity was assessed in each leg using the Modified Ashworth Scale (MAS)29. The Selective Control Assessment of the Lower Extremity (SCALE) was used to measure selective voluntary motor control30. Both measures were undertaken by an experienced Physiotherapist in accordance with the recommended methodologies. 4.3.2.1.3 MUSCLE STRENGTH A Biodex System-3 dynamometer (Biodex Medical Systems, Inc. Shirley, NY) was employed to assess isometric and isokinetic strength of the knee flexors (KF) and knee extensors (KE). Children performed three maximum isometric contractions, and three continuous maximum isokinetic repetitions, of the KF and KE bilaterally. The order of action type and side-tested was randomised. Isometric trials evaluated muscle peak torque normalised to body weight (PT/BW) 83 in a static posture with the knee flexed at 90°. Isokinetic trials assessed muscle peak torque (PT/BW) and joint power throughout range of motion at 60°/s. Continual verbal encouragement was provided throughout the assessment with adequate rest and recovery in between contractions to minimise fatigue. The peak torque is the maximum force that a muscle group can produce (either isometrically or isokinetically); whilst the joint power gives us an indication of how fast the muscle can develop force. A hand held dynamometer (HHD) (Model 01163, Lafayette Instrument Company) was used to determine maximal isometric strength of the gastrocnemius and tibialis anterior in standardised positions by a trained physiotherapist and provided a peak score in kilograms. For consistency of results, the same assessor completed all measurements for all assessment time points. 4.3.2.1.4 MUSCLE MORPHOLOGY Muscle volumes (MV) of the lower limbs were assessed using Magnetic Resonance Imaging (MRI). Scans were performed in the morning after a nights rest to standardise against factors such as exercise. Axial spin-echo T1-weighted MR images were acquired bilaterally from the level of the ankle malleoli to the iliac crest while subjects lay prone in a 1.5T whole body MR unit (Magnetom Sonata Maestro Class, Siemens Medical Solutions, Erlangen, Germany). Subjects were positioned in neutral hip rotation, maintained passively using standard patient positioning with foam pads. Images of the thigh and lower leg were collected using a repetition time of 572ms, echo time of 13ms, slice thickness of 5mm, and mean inter-slice gap between 5-7mm. A matrix size of 256×160mm was used for all thigh scans, and 256x144mm for lower leg, and the field of view (280-300mm) was varied to maximize in-plane resolution for each scan. The mean number of axial slices for the thigh was 30.27 (SD 1.53), and for the lower leg were 28.60 (SD 1.99). MR images were transferred to an independent workstation for digital reconstruction. Isotropic voxel size was obtained using a trilinear interpolation routine. Muscles were manually traced and segmented for all subjects using a digitisation tablet (Intuos2, Wacom Technology Corp., Vancouver, WA) and Mimics software (Version 9.0, Materialise, Leuven). The segmented muscles summed to produce hamstring (HS) values; semitendinosis, semimembranosis, and the biceps femoris, to produce quadriceps (Quads) values; rectus femoris, vastus lateralis and medialis, to produce plantar flexor (PF) values; medial and lateral gastrocnemius, and soleus, and dorsi flexor (DF) values; the tibialis anterior. Muscle volume was calculated by summing the number of voxels contained within each muscle and multiplying by the voxel dimension (1mm3). MV was normalized to femur length 84 for the HS and Quads, and tibia length for the PF and DF, as measured from MR images with Mimics Software, and presented as a percentage of MV (cm3) divided by bone length (cm). In previous research by the same authors of this study a two-way random effects intraclass correlation coefficient (ICC) was performed to quantify intra-and inter-rater reliability between two independent raters using this method of assessing morphology, and found that both intraand inter-rater reliability were high with ICC values consistently greater than 0.92 and 0.94 (95% CI), respectively for quadriceps an hamstring muscle volume31. 4.3.2.2 TRAINING PROGRAM Participants completed a home based strength training program, training three times a week for 10 weeks. Program coordination and progression was conducted fortnightly by a visiting exercise physiologist, with the remaining training sessions conducted by a trained family member. Each training session included manual and passive stretching of the lower limb muscle groups. The design of the strength program was based on the child’s initial strength assessment and their functional goals. Other muscle groups, aside from those reported in this paper, were also included in the strength programs. Strengthening exercises were progressive with repetitions and loading levels increasing as the child’s strength increased in accordance with the American College of Sports Medicine guidelines32. The exercises were performed in three sets bilaterally, with adequate rest between sets. The program initially focused on motor control; with manual resistance and the use of a Thera-band(s), and the establishment of base strength with ankle weights, increasing in number of repetitions and then loads. Over the 10 weeks of the training, the program progressed to more complex movements and functional tasks reflecting the child’s goals. Equipment was provided throughout the program, including ankle weights, thera-bands, Fit balls, and Duradiscs. Participants were requested not to take up any new activities and remain constant with regard to their usual therapy program, which was recorded, over the course of the study. 4.3.3 STATISTICAL ANALYSIS A two-tailed paired t-test was performed using mean scores of the eight children assessed in a control period and in the intervention period, with another paired t-test to determine if the change was significantly different between groups. Six months separated each assessment, with BoNT-A at 3months midway between each assessment. 85 In the intervention period, to determine changes in measures over strength training and normal care routine periods, a series of two-tailed paired t-Tests were performed for each pair-wise comparison over the investigated time points (i.e. PRE group measures at A1 paired with PRE group measures at A2). To determine if there was a differential effect of timing of strength training in relation to BoNT-A to the overall outcome, a mixed model linear ANOVA was performed, where the ‘group’ allocation was entered as a fixed effect. All of the above statistics were tested with a confidence interval of 95%, level=.05. Effect sizes were determined using Cohen’s d equation using the mean standard deviation of the two scores beings compared. 4.4 RESULTS 4.4.1 BONT-A COMPARED WITH BONT-A AND STRENGTH TRAINING Eight children, mean age 8yrs 3mo (SD 2yrs), (n=6 GMFCS I, n=2 GMFCS II), took part in a control phase prior to continuing onto the intervention phase. Muscle strength and morphology results are presented for the control and intervention phase below (Table 1). 4.4.1.1 MUSCLE STRENGTH 4.4.1.1.1 KNEE FLEXOR STRENGTH KF strength significantly increased in the intervention group in isometric PT/BW (p=.012, ES=0.53), isokinetic PT/BW (p=.047, ES=0.43), and muscle power (p=.008, ES=0.59). KF strength in the control group did not change significantly, however again the changes made over the control and intervention period did not differ significantly (p>.05) (Table 1). 4.4.1.1.2 KNEE EXTENSOR STRENGTH In the intervention group strength training was shown to increase KE strength as represented by significant increases in isometric PT/BW (p=.003, ES=0.66), Isokinetic PT/BW significantly (p=.002, ES=0.73) and muscle power (p=.031, ES=0.52). Comparatively, the control group significantly increased only in the measure of muscle power (p=.033, ES=0.75). Changes made over the control and intervention period did not differ significantly (p>.05) (Table 1). 86 4.4.1.1.3 ISOMETRIC ASSESSMENT OF MUSCLES Gastrocnemius (p=.046, ES=0.46) and tibialis anterior (p<.001, ES=0.61) strength showed significant increases following the strength training intervention period. However, the control group also had significant increases in gastrocnemius (p<.001, ES=1.29) and tibialis anterior (p=.012, ES=0.88) strength. There was a significant difference in change between groups for the gastrocnemius (p=.030, ES=1.09), though not in the tibialis anterior (Table 1). Table 1 Mean change in strength and muscle volume scores for eight children over a 6month control period of BoNT-A, and over a 6month intervention period of strength training and BoNT-A. ES=effect size, SD=standard deviation. *Denotes significance, p<.05, #Denotes approaching significance, p<.06. Control T value, P Value, ES Strength training T value, P Value, ES Between groups T value, P Value, ES Knee Flexor Strength Isometric Pk Torque (Nm/kg) 18.60 SD 35.28 t=-2.110, p=.052, # ES=0.46 28.52 SD 39.68 t=-2.874, p=.012, ES=0.53* t=-0.660, p=.518, ES=0.26 Isokinetic Pk Torque 60°/s (Nm/kg) 15.93 SD 34.10 t=-1.868, p=.081, ES=0.55 16.56 SD 30.71 t=-2.168, p=.047, ES=0.45* t=-0.037, p=.963, ES=0.02 Isokinetic Power 60°/s (Watts) 3.09 SD 6.64 t=-1.859, p=.083, ES=0.61 4.04 SD 5.26 t=-3.074, p=.008, ES=0.59* t=-0.334, p=.742 ES=0.16 Knee Extensor Strength Isometric Pk Torque (Nm/kg) 4.20 SD 40.37 t=-0.219, p=.829, ES=0.05 68.19 SD 76.75 t=-3.554, p=.003, ES=0.66* t=-2.09, p=.054, # ES=0.83 Isokinetic Pk Torque 60°/s (Nm/kg) 20.27 SD 37.25 t=-1.144, p=.271, ES=0.35 51.75 SD 54.87 t=-3.773, p=.002, ES=0.73* t=-1.125, p=.278, ES=0.50 Isokinetic Power 60°/s (Watts) 6.63 SD 11.33 t=-2.343, p=.033, ES=0.75* 5.31 SD 8.91 t=-2.386, p=.031, ES=0.52* t=0.278, p=.784, ES=0.13 Isometric Muscle strength Gastrocnemius (kg) 9.53 SD 6.07 t=-6.281, p<.001, ES=1.29* 3.13 SD 5.74 t=-2.179, p=.046, ES=0.46* t=2.396, p=.030, ES=1.09* Tibialis Anterior (kg) 3.33 SD 4.69 t=-2.839, p=.012, ES=0.88* 1.71 SD 1.28 t=-5.356, p<.001, ES=0.61* t=1.276, p=.221, ES=0.54 Muscle Volume HS Volume 3 (cm /cm) 0.82 SD 0.58 t=-5.673, p<.001, ES=0.60* 0.47 SD 0.44 t=-4.295, p=.001, ES=0.32* t=1.580, p=.135, ES=0.69 Quad Volume 3 (cm /cm) 0.68 SD 1.00 t=-2.718, p=.016, ES=0.23* 1.52 SD 0.88 t=-6.870, p<.001, ES=0.53* t=2.051, p=.058, ES=0.88 PF Volume 3 (cm /cm) 1.04 SD 0.81 t=-5.139, p=.001, ES=0.60* 0.75 SD 0.65 t=-4.660, p<.001, ES=0.40* t=0.952, p=.354, ES=0.39 DF Volume 3 (cm /cm) 0.08 SD 0.19 t=-1.763, p=.098, ES=0.29 0.25 SD 0.14 t=-6.875, p<.001, ES=0.80* t=-0.831, p=.417, ES=1.00 87 4.4.1.2 MUSCLE VOLUME HS volume increased significantly over the control period (p<.001, ES=0.60) and the strength training intervention period (p=.001, ES=0.32). Correspondingly the Quads also showed a significant increase over the control period (p=.016, ES=0.23) and the strength training period (p<.001, ES=0.53). MV for the PF had significant increases at both the control (p=.001, ES=0.60) and the strength training time period (p<.001, ES=0.40), whilst the MV for the DF increased significantly only over the strength intervention period (p<.001, ES=0.80). Changes made in MV over the control and intervention period did not differ significantly (Table 1). 4.4.2 TIMING OF STRENGTH TRAINING Fifteen children participated in the intervention phase of this study. Seven children, with a mean age of 8yrs 2mo (SD 1yr 9mo, three males, four females) were allocated into the PRE group training prior to receiving BoNT-A treatment, with eight children, mean age 8yrs 3mo (SD 2mo, five males, three females) in the POST group, training following receipt of BoNT-A treatment. 4.4.2.1 GOALS Following the strength training period, the mean GAS converted T-score for the PRE group significantly increased from 24.09 (SD 1.37) up to 66.74 (SD 11.24), (t(6)=-10.457, p<.001, ES=6.76). For the POST group the T-score increased from 29.93 (SD 11.59) to 52.68 (SD 17.26), (t(7)=-3.329, p=.013, ES=1.58). Between A1 and A4, with both groups undergoing strength training and BoNT-A treatment, the PRE group increased its T score by 23.69 (t(5)=-2.747, p=.040, ES=0.41), whilst the POST group increased by 28.67 (t(5)=3.490, p=.017, ES=1.58). 4.4.2.2 SPASTICITY Total scores from the MAS were summated to provide a representation of spasticity, with a lower score indicating less spasticity in the lower limbs. There was no significant change in spasticity over the course of the strength training for either group (p>.05). Each individual decreased their spasticity score, with a significant decrease in the entire sample of children’s measures of spasticity immediately following BoNT-A injection (t(15)=2.358, p=.033, ES=1.17). 88 4.4.2.3 MOTOR CONTROL Total SCALE scores were summated for each assessment and averaged for both legs, with a maximum achievable score of 10. The PRE group went from a mean SCALE of 8.14 (SD 1.49) up to 8.21 (1.47) after strength training, whilst the POST group went from a mean SCALE of 9.43 (SD 0.79) to 9.14 (SD 0.90). Between A1 and A4, the PRE group improved their average SCALE by 0.93, with the POST group improving by 1.23. Changes in SCALE were not statistically significant between the groups (p<.05), however SCALE scores for the entire sample significantly increased over the 6months from A1-A4 (t(13)=-2.686, p=.019, ES=0.56). 4.4.2.4 MUSCLE STRENGTH 4.4.2.4.1 KNEE FLEXOR As a direct result of the training program, changes in KF strength in the PRE group showed an increase in isokinetic PT/BW, which approached statistical significance (p=.053, ES=0.69) and reached statistical significance with an increase in muscle power (p=.004, ES=1.09) after strength training (Table 2, Figure 2). The POST group had a significant increase in isometric PT/BW (p=.010, ES=0.40) and muscle power (p=.002, ES=0.38). Over 6months from A1 to A4, KF strength measures showed statistically significant increases in the PRE group for isometric PT/BW (p=.035, ES=0.83), isokinetic PT/BW (p=.008, ES=0.88) and muscle power (p=.010, ES=1.05) (Table 2, Figure 2). Both groups displayed a general increase in isokinetic PT/BW and muscle power measures, between group changes did not differ statistically from each other (p>.05). 4.4.2.4.2 KNEE EXTENSOR The PRE group displayed no significant change in any strength variable for KE on completion of the strength training (p>.05). The POST group displayed significant improvements in isokinetic PT/BW (p=.033, ES=0.28) and (p=.009, ES=0.42) (Table 2, Figure 2). Over 6 months from A1 to A4, both the POST and PRE groups showed statistically significant increases in KE isometric PT/BW (PRE p=.017, ES=1.08, POST: p=.003, ES=0.34). Likewise, muscle power also approached a significant increase in the POST group (p=.052, ES=0.33), and reached significance for the PRE group (p=.025, ES=0.28). The PRE group had a significant increase in isokinetic PT/BW (p=.004, ES=0.86). Changes in KE strength over 6 months did not statistically differ statistically between the POST and PRE group (p>.05) (Table 2, Figure 2), although there was a tendency for the PRE group to display increased change scores across all variables of KE strength. 89 Table 2 Mean change in strength and muscle volume scores for both PRE (A1-A2) and POST (A3-A4) groups over their respective 10weeks of strength training and 6month intervention of strength training and BoNT-A (A1-A4). # ES=effect size, SD=standard deviation. *Denotes significance, p<.05, denotes approaching significance, p<.06. Isometric Pk Torque (Nm/kg) Isokinetic Pk Torque 60°/s (Nm/kg) Isokinetic Power 60°/s (Watts) Isometric Pk Torque (Nm/kg) Isokinetic Pk Torque 60°/s (Nm/kg) Isokinetic Power 60°/s (Watts) Gastrocnemius (kg) Tibialis Anterior (kg) HS Volume 3 (cm /cm) Quad Volume 3 (cm /cm) PF Volume 3 (cm /cm) DF Volume 3 (cm /cm) PRE POST PRE POST PRE POST PRE POST PRE POST PRE POST PRE POST PRE POST PRE POST PRE POST PRE POST PRE POST Mean group T value, P Value, change (10 wks) ES Knee Flexor Strength 20.04 t=-1.243, p=.233, SD 39.40 ES=0.64 17.23 t=-2.949, p=.010, SD 23.39 ES=0.40* 18.02 t=-2.126, p=.053, # SD 37.71 ES=0.69 4.22 t=-1.298, p=.076, SD 13.82 ES=0.13 4.19 t=-3.554, p=.004, SD 4.41 ES=1.09* 2.59 t=-3.869, p=.002, SD 2.68 ES=0.38* Knee Extensor Strength 29.26 t=-1.318, p=.210, SD 83.09 ES=0.44 17.94 t=-1.743, p=.102, SD 41.17 ES=0.16 26.97 t=-1.555, p=.114, SD 64.90 ES=0.53 21.04 t=-2.341, p=.033, SD 35.95 ES=0.28* 3.44 t=-1.473, p=.164, SD 8.74 ES=0.65 4.49 t=-3.015, p=.009, SD 5.96 ES=0.42* Isometric Muscle strength 2.46 t=-1.336, p=.204, SD 3.03 ES=0.30 5.74 t=-3.299, p=.004, SD 4.58 ES=0.83* 2.46 t=-3.037, p=.010, SD 3.03 ES=0.91* 1.78 t=-1.819, p=.085, SD 1.99 ES=0.67 Muscle volume 0.68 t=-4.168, p<.001, SD 0.55 ES=0.33* 0.39 t=-3.715, p<.002, SD 0.42 ES=0.42* 0.98 t=-4.249, p=.001, SD 0.87 ES=0.26* 0.83 t=-7.240, p<.001, SD 0.44 ES=0.45* 0.85 t=-5.232, p<.001, SD 0.61 ES=0.73* 0.77 t=-8.114, p<.001, SD 0.38 ES=0.48* 0.18 t=-4.877, p<.001, SD 0.14 ES=1.43* 0.15 t=-5.810, p<.001, SD 0.11 ES=0.62* Mean group change (A1-A4) T value, P Value, ES 27.72 SD 43.97 13.75 SD 29.97 22.95 SD 27.67 4.41 SD 27.42 4.11 SD 5.07 2.02 SD 5.39 t=-2.359, p=.035, ES=0.83* t=-1.835, p=.086, ES=0.27 t=-3.103, p=.008, ES=0.88* t=-0.644, p=.530, ES=0.12 t=-3.030, p=.010, ES=1.05* t=-1.499, p=.155, ES=0.27 66.20 SD 90.32 36.41 SD 42.03 52.19 SD 56.58 21.39 SD 46.48 6.05 SD 8.69 3.47 SD 6.57 t=-2.742, p=.017, ES=1.08* t=-3.465, p=.003, ES=0.34* t=-3.452, p=.004, ES=0.86* t=-1.841, p=.086, ES=0.29 t=-2.526, p=.025, ES=0.28* t=-2.110, p=.052, # ES=0.33 3.84 SD 6.70 5.95 SD 6.70 2.20 SD 2.60 3.58 SD 2.18 t=-2.921, p=.012, ES=0.60* t=-3.553, p=.003, ES=0.73* t=-3.167, p=.007, ES=1.01* t=-6.566, p<.001, ES=1.18* 0.49 SD 0.46 0.60 SD 0.40 1.63 SD 0.84 1.82 SD 1.18 0.78 SD 0.99 1.01 SD 0.35 0.23 SD 0.21 0.24 SD 0.15 t=-3.962, p=.002, ES=0.24* t=-5.920, p<.001, ES=0.54* t=-7.261, p<.001, ES=0.44* t=5.984, p<.001, ES=0.94* t=-2.950, p<.011, ES=0.35* t=-11.591, p<.001, ES=0.59* t=-4.084, p=.001, ES=0.82* t=-6.193, p<.001, ES=0.88* 90 4.4.2.4.3 ISOMETRIC ASSESSMENT OF TIBIALIS ANTERIOR AND GASTROCNEMIUS As a direct result of the training program, the PRE group showed statistically significant increases in the isometric strength tibialis anterior (p=.010, ES=0.91), whilst the POST group had a statistically significant increase in isometric strength the gastrocnemius (p=.004, ES=0.83)(Table 2, Figure 3). Over 6months between A1 and A4, both the PRE and POST groups significantly increased their isometric strength of the gastrocnemius (PRE: p=.012, ES=0.60, POST: p=.003, ES=0.73) and tibialis anterior (PRE: p=.007, ES=1.01, POST: p<.001, ES=1.18) (Table 2, Figure 3). 4.4.2.5 MUSCLE VOLUME The PRE group had a significant increase in normalised HS muscle volume (p<.001, ES=0.33) and Quads muscle volume (p=.001, ES=0.26). The POST group also had a significant increase in HS (p<.002, ES=0.42) and Quads muscle volume (p<.001, ES=0.45) after strength training (Table 2, Figure 2). Over 6 months, both the PRE and POST group had significant increases in HS muscle volume (PRE: p=.002, ES=0.24, POST: p<.001, ES=0.54) and in Quads muscle volume (PRE: p<.001, ES=0.44, POST: p<.001, ES=0.94) following strength training (Table 2, Figure 2). Changes in quads muscle volume over 6 months were significantly different between groups F(1,14)=4.892, p=.044, ES=0.52), with the POST group showing a larger increase (Figure 2). In the lower leg, the PRE group had a significant increase in the normalised PF (p<.001, ES=0.73) and the DF (p<.001, ES=1.43) muscle volume after strength training. The POST group also showed a significant increase in normalised PF (p<.001, ES=0.48) and DF (p<.001, ES=0.62) (Table 2, Figure 3). 91 Figure 2 Mean scores for the Knee Flexor (KF) and Knee Extensor (KE) strength, and the Hamstring (HS) and Quadriceps (Quads) muscle volumes for the PRE and POST group over assessment time points. The dashed line represents the timing of BoNT-A injection. *Denotes significance at p<.05, **denotes significance at p<.001. Over 6 months both the PF and DF increase in MV was significant for the PRE group (p<.011, ES=0.35, and p=.001, ES=0.82), and POST group (p<.001, ES=0.59, p<.001, ES=0.88), with no overall difference in muscle volume between the groups across the 6 months. 92 Figure 3 Mean scores for Gastrocnemius and Tibialis Anterior strength, and the Plantar Flexor (PF) and Dorsi Flexor (DF) muscle volumes for the PRE and POST group over assessment time points. The dashed line represents the timing of BoNT-A injection. *Denotes significance at p<.05, **denotes significance at p<.001. 4.5 DISCUSSION In the treatment of children with CP it is becoming increasingly apparent that the impairments of the muscle, spasticity and strength, should be considered together. A number of studies have advocated a multidisciplinary approach to spasticity reduction and specific muscle strengthening in the management of children with CP2, 33 however there is a paucity of evidence available to support this approach. This study investigated the combination of BoNTA therapy and strength training for improved muscle strength and morphology outcomes for children with CP. Despite subject normalisation of our strength and morphology data, we frequently report high standard deviations throughout the study; this is attributable to the large variability of children, classified as both GMFCS I and II, included in our sample. The spasticity measurements over the course of this study were in keeping with the current evidence regarding spasticity management; that is that the BoNT-A injections reduced spasticity21, 22 and the strength training did not increase it11. Furthermore, our post BoNT-A measures of muscle strength do not appear to show significant decreases in muscle strength, an observation reported in previous work done by our research team34. A control period, whereby children 93 continued with their normal BoNT-A treatment routine prior to entering the strength intervention phase, was included in the study. The results from the control period indicate that with natural growth and standard care programs, children receiving BoNT-A demonstrate muscle growth and increases in strength. However, after the addition of strength training, greater arrays of strength gains as well as increases in muscle volume were shown. Consistent with previously published literature12, 13, each of the muscle groups targeted in the strength training program had significant strength improvements. To our knowledge this is the first study to purposefully apply strength training in conjunction with the best practice of BoNT-A therapy, making these findings even more relevant for clinical decision making. Of particular interest are the increases measures of the gastrocnemius and the knee flexor strength after the strength training comparative to the control period. This is of particular importance, as the gastrocnemius and the HS muscles are frequently targeted for BoNT-A injection in this group of children. It is widely considered that the general principal for strength training is to weaken the overactive spastic muscle with BoNT-A, and target the antagonist muscle for strengthening. Given the positive response in the injected muscles to training, and corresponding increases in morphology, perhaps future strength training should be targeting the injected muscles. A particular point of investigation pertinent to clinicians was the timing of strength training in relation to the BoNT-A injections, an aspect that to authors’ knowledge, has not been formally considered throughout the literature. The timing of strength training in relation to BoNT-A treatment was also considered in this study. All of the children involved in this study showed strength gains regardless of what when they received the strength training. The overall outcomes (6 months) did not indicate any significant differences in muscle strength between the groups; thus one training regime did not result in a statistically significant superior improvement compared to the other. However, closer analysis of the results revealed emerging trends between the two groups that may have future application. In the immediate (10 week) response to strength training, the POST group consistently displayed a greater capacity for changes of strength, having the most significant increases across the assessed muscles. However the PRE group displayed greater changes at 6months. These two methods of assessing change in strength, as the immediate change or the change over 6 months, indicate opposing stories. This can be explained when we consider the role of BoNT-A (and spasticity) over the course of the study; with the PRE group commencing approximately 3 months after their last injection 94 (and at higher levels of spasticity) comparative to the POST group commencing approximately 4weeks after BoNT-A. Perhaps the (POST group) children who trained with BoNT-A active in their system (and lowered levels of spasticity), had an improved ability to train, possibly a greater range of movement, and may have also felt less fatigued at the time of training. It may be argued that these children’s pre-training strength may have simply started at a lower level because of the BoNT-A, but this was not the case as there were no significant drops in strength following BoNT-A. As for the greater improvements that were seen over the 6months in the PRE group, it is possible that after the BoNT-A had acted upon spasticity, the true strength gains from training prior to the BoNT-A were shown, and that perhaps this group of children were better equipped to reinforce their strength gains in activities over this time. Although none of the children in the study undertook any new or intensive interventions throughout the ‘normal care routine’ period, we did not control the exercise and activities they participated in. It is common that strength training of some form is incorporated as part of a child’s standard care, and it would have been un-ethical for us to direct them to not to do so in this time period. Therefore changes over 6months can not only be attributable to 10 weeks of strength training, but also from any activities and exercises undertaken in the weeks after BoNT-A. In saying this, it should be noted that there were far fewer significant changes in strength for children over the ‘normal care routine’ time periods. Comprised of movement repetition and progressing loads, the strength training program in this study addressed both neural and structural factors of muscle strength. Whilst it is likely that improvements in motor unit recruitment could be a factor behind the strength gains, we did not measure muscular activation per se; however our measure of selective motor control did indicate a significant improvement over the course of the study. Muscle volume was measured, and corresponding with strength gains were significant increases in muscle volumes of the HS, Quads, PF and DF muscle groups. The muscle hypertrophy following strength training is consistent with previous research20, and in addition also seen with the simultaneous use of BoNT-A therapy. It should be noted that increased muscle volumes, most likely attributable to natural growth, are also shown over the ‘normal care routine’ period, in particular for the quadriceps and gastrocnemius in the POST group. What needs to be considered is that whilst natural growth, as measured in the ‘normal care’ period, may afford an increase in muscle volume over time, is this increase enough, and do they match those of their typically developing peers? This is important to consider, with Barber and Colleagues (2011)35 suggesting that deficits in muscle volume may increase in the individual with spastic 95 CP as he or she grows older. Therefore, the gains strength training may offer may be even more advantageous in an adolescent population. The small sample size is a limitation of this study; however a post hoc power analysis based on the strength results in the current study revealed an average power of 0.88 to detect a meaningful difference over the intervention (alpha = 0.05). With small numbers, the inclusion of a larger control group (of BoNT-A only) and of an additional control group (of strength training only) was not possible, however we encourage further research with access to a larger sample of participants to investigate this. Our study was strongly influenced by clinical practice, which in itself also brought about certain limitations to the study; we did not prohibit children from participating in their usual physiotherapy (often including some form of strength training) in the ‘normal care periods’, we could not standardise the muscles being injected with BoNT-A, and we could not monitor each home session to ensure that training was performed at an optimal level. However these factors are also an advantage in that it means that our research results are highly clinically relevant. With the combination of neural and structural factors improving muscle strength, and the reduction of spasticity from BoNT-A, the functional outcome for children in this study was overwhelmingly positive. Scores from the GAS demonstrate that over the 6 months of this study, the combination of BoNT-A and strength training children were able to achieve their functional goals, with both groups significantly increasing their measure of GAS. This is possibly the most important outcome of this clinical study, when the overreaching aim of therapy is commonly directed towards improved functional ability36. Consistent with recent systematic reviews4, 11 this research has provided further evidence that strength training can improve muscle strength in children with CP, which can be associated with hypertrophy20. The morphology results could indicate the potential role of strength training in altering the rate of muscle growth, in an aim to improve the failure of muscle growth associated with CP37. What makes this study distinct is that strength training was administered in combination with BoNT-A therapy, and demonstrated that the concurrent treatment could achieve positive outcomes in terms of strength, spasticity and function. It has shown that muscles injected with BoNT-A can be successfully strengthened. We endeavoured to find if timing of strength training, in relation to BoNT-A would indicate a preference for better outcomes, and found that both groups made significant improvement that did not differ 96 significantly between groups. However, it did appear that the POST BoNT-A training group were able to utilise their increased muscle volume immediately, whereas the PRE group required their spasticity to be masked before their true strength gain could become apparent. 4.6 CLINICAL IMPLICATIONS Home based strength training, based on a child’s individual goals has been shown to be successful in improving strength and goal attainment in this study. This has been combined with BoNT-A therapy to target both muscle weakness and muscular spasticity in children with CP and has confirmed that either PRE or POST BoNT-A strength training may be individually adapted to suit the needs of the child for a successful outcome. PRE training may be more suitable for a child scheduled to receive serial casts following BoNT-A, whereas, POST BoNT-A training may be more appropriate in order to achieve immediate results for functional goals for some children. The muscles targeted in the strength training should include those injected by BoNT-A, with the results of this study demonstrating significant strength improvements in injected muscles. CP management is a lifelong challenge that requires therapists and clinicians to consider, and treat, the impairments affecting the child holistically. This study provides evidence for the successful combination of both BoNT-A therapy and strength training, over and above BoNT-A therapy alone. The potential economical benefit of combining therapies to maximise outcome should also be considered in the future. 4.7 ACKNOWLEDGEMENTS The authors would like to thank the Department of Paediatric Rehabilitation, PMH for their support and assistance with recruitment, the Department of Diagnostic Imaging, PMH for their assistance and knowledge in data collection and the contribution of the School of Sport Science, Exercise & Health at UWA for the use of equipment and facilities. Sincere thanks to Tania Shillington, Bree Dwyer and Martin Spits for their role with data collection, Nadine Smith for her input, and the children and families who volunteered to participate in this study. 97 4.8 REFERENCES 1. Reid S, Hamer P, Alderson J, Lloyd D. Neuromuscular adaptations to eccentric strength training for adolescents with cerebral palsy. Dev Med Child Neurol. 2010;52:358-63. 2. Wiley ME, Damiano DL. Lower-Extremity strength profiles in spastic cerebral palsy. Dev Med Child Neurol. 1998;40:100-7. 3. Ross SA, Engsberg JR. Relationships between spasticity, strength, gait, and the GMFM- 66 in persons with spastic diplegia Cerebral Palsy. Arch Phys Med Rehabil. 2007;88:1114-20. 4. Mockford M, Caulton J. Systematic review of progressive strength training in children and adolescents with cerebral palsy who are ambulatory. Pediatr Phys Ther. 2008;20:318-33. 5. Lieber R, Friden J. Functional and clinical significance of skeletal muscle architecture. Muscle Nerve. 2000;23:1647-66. 6. Barrett RS, Lichtwark GA. Gross muscle morphology and structure in spastic cerebral palsy: a systematic review. Dev Med Child Neurol. 2010;52:794-804. 7. Elder G, Kirk J, Stewart G, et al. Contributing factors to muscle weakness in children with cerebral palsy. Dev Med Child Neurol. 2003;45. 8. Stackhouse S, Binder-Macleod S, Lee S. Voluntary muscle activation, contractile properties and fatigability in children with and without cerebral palsy. Muscle Nerve. 2005;31:594-601. 9. Molenaers G, Van Campenhout A, Fagard F, De Cat J, Desloovere K. The use of botulinum toxin A in children with cerebral palsy, with a focus on the lower limb. J Child Orthop. 2010;4:183-95. 10. Flett P. Rehabilitation of spasticity and related problems in childhood cerebral palsy. J Paediatr Child Health. 2003;39:6-14. 11. Dodd K, Taylor N, Damiano D. A systematic review of the effectiveness of strength- training programs for people with cerebral palsy. Arch Phys Med Rehabil. 2002;83:1157-64. 12. Damiano D, Abel M. Functional outcomes of strength training in spastic cerebral palsy. Arch Phys Med Rehabil. 1998;79:119-25. 13. MacPhail A, Kramer J. Effect of isokinetic strength training on functional ability and walking efficiency in adolescents with cerebral palsy. Dev Med Child Neurol. 1995;37:763-75. 14. Taylor N, Dodd K, Damiano D. Progressive resistance exercise in physical therapy: a summary of systematic reviews. Phys Ther. 2005;85:1208-23. 98 15. Verschuren O, Ketelaar M, Takken T, Helders P, Gorter J. Exercise programs for children with cerebral palsy: a systematic review of the literature. Am J Phys Med Rehabil. 2008;87:404–17. 16. Antilla H, Autti-Ramo I, Suoranta J, Makela M, Malmivaara A. Effectiveness of physical therapy interventions for children with cerebral palsy: A systematic review. BMC Pediatrics. 2008;8:14. 17. Verschuren O, Ada L, Maltais DB, Gorter JW, Scianni A, Ketelaar M. Muscle strengthening in children and adolescents with spastic Cerebral Palsy: Considerations for future resistance training protocols. Phys Ther. 2011;91:1130-9. 18. Scianni, A., Butler J, Ada L, Teixeira-Salmela L. Muscle strengthening is not effective in children and adolescents with cerebral palsy: a systematic review. Aust J Physiother. 2009;55:81-7. 19. McBurney H, Taylor N, Dodd K, Graham H. A qualitative analysis of the benefits of strength training for young people with cerebral palsy. Dev Med Child Neurol. 2003;45:658–63. 20. McNee AE, Gough M, Morrissey MC, Shortland AP. Increase in muscle volume after plantarflexor strength training in children with spastic cerebral palsy. Dev Med Child Neurol. 2009:1-7. 21. Love S, Novak I, Kentish M, et al. Botulinum toxin assessment, intervention and after- care for lower limb spasticity in children with cerebral palsy: international consensus statement. Eur J Neurol. 2010;17:9-37. 22. Koman L, Mooney J, Smith B, Walker F, Leon J. Botulinum toxin type A neuromuscular blockade in the treatment of lower limb spasticity in cerebral palsy: a randomised double-blind placebo controlled trial. J Pediatr Orthop B. 2000;20:108-15. 23. Steenbeek D, Meester-Delver A, Becher J, Lankhorst G. The effect of botulinum toxin type A treatment of the lower extremity on the level of functional abilities in children with cerebral palsy: evaluation with goal attainment scaling. Clin Rehabil. 2005;19:274-82. 24. Fortuna R, Aurélio Vaz M, Rehan Youssef A, Longino D, Herzog W. Changes in contractile properties of muscles receiving repeat injections of botulinum toxin. J Biomech. 2011;44:39-44. 25. Yaraskavitch M, Leonard T, Herzog W. Botox produces functional weakness in non- injected muscles adjacent to the target muscle. J Biomech. 2008;41:897-902. 26. Gough M, Fairhurst C, Shortland AP. Botulinum toxin and cerebral palsy: time for reflection? Dev Med Child Neurol. 2005;47:709-12. 99 27. Schroeder A, Ertl-Wagner B, Britsch S, et al. Muscle biopsy substantiates long-term MRI alterations one year after a single dose of botulinum toxin injected into the lateral Gastrocnemius muscle of healthy volunteers. Mov Disord. 2009;24:1494-503. 28. Palisano R. Validity of goal attainment scaling in young infants with motor delays. Phys Ther. 1993;73:651-8. 29. Bohannon R, Smith M. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther. 1987;67:206-7. 30. Fowler EG, Staudt LA, Greenberg MB, Oppenheim WL. Selective Control Assessment of the Lower Extremity (SCALE): development, validation, and interrater reliability of a clinical tool for patients with cerebral palsy. Dev Med Child Neurol. 2009;51:607-14. 31. Pitcher C, Elliott C, Williams S, et al. Childhood muscle morphology and strength: alterations over six months of growth. Muscle Nerve. 2012;In press. 32. ACSM. Guidlines for exercise testing and prescription. 7th Edition ed. Philadelphia: Lippincot, Williams & Wilkins; 2006. 33. Dodd K, Taylor N, Graham H. A randomized clinical trial of strength training in young people with cerebral palsy. Dev Med Child Neurol. 2003;45:652–7. 34. Williams SA, Reid SL, Elliott CM, Shipman P, Valentine J. Morphological alterations in spastic muscles immediately following Botulinum Toxin Type-A treatment in children with Cerebral Palsy. Unpublished observations. 2012. 35. Barber L, Hastings-Ison T, Baker R, Barrett R, Lichtwark G. Medial gastrocnemius muscle volume and fascicle length in children aged 2 to 5 years with cerebral palsy. Dev Med Child Neurol. 2011;53:543-8. 36. Shepherd R, editor. Cerebral palsy in: Physiotherapy in paediatrics. Oxford: Butterworth-Heinemann; 1995. 37. Lampe R, Grassl S, Mitternacht J, Gerdesmeyer L, Gradinger R. MRT-measurements of muscle volumes of the lower extremities of youths with spastic hemiplegia caused by cerebral palsy. Brain Dev. 2006;28:500-6. 100 CHAPTER FIVE IMPROVING THE GAIT OF CHILDREN WITH CEREBRAL PALSY USING THE COMBINED INTERVENTIONS OF STRENGTH TRAINING AND BOTULINUM NEUROTOXIN TYPE-A. This manuscript was submitted for publication into the journal, Gait and Posture, in July 2012. Williams S, Elliott C, Valentine J, Reid S. Improving the gait of children with Cerebral Palsy using the combined interventions of strength training and Botulinum Neurotoxin Type-A. Gait Posture. 2012. In review. The PhD candidate, Sîan A Williams accounted for 80% of the intellectual property associated with the final manuscript. Collectively, the remaining authors contributed 20%. 101 FOREWORD The previous paper provided evidence for the successful combination of both Botulinum Neurotoxin Type-A (BoNT-A) therapy and strength training, over and above BoNT-A therapy alone. In addition to this, it demonstrated the combination of therapies to successfully improve the attainment of individual functional goals, set by the children in the study. Spasticity and muscular weakness are two impairments known to negatively impact walking ability in children with CP. This paper investigates the effect of the combined BoNT-A and strength training intervention on walking gait, with three-dimensional motion analysis. The Gait Deviation Index is used as a global measure of gait compared to non-pathological gait, joint kinetics of the hip, knee and ankle joint are also compared with an age-matched typically developing population. This paper provides novel information endorsing the combined use of BoNT-A and strength training for superior outcomes of gait. 102 5.1 ABSTRACT This study investigated the combined effects of strength training and Botulinum Neurotoxin Type-A (BoNT-A) on walking gait in children with CP. Fifteen children receiving BoNT-A for spasticity management, classified as Spastic Diplegic, GMFCS I-II, aged 5-12years (mean=8.52) participated in the study. Children were randomly allocated to 10 weeks of strength training either before or after BoNT-A, assessed twice over 6months. Eight of the 15 children also completed a control period of BoNT-A treatment only. Hamstring and gastrocnemius muscles were injected with BoNT-A as clinically indicated. Three-dimensional gait analysis determined the Gait Deviation Index (GDI) and kinetic profiles at hip, knee and ankle joints. During the intervention period, GDI significantly increased from 79.28 to 85.28 (p=.014, ES=0.65). Peak power generated at the hip significantly decreased; 2.31W/Kg to 1.39W/Kg (p=.002, ES=0.88), as did the knee peak power; 1.64W/Kg to 1.05W/Kg (p=.015, ES=0.62), with no change at the ankle. Absorption at the knee decreased; 26.77W/Kg to 14.83W/Kg (p=.001, ES=0.92). The combination of strength training with BoNT-A treatment indicated a positive impact on kinematic and kinetic profiles, resulting in more efficient use of energy transfer to drive forward locomotion. KEYWORDS: Cerebral Palsy, strength training, Botulinum Toxin, Muscle Weakness, spasticity, gait. 103 5.2 INTRODUCTION Spasticity and muscular weakness are primary motor impairments associated with Cerebral Palsy (CP). Together with increased muscle co-activation and impaired selective motor control, these impairments are responsible for disturbed movement patterns in walking and other daily life activities1. Inefficient ambulation, commonly targeted in therapeutic goals2, is one of the most significant functional limitations of CP3. Recent reports consider muscle weakness to be directly related to gross motor function and gait4, 5. Strength training is recognised as an effective intervention for improving muscular strength in children with CP6, with strength improvements translatable to gains in motor function6-8. Changes in gait kinematics has been reported with improvements in strength including; a more upright posture9, improved hip and knee extension9-12 and trends of improved ankle dorsi-flexion11, however few studies report gait kinetics following strengthening in the CP population. Engsberg and Colleagues (2006)11 reported inconclusive kinetic alterations following strength training, suggesting that future research should include the calculation of power. Defined as the work performed per unit of time, power may be used to document the net energy generation or absorption of the muscles during activity 13. Strengthening of the muscles is more likely to result in changes in the muscles force profiles than to alter kinematic profiles; investigating power may be a more effective method of evaluating the impact of strengthening. During typical gait, the ankle plantar-flexors act as the greatest contributors to forward propulsion14. In CP gait, particularly in kinetic variables at the ankle, muscle strength is linked with gait patterns5. Eek and Colleagues (2011)5 have also surmised that adequate strength around the hip and knee joints is needed for stability to allow plantar-flexor power generation at push off5. Considering the essential nature of the bi-articular plantar-flexors in locomotion, and the impaired function of these muscle groups in CP, it is important to understand the potential impact of treatment interventions targeting these muscle groups. Botulinum Neurotoxin Type-A (BoNT-A) is an established treatment for spasticity management in CP15. Along with benefits of reduced muscle tone16, research reports improvements in range of joint motion16, functional measures17-19, 20, and gait patterns16; with increases in ankle dorsiflexion21-23, knee extension21, and a normalisation of ankle kinetics21. Zurcher and Colleagues (2001)21 evaluated kinetics at the ankle in children with CP after BoNT-A injections, reporting 104 increased power during gait. BoNT-A and strength training both appear to have a positive impact on gait in children with CP, therefore it could be assumed that the combination of the therapies would also further improve gait function. The purpose of the present study was to investigate whether a combination of BoNT-A and strength training can improve walking gait in children with CP. 5.3 METHODS 5.3.1 PARTICIPANTS Ten boys and five girls with spastic diplegia, classified as Gross Motor Function Classification System (GMFCS) level I-II participated in this study. The children had a mean age of 8years 5mo (SD 1yr 10 mo, range 5-12yrs), average height of 129.87cm (SD 10.92cm) and weight of 27.97kg (SD 7.43kg). No child had a history of lower limb surgery, nor had undergone serial casting in the previous six months. Ethical approval for the study was obtained from the Ethics Committee of PMH (1766), and from the University of Western Australia. Written consent was obtained from the parents of all the participants. All 15 children were receiving BoNT-A treatment for spasticity management, and had already received a minimum of two series of BoNT-A prior to the study (maximum series=15, mean series=8.93). The muscle(s) selected for injection were based on clinical assessment and functional goal setting, the total dose of BoNT-A (Botox®, Allergan, Irvine, CA, USA) was empirically selected for each muscle. All participants received BoNT-A to bilateral medial gastrocnemius' (30 legs injected; 2-6U/kg), five participants also received BoNT-A to bilateral medial hamstrings (10 legs; 2-4U/kg). Other muscles injected included the soleus (4legs; 12U/kg) adductors (2 legs; 1U/Kg), rectus femoris (2 legs; 1U/Kg), and tibialis posterior (1 leg; 1U/Kg). No child had more than three muscles per leg injected. For comparison, average power profiles from a convenience sample of 16 typically developing (TD) children were used. Demographic characteristics of the TD children did not differ significantly from the CP group; 10 males, 6 females, mean age; 7yrs 5mo (SD 1yr 5mo, range 4-11yrs), average height; 122.50cm (SD 12.16), and average weight; 24.04kg (SD 5.74). 105 5.3.2 PROCEDURES The study design, dictated by clinical care, utilised a randomised cross-comparison design with a 6month pre-intervention baseline serving as a control period (Figure 1). For the control period, eight children completed assessments 12-14 weeks before their scheduled BoNT-A injection (B) and continued to receive normal clinical care both before and for 12 weeks after that injection. These eight, together with a further seven children were block randomised by age, gender and GMFCS level into either a PRE or POST BoNT-A strength training group. The PRE group completed strength training in the 10 weeks leading up to BoNT-A, and the POST group completed the training after BoNT-A, commencing approximately 5 weeks (SD 1week, range 3-6 weeks) after the injection. In the alternative weeks they continued with their normal care routine. Children completed two assessments; Assessment 1 (A1) timed approximately 12 weeks prior to their scheduled BoNT-A injection and Assessment 2 (A2) approximately 14 weeks post injection. A1 BoNT-A B Normal Care Routine Normal Care Routine Control Period n=8 W-26 W-12 W0 A2 BoNT-A PRE strength training Normal Care Routine Normal Care Routine POST strength training Intervention period n=15 W12 W26 Figure 1 Cross-comparison study design, with a pre-intervention baseline assessment (B) for 8 participants forming a control period, and 15 children completing the intervention period. Vertical dashed lines represent the timing of Botulinum Toxin injections 5.3.2.1 3D CLINICAL GAIT ANALYSIS (3DGA) Three-dimensional gait analysis (3DGA) was performed using two AMTI force platforms (2000Hz) and Vicon® (250Hz, MX system Oxford metrics, UK), allowing for the collection of kinematic and kinetic data. Retro-reflective markers were placed on each participant in accordance with the University of Western Australia’s lower limb 3DGA protocol24. Participants were asked to walk barefoot in their usual manner along a 10 meter walkway to capture five successful trials (upon where a clean foot strike on a force platform was achieved) representative of the child’s usual gait pattern. The Gait Deviation Index (GDI)25 utilises information from 3DGA to provide a better global understanding of the overall gait pathology. The GDI compares nine kinematic variables of a 106 subject's gait against those of a control group. This method of comparison aims to reflect the extent of gait variation; a GDI score of 100 (+/- 10) denotes non-pathological gait, and each 10 point decrement below 100 indicates 1 standard from normal kinematics25. All graphs obtained from 3DGA were normalised as a percentage of the gait cycle; a representative trial for each participant was input into the electronic addendum provided with the GDI paper (using the control data provided)25. Joint kinetics (power) was calculated using inverse dynamics, and normalised to body weight to permit between subject comparisons. Power profiles for hip, knee and ankle joints in the sagittal plane were calculated for bilaterally. Peak power generation (maximum positive value) and power absorption were used for analysis. Power absorption was defined as the sum of the area under the curve (using the Trapezoidal Rule for integration26) in the stance phase of the gait cycle. 5.3.2.2 TRAINING PROGRAM Participants completed a home based progressive strength training program, training three times a week for 10weeks. Program coordination and progression was conducted fortnightly by a visiting exercise physiologist, with remaining sessions conducted by a trained family member. Each session included manual and passive stretching of the lower limb muscle groups. The design of the program was based on the child’s initial strength assessment and individual functional goals and was progressed in accordance with guidelines27. Exercises were performed in three sets bilaterally, with adequate rest between sets. Further details of the strength program are detailed elsewhere28. 5.3.3 DATA ANALYSIS Analysis A: To estimate changes in gait over the control period (B to A1), the mean and 95% confidence interval of within-subject change of each outcome score was calculated. A descriptive comparison of measures of joint power between the CP and TD children is also included. Statistical significance was assessed with a 2-tailed T-test, and considered significant if p<0.05. Analysis B: To estimate whether the timing of the strength training preceding or following BoNT-A resulted in a differential outcome, the mean within-subject change of each score over 107 the intervention period for the PRE group was compared with the POST group. The mean within-subject change of each score over the intervention period for the total cohort of children was calculated to estimate the effect of strength training, independent of timing. A descriptive comparison of measures of joint power for the CP and TD sample of children is also included. Effect sizes were determined using Cohen’s d equation29. 5.4 RESULTS 5.4.1 ANALYSIS A: CONTROL GROUP (N=8 CHILDREN) 5.4.1.1 GDI During the control period there was no statistically significant change in group mean GDI score (t(15)=0.413, p=.685, ES=0.01); from an average of 84.77 (SE 2.12, range: 69.25-97.92), to 83.72 (SE 2.41, range: 69.64-98.23). 5.4.1.2 POWER PROFILE 5.4.1.2.1 HIP JOINT Peak power generated at the hip joint increased significantly over the control period (t(15)=2.518, p=.023, ES=1.09), bringing the group average from 1.44W/Kg (SE 0.15), to 2.45W/Kg (SE 0.32), higher than the TD average hip peak joint power (2.05W/Kg, SE 0.25). Power absorption did not change significantly (t(15)=1.452, p=.167, ES=0.66), and was larger than the TD average (8.82W/Kg, SE 0.87) (Figure 2). 5.4.1.2.2 KNEE JOINT Peak power generated at the knee joint increased significantly over the control period (t(15)=3.293, p=.005, ES=1.39), bringing the group average from 0.97W/Kg (SE 0.09) to 2.11W/Kg (SE 0.33), larger than that of the TD (1.53W/Kg, SE 0.10). Power absorption had an increasing trend, from 18.36W/Kg (SE 2.26) to 29.36 (SE 4.36), but was not statistical significance (t(15)=1.946, p=.071, ES=0.83), yet was evidently larger than the TD average (8.91W/Kg, SE 0.87) (Figure 2). 108 5.4.1.2.3 ANKLE JOINT Peak power generated at the ankle joint increased significantly over the control period (t(13)=2.763, p=.016, ES=0.61), from 1.78W/Kg (SE 0.33), to 2.55W/Kg (SE 0.32), below the TD average (3.45 W/Kg, SE 0.13). Power absorption at the ankle joint showed no significant change (t(15)=0.056, p=.956, ES=0.02), but was higher than the TD value (8.04W/Kg, SE 0.66) (Figure 2). Figure 2 Average power generation (peak), and power absorption (area) at the hip, knee and ankle joints through stance, before and after a control period (of BoNT-A with normal clinical care) for eight children. Dashed vertical lines represent the BoNT-A injection, horizontal solid lines indicate the average from the typically developing population and the * denotes a signifcant increase p<.05 109 5.4.2 ANALYSIS B: INTERVENTION GROUP (N=15 CHILDREN) 5.4.2.1 GDI Over the intervention, the grouped mean GDI scores significantly increased (t(29)=-2.601, p=.014, ES=0.65), as did scores for the POST group (t(15)=-2.165, p=.047, ES=0.49). The PRE group did not increase significantly, (t(13)=-1.493, p=.159, ES=0.65) (Table 1). Table 1 Mean within-subject changes of the Gait Deviation Index (GDI), and the Hip, Knee and Ankle joint power generation and absorption over 6months of the PRE group (training before BoNT-A), of the POST group (training after BoNT-A), and of the entire CP cohort.* Significance at p<.05. Relative scores for our typically developing sample (TD) of children are also included for reference. TD score (SE) GDI Hip Joint Knee joint Ankle joint Power Generation (W/Kg) Power Absorption (W/Kg) Power Generation (W/Kg) Power Absorption (W/Kg) 92.29 (1.28) 2.05 (0.25) 8.82 (0.87) 1.53 (0.10) 8.91 (0.87) Power Generation (W/Kg) 3.45 (0.13) Power Absorption (W/Kg) 8.04 (0.66) Group Initial score (SE) Change after 6months (SE) PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All 81.34 (2.64) 77.48 (3.47) 79.28 (2.22) 1.85 (0.22) 2.74 (0.30) 2.31 (0.20) 10.85 (1.46) 12.00 (1.70) 11.44 (1.13 1.39 (0.23) 2.04 (0.33) 1.74 (0.30) 24.06 (1.17) 29.15 (0.79) 26.77(3.08) 2.35 (0.36) 2.12 (0.26) 2.24 (0.22) 8.09 (0.09) 9.03 (0.27) 8.59 (1.10) 5.59 (3.75) 6.34 (2.93)* 5.99(2.30)* -0.83 (0.31)* -0.98 (0.43)* -0.91 (0.26)* -3.66 (2.57)* -5.80 (1.52) -4.43 (1.53)* -0.42 (0.44) -1.01 (0.33)* -0.72 (0.27)* -12.94 (4.47)* -11.77 (4.58)* -11.58 (3.26)* -0.61 (0.66) -0.57 (0.32) -0.59 (0.36) 0.54 (1.71) -1.97 (1.55) -0.63 (1.19) 5.4.2.2 POWER PROFILE 5.4.2.2.1 HIP JOINT The cohort mean peak hip power decreased significantly (t(29)=3.434, p=.002, ES=0.88) over the intervention period to below the TD average. Both the PRE (t(13)=2.652, p=.020, ES=1.13) and POST (t(15)=2.279, p=.039, ES=0.88) groups significantly decreased hip joint power generation. 110 Power absorption significantly decreased at the hip joint (t(29)=3.044, p=.005, ES=0.85) for the entire cohort, to an average below the TD sample. The PRE group displayed a significant decrease in hip joint power absorption (t(13)=3.808, p=.002, ES=1.44), however the POST group did not (t(15)=1.426, p=.174, ES=0.58) (Table 1, Figure 3). 5.4.2.2.2 KNEE JOINT At the knee joint, a significant decrease in joint power generation for the entire cohort was observed over the intervention (t(29)=2.585, p=.015, ES=0.62), to an average below the TD score. The PRE group did not show a significant change in knee peak power generation (t(15)=0.943, p=.363, ES=0.38), whilst the POST group significantly decreased over the intervention (t(15)=2.916, p=.011, ES=0.88). Knee power absorption significantly decreased for the entire cohort over the intervention (t(29)=-3.668, p=.001, ES=0.92), but remained comparatively larger than the TD average. The POST group significantly decreased power absorption at the knee joint (t(15)=-2.41, p=.029, ES=0.79), as did the PRE group (t(13)=-2.706, p=.018, ES=1.17) (Table 1, Figure 3). 5.4.2.2.3 ANKLE JOINT There was no significant change in peak ankle power generation for the entire cohort (t(29)=1.653, p=.110, ES=0.36), the PRE (t(13)=1.811, p=.093, ES=0.38) or POST group (t(15)=0.931, p=.369, ES=0.33). Power absorption at the ankle joint did not change significantly over the intervention period for the entire cohort (t(29)=0.670, p=.508, ES=0.12), PRE (t(13)=-0.293, p=.774, ES=0.09) or POST group (t(15)=1.269, p=.244, ES=0.27),(Table 1,Figure 3). 111 Figure 3 Average power generation (peak), and average power absorption (area) at the Hip, Knee and Ankle joints through the stance phase of gait for the children in the PRE and POST group, and of all the children in the study grouped together. Dashed vertical lines represent the BoNT-A injection, whilst the solid horizontal line indicates the average of the typically developing group. 5.5 DISCUSSION This paper has investigated the outcomes of the combined treatments of BoNT-A and strength training on walking gait. Whilst children showed no change in GDI over the control period, significant increases were measured over the intervention. Initial GDI scores reveal that our sample of children, classified as GMFCS I’s and II’s, were already walking at a high functional level, with an average score of 79.28 (SE 2.22), where 100 (+/-10) denotes non-pathological gait25. The fact that these children could show significant improvements in this global measure of gait is positive, highlighting the possibilities for interventions in higher functioning children with CP. We believe the changes in GDI from the combined interventions, though small, to be 112 clinically important. Whilst the GDI provides a practical global reflection of gait calculated from kinematic variables, the use of kinetic variables can provide a better understanding of how each joint is functioning during gait. Previous research has linked muscle strength and kinetics in the CP population, with a focus on the ankle at toe-off (power generation)5. This study showed the combination of lower limb strength training with BoNT-A treatment to alter joint power outputs at the hip and knee. In contrast to increasing trends over the control period, levels of power generated at the hip joint decreased over the intervention, as did levels of power absorption at the knee joint, to levels more closely matching the TD population. Matched with the measured improvements in GDI, perhaps this indicates an improved efficiency of muscles working to facilitate gait, and that the intervention may have promoted better motor recruitment and activation strategies. Strength training, coupled with the BoNT-A treatment in the plantar flexors may have served to increase dorsi-flexion and knee extension range of motion21-23, resulting in better limb positioning for more effective absorption and production of power. This theory is supported by the reduced power absorption measured at the knee joint, possibly reflective of reduced knee flexion throughout gait9, 10, 11. Unlike the hip and ankle, the role of the knee joint in gait is not for driving forward locomotion, but rather to act as a power transfer agent between the ankle and hip; a reduction in loading at the knee may be protective against longer term injury and pain. In light of the decreases in both knee power generation and absorption over the intervention period, compared to the increasing trends over the control period, we suggest that the combination of strength training and BoNT-A facilitated a more efficient power transfer through the muscles of the lower limb. Within the CP population, literature has observed a general shift in power generation from the ankle to the hip joint through walking gait5, 30. Similar to Eek et al.,(2011)5, this study measured decreased power generation (peak power in at terminal stance) around the ankle joint in the children with CP, but in contrast we did not measure greater values of peak power generation at the hip joint5. However, here we have reported values of peak power, whereas Eek et al., (2011)5 reported power summation. The combined interventions of BoNT-A and strength did not alter power generation at the ankle joint. This is not altogether unexpected, reflective of the strength training administered in this study and the muscles targeted for BoNT-A. Due to varying degrees of contracture, and 113 personalised goals, muscles around the ankle were not targeted as frequently for strengthening, whereas every child trained muscles around the hip and knee. Whilst strength in the ankle plantar flexors is important in gait14, and are a commonly targeted muscle group for BoNT-A treatment in diplegic CP, the strength of the muscles around the hip and knee joints are also considered to be important for improving gait, providing stabilisation for effective push off at the ankle5, 31. The timing of strength training in relation to BoNT-A was also considered; in terms of improvement in the GDI, the POST group measured the greatest changes over the intervention. We suggest that children training with BoNT-A active in their system (and lowered levels of spasticity) were able to achieve a greater range of movement throughout exercises16, and perhaps a better ability to train. In terms of the power produced around the joints, both groups showed similar declines in power generated at the hip joint, to levels below our TD sample. The results from this study suggests to clinicians that training after BoNT-A injections may be more beneficial for achieving a style of walk closer resembling the TD population, however there appears to be no difference in terms of power generation or absorption. 5.6 CONCLUSION These results demonstrate positive changes in gait profiles and kinetics from the combination of strength training and BoNT-A injections compared with BoNT-A alone. Children with CP significantly improved their GDI’s, without the need to increase the levels of power generated at the hip, knee and ankle joints suggesting an improved efficiency of the muscles. Knee absorption was also significantly reduced during the stance phase of gait. The intervention improved power profiles at hip and knee joints to levels closely matching the TD sample. Minimal kinetic changes were demonstrated at the ankle joint, a reflection of the muscles targeted for strength training. Administering strength training after BoNT-A treatment can result in superior outcomes for gait. 5.7 ACKNOWLEDGEMENTS This project was supported by Princess Margaret Hospital (PMH) Foundation Grant. The authors would like to thank the Department of Paediatric Rehabilitation, PMH for their support and assistance with recruitment. Authors would also like to acknowledge the contribution of 114 the School of Sport Science, Exercise & Health at UWA for the use of equipment and facilities. Sincere thanks go to the children and families who volunteered to participate in this study and to Nadine Smith (Physiotherapist, PMH) for advice and assistance with the strengthening program. 115 5.8 REFERENCES 1. Morris C. Definition and classification of cerebral palsy: a historical perspective. Dev Med Child Neurol. 2007;109:3-7. 2. Shepherd R. Cerebral palsy. In: Shepherd R, editor. Physiotherapy in paediatrics. Oxford: Butterworth-Heinemann; 1995. p. 110-4. 3. Eaglton M, Iams A, McDowell J, Morrison R, Evans C. The effects of strength training on gait in adolescents with cerebral palsy. Pediatr Phys Ther. 2004;16:22-30. 4. Ross SA, Engsberg JR. Relationships between spasticity, strength, gait, and the GMFM- 66 in persons with spastic diplegia Cerebral Palsy. Arch Phys Med Rehabil. 2007;88:1114-20. 5. Eek MN, Tranberg R, Beckung E. Muscle strength and kinetic gait pattern in children with bilateral spastic CP. Gait Posture. 2011;33:333-7. 6. Dodd K, Taylor N, Damiano D. A systematic review of the effectiveness of strength- training programs for people with cerebral palsy. Arch Phys Med Rehabil. 2002;83:1157-64. 7. Damiano D, Abel M. Functional outcomes of strength training in spastic cerebral palsy. Arch Phys Med Rehabil. 1998;79:119-25. 8. MacPhail A, Kramer J. Effect of isokinetic strength training on functional ability and walking efficiency in adolescents with cerebral palsy. Dev Med Child Neurol. 1995;37:763-75. 9. Unger M, Faure M, Frieg A. Strength training in adolescent learners with cerebral palsy: a randomized controlled trial. Clin Rehabil. 2006;20:469-77. 10. Damiano D, Kelly L, Vaughan C. Effects of quadriceps femoris muscle strengthening on crouch gait in children with spastic diplegia. Phys Ther. 1995;75:658-67. 11. Engsberg J, Ross S, Collins D. Increasing ankle strength to improve gait and function in children with cerebral palsy: a pilot study. Pediatr Phys Ther. 2006;18:266-75. 12. Damiano DL, Arnold AS, Steele KM, Delp SL. Can strength training predictably improve gait kinematics? A pilot study on the effects of hip and knee extensor strengthening on lowerextremity alignment in cerebral palsy. Phys Ther. 2010; 90:269-79. 13. Gage J. Gait Analysis in Cerebral Palsy. Oxford: MacKeith Press; 1991. 14. Gage J. A qualitative description of normal gait: The treatment of gait problems in cerebral palsy. Gage J, editor. London: Mac Keith Press; 2004. 116 15. Love S, Novak I, Kentish M, et al. Botulinum toxin assessment, intervention and after- care for lower limb spasticity in children with cerebral palsy: international consensus statement. Eur J Neurol. 2010;17:9-37. 16. Koman L, Mooney J, Smith B, Walker F, Leon J. Botulinum toxin type A neuromuscular blockade in the treatment of lower limb spasticity in cerebral palsy: a randomised double-blind placebo controlled trial. J Pediatr Orthop B. 2000;20:108-15. 17. Love S, Valentine J, Blair E, Price C, Cole J, Chauve lP. The effect of botulinum toxin type A on the functional ability of the child with spastic hemiplegia: a randomized controlled trial. Eur J Neurol. 2001;8:50-8. 18. Steenbeek D, Meester-Delver A, Becher J, Lankhorst G. The effect of botulinum toxin type A treatment of the lower extremity on the level of functional abilities in children with cerebral palsy: evaluation with goal attainment scaling. Clin Rehabil. 2005;19:274-82. 19. Linder M, Schindler G, Michaelis U, et al. Medium-term functional benefits in children with cerebral palsy treated with botulinum toxin type A: 1-year follow-up using gross motor function measure. Eur J Neurol. 2001;8:120-6. 20. Heinen F, Linder M, Mall V, Kirschner J, Korinthberg R. Adductor spasticity in children with cerebral palsy and treatment with botulinum toxin type A: the parents view of functional outcome. Eur J Neurol. 1999;6:47-50. 21. Zurcher A, Molenaers G, Desloovere K, Fabry G. Kinematic and kinetic evaluation of the ankle after intramuscular injection of botulinum toxin A in children with cerebral palsy. Acta Orthopædica Belgica. 2001;67:475-80. 22. Sutherland DH, Kaufman KR, Wyatt MP, Chambers HG, Mubarak SJ. Double-blind study of botulinum A toxin injections into the gastrocnemius muscle in patients with cerebral palsy. Gait Posture. 1999;10:1-9. 23. Corry I, Cosgrove A, Duffy C, McNeill S, Taylor T, Graham H. Botulinum Toxin A compared with stretching casts in the treatment of spastic equinus: A randomised prospective trial. J Pediatr Orthop. 1998;18:304-11. 24. Besier T, Sturnieks D, Alderson J, Lloyd D. Repeatability of gait data using a functional hip joint centre and a mean helical knee axis. J Biomech. 2003;36:1159-68. 25. Schwartz M, Rozumalski A. The Gait Deviation Index: a new comprehensive index of gait pathology. Gait Posture. 2008;28:351–7. 26. Engsberg J, Ross SA, Collins D, Sung Park T. Effect of selective dorsal rhizotomy in the treatment of children with cerebral palsy. J Neurosurg. 2006;105:8-15. 117 27. ACSM. Guidlines for exercise testing and prescription. 7th Edition ed. Philadelphia: Lippincot, Williams & Wilkins; 2006. 28. Williams S, Elliott C, Valentine J, Gubbay A, Shipman P, Reid S. Combining strength training and botulinum neurotoxin intervention in children with cerebral palsy: The impact on muscle morphology and strength. Disabil Rehabil. 2012;Accepted for publication. 29. Kenny DA. The two-group design. Statistics for the social and behavioral sciences. Boston: Brown Little; 1987. p. 215. 30. Riad J, Haglund-Akerlind Y, Miller F. Power generation in children with spastic hemiplegic cerebral palsy. Gait Posture. 2008;27:641-7. 31. Eek M, Tranberg R, Zügner R, Alkema K, Beckung E. Muscle strength training to improve gait function in children with cerebral palsy. Dev Med Child Neurol. 2008;50:759- 64. 118 CHAPTER SIX THE COMBINATION OF STRENGTH TRAINING AND BOTULINUM NEUROTOXIN TYPE-A IN CHILDREN WITH CEREBRAL PALSY: THE EFFECT ON ACTIVITY, PARTICIPATION AND QUALITY OF LIFE This manuscript was submitted for publication into the journal, Disability and Rehabilitation, in July 2012. Williams S, Reid S, Valentine J, Blair E, Smith N, Shillington T, Elliott C. The combination of strength training and Botulinum Neurotoxin Type-A in children with Cerebral Palsy: The effect on activity, participation & quality of life. Disabil Rehabil. 2012. In Review The PhD candidate, Sîan A Williams accounted for 80% of the intellectual property associated with the final manuscript. Collectively, the remaining authors contributed 20%. . 119 FOREWORD The previous two papers have demonstrated the combination of BoNT-A and strength training to be effective in improving outcomes at the level of body structure and function of the ICF, over and above BoNT-A therapy in the normal care routine. Chapter four demonstrated increases in muscle strength and reductions in spasticity, with improved attainment of individually set functional goals. This was important in that it reflected the success of our home based strength training (combined with BoNT-A) in the area of body functions and structures being targeted in the intervention. Chapter five continued within the domain of body structures and function, and demonstrated the positive effect of the combined interventions leading to improvements in walking gait. Employing three-dimensional motion analysis, children demonstrated gait profiles closer resembling that of the non-pathological populations’ gait, without increases in the required power generated at the hip, knee and ankle joints. This suggested an improved efficiency of the muscles working to execute gait. The final paper of this thesis investigates whether the positive changes measured in the body structures and function level of the ICF, extends to improvements in other aspects of the ICF, namely in measures of activity, participation and quality of life. 120 6.1 ABSTRACT Aim: To investigate the combined effects of strength training and Botulinum Neurotoxin typeA (BoNT-A) treatment on activity, participation and quality of life (QoL) in children with cerebral palsy (CP). Method: Fifteen children, aged between 5-12 years (mean= 8years 5mo, SD 1yr 10 mo) with spastic diplegic CP, GMFCS I-II, currently receiving BoNT-A for spasticity management took part in the study. Children undertook a 10 week individualised lower limb strength training program, based on the child’s goals. They completed up to 3 sessions weekly, and were assessed four times over 6 months based around their scheduled BoNT-A injections. Hamstring and gastrocnemius muscles were injected with BoNT-A as clinically indicated by goal setting and clinical assessment. Eight of the 15 children took part in a 6month pre-intervention baseline phase which served as a control group. Activity was assessed via the Timed-Up-andGo (TUG) and the Six Minute Walk Test (6MWT), participation was assessed with the Assessment of Life Habits for children (LIFE-H), the Canadian Occupational Performance Measure (COPM) assessed goal attainment across both activity and participation, and the Cerebral Palsy Quality of Life Questionnaire for Children (CP-QoL) measured QoL. Results: The intervention resulted in a significant improvement in the TUG (p=.043, ES=0.55), but no effect on the 6MWT at the level of activity. The LIFE-H indicated increased domains of relationships (p=.043, ES=1.44), nutrition (p=.017, ES=0.44), and education (p=.037, ES=0.16). The COPM showed a clinically significant improvement (a score of 2 or above) in parent rated performance, but not in satisfaction. CP QoL indicated increases in the areas of family health (p=.023, ES=0.30) and emotional well-being and self-esteem (p=.053, ES=0.29). Interpretation: By targeting two primary motor impairments of CP; spasticity and muscular weakness with combined interventions of strength training and Botulinum Toxin Type-A, this study has demonstrated some positive effects at the levels of activity, participation and QoL. In view of reports of decreasing participation and QoL over time for children with CP, these results are encouraging. KEYWORDS: Muscle weakness, Spasticity, Cerebral Palsy, The ICF, Activity, Participation, Quality of Life. 121 6.2 INTRODUCTION In children with cerebral palsy (CP), spasticity and muscular weakness are considered to be two primary impairments related to motor dysfunction1, which, along with increased muscle co-activation and impaired selective motor control, are responsible for disturbed movement patterns in walking and other daily life activities2. Children with CP are also reported to experience a lower quality of life (QoL)3, 4, and it is suggested they are at risk of experiencing participation restrictions5, greater activity limitations and are less physically active then their typically developing peers6-8. The International Classification of Functioning, Disability and Health (ICF) framework9 across dimensions of body function, activity and participation allows for a holistic approach to evaluating current and future treatment options. Understanding the impact of therapeutic interventions on all dimensions of the ICF is imperative for determining the optimal management of the impairments associated with CP. For people with diplegic CP, therapeutic goals are often directed towards improving the ability to walk10. Impairment of walking is significantly associated with reduced participation in most domains of the Assessment of Life Habits (LIFE-H) questionnaire11. Consistent with previous literature12-14, a recent study by Calley and Colleagues (2012)15 reported that compared with typically developing peers, children with CP had difficulties participating in activities across home, school and in the wider community as a result of restrictions in physical functioning and mobility, with concomitant reductions in QoL15. Of particular concern to parents and clinicians is that well-being, a ‘broad notion’ used by researchers that considers QoL16, is generally reported to be lower amongst children with CP16. Therefore QoL, relating to a person’s individual perception or feelings of well-being across a number of domains (e.g. physical, social, emotional, spiritual)17, is an important outcome that needs to be considered in treatment evaluation. Botulinum Neurotoxin Type-A (BoNT-A) is an established and commonly utilised treatment for spasticity management for children with CP18-23 24 with the reported improvements in muscle 24 tone , range of joint motion and functional measures25, 26, 27. However, BoNT-A treatment has a limited effect on daily activities28, and there is little information concerning its effects on participation and QoL. Similarly, little information is available on the effects of strength training on the activity and participation29. Research has confirmed the benefits of strength training in children with CP to improve muscle strength29-31, flexibility, posture and balance32, and has been associated with improvements relating to walking29, 30, 33-36 . Despite this, the effect of strength training programs on mobility, function, or the ability to participate in 122 normal societal roles remain undetermined29, whilst the impact on QoL, to our knowledge, has not yet been subjected to controlled assessment. Consequently there is a call for health care providers to investigate the outcomes of strength and BoNT-A at the ICF levels of activity, participation and QoL. Whilst strength training targets muscular weakness, BoNT-A targets muscle spasticity23. Our previous research has investigated the combined effects of BoNT-A and strength training at the level of impairment, reporting improvements in spasticity, muscle strength, muscle morphology, functional goals31 and three-dimensional outcomes of gait37. However, it is unknown if these benefits at the impairment level translate to improvements in other aspects of the ICF. Therefore, this study aims to investigate the combination of BoNT-A and strength training at the activity, participation and QoL domains of the ICF. Furthermore, we investigated the effects of varying timing of strength training in relation to BoNT-A, administered either before or after the injection. 6.3 METHODS 6.3.1 PARTICIPANTS Ten boys and five girls with spastic diplegic CP, classified as Gross Motor Function Classification System (GMFCS) level I-II were recruited from the Cerebral Palsy Mobility Service (CPMS). All children matching our inclusion criteria (aged 5-12, GMFCS I-II, classified as spastic diplegic CP, free of any history of surgery and cognitively able to follow instructions) were identified and contacted by CPMS to ask if they would like to be contacted about participation in research. Families that responded were then contacted by the researchers, provided information on this study and invited to participate. The fifteen participating children had a mean age of 8years 5mo (SD 1yr 10 mo, range 5-12yrs), an average height of 129.87cm (SD 10.92cm) average weight of 27.97kg (SD 7.43kg) and Body Mass Index of 16.34 (SD 2.4). No child had undergone serial casting in the previous six months and no child had a history of lower limb surgery. Ethical approval for the study was obtained from the Ethics Committee of PMH (# 1766), and from the University of Western Australia. Written consent was obtained from the parents of all the participants. All 15 children were receiving BoNT-A treatment for spasticity management bilaterally in their lower limbs, and had already received a minimum of two series of BoNT-A prior to the injection series included in the study (maximum=15 series, mean=8.93 series). The muscle(s) 123 selected for injection were determined by the child’s physician based on clinical assessment and functional goal setting, the total dose of BoNT-A (Botox®, Allergan, Irvine, CA, USA) was empirically selected for each muscle. All participants received BoNT-A to bilateral medial gastrocnemius' (30 legs injected; 2-6U/kg), and five participants also received BoNT-A to bilateral medial hamstrings (10 legs; 2-4U/kg). Other muscles injected included the soleus (4legs; 1-2U/kg) adductors (2 legs; 1U/Kg), rectus femoris (2 legs; 1U/Kg), and tibialis posterior (1 leg; 1U/Kg). No child had more than three muscles injected per leg. 6.3.2 PROCEDURES The study design, dictated by current clinical care, utilised a repeated measures crosscomparison design with a 6month pre-intervention baseline phase serving as a control period (Figure 1). For the control period, eight children completed a baseline (B) assessment 12 (+/- 2) weeks before their next scheduled BoNT-A injection and continued to receive normal clinical care both before and for 12 weeks after that injection when they were again assessed at Assessment 1 (A1). These eight, together with a further seven children were block randomised by age, gender and GMFCS level into either a PRE or POST BoNT-A strength training group. Children completed four assessments; (A1) timed approximately 12 weeks prior to their scheduled BoNT-A injection, Assessment 2 (A2) approximately 2 weeks prior to their scheduled injection, Assessment 3 (A3) on average 5 weeks (SD 1week, range 3-6weeks) post injection and Assessment 4 (A4) approximately 14 weeks post injection. The PRE strength training group completed strength training in the weeks between A1-A2 and the POST strength training group completed the training between A3-A4 (Figure 1). In the weeks where the children were not allocated strength training, they continued with their normal care routine, without participating in any new activities. BoNT-A Normal Care Routine Normal Care Routine Control Period n=8 W-26 W-12 BoNT-A A2 A3 A1 B A4 PRE strength training Normal Care Routine Normal Care Routine POST strength training Intervention period n=15 W0 W12 W26 Figure 1 Cross-comparison study design, with a pre-intervention baseline assessment (B) for 8 participants forming a control period, and 15 children completing the intervention period. Vertical dashed lines represent the timing of Botulinum Neurotoxin injections. 124 6.3.2.1 ACTIVITY 6.3.2.1.1 FUNCTIONAL MOBILITY The 6-minute Walk Test (6MWT) and the Timed-up-and-Go test (TUG) were used to measure functional walking capacity38 and were selected as common standard assessments for clinical assessment. For the 6MWT, the total distance walked was recorded. Children performed the TUG assessment from an adjustable-height chair in accordance with the test protocol39 (with the fastest of 3 trials being recorded). Both assessments were completed barefoot. Reliability and validity of TUG has been examined in children with physical disabilities, with high levels of test-retest reliability (ICC = 0.83), and shown to be responsive to change39, whilst the 6MWT has been shown as a reliable test for independently ambulant children with CP40. 6.3.2.2 P ARTICIPATION 6.3.2.2.1 THE CANADIAN OCCUPATIONAL PERFORMANCE MEASURE (COPM) The Canadian Occupational Performance Measure (COPM)41 defined individual goals by an experienced occupational therapist. The COPM is based on an interview, which allows individuals to identify goals, based on activities they consider important but find difficult to perform. Goals were both activity and participation based. Participants were then required to rate their performance, and satisfaction with that level of performance for each of their selfselected goals. Both performance and satisfaction are rated on a 1-10 numeric rating scale (1= not able to perform at all, or not satisfied at all, 10= able to perform extremely well, or extremely satisfied). Whilst both the child and parent were interviewed for goal setting only the parent scores were used in the analysis. The COPM scores collected before and after the child’s strength training period are reported. 6.3.2.2.2 THE ASSESSMENT OF LIFE HABITS, CHILD SHORT FORM (THE LIFE-H) Participation was assessed with the Assessment of Life Habits, children short form (LIFE-H)42, which was completed by the parent due to time constraints. The LIFE-H considers the way in which the young person accomplishes their life habits at home, at school and in the wider community. The LIFE-H comprises 62 items grouped into 11 domains covering both daily activities and social roles. One question about sexual relations was omitted as it was not age appropriate for the children in this study. The LIFE-H can be used for children with a variety of disabilities aged between 5–13 years42. It has moderate to high intra and inter-rater reliability (0.78 or higher for 10 out of 11 categories—interpersonal relationships scored an intra-rater correlation coefficient of 0.58) and has been validated for children with CP42. The scoring 125 system scores participation as lower not only if the child has greater difficulty in participation but also if more assistance is needed. 6.3.2.3 QUALITY OF LIFE 6.3.2.3.1 CEREBRAL PALSY QUALITY OF LIFE QUESTIONNAIRE FOR CHILDREN (CP QoL-CHILD) Quality of life was measured with the parent proxy version of the Cerebral Palsy Quality of Life Questionnaire for Children (CP QoL-Child)43, suitable for children aged 4 to 12 years. The CP QoL-Child assesses seven domains of QoL including social well-being and acceptance, feelings about functioning, participation, and physical health, emotional well-being, access to services, pain and feeling about disability and family health. This tool is considered to be psychometrically sound44, and a recent review of the QoL measures for children with CP, found the CP QoL-Child to be one of the strongest measures of QoL in children with CP and the only one to wholly fulfil the definitional criteria of QoL45. Both the LIFE-H and the CP-QoL questionnaires were completed by the same parent at each assessment time point. 6.3.3 TRAINING PROGRAM Participants completed a home based strength training programme, training three times a week for 10 weeks (completing a minimum of 20 sessions). Programme coordination and progression was conducted fortnightly by a visiting exercise physiologist, with the remaining training sessions conducted by a trained family member. Each training session included manual and passive stretching of the lower limb muscle groups. The design of the strength program was based on the child’s initial strength assessment and the functional goals. The program initially focused on motor control; with manual resistance and the use of a thera-band(s), then establishing base strength with ankle weights, increasing first the number of repetitions and then loads. During the 10 weeks of the training, the program progressed to more complex movements and functional tasks reflecting the child’s goals (e.g. running, stepping up kerbs, kicking a ball etc.). Participants were requested not to take up any new activities but to maintain, and record, their usual therapy program throughout the study. 6.3.4 STATISTICAL ANALYSIS Analysis A: To estimate the effect of strength training with respect to BoNT-A injection, the mean and 95% confidence interval of within subject change of each outcome score over the control period (B to A1) was compared with changes for the same eight subjects over the 126 intervention period (A1 to A4). Statistical significance was assessed with a 2-tailed t-test, and considered statistically significant if p<0.05. Analysis B: To estimate whether the timing of the strength training was important, the mean of within subject change of each score over the strength training period for those in the PRE group (A1-A2) was compared with those of the POST group (A3-A4). Similarly, mean within subject changes were also calculated over the entire intervention period for both groups (A1A4). Effect sizes were determined using Cohen’s d equation46. 6.4 RESULTS 6.4.1 ANALYSIS A: CONTROL AND INTERVENTION GROUP, INDEPENDENT OF TIMING (N=8 CHILDREN) 6.4.1.1. ACTIVITY 6.4.1.1.1 FUNCTIONAL MOBILITY (TUG, 6MWT) Children completing the control period had no statistically significant changes in TUG or 6MWT over the control period (Table 1), however the same group of children were significantly faster in performing the TUG (t(7)=2.464, p=.043, ES=0.55) after the intervention period, with an average within subject improvement of 0.54sec (SE 0.22). 6.4.1.2 PARTICIPATION 6.4.1.2.1 THE ASSESSMENT OF LIFE HABITS (THE LIFE-H) Over the control period there was no statistical significance change in levels of participation (Table 1). Over the intervention period, changes in levels of participation were more likely to be positive (6 domains) than in the control period, with improvements reaching statistical significance in the domains of nutrition (t(6)=-3.283, p=.017, ES=0.44), relationships (t(6)=2.550, p=.043, ES=1.44) and education (t(6)=-2.669, p=.037, ES=0.16), albeit with a small effect size. 6.4.1.3 QUALITY OF LIFE 6.4.1.3.1 CEREBRAL PALSY QUALITY OF LIFE QUESTIONNAIRE FOR CHILDREN (CP QoL-CHILD) Children showed no statistically significant change in QoL over the control period. Over the intervention period the average within subject change of 5.47 (SE 1.75) was statistically significant with respect to QoL in family health (t(6)=-3.041, p=.023, ES=0.30). For emotional well-being and self-esteem the average within subject change of 4.17 (SE 2.84) approached statistical significance but with a small effect size (t(6)=-2.397, p=.053, ES=0.29). 127 Table 1 Mean within-subject change of scores for outcome measures of activity, participation and QoL for the control and intervention period (n=8). *Significance at p<.05. # Approaching significance at p<.06. ICF level Outcome measure Mean within subject change (SE) Control Intervention TUG (sec) 0.18 (0.27) -0.54 (0.22)* 6MWT distance (m) 10.64(14.01) 12.29 (16.44) Nutrition 0.31 (0.22) 0.79 (0.38)* Fitness -0.07 (0.33) 0.60 (0.74) Personal care -0.07 (0.40) 0.55 (0.70) Mobility 0.76 (0.25) 0.52 (0.39) Responsibilities 0.38 (1.12) -0.08 (1.19) Relationships -0.61 (0.27) 0.77 (0.30)* Education -0.46 (0.56) 0.42 (0.26)* Recreation -0.41(0.45) -0.23(0.17) Social well-being and acceptance 0.00 (1.77) 1.28 (2.01) Functioning -0.84 (1.14) -0.12 (1.54) Participation & physical health 3.98 (2.34) -3.27 (2.39) Emotional well being & self esteem -3.39 (2.23) 4.17 (2.84) Access to services -6.45 (4.64) 5.60 (3.52) Pain & disability 9.07 (5.75) -0.08 (5.19) Family health -0.39 (3.89) 5.47 (1.75)* Activity Participation (LIFE-H) QoL (CP-QoL) # 6.4.2 ANALYSIS B: INTERVENTION GROUP (N=15 CHILDREN), WITH TIMING OF TRAINING CONSIDERED. 6.4.2.1 ACTIVITY 6.4.2.1.1 FUNCTIONAL MOBILITY (TUG, 6MWT) The PRE group had a statistically significant decrease of 0.42 sec (SE 0.13) in TUG time following (A1-A2) 10 weeks of strength training (t(6)=3.251, p=.017, ES=0.45). The POST group significantly decreased in TUG time by an average change of 0.62sec (SE 0.17) over 10 weeks of strength training (A3-A4), (t(7)=3.579, p=.009, ES=0.81) (Table 2). 128 Over the 6 month intervention period (A1-A4), there was a significant decrease in TUG time for all 15 children, with an average within subject decrease of 0.59sec (SE 0.13) (t(14)=4.623, p<.001, ES=0.68). Both the PRE (t(6)=3.208, p=.018, ES=0.56) and POST (t(7)=3.123, p=.017, ES=0.80) group performed the TUG significantly faster over the 6months (PRE: 0.58sec, SE 0.18, POST: 0.59sec, SE 0.19) (Table 2). There were no significant changes made in distance covered in the 6MWT for either group over the entire 6month intervention period (p>.05). However, over the 10weeks of strength training, the increase in the distance covered by the PRE group approached statistical significance, mean=46.86m, (t(6)=-2.828, p=.060, ES=0.63), and the POST group, mean=37.79m (t(7)=-2.687, p=.031, ES=0.35) reached statistical significance (Table 2). 6.4.2.2 PARTICIPATION 6.4.2.2.1 THE CANADIAN OCCUPATIONAL PERFORMANCE MEASURE (COPM) A change of two points or more on the COPM is considered clinically significant41. A total of 16 goals were set by the children participating in the PRE group, of these, 11 (69%) had a clinically significant improvement in the parent score for satisfaction and 13 (81%) demonstrated a clinically significant improvement in the parents score for performance. As a group the PRE group displayed a mean within subject change of 2.17 and 2.61 for performance and satisfaction respectively. In the POST group a total of 15 goals were set; of these 11 (73%) showed a clinically significant improvement in satisfaction and 8 (53%) demonstrated a clinically significant improvement in performance. As a group, the POST group displayed a mean change of 1.64 and 1.50 for satisfaction and performance. The COPM scores for the entire cohort grouped together increased by 1.90 for the parent score of satisfaction, and 2.05 for the parent score of performance. 6.4.2.2.2. THE ASSESSMENT OF LIFE HABITS (THE LIFE-H) Neither the PRE or POST group showed significant changes in level of participation either over 10 weeks or over 6 months across the domains of the LIFE-H (p>.05). Nor were significant changes evident for the entire cohort over the 6months of the study on the LIFE-H (Table 2). 129 Table 2 Mean within-subject changes for outcome measures of Activity, Participation and QoL, with changes shown over the 10 weeks of strength training and 6 months.*Significance at p<.05, #Approaching significance at p<.06. ICF Level Outcome measure TUG (sec) Activity 6MWT (m) Nutrition Fitness Personal care Mobility Participation (LIFE-H) Responsibilities Relationships Education Recreation Social well-being and acceptance Functioning Participation & physical health QoL (CP-QoL) Emotional well being & self esteem Access to services Pain & disability Family health Group PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All PRE POST All Initial score (SE) 4.71 (0.38) 4.91 (0.23) 4.82 (0.21) 537.03 (31.16) 493.35 (26.32) 515.33 (20.66) 6.19 (1.12) 7.87 (0.73) 7.09 (0.67) 8.33 (0.71) 9.06 (0.27) 8.72 (0.36) 6.33 (1.03) 7.57 (0.51) 6.99 (0.56) 7.64 (0.96) 7.34 (0.87) 7.50 (0.63) 6.65 (1.21) 7.66 (0.68) 7.19 (0.66) 9.10 (0.33) 8.64 (0.70) 8.85 (0.40) 5.83 (0.99) 8.19 (0.64) 7.09 (0.64) 6.49 (1.28) 8.13 (1.11) 7.37 (0.84) 83.28 (11.06) 86.79 (4.18) 85.15 (2.63) 77.90 (4.16) 87.26 (4.66) 82.89 (3.29) 74.35 (4.72) 81.53 (4.37) 78.18 (3.24) 77.02 (3.52) 88.80 (3.92) 83.31 (3.56) 69.97 (7.58) 82.19 (2.86) 76.48 (4.04) 38.07 (8.10) 20.20 (4.09) 28.54 (4.82) 67.86 (6.71) 84.38 (4.92) 71.04 (4.61) Change after 10weeks (SE) -0.42 (0.13)* -0.62 (0.17)* # 46.86 (20.53) 37.79 (11.83)* 1.90 (0.66) 0.01 (0.49) 0.32 (0.63) -0.56 (0.45) 0.24 (0.69) 0.00 (0.27) 0.16 (0.46) 1.43 (0.73) -0.77 (0.83) -0.91 (0.85) 0.52 (0.28) -0.13 (0.08) 0.84 (0.62) -0.32 (0.16) 0.19 (0.35) 1.02 (0.40) 2.60 (2.96) -1.38 (2.86) 5.90 (1.67)* -0.46 (1.49) 4.38 (3.18) -1.58 (2.74) 4.76 (5.61) -2.08 (2.43) 8.15 (3.07)* -10.98 (10.91) -7.05 (4.21) -2.15 (3.10) 4.76 (6.13) 2.73 (3.20) Change after 6months (SE) -0.58 (0.18)* -0.59 (0.19)* -0.59 (0.13)* 32.44 (32.26) 56.09 (34.20) 45.05 (23.02) 1.98 (0.60) 0.34 (1.08) 1.16 (0.64) 0.63 (0.82) 0.16 (0.41) 0.40 (0.44) 0.66 (0.69) -0.25 (0.53) 0.20 (0.44) 0.20 (0.16) 2.06 (0.93) 1.13 (0.52) 0.60 (1.37) 0.59 (0.77) 0.59 (0.75) 0.79 (0.31) 1.36 (0.82) 1.07 (0.43) 1.42 (0.53) 0.58 (0.40) 1.00 (0.34) 0.85 (0.55) 1.93 (1.22) 1.39 (0.66) 5.19 (2.99) -3.41 (3.35) 0.61 (2.47) 3.83 (2.38) -2.67 (1.39) 0.32 (1.56) 3.57 (3.56) -1.99 (2.51) 0.61 (2.18) 9.29 (3.87)# -1.30 (4.90) 3.64 (3.38) 0.86 (4.05) -12.39 (9.28) -6.20 (5.42) -3.25 (4.70) -0.86 (4.42) -1.98 (3.12) 6.70 (2.20)* 16.41 (12.07) 11.88 (6.44) 130 6.4.2.3 QUALITY OF LIFE 6.4.2.3.1 CEREBRAL PALSY QUALITY OF LIFE QUESTIONNAIRE FOR CHILDREN (CP QoL-CHILD) Children in the PRE group had significant within subject increases of 5.90 (SE 1.67) in functioning (t(6)=-3.525, p=.012, ES=0.51) and of 8.15 (SE 3.07) (t(6)=-2.655, p=.038, ES=0.41) in access to services over the 10 weeks of strength training (A1-A2) (Table 2). When assessed over 6 months, the PRE group showed a significant increase in score of 6.70 (SE 2.20) in family health (t(6)=-3.041, p=.023, ES=0.42) and the increase in emotional well-being and self-esteem of 9.29 (SE 3.87), (t(6)=-2.397, p=.053, ES=0.70) approached statistical significance. The POST group showed no significant changes in QoL over the course of the study (p>.05) (Table 2). As a whole, the 15 children in the intervention group showed no significant changes in within subject changes QoL over the intervention period p>.05) (Table 2) 6.5 DISCUSSION This study combined two commonly used treatment interventions, BoNT-A and strength training, to target two primary motor impairments of CP; spasticity, and muscular weakness 1. Previously published work from this project successfully demonstrated a simultaneous decrease in spasticity and increases in muscle strength, which had associations with improved performance in functional goals31 and gait37. However, a comprehensive treatment approach needs to consider all levels of functioning, not just target impairments. This study found children with CP showed some improvements in the activity, participation and QoL domains of the ICF after treating both spasticity and muscle weakness at the impairment level. There was no change in the TUG times for (eight) participants over the 6month control phase, but during the intervention period there were significant improvements seen immediately after 10 weeks (of strength training) and over 6 months. Separately, BoNT-A injections and strength training have each been shown to result in improvements in the TUG47, 48 within the adult population. A potential mechanism for BoNT-A could be reduced co-activation patterns48, whilst the strength training may have increased muscle size31, 49, and improved inter-muscle coordination50. The TUG test measures components of the ICF; including the ability to change and maintain body position and walking51, changes in TUG scores may reflect alterations in muscle strength. The 6MWT, which reflects functional endurance, however was 131 not altered by the addition of strength training. Thus, our strength training intervention improved coordination, maintenance of body position and walking initiation but did not affect functional endurance capacity. Future strength training interventions perhaps should endeavour to include components of fitness and endurance to increase walking endurance. The LIFE-H assessment of participation in daily and social activities, demonstrated no significant changes in participation following the combined intervention when all fifteen children in the study were considered. However, it should be noted that for the eight children who also participated in a control period, levels of participation were more likely to be positive after the intervention, and were significantly improved in the domains of nutrition, education and (most notably) relationships. Being a home based strength intervention whereby the parents were responsible for assisting and supervising at least one (more commonly two) of the three sessions each week, it could be suggested that the additional interaction between the parents and the child played a role in the increases seen in the relationship domain of participation. This was an unplanned but positive secondary outcome of the intervention program, however this result should be viewed with caution as the ‘relationships’ category of the LIFE-H is reported to have a lower intra–rater reliability (0.58) than other categories of the LIFE-H. As for improvements in participation within the domains of nutrition and education, perhaps by participating in the strength training there was an increased awareness of the child’s capabilities or even an increased encouragement for participation in these areas from the parent after first completing the questionnaire. These reasons are more likely to explain perceived improvements rather than the actual intervention itself. The results from the COPM indicated a clinically significant improvement in performance of goals as perceived by the parent, and a trend for improvement in scores for satisfaction. The measurement of satisfaction is possibly confounded by the parent’s expectations and their level of comparison with the typically developing population, and there may also be an element of a ceiling effect. Few intervention studies have looked at participation as an outcome, and those that have, have used different measures of participation. Looking at the effect of BoNT-A alone, Bjornson et al., (2007), reported no effect as measured by COPM satisfaction scores and the Goal Attainment Scale52. Two studies looking at the effect of exercise programs have reported increases in participation (as measured by a semi structured interview, and The Children’s Assessment of Participation and Enjoyment)32, 53. Changes measured in the group completing both control and intervention periods (n=8) agree with the exercise program literature. However, the results of all 15 children in the study are conflicting, with no significant changes shown over the intervention period. This may be a chance effect due to the small sample size. Or perhaps the parents of the control-intervention group perceived better results after being 132 involved in the study for longer period before receiving strength training. Research with larger sample sizes would be beneficial in producing greater statistical power and confidence in interpreting changes. A limitation of this study was the use of the LIFE-H instrument to measure participation as it does not capture frequency of participation; a measure including frequency would have provided greater detail and may be more sensitive to change. This study supports the inclusion of a participation measurement for intervention outcome; however it also highlights the need for more precise measures of participation in the CP population. As with participation, there is little research pertaining to the effect of either BoNT-A or strength training on QoL. Whilst one study found no effect of BoNT-A injections on QoL54 (using the Pediatric Quality of Life Inventory), a number of studies have indicated a positive impact of strength training on QoL in children with CP36, 53,55 (as measured by the Pediatric Quality of Life Inventory, the Children’s Health-Related Quality of Life, the Pediatric Outcomes Data Collection Instrument and the Child Caregiver Questionnaire). That being said, these results are difficult to compare with the present study as different measures of QoL were used, and were not condition specific. Tsoi et al., (2012)56 suggested that if improvements in QoL are to be expected in the management of CP, there is a need for comprehensive treatment approaches. In this study, QoL improvements were indicated in domains of family health, and emotional well-being and self esteem after the intervention that were not seen in the control period. The increase in time that the child and parent spent together, as necessitated by the nature of the intervention, may be accountable for the improved QoL for family health and perhaps even in the improved emotional well-being and self esteem. The latter may also be attributed to the positive changes occurring at the level of impairment, possibly leading to improvements in functional ability. This is an especially interesting outcome, with previous research reporting children with CP experience a lower QoL across all domains, in particular physical and emotional wellbeing3, 4. Whilst this study did not result in improvements in the participation and physical health domains of the CP-QoL, the intervention implemented in this study was targeted at the impairment level, and not at participation or QoL. Whilst we do report (limited) positive effects on participation and QoL, future research should investigate implementing additional interventions directly targeting the participation and QoL. A limitation of this study was that the children themselves did not complete the CP-QoL, LIFE-H or score the COPM. However, lengthy questionnaires were inappropriate for children as young as five. Despite these limitations, these results are positive, and demonstrate potential for combining treatment modalities for improving participation and QoL for children with CP. 133 The majority of outcome measures did not differ by the timing of strength training with respect to BoNT-A. The exceptions were the perceived level of performance of and satisfaction with clinical goals, as assessed by the COPM, and the domains of family health and emotional well-being and self esteem from the CP-QoL, which all favoured the PRE group. In contrast to the PRE group, the POST group did not show any clinical improvements in either satisfaction or performance with defined COPM goals over the strength training period. The assessment of the COPM after BoNT-A for the POST group, may have modified parental perception; the parents scored the child higher to begin with because they felt the BoNT-A was in effect (therefore there was less room for improvement for these children). In terms of the PRE group’s superior performance in the CP-QoL, it is suggested that participating in strength training prior to the injection of BoNT-A allowed the participants parents’ more time for reflection of the changes made from the intervention, comparative to the POST group. A follow up assessment may have confirmed or refuted this reasoning. The results of this study are limited by our small sample size, and it should be noted that this study included a group of highly motivated and proactive families; to enrol in such an extensive study in the first place is reflective of this. It is likely that within such a family, outcomes such as participation may already be higher than in children of those families who declined involvement in this study. Comparisons of our sample of CP children to typically developing (TD) children were not formally performed, however previous research in a similar population of children with CP (GMFCS I-II) has reported this, and found children with CP to generally experience lower QoL in domains such as social well-being and acceptance, emotional wellbeing and self esteem and family health, and were statistically lower with respect to functioning and participation and physical health15. This was similar to levels of participation, with generally lower levels of participation compared to a TD population across most domains of the LIFE-H15. This tells us that relatively high functioning children with CP (as reflected by their GMFCS level) still require attention for improvements in these aspects of functioning. 6.6 CONCLUSION The combination of BoNT-A and strength training provided a comprehensive treatment targeting two key impairments of CP. This study made a holistic investigation of the impact of combined interventions on the activity, participation and QoL domains of the ICF. A positive effect on activity, as assessed by the TUG was observed, however no effect was observed on the 6MWT. Some improvements were observed in participation, measured by the LIFE-H, in 134 the areas of nutrition, education and relationships, whilst QoL improved in the areas of family health and emotional well-being and self esteem (assessed by the CP-QoL). The COPM indicated a clinically significant improvement in performance of functional goals. It is suggested that these positive results are a consequence of both reducing impairments (spasticity and muscle weakness), and increasing the time the parent spent with their child. This study supports the use of a multidimensional assessment of treatment interventions. Future research should continue to develop more effective measurement outcomes particularly for participation, and endeavour to consider assessments at all levels of the ICF to determine optimal treatment planning. 6.7 ACKNOWLEDGEMENTS This project was supported by Princess Margaret Hospital (PMH) Foundation Grant. The authors would like to thank the Department of Paediatric Rehabilitation, PMH for their support and assistance with recruitment. Authors would also like to acknowledge the contribution of the School of Sport Science, Exercise & Health at UWA for the use of equipment and facilities. Sincere thanks go to the children and families who volunteered to participate in this study. 135 6.8 REFERENCES 1. Wiley ME, Damiano DL. Lower-Extremity strength profiles in spastic cerebral palsy. Dev Med Child Neurol. 1998;40:100-7. 2. Morris C. Definition and classification of cerebral palsy: a historical perspective. Dev Med Child Neurol. 2007;109:3-7. 3. Liptak GS, O’Donnell M, Conaway M, et al. Health status of children with moderate to severe cerebral palsy. Dev Med Child Neurol. 2001;43:364-70. 4. Dickinson H, Parkinson K, Ravens-Sieberer U, et al. Self-reported quality of life of 8–12 year-old children with cerebral palsy: a cross-sectional European study. Lancet. 2007;369:2171–8. 5. Shelly A, Davis E, Waters E, et al. The relationship between quality of life and functioning for children with cerebral palsy. Dev Med Child Neurol. 2008;50:199-203. 6. Maher C, Williams M, Olds T, Lane A. Physical and sedentary activity in adolescents with cerebral palsy. Dev Med Child Neurol. 2007;49:450-7. 7. Bjornson K, Belza B, Kartin D, Logsdon R, McLaughlin J. Self-reported health status and quality of life in youth with cerebral palsy and typically developing youth. Arch Phys Med Rehab. 2008;89:121-7. 8. Van Zelst B, Miller M, Russo R, Murchland S, Crotty M. Activities of daily living in children with hemiplegic cerebral palsy: a cross- sectional evaluation using the assessment of motor and process skills. Dev Med Child Neurol. 2006;48:723-7. 9. WHO. International Classification of Functioning, Disability and Health: Introduction. Geneva: WHO; 2001 [cited 2006 January]. 10. Shepherd R. Cerebral palsy. In: Shepherd R, editor. Physiotherapy in paediatrics. Oxford: Butterworth-Heinemann; 1995. p. 110-4. 11. Fauconnier J, Dickinson H, Beckung E, et al. Participation in life situations of 8-12 year old children with cerebral palsy: cross sectional European study. BMJ. 2009;338:b1458. 12. Tuzun E, Eker L, Daskapan A. An assessment of the impact of cerebral palsy on children's quality of life. WFizyoterapi Rehabilitasyon 2004;15:3-8. 13. Vargus-Adams J. Health-related quality of life in childhood cerebral palsy. Arch Phys Med Rehab. 2005;86:940-5. 14. Varni J, Burwinkle T, Sherman S, et al. Health related quality of life of children and adolescents with cerebral palsy: Hearing the voices of the children. Dev Med Child Neurol. 2005;47:592-7. 136 15. Calley A, Williams S, Reid S, et al. A Comparison of activity, participation and quality of life in children with and without spastic diplegia cerebral palsy. Disabil Rehabil. 2012;34:130610. 16. Livingston M, Rosenbaum P, Russell D, Palisano R. Quality of life among adolescents with cerebral palsy: what does the literature tell us? Dev Med Child Neurol. 2007;49:225-31. 17. Bjornson K, McLaughlin J. The measurement of health related quality of life (HRQL) in children with cerebral palsy. Eur J Neurol. 2001;8:183-93. 18. Boyd RN, Graham HK. Objective measurement of clinical findings in the use of botulinum toxin type A for the management of children with cerebral palsy. Eur J Neurol. 1999;6:23-35. 19. Jefferson RJ. Botulinum toxin in the management of cerebral palsy. Dev Med Child Neurol. 2004;46:491-9. 20. Carr L, Cosgrove A, Gringras P, Neville B. Position paper on the use of botulinum toxin in cerebral palsy. UK Botulinum Toxin and Cerebral Palsy Working Party. Arch Dis Child 1998;79:271-3. 21. Graham H, Aoki K, Autti-Ramo I, et al. Recommendations for the use of botulinum toxin type A in the management of cerebral palsy. Gait Posture. 2000;11:67-79. 22. Morton RE, Hankinson J, Nicholson J. Botulinum toxin for cerebral palsy; where are we now? Arch Dis Child. 2004;89:1133-7. 23. Love S, Novak I, Kentish M, et al. Botulinum toxin assessment, intervention and after- care for lower limb spasticity in children with cerebral palsy: international consensus statement. Eur J Neurol. 2010;17:9-37. 24. Koman L, Mooney J, Smith B, Walker F, Leon J. Botulinum toxin type A neuromuscular blockade in the treatment of lower limb spasticity in cerebral palsy: a randomised double-blind placebo controlled trial. J Pediatr Orthop B. 2000;20:108-15. 25. Steenbeek D, Meester-Delver A, Becher J, Lankhorst G. The effect of botulinum toxin type A treatment of the lower extremity on the level of functional abilities in children with cerebral palsy: evaluation with goal attainment scaling. Clin Rehabil. 2005;19:274-82. 26. Linder M, Schindler G, Michaelis U, et al. Medium-term functional benefits in children with cerebral palsy treated with botulinum toxin type A: 1-year follow-up using gross motor function measure. Eur J Neurol. 2001;8:120-6. 27. Heinen F, Linder M, Mall V, Kirschner J, Korinthberg R. Adductor spasticity in children with cerebral palsy and treatment with botulinum toxin type A: the parents view of functional outcome. Eur J Neurol. 1999;6:47-50. 28. Boyd R, Hays R. Current evidence for the use of botulinum toxin type A in the management of children with cerebral palsy. Eur J Neurol. 2001;8:1-20. 137 29. Dodd K, Taylor N, Damiano D. A systematic review of the effectiveness of strength- training programs for people with cerebral palsy. Arch Phys Med Rehabil. 2002;83:1157-64. 30. MacPhail A, Kramer J. Effect of isokinetic strength training on functional ability and walking efficiency in adolescents with cerebral palsy. Dev Med Child Neurol. 1995;37:763-75. 31. Williams S, Elliott C, Valentine J, Gubbay A, Shipman P, Reid S. Combining strength training and botulinum neurotoxin intervention in children with cerebral palsy: The impact on muscle morphology and strength. Disabil Rehabil. 2012;Accepted for publication. 32. McBurney H, Taylor N, Dodd K, Graham H. A qualitative analysis of the benefits of strength training for young people with cerebral palsy. Dev Med Child Neurol. 2003;45:658–63. 33. Damiano D, Abel M. Functional outcomes of strength training in spastic cerebral palsy. Arch Phys Med Rehabil. 1998;79:119-25. 34. Damiano D, Kelly L, Vaughan C. Effects of quadriceps femoris muscle strengthening on crouch gait in children with spastic diplegia. Phys Ther. 1995;75:658-67. 35. Unger M, Faure M, Frieg A. Strength training in adolescent learners with cerebral palsy: a randomized controlled trial. Clin Rehabil. 2006;20:469-77. 36. Engsberg J, Ross S, Collins D. Increasing ankle strength to improve gait and function in children with cerebral palsy: a pilot study. Pediatr Phys Ther. 2006;18:266-75. 37. Williams S, Elliott C, Valentine J, Blair E, Reid S. Improving the gait of children with Cerebral Palsy using the combined interventions of strength training and Botulinum Neurotoxin Type-A. Unpublished observations. 2012. 38. American Thoracic Society. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111-7. 39. Williams E, Carroll S, Reddihough D, Phillips B, Galea M. Investigation of the Timed ‘Up & Go’ Test in children. Dev Med Child Neurol. 2005;47:518-24. 40. Maher C, Williams M, Olds T. The six-minute walk test for children with cerebral palsy. Int J Rehabil Res. 2008;31:185-8. 41. Law M, Baptise S, Carswell A, McColl M, Polatajko H, Pollock N. Canadian Occupational Performance Measure. Third ed. Ottawa: CAOT Publications ACE; 1998. 42. Noreau L, Lepage C, Boissiere L, et al. Measuring participation in children with disabilities using the assessment of life habits. Dev Med Child Neurol. 2007;49:666-71. 43. Waters E, Davis E, Boyd R, et al. Cerebral Palsy Quality of Life Questionnaire for Children (CP QOL-Child) Manual. Melbourne: Deakin University2006. 44. Waters E, Davis E, Mackinnon A, et al. Psychometric properties of the quality of life questionnaire for children with CP. Dev Med Child Neurol. 2007;49:49-55. 138 45. Carlon S, Shields N, Yong K, Gilmore R, Sakzewski L, Boyd R. A systematic review of the psychometric properties of Quality of Life measures for school aged children with cerebral palsy. BMC Pediatrics. 2010;10:81. 46. Kenny DA. The two-group design. Statistics for the social and behavioral sciences. Boston: Brown Little; 1987. p. 215. 47. Maanum G, Jahnsen R, Stanghelle J, Sandvik L, Keller A. Effects of Botulinum toxin A in ambulant adults with spastic cerebral palsy: A randomized double-blind placebo controlled trial. J Rehabil Med. 2011;43:338-47. 48. Andersson C, Grooten W, Hellsten M, Kaping K, Mattsson E. Adults with cerebral palsy: walking ability after progressive strength training. Dev Med Child Neurol. 2003;45:220-8. 49. McNee AE, Gough M, Morrissey MC, Shortland AP. Increase in muscle volume after plantarflexor strength training in children with spastic cerebral palsy. Dev Med Child Neurol. 2009:1-7. 50. Ozmun J, Mikesky A, Surburg P. Neuromuscular adaptations following prepubescent strength training. Med Sci Sports Exerc. 1994;26:510-4. 51. WHO. International classification of functioning, disability and health. Geneva: World Health Organisation; 2001. 52. Bjornson K, Hays R, Graubert C, et al. Botulinum toxin for spasticity in children with cerebral palsy: A comprehensive evaluation. Pediatrics. 2007;120:49-58. 53. Verschuren O, Ketelaar M, Gorter J, Helders PJM, Uitervaal CSPM, Takken T. Exercise training program in children and adolescents with cerebral palsy. A randomised controlled trial. Arch Pediatr Adolesc Med. 2007;161:1075-81. 54. Russo R, Crotty M, Miller M, Murchland S, Flett P, Haan E. Upper-limb botulinum toxin A injection and occupational therapy in children with hemiplegic cerebral palsy identified from a population register: a single-blinded, randomized, controlled trial. Pediatrics. 2007;119:114958. 55. Coutinho dos Santos LH, Bufara Rodrigues DC, Simoes de Assis TR, Bruck I. Effective results with botulinum toxin in cerebral palsy. Pediatr Neurol. 2011;44. 56. Tsoi WSE, Zhang LA, Wang WY, Tsang KL, Lo SK. Improving quality of life of children with cerebral palsy: a systematic review of clinical trials. Child Care Health Dev. 2012;38:21-31. 139 CHAPTER SEVEN SYNTHESIS OF RESULTS AND CONCLUSION 7.1 SUMMARY Cerebral Palsy (CP) is one of the most common childhood physical disabilities in the world1. With no known cure, the aim of many current treatment modalities is to manage outward expressions of the disorder2. For most children with CP, the associated motor impairments affect many aspects of the child’s life, and many different management strategies are required. Spasticity and muscular weakness are two major motor impairments associated with CP3, both receiving substantial attention throughout the literature. Botulinum Neurotoxin Type-A (BoNT-A) is a commonly used treatment for spasticity management, whilst strength training is shown to be an effective therapeutic option for targeting muscle weakness4-8. Whilst a number of studies have advocated a multifaceted approach to spasticity reduction and specific muscle strengthening in the management of children with CP9, 10, apart from one recent pilot study11, no research has formally combined BoNT-A therapy and strength training in multiple muscles of the lower limb in children with CP. The International Classification of Functioning Disability and Health (ICF)12 is a theoretical classification framework, devised by the World Health Organisation, that incorporates all aspects of functioning, and captures the breadth of difficulties experienced by those with CP13. The ICF promotes a broad application of outcome measures to ensure interventions and rehabilitation programs are being evaluated, not only at the level of the organ system (impairments), but also at the individual (activity limitations) and societal levels (participation restrictions)14. Therefore to provide a comprehensive evaluation of the combination of lower limb strength training in children with CP receiving BoNT-A injections, the use of the ICF is of great relevance. Therefore this research aimed to evaluate the effects at all levels of the ICF of a home based, goal directed, and individualised strength training program combined with BoNT-A injections for spasticity management for children with CP. Specific outcome measures include muscle strength, spasticity, muscle morphology, gait, activity, participation, quality of life, and the attainment of functional goals. A secondary aim of this study was to determine the best practice in terms of timing of a strength training intervention in relation to reception of BoNT-A for children with CP. Specifically to establish whether outcomes are most improved 140 if training is undertaken in the weeks preceding the BoNT-A injection, or in the weeks after the injection. The research questions outlined above were addressed using four interrelated studies. This chapter will summarise the findings of each of these studies with respect to the hypotheses developed in Chapter One, draw conclusions based on the results of each of these studies, and make recommendations for clinical implications and future research. 7.1.1 CHAPTER THREE MORPHOLOGICAL ALTERATIONS IN SPASTIC MUSCLES IMMEDIATELY FOLLOWING BOTULINUM NEUROTOXIN TYPE-A TREATMENT IN CHILDREN WITH CEREBRAL PALSY. Children with CP have a good functional response following BoNT-A treatment15-17, however there is evidence for an atrophic effect of BoNT-A documented in typically developing muscles in human18 and animal19, 20 research. To the authors’ knowledge, this change in muscle size has not yet been investigated in pathological muscles. Chapter Three aimed to provide the first known documentation of the morphologic alterations of spastic muscles in response to BoNTA. To report the comprehensive effect of the neurotoxin, we also aimed to investigate the morphologic response in synergist and antagonist muscle to BoNT-A treatment in spastic muscle, and finally, we aimed to increase understanding of the effect of BoNT-A treatment on muscle strength in children with CP. The first hypothesis that; ‘Muscles injected with BoNT-A will undergo a reduction in muscle volume’ is supported. The injected gastrocnemius muscles showed an average of 4.5% atrophy, a statistically significant decrease in the 15 children in the study. For five children receiving BoNT-A into the medial hamstrings, there was an average decrease of 5.9% in muscle volume, however this did not reach statistical significance. Interestingly, the synergist for the gastrocnemius muscle, the soleus, displayed statistically significant increase in muscle volume of almost 4%, which appeared to compensate for the atrophy of the gastrocnemius, to result in no change in the entire plantar flexor muscle group volume (the sum of the gastrocnemius and soleus muscle volume). There was no change in muscle size of the antagonist muscles. 141 The second hypothesis that; ‘BoNT-A induced muscle atrophy would also result in a reduced force generating capacity’ was partially supported. Measures of gastrocnemius atrophy were not concurrent with a reduction in our measure of plantar flexor muscle strength, however i) as already stated, whole plantar flexor muscle volume did not change, and ii) the use of the hand-held dynamometer to measure for plantar flexor strength may have provided insufficiently reliable results. Isokinetic knee flexor strength did demonstrate a significant reduction in torque generation, it is suggested that this may have been a result of the gastrocnemius contribution in knee flexion, which would in fact support our hypothesis. In the group of five children who had both the gastrocnemius and medial hamstring muscle targeted for injection, there were decreases in torque generation; however the decrease was not sufficiently large to attain statistical significance. To the knowledge of the authors, this was the first study to report upon the immediate morphological, and strength alterations in spastic muscles following BoNT-A treatment. The atrophy measured in our sample of children with CP was not as large as that reported in animal and healthy muscle research. However it must be noted that this was not the muscles first response to BoNT-A, as children had already received a minimum of two series of BoNT-A prior to the study. Whilst strength deficits were not seen following a single site injection in this study, and there were no detrimental effects on the children’s functional performance, attention should be paid to muscle alterations of children undergoing treatment to several sites on multiple occasions. 7.1.2 CHAPTER FOUR COMBINING STRENGTH TRAINING AND BOTULINUM NEUROTOXIN TYPE-A INTERVENTION IN CHILDREN WITH CEREBRAL PALSY: THE IMPACT ON MUSCLE MORPHOLOGY AND STRENGTH. Consistent evidence has demonstrated reduced muscle volume in affected muscles for children with CP21, potentially influencing the ability of muscle to generate torque22 and power21. Strength training in the CP population is shown to be a successful intervention for muscular weakness4-8, and may also increase muscle size23. With both muscular weakness and spasticity considered to be significantly detrimental to function in children with CP24, it seems logical to administer strength training concurrently with BoNT-A treatment to further improve clinical outcome for patients. 142 Chapter Four aimed to combine a 10 week, home based, strength training program with BoNTA injections and measure the effects on muscular weakness and spasticity in CP. The papers’ primary aim was to determine if the combined interventions would be more successful in improving muscle strength than BoNT-A and normal care. Secondly, this paper aimed to determine if changes in muscle strength could be attributed to alterations in muscle morphology. And thirdly, to report if the combination of therapies would successfully improve individual functional goals set by the children (with parental assistance) in this study. Clinical funding structures, family life, and other treatment plans all inhibit year-round strength interventions, therefore it is also of importance to determine if the timing of strength training, whether it be administered before or after BoNT-A injections, affects outcome. The first hypothesis that; ‘The combination of strength training and BoNT-A will result in the simultaneous increase of muscle strength and reduction in muscle spasticity’ was supported. The results demonstrated a significant reduction in spasticity scores, with significant increases in our measures of muscle strength of the knee flexors and extensors, and the gastrocnemius and tibialis anterior. However, the strength improvements are tempered by some strength gains also indicated by children over the control period (BoNT-A with standard clinical care). This may be in part due to normal growth, but it is also common that strength training of some form is incorporated as part of a child’s standard clinical care. The second hypothesis that; ‘The 10 week strength intervention will evoke increases in the muscle size of targeted muscles’ was partially supported. Significant increases in muscle volume were shown in all assessed muscle groups (including those injected by BoNT-A), measured directly over the 10 weeks of strength training, and over 6 months including BoNT-A injections. However, increases in hamstring, quadriceps and plantar flexor volume were also measured in the control period, and were not dissimilar to changes measured over the intervention period. Again, the change in the control period may be attributable to normal growth and to uncontrolled activities as part of the children’s standard clinical care. 143 The third hypothesis that; ‘The combined intervention program, including individual goal-directed strength exercises, will result in functional goal-attainment, as measured by the Goal Attainment Scale (GAS).’ was supported. Scores from the GAS demonstrate that over the 6months of the study, with the combination of BoNT-A and strength training, children were able to achieve their functional goals, with all children achieving a statistically significantly increase in their GAS score. However, these results are limited by a lack of direct control data. The final hypothesis that; ‘Children undertaking strength training in the weeks after BoNT-A treatment will have better outcomes of muscle strength, morphology and functional goals than those receiving strength training before BoNT-A treatment’ was not supported. The overall outcomes (6months) did not indicate any significant differences in muscle strength between the PRE (training prior to BoNT-A) or the POST (training after BoNT-A) groups. However, the results did reveal an emerging trend; in the immediate (10week) response to strength training, the POST group consistently displayed greater increases in strength, having the most significant increases across the assessed muscles, whilst the PRE group displayed greater changes at 6months. The outcomes from this paper report the combination of a home based strength training program, applied either before or after BoNT-A injections, to be successful in improving muscular strength, decreasing spasticity and in achieving functional goal attainment for children with CP. What makes this study novel, and particularly pertinent to the CP population, is that it has demonstrated these positive changes simultaneously in the lower limb, by combining the use of these two common therapies targeting two major motor impairments for children with CP. This is one of the first studies to purposefully apply strength training in conjunction with the best practice of BoNT-A therapy, making these findings even more relevant for clinical decision making. With recent publications of two separate pilot studies pertaining to this topic this year25, 11, it is evident that this direction of research has potential for future therapy for the CP population. Elvrum and Colleagues (2012)25 investigated the combination of resistance training and BoNT-A in the hand25, whilst Bandholm and Colleagues (2012)11 included progressive resistance training in their physical rehabilitation program following BoNT-A treatment of the ankle plantar flexors11. Both studies reported positive 144 outcomes of strength training, with the latter also indicating trends of improvements in function11 and the former concluding that more task-related resistance training may be required25. In the present study, the strength training was a home based program, centred on each child’s individually set goals, and focused on multiple muscles of the lower limb. Whilst improvements were seen in all of muscles targeted for training, of distinct interest were the increases measured in the gastrocnemius and the knee flexor strength after the strength training (comparative to the control period). This is of particular importance, as the gastrocnemius and the hamstring muscles are frequently targeted for BoNT-A injection in this group of children. Given the positive strength increases in the injected muscles following training, and corresponding increases in morphology, the results suggest that perhaps future strength training should be targeting the injected muscles. Finally, this study also questioned the timing of strength training, whether it be more effective if administered before or after BoNT-A injection. There appeared to be no distinction in the timing of the strength training, however PRE training may be more suitable for a child scheduled to receive other interventions following BoNT-A (i.e. serial casting) as they had the better longer term outcomes, whereas, POST BoNT-A training may be more appropriate in order to achieve immediate results for functional goals for some children. This study supports the future application of combined BoNT-A treatment with strength training for children with spastic CP. As a home based, individualised and goal directed strength program, it also provides clinically relevant evidence that should be considered as a potential treatment direction, and transitioned into clinical care. 7.1.3 CHAPTER FIVE IMPROVING THE GAIT OF CHILDREN WITH CEREBRAL PALSY USING THE COMBINED INTERVENTIONS OF STRENGTH TRAINING AND BOTULINUM NEUROTOXIN TYPE-A. Commonly targeted in therapeutic goals26, inefficient ambulation, is one of the most significant functional limitations of CP27. Muscular weakness is considered to be directly related to gross motor function and gait24, 28 in children with CP, and strengthening programs have demonstrated improvement in gait kinematics29-32. Lower limb muscle strength has been linked with gait patterns in CP gait28, particularly in kinetic variables at the ankle. Yet, there 145 have been minimal investigations into alterations in joint power in gait following strengthening, and of the limited studies available, results have been inconclusive31. Separately, BoNT-A treatment and strength training both appear to have a positive impact on gait in children with CP, therefore it could be assumed that the combination of the therapies would also further improve gait function. The primary aim of this paper was to measure the effects of combining a 10 week, home based, strength training program with BoNT-A injections in CP on walking gait, evaluated with the Gait Deviation Index (GDI) and kinetic power profiles. The decision to include the GDI was made to provide a global measure of the kinematic variables of gait, rather than reporting on a multitude of variables. A secondary aim of this paper was to determine if the timing of strength training, affects outcomes, thereby indicating whether there is an optimal timing of strength training. Finally, with this information this paper aimed to provide guidelines for further rehabilitation planning to enhance therapy outcomes for children with CP. The hypothesis that; ‘The combination of strength training and BoNT-A will improve measures of the GDI.’ was supported. Following the combination of therapies, children in our study demonstrated a significant increase in GDI. In contrast, the children in the control period showed no significant change in GDI. The secondary hypothesis that; ‘The 10 week strength intervention will improve kinetic power profiles at the hip, knee and ankle joints so that they more closely resemble those of typically developing peers.’ was partially supported. In terms of power generation, peak values significantly decreased at the hip and knee joint to below the average calculated for our typically developing sample of children. This is in contrast to the significant increases measured in power generation at the hip, knee and ankle joints over the control period. Over the intervention period, power absorption also significantly decreased at the hip joint, to levels below the typically developing average, whilst power absorption at the knee joint also significantly decreased, to a level closer matching, yet still higher, than the typically developing average. This may have an effect on protecting the joint from long term injury and pain. No changes in power generation or absorption were measured at the ankle joint. This was not altogether unexpected however, as 146 the muscles around the ankle joint were not targeted in the strength training as commonly as other muscles, such as those around the hip and knee joints. The last hypothesis that; ‘Children undertaking strength training after BoNT-A treatment will have better GDI outcomes than children undertaking strength training in the weeks preceding BoNT-A treatment’ was supported. Whilst both the PRE and POST group achieved significant increases in the GDI, children in the POST group demonstrated a greater increase in GDI. The results from this paper demonstrate positive changes in gait profiles and kinetics from the combination of strength training and BoNT-A injections compared with BoNT-A alone. The GDI indicated children with CP to be walking in a style closer matching the non-pathological population following the intervention; this is in contrast with the children in the control group, demonstrating no change in GDI. The fact that the children in this study were already walking at a relatively high functional level prior to the intervention (a GDI of 79), and were still able to achieve an improvement from the combined therapies is positive, highlighting the possibilities for interventions in higher functioning children with CP. Previous research has linked muscle strength and kinetics in the CP population, with a focus on the ankle at toe-off (power generation)28. This study showed the combination of lower limb strength training with BoNT-A treatment to alter joint power outputs at the hip and knee. In contrast to increasing trends over the control period, levels of power generated at the hip joint decreased over the intervention, as did levels of power absorption at the knee joint, to levels more closely matching the TD population. It is suggested that these results indicate an improved efficiency; that the combination of strength training and BoNT-A facilitated a more efficient power transfer through the muscles of the lower limb. Similar to Chapter Four, this paper also endeavoured to determine the more effective timing of strength training in relation to the BoNT-A injection: Neither group showed any distinction in the kinetic measures of power at the hip, knee or ankle, and both groups showed significant increases in the GDI. However the POST group, training with BoNT-A active in their system, appeared to show the greatest improvements in GDI. With this, it is recommended to clinicians 147 to endeavour to apply strength training after BoNT-A injections, however, it does not appear to be a critical difference. 7.1.4 CHAPTER SIX THE COMBINATION OF STRENGTH TRAINING AND BOTULINUM NEUROTOXIN TYPE-A IN CHILDREN WITH CEREBRAL PALSY: THE EFFECT ON ACTIVITY, PARTICIPATION AND QUALITY OF LIFE. The International Classification of Functioning, Disability and Health (ICF) framework33 allows for a holistic approach to evaluating current and future treatment options. Understanding the impact of therapeutic interventions on all dimensions of the ICF is imperative for determining the optimal management of the impairments associated with CP. Chapter Six completes the evaluation of the combination effects of strength training and BoNT-A therapy, by evaluating the effect on activity, participation and QoL. Children with CP are reported to experience greater activity limitations and are less physically active then their typically developing peers34-36. In addition to this, literature has reported children with CP to report difficulties in participation37-40, and to experience a lower QoL than children who are typically developing35, 40-42 across all domains, in particular physical and emotional well-being41, 42. Very little research has investigated the effect of BoNT-A on activity, participation or QoL in children with CP. Those that have, demonstrated improvements in some measures of activity43, 44 , indicated a possible positive effect on QoL45 (however with mixed results46, 47), but have not reported an effect on participation48, 49. Similarly, few studies have included effects of strength training in this area; literature has demonstrated a positive impact of strength training on QoL31, 49 , with some examples of improved participation48, 50 , and little support for improvements in activity8, 51,. The combination of therapies has not been evaluated from this perspective. Therefore, this paper aimed to determine if a combined 10 week, home based, strength training program with BoNT-A injections can evoke changes at the activity, participation or QoL domains of the ICF, compared with BoNT-A injections and normal care. Similar to the previous two papers, this paper also aimed to determine if the timing of the strength training program, administered around scheduled BoNT-A injections would produce different outcomes on the activity, participation and QoL domains of the ICF. 148 The first hypothesis that; ‘The combined interventions will improve measures of activity, as assessed by the Timed Up and Go (TUG) and the Six-Minute Walk Test (6MWT)’ was partially supported. Results from the TUG support this hypothesis; with a statistically significant improvement over the intervention period, whilst there was no change over the control period. The 6MWT, however was not altered by the addition of strength training with BoNT-A. It is reasoned that the 6MWT reflects functional endurance, whereas the TUG moreso reflects changes made in strength. The second hypothesis that; ‘Children with CP will have improved outcomes of participation following their involvement in the study (as assessed by the Assessment of Life-Habits, the LIFE-H, for children, and the Canadian Occupational Performance Measure, COPM).’ was not completely supported. There were no significant changes in participation following the combined interventions when the entire cohort (n=15) was evaluated. However, the control group of children (n=8), reported significant improvements after completing the intervention in the LIFE-H domains of nutrition, education and relationships. In addition to this, for the entire cohort, the COPM indicated a clinically significant improvement in the parent score for performance of goals, but not for satisfaction. The final hypothesis that; ‘Children with CP will have improved outcomes of QoL following their involvement in the study (as assessed by the Cerebral Palsy Quality of Life Questionnaire for Children, CP QOL)’ was supported. The domains of family health and emotional well–being/self-esteem of the CPQoL showed improvements after the intervention period that was not measured in the control period. This paper completed a holistic evaluation of the impact of combined interventions on the activity, participation and QoL domains of the ICF. A positive effect on activity, as assessed by the TUG was observed, however there was no effect on the 6MWT. Some improvements were observed in participation, measured by the LIFE-H, in the domains of nutrition, education and relationships, whilst QoL improved in the areas of family health and emotional well-being and 149 self-esteem. The increase in time that the child and parent spent together, as necessitated by the nature of the intervention, may be accountable for the improved QoL for family health and perhaps even in the improved emotional well-being and self-esteem, as well as the improved ‘relationship’ domain in participation. The COPM indicated a clinically significant improvement in performance of functional goals. It is suggested that these positive results are a consequence of both reducing impairments (spasticity and muscle weakness), and increasing the time the parent spent with their child. 7.2 CONCLUSIONS This thesis has, for the first time, provided an in depth investigation into the immediate morphological responses to BoNT-A injections of muscles of the lower limbs in children with CP. This confirmed our hypothesis that BoNT-A therapy would lead to atrophy of injected muscles in children with CP, however the degree of atrophy, and concomitant reductions in muscle strength were not as large as the literature has suggested may occur. It is likely that the multiple number of BoNT-A injections our participants had received prior to this study may have been a mediating factor for the small changes measured. Despite this, with the knowledge that children with spastic diplegic CP i) experience spasticity3 ii) are typically weaker9, (iii) have smaller muscles21 than their typically developing peers and that iv) both spasticity and muscular weakness are reported as significant motor impairments effecting function52-55, the new information presented in this thesis is particularly pertinent to the future application and research of BoNT-A. Whilst the results of this study are optimistic for the continued future of BoNT-A use, essential research investigating the response of naive muscles to initial BoNT-A injections is needed. Combined, these studies have also been the first study to investigate the comprehensive effect of the combined therapies of BoNT-A and strength training across all levels of the ICF in children with CP. With this, it is also the first to question the timing of strength training in relation to BoNT-A injection. Irrespective of timing, the combination of BoNT-A injections, and a home based, goal directed strength training program was effective in increasing muscular strength that was simultaneous to spasticity reduction. Concurrent with the increases in muscle strength were increases in muscle volume, however it should be noted that children in the control period also displayed 150 increases in measures of muscle strength and muscle volumes for some of the muscle groups. Functional improvements were shown over the intervention (BoNT-A and strength training) period, with clinically significant improvements in the attainment of functional goals (GAS), and with significant improvements in walking gait. Using the GDI, children with CP were shown to significantly improve patterns of walking gait, walking in a pattern resembling nonpathological gait after the intervention. This outcome was further supported by the lack of change in GDI by children over the control period. Kinetic (power) gait profiles demonstrated that this improved walking gait was achieved with reduced power profiles at the hip and knee, resembling that of the TD population. These results may be indicative of improved efficiency of the muscles, and may also implicate a reduced risk of joint injury and pain in the long term and in the adult CP population. With improvements demonstrated across the level of body structures and function, the combination of BoNT-A and strength training also indicated some improvements in activity and participation measures; the TUG demonstrated significant improvements, however, the 6MWT, more a measure of functional endurance rather than muscular strength, was not affected. Participation, as measured from the parents’ perspective (using the LIFE-H), was shown to improve in domains of nutrition, education and relationships, whilst the results from the COPM indicated a clinically significant improvement in performance of goals as perceived by the parent, and a trend for improvement in scores for satisfaction. The combination of therapies also evoked improvements in the parents perception of their child’s QoL in the domains of family health and emotional well-being and self-esteem. From these results, it can be concluded, and recommended to clinicians, that strength training, targeting muscular weakness, be applied simultaneously with BoNT-A therapy for spasticity management to improve outcomes for patients across all levels of the ICF. With regards to the most effective timing of strength training in relation to BoNT-A injections, neither training PRE or POST can be definitively stated as the preferred time. The PRE training group generally displayed superior results in the perceived level of performance of and satisfaction with clinical goals, as assessed by the COPM, and the domains of family health and emotional well-being and self-esteem from the CP QoL. The PRE training option also appeared to result in greater changes in measures of strength when assessed over the 6month intervention. However, in terms of improving muscle strength over the 10weeks of strength training, what is referred to in Chapter Four as the ‘immediate’ response to strength training, the POST training option consistently displayed a greater capacity for changes of strength, having the most significant increases across the assessed muscle groups. POST training also appeared to result in larger improvements on the GDI. It appears that applying strength 151 training either before or after BoNT-A can positively impact a child with CP at all levels of the ICF. It is up to the clinician, parents and child to individually determine the more appropriate timing for them depending on their individual situations, until further research can confirm otherwise. 7.2.1 FUTURE RESEARCH In regards to the effect of BoNT-A on muscle morphology, muscular strength and function, it is highly recommended that further research investigate the response of spastic muscles to the first (and subsequent) series of BoNT-A. Ideally, muscles should be assessed prior to having received any BoNT-A, providing a baseline measure, that could be referred to over each subsequent injection of BoNT-A. Furthermore, measurements should be taken at differential timing of the BoNT-A’s effect; this study assessed the muscles response at a time corresponding with the BoNT-A’s peak effect, future longitudinal research would follow this with repeat assessments over time as the effect of the BoNT-A wears off. Based on the positive results of this thesis, the combination of strength training and BoNT-A needs to be translated into standard clinical care; it is strongly recommended that further research with larger sample sizes are conducted. This can provide further evidence for funding for clinic services to include strength training for children with CP who are receiving BoNT-A for spasticity management. This study has shown that strength training can be applied around BoNT-A injections, as suitable for each individual circumstance. In terms of future research into combining strength training and BoNT-A, an obvious recommendation would be to conduct this study with a larger sample size. This could potentially allow for a randomised controlled study with three control groups; BoNT-A with normal care, strength training with normal care, and a no-intervention normal care group (however these groups would likely involve ethical implications). The effects of each control group could be compared with the combination of strength training (either PRE or POST) to provide a more thorough understanding on how each intervention is impacting on each aspects of the child’s function. Following up with further assessments (i.e. of at least 6 months after) would provide a better idea of changes in areas such as participation and QoL, whereby the timeframe in this study is likely to have been too short to look at changes in these areas. With changes predominantly seen at the level of impairment and activity from this study, it would be interesting to also implement an aspect of participation into the intervention program, in an aim to evoke greater changes in participation. For example, the functional goals targeted throughout the program should then 152 be applied at the end of the program into a form of participation, whereby the child is assisted with the development of their functional goals into the community. We strongly recommend future research to include outcome measures across all levels of the ICF, however in doing so, to carefully select appropriate measures. For a childhood population, and one such as CP, finding the right selection of measures is a challenging one, we encourage researchers to strive to determine more effective measures that can be used in this population, in particular for measures of muscle strength and activity. It would also be useful to investigate the economical benefit of a home based strength program around BoNT-A; if an affordable and effective option of therapeutic intervention can be offered, perhaps more families will have the opportunity to implement the program. Expanding the program to include an investigation of the associated short term and long term health economics may also provide stronger support for this intervention. Based on the results of this study, with evidence of atrophy of injected muscles and indications of synergist hypertrophy, we suggest that future research and clinical practice consider targeting muscles that have been injected with BoNT-A into strength training programs, which may result in greater benefits of strengthening. 7.2.2 SIGNIFICANCE OF THIS RESEARCH CP management is a lifelong challenge that requires a coordinated approach to treat the impairments affecting the child holistically, involving both clinicians and the child’s family. Treating spasticity and muscular weakness simultaneously is an obvious step in the right direction for children with CP. This research has outlined the efficacy of implementing a home based, goal directed strength training program for children with CP receiving BoNT-A injections for spasticity management. Positive outcomes were achieved across numerous levels of functioning, over and above BoNT-A alone (with standard clinical care). By including an evaluation of the timing of strength training, this research indicated that significant improvements in different dimensions of function could be achieved whether the training be applied before or after BoNT-A injections. These findings have the potential to greatly impact the prescription of strength training in combination with BoNT-A therapy in children with CP, not only supporting its application, but also providing clinicians, and families, with an optional time in treatment application. For example, a child scheduled to receive serial casting after BoNT-A, now has the option to undertake strength training prior to their scheduled injection. In CP, management in the childhood population not only involves the clinician and the child, but also involves the family. Allowing more options for effective treatment can only serve to 153 increase the number of families able to be included in the future. Furthermore, the potential affordability of this program also supplements this suggestion. A limitation, and strength, of this study is how closely it matches clinical reality. The fact that a home based strength training program, with sessions predominantly supervised by the parents, and relatively basic equipment, is shown to successfully improve a children’s function across all levels of the ICF is incredibly promising for the future therapy for children with CP. In addition to this, it also demonstrates how important the role a family can play in their child’s therapy. The real significance of this research is clearly portrayed by the children and parents who made some impacting statements in their post strength training interviews; “We could see progress/strengthening as the program went on – it was good for confidence, and desire to do more! We would definitely recommend”. Another parent stated; “It’s been great, he has definitely benefited from the program, other people have noticed that he must have been doing something different. He played a full game of Rugby, on a full sized pitch; at the beginning of the program he would never have done that. There is natural getting stronger with age, but this has brought him to another level. He could see some tangible benefits.” Whilst one of the children commented; “It really showed in the sports carnival when I came a higher place than usual; I came fifth... I usually get last.” 154 7.3 REFERENCES 1. Paneth N, Hong T, Korzeniewski S. The descriptive epidemiology of cerebral palsy. Clin Perinatol. 2006;33:251-67. 2. Berker N, Yalçin S. Cerebral Palsy: Orthopedic Aspects and Rehabilitation. Pediatr Clin N Am. 2008;55:1209-25. 3. Gormley MT. Treatment of neuromuscular and musculoskeletal problems in cerebral palsy. Pediatr Rehabil. 2001;4:5-16. 4. Mockford M, Caulton J. Systematic review of progressive strength training in children and adolescents with cerebral palsy who are ambulatory. Pediatr Phys Ther. 2008;20:318-33. 5. Dodd K, Taylor N, Damiano D. A systematic review of the effectiveness of strength- training programs for people with Cerebral Palsy. Arch Phys Med Rehabil. 2002;83:1157-64. 6. Taylor N, Dodd K, Damiano D. Progressive resistance exercise in physical therapy: a summary of systematic reviews. Phys Ther. 2005;85:1208-23. 7. Verschuren O, Ketelaar M, Takken T, Helders P, Gorter J. Exercise programs for children with cerebral palsy: a systematic review of the literature. Am J Phys Med Rehabil. 2008;87:404–17. 8. Antilla H, Autti-Ramo I, Suoranta J, Makela M, Malmivaara A. Effectiveness of physical therapy interventions for children with cerebral palsy: A systematic review. BMC Pediatrics. 2008;8:14. 9. Wiley ME, Damiano DL. Lower-Extremity strength profiles in spastic cerebral palsy. Dev Med Child Neurol. 1998;40:100-7. 10. Dodd K, Taylor N, Graham H. A randomized clinical trial of strength training in young people with cerebral palsy. Dev Med Child Neurol. 2003;45:652–7. 11. Bandholm T, Jensen B, Nielsen L, et al. Neurorehabilitation with versus without resistance training after botulinum toxin treatment in children with cerebral palsy: A randomized pilot study. NeuroRehabilitation. 2012;30:277-86. 12. Üstün T, Chatterji S, Bickenbach J, Kostanjsek N, Schneider M. The International Classification of Functioning, Disability and Health: a new tool for understanding disability and health. Disabil Rehabil. 2003;25:565-71. 13. Vargus-Adams J. Understanding function and other outcomes in cerebral palsy. Phys Med Rehabil Clin N Am. 2009;20:567-75. 14. Majnemer A, Mazer B. New directions in the outcome evaluation of children with cerebral palsy. Semin Pediatric Neurology. 2004;11:11-7. 155 15. Koman L, Mooney J, Smith B, Walker F, Leon J. Botulinum toxin type A neuromuscular blockade in the treatment of lower limb spasticity in cerebral palsy: a randomised double-blind placebo controlled trial. J Pediatr Orthop B. 2000;20:108-15. 16. Steenbeek D, Meester-Delver A, Becher J, Lankhorst G. The effect of botulinum toxin type A treatment of the lower extremity on the level of functional abilities in children with cerebral palsy: evaluation with goal attainment scaling. Clin Rehabil. 2005;19:274-82. 17. Linder M, Schindler G, Michaelis U, et al. Medium-term functional benefits in children with cerebral palsy treated with botulinum toxin type A: 1-year follow-up using gross motor function measure. Eur J Neurol. 2001;8:120-6. 18. Schroeder A, Ertl-Wagner B, Britsch S, et al. Muscle biopsy substantiates long-term MRI alterations one year after a single dose of botulinum toxin injected into the lateral Gastrocnemius muscle of healthy volunteers. Mov Disord. 2009;24:1494-503. 19. Fortuna R, Aurélio Vaz M, Rehan Youssef A, Longino D, Herzog W. Changes in contractile properties of muscles receiving repeat injections of botulinum toxin. J Biomech. 2011;44:39-44. 20. Ma J, Elsaidi G, Smith T, et al. Time course of recovery of juvenile skeletal muscle after Botoxulinum Toxin A injection. Am J Phys Med Rehabil. 2004;83:774-80. 21. Barrett RS, Lichtwark GA. Gross muscle morphology and structure in spastic cerebral palsy: a systematic review. Dev Med Child Neurol. 2010;52:794-804. 22. Lieber R, Friden J. Functional and clinical significance of skeletal muscle architecture. Muscle Nerve. 2000;23:1647-66. 23. McNee AE, Gough M, Morrissey MC, Shortland AP. Increase in muscle volume after plantarflexor strength training in children with spastic cerebral palsy. Dev Med Child Neurol. 2009:1-7. 24. Ross SA, Engsberg JR. Relationships between spasticity, strength, gait, and the GMFM- 66 in persons with spastic diplegia Cerebral Palsy. Arch Phys Med Rehabil. 2007;88:1114-20. 25. Elvrum A-K, Braendvik S, Saether R, Lamvik T, Vereijken B, Roeleveld K. Effectiveness of resistance training in combination with botulinum toxin-A on hand and arm use in children with cerebral palsy: A pre-post intervention study. BMC Pediatrics. 2012;12:Epub ahead of print. 26. Shepherd R. Cerebral palsy. In: Shepherd R, editor. Physiotherapy in paediatrics. Oxford: Butterworth-Heinemann; 1995. p. 110-4. 27. Eaglton M, Iams A, McDowell J, Morrison R, Evans C. The effects of strength training on gait in adolescents with cerebral palsy. Pediatr Phys Ther. 2004;16:22-30. 28. Eek MN, Tranberg R, Beckung E. Muscle strength and kinetic gait pattern in children with bilateral spastic CP. Gait Posture. 2011;33:333-7. 156 29. Unger M, Faure M, Frieg A. Strength training in adolescent learners with cerebral palsy: a randomized controlled trial. Clin Rehabil. 2006;20:469-77. 30. Damiano D, Kelly L, Vaughan C. Effects of quadriceps femoris muscle strengthening on crouch gait in children with spastic diplegia. Phys Ther. 1995;75:658-67. 31. Engsberg J, Ross S, Collins D. Increasing ankle strength to improve gait and function in children with cerebral palsy: a pilot study. Pediatr Phys Ther. 2006;18:266-75. 32. Damiano DL, Arnold AS, Steele KM, Delp SL. Can strength training predictably improve gait kinematics? A pilot study on the effects of hip and knee extensor strengthening on lowerextremity alignment in cerebral palsy. Phys Ther. 2010; 90:269-79. 33. WHO. International Classification of Functioning, Disability and Health: Introduction. Geneva: WHO; 2001 [cited 2006 January]. 34. Maher C, Williams M, Olds T, Lane A. Physical and sedentary activity in adolescents with cerebral palsy. Dev Med Child Neurol. 2007;49:450-7. 35. Bjornson K, Belza B, Kartin D, Logsdon R, McLaughlin J. Self-reported health status and quality of life in youth with cerebral palsy and typically developing youth. Arch Phys Med Rehab. 2008;89:121-7. 36. Van Zelst B, Miller M, Russo R, Murchland S, Crotty M. Activities of daily living in children with hemiplegic cerebral palsy: a cross- sectional evaluation using the assessment of motor and process skills. Dev Med Child Neurol. 2006;48:723-7. 37. Tuzun E, Eker L, Daskapan A. An assessment of the impact of cerebral palsy on children's quality of life. WFizyoterapi Rehabilitasyon 2004;15:3-8. 38. Vargus-Adams J. Health-related quality of life in childhood cerebral palsy. Arch Phys Med Rehab. 2005;86:940-5. 39. Varni J, Burwinkle T, Sherman S, et al. Health related quality of life of children and adolescents with cerebral palsy: Hearing the voices of the children. Dev Med Child Neurol. 2005;47:592-7. 40. Calley A, Williams S, Reid S, et al. A Comparison of activity, participation and quality of life in children with and without spastic diplegia cerebral palsy. Disabil Rehabil. 2012;34:130610. 41. Liptak GS, O’Donnell M, Conaway M, et al. Health status of children with moderate to severe cerebral palsy. Dev Med Child Neurol. 2001;43:364-70. 42. Dickinson H, Parkinson K, Ravens-Sieberer U, et al. Self-reported quality of life of 8–12 year-old children with cerebral palsy: a cross-sectional European study. Lancet. 2007;369:2171–8. 43. Bjornson K, Hays R, Graubert C, et al. Botulinum toxin for spasticity in children with cerebral palsy: A comprehensive evaluation. Pediatrics. 2007;120:49-58. 157 44. Maanum G, Jahnsen R, Stanghelle J, Sandvik L, Keller A. Effects of botulinum toxin A in ambulant adults with spastic cerebral palsy: A randomized double-blind placebo controlledtrial. J Rehabil Med. 2011;43:338-47. 45. Coutinho dos Santos LH, Bufara Rodrigues DC, Simoes de Assis TR, Bruck I. Effective results with botulinum toxin in cerebral palsy. Pediatr Neurol. 2011;44. 46. Redman T, Finn J, Bremner A, Valentine J. Effect of upper limb botulinum toxin-A therapy on health-related quality of life in children with hemiplegic cerebral palsy. J Paediatr Child Health. 2008;44:409-14. 47. Russo R, Crotty M, Miller M, Murchland S, Flett P, Haan E. Upper-limb botulinum toxin A injection and occupational therapy in children with hemiplegic cerebral palsy identified from a population register: a single-blinded, randomized, controlled trial. Pediatrics. 2007;119:114958. 48. McBurney H, Taylor N, Dodd K, Graham H. A qualitative analysis of the benefits of strength training for young people with cerebral palsy. Dev Med Child Neurol. 2003;45:658–63. 49. Verschuren O, Ketelaar M, Gorter J, Helders PJM, Uitervaal CSPM, Takken T. Exercise training program in children and adolescents with cerebral palsy. A randomised controlled trial. Arch Pediatr Adolesc Med. 2007;161:1075-81. 50. Darrah J, Wessel J, Nearingburg P, O'Connor M. Evaluation of a community fitness program for adolescents with cerebral palsy. Pediatr Phys Ther. 1999;11:18-23. 51. Scholtes VA, Becher JG, Comuth A, Dekkers H, Van Dijk L, Dallmeijer AJ. Effectiveness of functional progressive resistance exercise strength training on muscle strength and mobility in children with cerebral palsy: A randomized controlled trial. Dev Med Child Neurol. 2010;52:107-13. 52. Berger W, Quintern J, Dietz V. Pathophysiology of gait in adolescents with cerebral palsy. Electroencephalogr Clin Neurophysiol. 1982;53:538-48. 53. Graves P. Therapy methods for cerebral palsy. J Paediatr Child Health. 1995;31:24-8. 54. MacPhail A, Kramer J. Effect of isokinetic strength training on functional ability and walking efficiency in adolescents with cerebral palsy. Dev Med Child Neurol. 1995;37:763-75. 55. Mayston M. People with cerebral palsy: Effects of and perspectives for therapy. Neural Plast. 2001;8:122-8. 158 APPENDICES APPENDIX A- PUBLISHED MANUSCRIPT A COMPARISON OF ACTIVITY, PARTICIPATION AND QUALITY OF LIFE IN CHILDREN WITH AND WITHOUT SPASTIC DIPLEGIA CEREBRAL PALSY. 159 160 161 162 163 164 APPENDIX B- ACCEPTED ABSTRACTS Presented at the American Academy of Cerebral Palsy and Developmental. AACPDM 66th Annual Meeting. 2012, Toronto, ON, Canada. Combining Strength Training and Botulinum Neurotoxin intervention in children with CP: The impact on Muscle Morphology and Strength. S WilliamsA, C ElliottB, J ValentineB,C, A GubbayC, P ShipmanD, S ReidA. A School of Sport Science, Exercise & Health, The University of Western Australia, Perth, Australia. B School of Paediatrics and Child Health, The University of Western Australia, Perth, Australia. C Department of Paediatric Rehabilitation, Princess Margaret Hospital, Perth, Australia. D Department of Diagnostic Imaging, Princess Margaret Hospital, Perth, Australia. Background/Objectives: Spasticity and weakness are significant impairments for children with Cerebral Palsy (CP). Strength training is an effective intervention for improving muscular strength, whilst Botulinum Toxin Type-A (BoNT-A) is an established treatment for spasticity management. This study investigated combined effects of strength training and BoNT-A on strength and muscle morphology in children with CP. Study Design: A repeated measures cross-comparison randomised trial. Study Participants: 15 children with CP receiving BoNT-A for spasticity management. Children were classified as Spastic Diplegic, GMFCS I-II, & aged 5-12 years (m=8.52, SD 1.59). Study setting: Tertiary paediatric hospital. Materials/Methods: Spasticity was assessed using the Modified Ashworth Scale. The Goal Attainment Scale (GAS) assessed achievement of functional goals. Muscle volume (MV) was assessed using Magnetic Resonance Imaging (1.5T Sonata, Siemens). Lower limb muscle strength was assessed using instrumented (Biodex Medical Systems) and hand held (Lafayette Instrument Company) dynamometry. Children were randomly allocated to 10weeks of home based lower limb strength training either before (PRE) or after (POST) receipt of BoNT-A, children completed 3 supervised sessions weekly. Strength training was progressive, initially focussing on motor control and base strength, through to complex movements and functional goals. Eight children also 165 completed a 6month control period of BoNT-A without strength training. All children were assessed four times over 6months. T-Tests and a mixed model ANOVA determined significant differences between assessment points and groups. Results: During the intervention period children made significant strength gains (mean p=.02, ES=.58) compared to the control period (mean p=.22, ES=.46). Significant strength improvements were seen immediately (e.g. mean gluteus: p=.011, ES=.83), and over 6months (mean gluteus: p=.009, ES=.71) for both groups, but did not differ significantly between groups (p=0.795). The POST group showed greater immediate strength gains, whilst the PRE group incurred greater strength gains over 6months. MV significantly increased in assessed muscle groups immediately after training (mean p<.001, mean ES =.58) and over 6months (mean p<.001, mean ES=.60) for both groups. Both training groups showed significant improvements in GAS scores immediately after training (mean p=.007, ES=4.17) and over 6months (mean p=.029, ES=.99), GAS outcome did not differ significantly between groups (p=0.35). Spasticity significantly reduced following BoNT-A (p=.011, ES=-1.17). Conclusions/Significance: The simultaneous use of BoNT-A and strength training was successful in spasticity reduction, improving strength, and achieving functional goals for children with CP, over and above treatment with BoNT-A alone. Adaptations in MV suggest that the strength gains may be attributable to hypertrophy. The results suggest that strength training after BoNT-A may enhance immediate muscle strength, however children who receive PRE BONT-A training may have better long-term improvements in strength. 166 Presented at the Australasian Academy of Cerebral Palsy and Developmental. AusACPDM 6th Biannual conference. 2012 Brisbane, QLD, Australia Strength Training Results in Stronger but not necessarily bigger Muscles for Children with Cerebral Palsy. S WilliamsA, C ElliottC, J ValentineB, N SmithB, T ShillingtonB, M SpitsB, S ReidA, A School of Sport Science, Exercise and Health, University of Western Australia, Perth, Australia. Princess Margaret Hospital for Children, Perth, Australia C School of Paediatrics and Child Health, Australia B Objective: To investigate how a 10 week strength program impacts muscular strength and morphology for children with CP. Study design: A randomised controlled intervention study. Study Participants: Fifteen children diagnosed with Spastic Diplegic Cerebral Palsy GMFCS I-II, aged between 5-12 years (mean age= 8.52yrs, ±1.59) were enrolled in the study. Children were block randomised by age, gender and GMFCS level to the training group (n=7) or control group (n=8). Methods: The training group undertook a 10 week home-based supervised strength training program focusing on their lower limbs. Children completed up to 3 supervised sessions weekly. The program was progressive, initially focussing on motor control and the establishment of base strength and progressed to more complex functional movements reflecting the child’s goals. Isometric and isokinetic strength assessments of the knee flexor/extensor muscle groups were completed using a Biodex System3 dynamometer (Biodex Medical Systems, Inc. Shirley, NY). A 1.5-T whole body MR unit (Sonata, Siemens) was used to acquire bilateral transverse plane images. MR images were transferred to Mimics software (Version 9.0, Materialise, Leuven) for manual digitisation of each muscle of the quadriceps and hamstring along the length of the muscle, to ascertain muscle volume (MV) and cross sectional area (CSA). Results: Children in the training group showed significant (p<0.05, ES=-0.84) increases in quadriceps (m=26.97±64.90) and hamstring (m=18.02±31.71) isokinetic strength compared to the control group (quadriceps m=-16.68 ±34.51; hamstring m=-8.57±34.63). Hamstring MV increased significantly in the training group (change = 0.75cm3/cm) compared with the control group (change = 0.25cm3/cm) (p=0.01, ES=-0.91). However, no significant difference in 167 quadriceps morphology was observed between the training and control groups (p>0.05; quads MV ES=-0.44, CSA ES=-0.16). Conclusion: Strength training resulted in significant improvements in isokinetic strength. The improvements in strength may reflect improved patterns of muscle fibre recruitment and utilisation, suggesting that short term strength training programmes alter muscle innervation, not necessarily muscle morphology. 168 Presented at the Australasian Academy of Cerebral Palsy and Developmental. AusACPDM 6th Biannual conference. 2012 Brisbane, QLD, Australia The Immediate Effect of Botulinum Toxin Type-A on Muscle Morphology and Strength in Children with Cerebral Palsy. S WilliamsA, C ElliottC, J ValentineB, A GubbayB, M SpitsB, S ReidA. A School of Sport Science, Exercise and Health, UWA, Perth, WA, Australia. Princess Margaret Hospital for Children, Perth, WA, Australia C School of Paediatrics and Child Health, UWA, Australia B Objectives: To investigate whether BoNT-A injections have an immediate effect on muscle morphology and strength of the lower limbs in children with CP. Study design: Single group repeated measures design. Study Participants: Fifteen children with CP currently receiving BoNT-A for spasticity management. All children were classified as Spastic Diplegic, GMFCS I-II, aged between 5-12 years (mean age= 8.52yrs, ±1.59, ten males and five females). Methods: Children completed two assessments; 1) approximately 2 weeks prior to BoNT-A and 2) approximately 4-6weeks post injection. Children underwent strength assessments and a muscle MRI at each time point. All children received BoNT-A treatment to the gastrocnemius and a subset of five children also received treatment to the hamstrings. A 1.5-T whole body unit (Sonata, Siemens) was used to acquire bilateral transverse images from the ankle malleoli to iliac crest. MR images were transferred to Mimics software (Version 9.0, Materialise, Leuven) for manual digitisation of each muscle of the hamstring and plantarflexor groups, to ascertain muscle volume (MV) and cross sectional area (CSA). Isometric and isokinetic strength assessments of the knee flexor muscle group were completed using a Biodex System3 dynamometer (Biodex Medical Systems, Inc. Shirley, NY). A hand held dynamometer (HHD) (Model 01163, Lafayette Instrument Company) was used to determine isometric strength of the plantarflexors. Results: A significant decrease in isokinetic muscle work (p=0.03) was observed following hamstring BoNT-A injection. However, no change in isometric strength was evident in the plantarflexors. Whilst total muscle group morphology remained unchanged, individual muscle alterations were evident. A significant decrease in medial gastrocnemius MV (p=0.001) and significant increase in soleus MV (p=0.024) was observed following BoNT-A treatment. 169 Following hamstring treatment the CSA of semitendinosis was observed to decreased significantly (p=0.01). Conclusion: BoNT-A injections do not appear to have an immediate effect on total muscle group morphology as assessed via MV and CSA. This work provides some evidence of individual muscle decline and synergist compensation following treatment. Results reveal a potential effect of BoNT-A on decreasing the muscles ability to perform work for some children. 170 Presented at the American Academy of Cerebral Palsy and Developmental. AACPDM 65th Annual meeting. 2011 Las Vegas, Nevada, USA. *Received Mac Keith Press Promising Career Award for best paper. The Immediate Effect of Botulinum Toxin Type-A on Muscle Morphology and Strength in Children with Cerebral Palsy. S WilliamsA, C ElliottC, J ValentineB, A GubbayB, M SpitsB, P ShipmanB, S ReidA. A School of Sport Science, Exercise & Health, University of Western Australia, Perth, WA, Australia. B Princess Margaret Hospital for Children, Perth, WA, Australia C School of Paediatrics and Child Health, WA, Australia Background/Objectives: Both spasticity and muscular weakness are significant impairments on the ability to function for children with spastic Cerebral Palsy (CP). The application of Botulinum Toxin Type-A (BoNT-A) in the management of spasticity is an established treatment option for children with CP. Due to the mechanisms of BoNT-A, muscle weakness in the targeted muscle is to be expected; however it is unknown if this weakness is related to altered muscle morphology. This research aims to investigate whether BoNT-A injections have an immediate effect on muscle morphology and strength of the lower limbs in children with CP. Study design: Single group repeated measures design. Study Participants: Fifteen children with CP currently receiving BoNT-A for spasticity management. All children were classified as Spastic Diplegic, GMFCS I-III, aged between 5-12 years (x age= 8.52yrs, ±1.59, ten males & five females). Study settings: Tertiary paediatric hospital setting. Materials/Methods: Muscle morphology (muscle volume (MV) & cross sectional area (CSA)) of the lower limb was assessed using Magnetic Resonance Imaging (MRI). A 1.5-T whole body unit (Sonata, Siemens) was used to acquire bilateral transverse plane images from the ankle malleoli to iliac crest. MR images were transferred to Mimics software (Version 9.0, Materialise, Leuven) for digitisation. The slice areas of each muscle in the hamstring & plantar flexor (PF) muscle groups were manually traced along the length of the muscle. Strength assessments of the knee flexor muscle group were completed using a Biodex System3 dynamometer (Biodex Medical Systems, Inc. Shirley, NY). The assessments involved isometric contractions with the knee flexed at 90°, & a series of isokinetic contractions at velocities of 171 60o/s & 90o/s. A hand held dynamometer (HHD) (Model 01163, Lafayette Instrument Company) was used to determine maximal isometric strength of the PF in standardised positions. Children completed two assessments; 1) approximately 2 weeks prior to BoNT-A & 2) approximately 4-6weeks post injection. Hamstring & gastrocnemius muscles were injected with BoNT-A as clinically indicated through goal setting & clinical assessment. Results: Minimal decreases in strength were evident after BoNT-A, but did not approach statistical significance (p>0.05, x work & Isometric ES=0.29). No change in strength was evident in the PF, however small changes occurred at the hamstrings particularly in measures of isokinetic strength for some children with decrements of 9-12%. There were no significant differences (p<0.05) in muscle morphology (MV or CSA) for the hamstring or PF muscle groups across the two time points. Conclusion/significance: This research indicates that BoNT-A injections are safe and do not have an immediate effect on muscle morphology as assessed via MV and CSA. Similarly, no significant decrease in strength is reported after BoNT-A, however results may reveal a potential effect of BoNT-A on decreasing the muscles ability to perform work through range for some children. Changes observed in work capacity are not a result of change in muscle morphology, but instead signal the neurological effect of BoNT-A. 172 Presented at the American Academy of Cerebral Palsy and Developmental. AACPDM, 64th annual meeting. 2010 Washington, DC, USA. Does MRI-derived muscle size relate to strength in children with and without CP? C ElliottA , C PitcherB, S WilliamsB, A KuenzelA, P ShipmanA, J ValentineA, S ReidB A Princess Margaret Hospital, Western Australia B School of Sports Science Exercise and Health, University of Western Australia Background / Objective: Measures of muscle size are directly proportional to the maximum force-generating capacity of muscles in adults (Akagi et al., 2009). However this relationship is yet to be established in children. The aim of this study was to compare strength to muscle size in typically developing children (TD) and children with spastic diplegic CP. Study Design: A prospective cross sectional study with a normative comparison population. Study participants and setting: Ten participants with spastic diplegia CP age range 6 – 10 years (mean age 7.2y [SD 1.32y], GMFCS I-III) and twenty TD aged 5 to 11 years (mean age 7.5y [SD1.74y] were recruited. Exclusion criteria were orthopaedic surgery, neurosurgery or Botulinum toxin injections within 5 months of testing. Materials/Methods: Strength assessments were completed using a Biodex System-3 dynamometer (Biodex Medical Systems, Inc. Shirley, NY). Participants performed isometric trials and a series of isokinetic concentric trials at 60° and 90°/sec. Axial spin-echo T1-weighted MR images were acquired bilaterally from the level of the ankle malleoli to the iliac crest while subjects lay prone in a 1.5T whole body magnetic resonance unit (Magnetom Sonata Maestro Class, Siemens Medical Solutions, Erlangen, Germany). Muscles were manually segmented using Mimics software (Version 9.0, Materialise, Leuven); these included the rectus femoris, vastus lateralis, vastus medialis, semitendinosis, biceps femoris, and semimembranosis. Muscle volume (MV) and muscle cross-sectional area (CSA) defined muscle size. Results: Children with CP were weaker than their TD peers on all strength variables (p>0.003). CSA of the hamstrings (t=3.34; p<.000) and quadriceps (t=6.18; p <.000) were smaller in children with CP than their TD peers. A significant difference was established between the two groups for hamstring MV (t=3.436; p <.002) but not for the quadriceps MV (t=2.976; p <.006). The strongest relationship existed between isometric strength and MV for both the quadriceps (CP r=.793, TD r=.77) and the hamstrings (CP r=.738, TD r=.84). 173 Conclusions / Significance: This research concurs with evidence that children with CP are weaker and have smaller muscles than TD children. MRI-derived MV better predicts strength capacity in both CP and TD children. Whilst TD children display the same size strength relationship as adults, children with CP do not. Children with CP appear to be underpowered relative to their muscle size. This data provides an understanding of muscle strength and size, and further investigation is required of pathology of the muscles of children with CP References: Akagi R, Takai Y, Ohia M, Kanehisa H, et al.; Muscle volume compared to crosssectional area is more appropriate for evaluating muscle strength in young and elderly individuals. Age and Ageing 2009; 38: 1-6 Acknowledgments: The authors would like to acknowledge the support of; The Raine Medical Research Foundation and UWA Research Development Awards. 174 Presented at the Australasian Academy of Cerebral Palsy and Developmental Medicine (AusACPDM) Conference, Christchurch, New Zealand, 2010 The Relationship between Muscle Morphology and Strength in Children with and Without Cerebral Palsy Elliott C1, Reid S2 Pitcher C1&2, William, S1&2 Kuenzel A3, Valentine J1. 1 Department of Paediatric Rehabilitation, Princess Margaret Hospital for Children, Perth, WA, Australia 2 School of Sport Science, Exercise & Health, University of Western Australia, Perth, WA, Australia 3 Department of Diagnostic Imaging, Princess Margaret Hospital for Children, Perth, WA, Australia Objective: This research aims to establish the nature of the relationship between measures of muscle morphology (muscle cross-sectional area-CSA and muscle volume as determined via MRI) and measures of muscular strength (evaluated through isokinetic dynamometry) in children with and without CP. Design: Cross-sectional cohort study. Method: Eight children with CP GMFCS level II & III aged 5 – 11 years (mean 6.38 years, SD 1.3), including 6 male and 2 females participated. This data was compared to that of 18 typically developing children aged 5-11 years (mean 7.5 years, SD 1.72), including 8 males and 10 females. Written informed consent was provided by all participating families. Bilateral axial T1 MRI images of the thigh were performed using a 1.5T whole body magnetic resonance unit (Signa, General Electric Medical Systems, Milwaukee). MR images were transferred and isotropic voxel size obtained using a trilinear interpolation routine. The hamstrings were manually traced and segmented in single slices and re-sampled using bilinear and cubic interpolation to calculate muscle volume and cross-sectional area (CSA). CSA of each muscle group was defined as the mean area of the three slices exhibiting the greatest muscle area. Children performed strength assessments of knee flexors and extensors bilaterally using a Biodex Dynamometer (System 3). Isokinetic assessments were completed at 60° and 90°/sec, and children completed three consecutive trials at each velocity. Variables of interest included peak torque/body mass (PT/BM), work/body mass (W/BM) and average power. Results: The correlation between muscle volume and PT/BM was strong for typically developing children (0.72), and weaker for children with CP (0.38). Similar correlations were established between muscle CSA and PT/BM (typically developing=0.66; CP=0.44). The 175 correlations between muscle morphology (volume and CSA) and muscle strength (W/BM and power) were consistently higher in typically developing children compared to children with CP. Conclusion: The moderate to strong correlation between muscle volume and torque in typically developing children reflects the relationship identified in the adult population. This relationship is not as strong in the population of children with CP indicating that children with CP are under powered relative to the size of their muscle bulk. 176 Poster displayed at the Australian and New Zealand Society for Paediatric Radiology (ANZSPR), 2010, Margaret River, Western Australia The Effectiveness of Pre-MRI Practice to Prepare Children for MRI Scans. Williams S1&2, Reid S2, Valentine J1, Dwyer B3, Shipman P1, Elliott C1 1 Department of Paediatric Rehabilitation, Princess Margaret Hospital for Children, Perth, WA, Australia 2 School of Sport Science, Exercise & Health, University of Western Australia, Perth, WA, Australia 3 Department of Diagnostic Imaging, Princess Margaret Hospital for Children, Perth, WA, Australia Objective: To prepare children to complete successful MRI scans using MRI practice, thereby reducing the need for general anaesthetic or sedation. Method: Forty one children, 15 with Cerebral Palsy (mean 7.4 years, SD 1.6; 5 females, 10 males) and 26 typically developing children (mean age 7.4 years, SD 1.9; 14 females, 12 males) aged 3-11 years took part in pre-MRI practice, prior to undergoing a lower limb anatomical MRI at PMH. Participants received pre-MRI preparation within one week of having their MRI scan. The training took 45minutes, and centred on familiarising the child with the procedure using age appropriate play and education. The session included a short video that featured other children explaining what happens and what to expect in an MRI. Children were familiarised to the sound of the MRI machine, as well as developed other competencies required for an MRI scan such as lying still for a period of time. The child’s learning was reinforced with an individualised storybook and activity sheets. Results: All Forty-one children successfully completed MRI’s without the need for sedation. The children were able to lay still for a readable scan. Children were required to lay still for 6minutes at a time for scans. Twenty-one typically developing children and 9 children with Cerebral Palsy have since returned for follow up scans, without the need for further training, just re-familiarisation with the individualised story-book. Conclusion: Anxiety related associations with MRI scans can be experienced in patients of all ages, not just children24. However, for younger children, the unfamiliar environment, people, equipment and the noise can be so overwhelming that scans are either not begun, are incomplete or are unsuccessful because of movement artefact25. Patient preparation has 177 become commonplace for many medical procedures. MRI preparation with practice has the potential to greatly reduce anxiety, and the need for expensive sedation and increase the success rate of the MRI scans. Overall, practice MRI created a positive hospital experience for the child and there family, and allows the development of skills which can be employed in other areas of their life. 178 APPENDIX C- SUPPLEMENTARY DATA FOR CHAPTER THREE MORPHOLOGICAL ALTERATIONS IN SPASTIC MUSCLES IMMEDIATELY FOLLOWING BOTULINUM NEUROTOXIN TYPE-A TREATMENT IN CHILDREN WITH CEREBRAL PALSY. MUSCLE MORPHOLOGY Table 1 PRE and POST individual muscle volumes of the lower leg for 15 children (30 legs) receiving BONT-A to the gastrocnemius muscle group. All values for muscle volume (MV) are expressed as % of muscle volume (cm3) divided by tibia length (cm). ID WL _R WL_L TR_R TR_L TK_R TK_L SB_R SB_L RM_R RM_L MR_R MR_L MH_R MH_L LS_R LS_L LD_R LD_L JZ_R JZ_L JC_R JC_L JB_R JB_L DJ_R DJ_L ER_R ER_L DM_R DM_L Average Gastroc. 1.88 1.43 3.71 3.67 2.97 2.76 2.35 2.16 2.64 2.64 5.05 4.54 3.04 2.59 2.27 1.57 1.93 1.99 4.47 3.97 2.57 3.08 3.49 3.48 2.39 2.25 3.86 4.06 3.62 3.49 3.00 Pre- BoNT-A injection Soleus PF total 2.57 4.45 2.09 3.52 4.22 7.93 4.26 7.93 3.49 6.46 3.78 6.55 2.21 4.55 2.76 4.93 4.30 6.93 4.45 7.09 6.40 11.45 7.59 12.13 3.94 6.98 4.35 6.94 4.70 6.97 2.80 4.38 2.83 4.76 3.24 5.23 5.25 9.73 5.55 9.52 3.62 6.19 3.88 6.96 4.01 7.50 4.23 7.71 3.77 6.17 3.90 6.15 5.71 9.58 6.84 10.90 6.36 9.98 6.62 10.11 4.32 7.32 DF 0.86 0.72 0.97 1.20 0.99 1.17 0.56 0.89 1.30 1.27 1.41 1.80 1.24 1.26 0.93 1.18 0.82 1.05 1.44 2.00 1.47 1.72 1.62 1.63 1.15 1.40 1.62 1.71 1.30 1.53 1.27 Gastroc. 1.97 1.40 3.35 2.92 2.45 2.67 2.27 2.14 2.42 2.78 4.50 4.36 2.71 2.50 1.93 1.35 2.56 2.09 3.81 3.70 2.58 3.13 3.55 3.58 2.08 1.79 3.77 4.20 3.65 3.09 2.84 Post BoNT-A injection Soleus PF total 2.55 4.51 2.03 3.43 4.58 7.93 4.42 7.35 4.15 6.60 3.53 6.20 2.41 4.68 2.78 4.92 4.28 6.69 4.17 6.95 6.49 10.99 8.11 12.47 3.82 6.54 5.06 7.57 4.85 6.78 2.86 4.21 3.61 6.17 3.67 5.76 4.97 8.78 5.60 9.30 3.86 6.44 4.23 7.36 4.14 7.69 4.30 7.87 4.16 6.24 4.37 6.16 5.73 9.50 6.74 10.94 6.09 9.74 6.28 9.37 4.46 7.30 DF 0.88 0.67 1.19 1.14 1.20 1.34 0.67 0.91 1.27 1.26 1.37 1.79 0.94 1.31 0.96 1.00 1.06 1.21 1.62 1.82 1.61 1.77 1.47 1.53 1.10 1.42 1.40 1.75 1.35 1.70 1.29 179 Table 2 PRE and POST individual muscle volumes of the thigh for 10 children (20 legs) receiving BoNT-A to the gastrocnemius muscle group. All values are expressed as % of muscle volume (cm 3) /femur length (cm). ID TR_R TR_L TK_R TK_L MR_R LMR_L MH_R MH_L LS_R LS_L LD_R LD_L JZ_R JZ_L JC_R JC_L JB_R JB_L DM_R DM_L Average Med HS 3.00 2.85 2.81 2.62 5.34 5.22 3.21 3.01 3.00 2.49 2.82 2.74 5.28 5.07 3.63 3.53 3.28 3.29 3.71 3.52 3.52 Pre- BoNT-A injection Biceps Total HS Femoris 2.37 5.37 2.52 5.37 1.85 4.67 1.54 4.16 3.77 9.11 3.40 8.62 2.71 5.92 3.04 6.05 2.24 5.24 1.67 4.16 2.36 5.18 2.18 4.92 2.87 8.15 3.28 8.35 2.39 6.02 2.70 6.23 2.62 5.90 2.79 6.08 2.70 6.42 3.03 6.55 2.60 6.12 Quads Med HS 10.60 12.95 10.91 11.03 18.05 18.41 11.82 12.05 11.49 9.53 8.61 8.26 15.67 15.01 10.15 11.46 12.39 13.03 14.26 14.45 12.51 3.43 2.88 3.10 2.81 5.18 5.30 3.04 3.14 3.08 2.43 2.95 2.89 4.61 5.11 3.91 3.64 3.35 3.62 3.33 3.33 3.56 Post BoNT-A injection Biceps Total HS Femoris 2.79 6.22 2.61 5.49 2.15 5.25 1.72 4.53 3.54 8.71 3.75 9.05 2.59 5.63 3.03 6.17 2.64 5.71 1.57 4.00 2.35 5.30 2.47 5.36 3.21 7.83 3.51 8.62 2.60 6.51 2.80 6.44 2.48 5.84 2.53 6.15 2.77 6.10 3.05 6.38 2.71 6.26 Quads 11.56 13.49 12.55 12.34 17.96 18.32 12.47 12.97 11.55 9.15 9.62 9.26 15.28 15.54 10.99 10.76 12.45 13.43 14.67 14.75 12.96 Table 3 PRE and POST individual muscle volumes of the thigh for 5 children (10 legs) receiving BoNTA to the medial hamstrings and gastrocnemius. All values are expressed as % of muscle volume (cm3) /femur length (cm). ID WL _R WL_L SB_R SB_L RM_R RM_L DJ_R DJ_L DM_R DM_L Average Med HS 2.54 2.42 2.67 2.57 3.30 2.87 2.49 2.62 3.71 3.52 2.87 Pre- BoNT-A injection Biceps Total HS Femoris 2.02 4.56 2.17 4.59 1.81 4.48 1.85 4.42 2.66 5.95 2.48 5.35 2.30 4.80 2.35 4.97 2.70 6.42 3.03 6.55 2.34 5.21 Quads Med HS 10.29 10.06 10.40 10.82 11.60 11.44 15.86 14.92 14.26 14.45 12.41 2.20 2.47 2.65 2.55 2.37 2.83 2.53 2.56 3.33 3.33 2.68 Post BoNT-A injection Biceps Total HS Femoris 1.69 3.90 2.22 4.70 2.00 4.64 1.91 4.47 2.34 4.71 2.26 5.09 2.43 4.96 2.37 4.93 2.77 6.10 3.05 6.38 2.31 4.99 Quads 9.80 9.93 9.95 10.75 11.60 11.59 16.30 15.03 14.67 14.75 12.44 180 MUSCLE STRENGTH Table 2 PRE and POST isometric peak torque for knee flexor and knee extensor strength, in 10 children (20 legs) receiving BoNT-A to the gastrocnemius muscle group. Values are normalised to body weight. Pre- BoNT-A injection Post BoNT-A injection Knee Flexion Knee Extension Knee Flexion Knee Extension TK_R TK_L TR_R TR_L MR_R LMR_L MH_R MH_L LS_R LS_L LD_R LD_L JZ_R JZ_L JC_R JC_L JB_R JB_L ER_R ER_L 40.3 33.3 66 68.9 30 31.1 72.2 62.1 58.3 30.3 71.7 82.6 151.7 126.3 61.9 167.5 132.2 164.4 142.6 109.4 84.6 148.6 155.4 53.7 77.2 221.8 210.8 158.9 120 165.9 157.7 185.4 177.7 316 252.2 463.8 421.9 364.5 271.7 54.4 44.2 81.1 82.2 49 63 56.3 51.6 38.5 19.5 61.3 56.5 131.5 24.5 59.46 168.3 150.4 82 101.1 174.0 89.0 168.1 133.7 103.5 136.0 182.3 245.6 133.1 111.8 196.3 169.4 253.0 228.1 253.0 237.7 478.7 502.5 242.4 198.8 Average 83.86 205.86 72.36 211.85 ID Table 3 PRE and POST isometric peak torque for knee flexor and knee extensor strength, in 5 children (10 legs) receiving BoNT-A to the medial hamstrings and gastrocnemius. Values are normalised to body weight. ID Pre- BoNT-A injection Post BoNT-A injection Knee Flexion Knee Extension Knee Flexion Knee Extension WL _R WL_L SB_R SB_L RM_R RM_L DM_R DM_L DJ_R DJ_L 65.4 60.0 67.1 58.9 68.8 57.4 52.6 53.8 63.6 79.2 261.3 179.7 193.8 208.2 180.1 214.0 167.1 170.3 240.5 256.0 78.6 50.4 48.2 28.6 51.5 42.2 64.4 59 75.1 62.9 197.6 250.2 185.4 175.1 248.5 260.4 173.6 181.1 294.8 255.7 Average 62.68 207.10 56.09 224.98 181 Table 4 PRE and POST values for plantar (PF) and dorsi flexor (DF) strength, in 15 children (30 legs) receiving BoNT-A to gastrocnemius. Values are presented in kilograms. Pre- BoNT-A injection Post BoNT-A injection ID PF DF PF DF WL _R WL_L TR_R TR_L TK_R TK_L SB_R SB_L RM_R RM_L MR_R MR_L MH_R MH_L LS_R LS_L LD_R LD_L JZ_R JZ_L JC_R JC_L JB_R JB_L DJ_R DJ_L ER_R ER_L DM_R DM_L 21.5 24.3 25.7 20.2 20.2 23.4 26.7 28.5 32.2 25 26.9 32.8 31 31.7 18.1 16.4 22.3 25 28.5 28.7 36.9 40.4 40.6 41.2 43.1 42.1 33.4 36.5 38.9 31.9 9.5 10.1 14.2 10.4 7.1 5.9 12.4 12.4 15.2 14.2 16.1 17.7 12.9 14.2 0 0 9.4 9.4 10.6 10.7 17.1 20.5 13 11.2 20.5 15.9 12.7 11.1 12.3 14.4 28.9 22.3 24.3 19.3 20.9 23.5 17.4 21.2 31.3 33 33.6 35.8 35.1 33.1 15.9 12.8 31.9 29.9 26.4 29.3 40 45.5 38.2 42.4 43.1 38.4 36.6 43.6 29.6 30.4 11.7 11.1 9.1 9.5 6.8 7.9 8.2 7.3 16.2 15.8 16.7 17.4 15.5 13.8 4.4 5.1 11.8 12.4 12.6 8.9 16.5 15.6 11.5 9.7 16.8 15.5 17.9 14.9 12.6 13.6 Average 29.8 12.0 30.5 12.2 . 182 FUNCTION Table 5 PRE and POST values for the Timed Up and Go (TUG) (seconds) and the 6Minute Walk Test (6MWT) (meters), in 10 children (20 legs) receiving BoNT-A to the gastrocnemius. Pre- BoNT-A injection Post BoNT-A injection ID TUG 6MWT TUG 6MWT JB LD TK LS JC MH TR ER MR JZ 3.98 6 5.41 4.73 3.68 5.79 4.05 3.2 4.26 3.89 652 508 496.5 447.8 633 627.5 590.6 672 564 583.5 3.98 5.55 5.26 5.47 3.75 5.79 4.98 3.17 5.26 3.37 612.2 497.9 491.5 420.5 621.5 552 538 631 607.3 627 Average 4.50 577.49 4.66 559.89 Table 6 PRE and POST values for the Timed Up and Go (TUG) (seconds) and the 6Minute Walk Test (6MWT) (meters), in 5 children (10 legs) receiving BoNT-A to the medial hamstrings and gastrocnemius. Pre- BoNT-A injection Post BoNT-A injection ID TUG 6MWT TUG 6MWT SB WL DM DJ RM 6.16 4.46 3.95 4.08 5.14 407.5 500 649.4 583.9 423.3 5.76 3.88 4.68 3.98 5.09 392 559.16 653.9 525.7 457 Average 4.76 512.82 4.68 517.55 183 APPENDIX D- PRINCESS MARGARET HOSPITAL ETHICAL APPROVAL 184 185 APPENDIX E- THE UNIVERSITY OF WESTERN AUSTRALIA ETHICAL APPROVAL 186 APPENDIX F- PARENT AND PARTICIPANT INFORMATION AND CONSENT FORMS 187 School of Sport Science, Exercise and Health M408 The University of Western Australia 35 Stirling Highway Crawley Western Australia 6009 Phone Fax Web +61 8 6488 +61 8 6488 1039 www.sseh.uwa.edu.au CRICOS Provider Code: 00126G Parkway (Entrance No 3) Nedlands Participant information Sheet Strength Training for Children with Cerebral Palsy who are having Botox® WHY? Botulinum toxin helps to improve muscle tightness in children with cerebral palsy. Reduced muscle tightness makes it easier to walk, and join in with activities with friends and family. Strong muscles are also just as important, and doing special strength exercises can help to make walking and these activities even easier. This study will help us understand how Botulinum toxin and strength training can help children with cerebral palsy. WHO CAN HELP? Children with cerebral palsy between the ages of 5 and 10 years WHAT WILL HAPPEN? You and your parent / guardian will come to the School of Sport Science, Exercise and Health at the University of Western Australia to do lots of fun and interesting things. A physiotherapist will look at how tight your leg muscles are and how much they move. Then you will have shiny markers put on your legs, so we can understand how you walk. You will do some short walks and you will get to see yourself walking on the special computer. You will then sit in a big chair and move your legs so we can see how strong your legs are. You will get to see what some of your leg muscles look like with a special machine called an Ultrasound. And finally you will get to know about what will happen when you go to have an MRI at the Children’s Hospital. With the help of your parent / guardian you will fill out two forms about the different activities you do. You will spend about two-three hours at the University of Western Australia. These are the shiny markers your will wear on your legs while you walk This is the chair you sit in when we test how strong your legs are 188 Then on another day you will actually get to have an MRI. An MRI takes lots of really great pictures of all the muscles in your legs. It takes about 20mins, so you can even bring your favourite DVD to watch at the same time. STRENGTH TRAINING After your first visit, you will get your very own set of strength training exercises especially made for you to help you get stronger. You will be able to do your exercises at your own home, with help from us as you go through your program. The exercises will take about 30min, and you will need to do them 3 times a week to get the best out of your program. WILL ANYTHING HURT? Some children, but not many, find the shiny markers itchy. The tape used to stick the markers is special and if it does itch it will not last for long. Sometimes you might find that you have slightly sore muscles the next day after working your leg muscles really hard, this won’t last more than a day. The MRI makes a loud noise when it takes its pictures, but you get to wear headphones that let you listen to your DVD, and your Mum or Dad can stay with you the whole time. WHAT ELSE DO I NEED TO KNOW? You do not have to participate in this research. You are free to pull out from the study at any time for any reason. You do not need to give a reason for pulling out. All your information will only been seen by us, we will not share it with other people. If we publish the results of this research your name or identity will not be revealed. PARTICIPANT BENEFITS If you participate in this study you will be provided with a report of your muscle tightness, muscle strength and how much your legs move. You will also get your very own set of strength exercises that will help to make you stronger in the muscles that are important for you. Your results will also help improve our understanding of how Botulinum toxin and strength training can help other children with cerebral palsy. If you would like any more information about this study please feel free to contact one of the research team. We are happy to answer your questions. Yours sincerely, Sîan Williams PhD Candidate Ph: ********** [email protected] Dr. Siobhán Reid Research Supervisor Dr. Catherine Elliott Research Supervisor Ph: ********** [email protected] Ph: ********** [email protected] Dr. Anna Gubbay Clinical Supervisor Ph: ********** [email protected] Nadine Williams Clinical Supervisor Ph: ********** [email protected] 189 School of Sport Science, Exercise and Health M408 The University of Western Australia 35 Stirling Highway Crawley Western Australia 6009 Phone Fax Web +61 8 6488 +61 8 6488 1039 www.sseh.uwa.edu.au CRICOS Provider Code: 00126G Parkway (Entrance No 3) Nedlands INFORMATION SHEET Lower Limb Strength Training for Children with Cerebral Palsy receiving Botulinum Toxin Purpose Botulinum Toxin (Botox) has been proven to be a safe and effective treatment of spasticity in children with Cerebral Palsy (CP). Botox® has been used at Princess Margaret Hospital for the past ten years to help children with CP. Muscular weakness has been identified as an area of concern for children with CP, with links to impaired functional ability. Strength training has been shown as an effective method of addressing this, with reported benefits to muscular strength extending to functional and psychosocial benefits. With both spasticity and muscular weakness acting as significant impairments on functional ability, this research will investigate the effects of combining Botox® therapy and targeted lower limb strength training for children with CP. This study aims to look at strength, tone, muscle morphology, function and quality of life of all children with CP. Finally, this study will investigate the most effective timing of strength training relative to children having Botox®. The data from these children will be compared to see if targeted lower limb strength training a) should be implemented into future therapy for children with CP, and b) when it should be implemented relative to Botox® injections. PARTICIPANT INCLUSION CRITERIA All participants must meet the following inclusion criteria to be eligible for this study: Be diagnosed with Cerebral Palsy Be between the ages of 5 and 10 years Have the ability to follow simple instructions Be able to walk indoors and outdoors on a level surface (with or without the use of a mobility device). Benefits It is anticipated that the addition of targeted strength training to current Botox® treatment regimens will result in benefits to strength, gait, functional ability and overall quality of life for children with CP. Your child will receive an individualized lower limb strength training program, which will be monitored and adjusted to suit your child’s needs. In addition to this, your child will receive additional clinical assessments that will be passed on to their hospital records and provide valuable information in monitoring your child’s progress. 190 This research will help with the development of ‘best practice’ standards of care for the long term use of Botox® in children with CP. The research has the potential to improve current treatment options available to children with CP. PROCEDURES Your child’s participation will require you and your child to attend four assessments, each involving a session at the University of Western Australia (UWA) and a visit to Princess Margaret Hospital (PMH) over a 26 week time period. Sessions at UWA will take approximately 3 hours, with the visit to PMH taking less than 30minutes. The visit to UWA and PMH will be within 1 week of each other. Assessment schedule is as follows: Assessment 1: 10 weeks before your child’s scheduled upcoming Botox® injection, Assessment 2: Within 1 week before receiving Botox®, Assessment 3: 1-2 weeks after receiving Botox® Assessment 4: 10 weeks after Assessment 3 UWA At the testing session at The University of Western Australia, strength assessments, gait motion analysis and clinical assessments will be performed. Strength will be assessed on a specialized piece of equipment which records muscle strength. Gait motion analysis will be assessed using a specialized infrared camera system. Reflective markers will be placed on your child’s skin at selected landmarks of the trunk and lower limb. Your child will then be asked to walk for 10 meters (a number of trials will be conducted) in a testing area with 7 infrared cameras recording their lower limb movement. Ultrasound measures of the size and length of two of your child’s leg muscles will be recorded. The ultrasound pictures are taken with a probe above the muscles on the skin surface. Your child will get to lie down and rest during this procedure which will take about 15-20mins. Most children find it relaxing, rather like a muscle massage. Lower limb anthropometric measures (lengths, breadths and circumferences), range of movement and a clinical assessment of spasticity will all be completed in the manner of a full physiotherapy clinical assessment. You and your child will be asked to complete a series of questionnaires relating to the physical abilities of your child and relate to quality of life, participation and activity. Also at UWA, your child will be familiarized with what will happen for their Magnetic Resonance Image (MRI) scan. This will be done by discussion of pictures in a storybook about having an MRI, and an opportunity to practice skills required in an MRI through play and simulation. The session includes listening to the sounds of the MRI unit, wearing headphones and watching a DVD of a child having an MRI. As a parent you will have the opportunity to ask questions during the practice session and discuss whether you would like to be in the room with your child when they have their MRI scan. PMH Following the session at UWA, the same person who did the MRI training will meet you at PMH for your child’s MRI scan. MRI is an advanced technology that lets your doctors see muscles and joints. The MRI scan will be used to provide excellent quality images of your child’s muscles. Your MRI appointment in the Department of Radiology at PMH will take approximately 30mins. Your child can take along a favourite CD or DVD to watch whilst the scan is happening, and you can stay in the room the whole time. You child will have two scans each taking approximately 6 minutes, during this time your child will have to lie very still. One scan will take pictures of the top of the legs, and the second scan will take pictures of the bottom of the legs Strength Training Your child will be provided with an individualized strength training program that will target specific muscles of lower limb including those injected with Botox®. The strength training will be a home based program that will take no longer than 30 minutes per session. Your child will be required to complete 3 sessions per week (e.g. Mon, Wed, Fri), for a total of 10 weeks. The program will be developed either between assessment 1 and 2, OR between assessments 3 and 4. You and your child will receive regular contact and assistance with the program to help with progression of the training exercises and any problems should they arise. RISKS / RESTRICTIONS Strength training Strength training may result in slight muscular soreness; however this will be temporary and minimal. Gait analysis There is a slight risk of skin irritation from the adhesive tape that attaches markers to the skin. The tape is low-allergenic and any irritation experienced will be short term. A very small percentage of children experience these skin reactions. Magnetic Resonance Imaging MRI is very safe; in fact it makes use of natural forces and has no known harmful effects. It’s important to know that MRI will not expose you or your child to radiation. Because MRI machines use a strong magnetic field metal objects can interfere with the exam. It is important that your child does not have any jewellery on them when they do the scan or any metal on their clothing (zips, studs or glittery writing). You will complete a formal sheet that asks whether or not your child has any other forms of metal that may be interfered with in the MRI e.g. pacemaker, metal implants, cochlear implants etc. 192 If you would like to be in the room with your child while they have a scan you must also let the doctor know if you have any of the above and make sure you have no metal objects on. There are no restrictions for your child after the scan and they can go right back to their everyday activities. Often children will feel very well rested after an MRI as they have been lying down doing absolutely nothing. PARTICIPANT RIGHTS Participation in this research is voluntary and you are free to withdraw your child from the study at any time and for any reason, without prejudice in any way. You need give no reason or justification for such a decision. However, all research data has to be retained even in the event of withdrawal from a study. If you withdraw from the study this will not prejudice your status and rights as a patient of Princess Margaret Hospital. Your child’s participation in this study does not prejudice any right to compensation, which you may have under the statute of common law. Participant confidentiality will be respected at all times. The results of this research may be published, however neither your child’s name nor identity shall be revealed, all data will be coded so as to preserve the identity and confidentiality of your child. If you have any queries or questions regarding this information, please do not hesitate to contact us to discuss. If you would like to make a complaint about the conduct of this study please contact Dr Geoff Masters, Executive Director of Medical Services on 9340 8245. Thank you for your time and consideration. Yours sincerely, Sîan Williams PhD Candidate Ph: ********** [email protected] Dr. Siobhán Reid Research Supervisor Ph: ********** Dr. Catherine Elliott Research Supervisor Ph: ********** [email protected] [email protected] Dr. Anna Gubbay Clinical Supervisor Ph: ********** [email protected] Nadine Williams Clinical Supervisor Ph: ********** [email protected] 193 FORM OF CONSENT PLEASE NOTE THAT PARTICIPATION IN RESEARCH STUDIES IS VOLUNTARY AND SUBJECTS CAN WITHDRAW AT ANY TIME WITH NO IMPACT ON CURRENT OR FUTURE CARE. I ............................................................................................ have read the information explaining the study entitled Given Names Surname Lower Limb Strength Training for Children with Cerebral Palsy receiving Botulinum Toxin I have read and understood the information given to me. Any questions I have asked have been answered to my satisfaction. I agree to allow...................................................................................................................................................................................... (full name of participant and relationship of participant to signatory) to participate in the study. I understand my child may withdraw from the study at any stage and withdrawal will not interfere with routine care. I agree that research data gathered from the results of this study may be published, provided that names are not used. Dated ........................................... Parent or Guardian’s Signature .................................................... Child’s Signature ............................................................................. (Where appropriate) I, ........................................................................... have explained the above to the signatories who stated that (Investigator’s full name) he/she understood the same. Signature ............................................................................................... The Human Research Ethics Committee at the University of Western Australia requires that all participants are informed that, if they have any complaint regarding the manner, in which a research project is conducted, it may be given to the researcher or, alternatively to the Secretary, Human Research Ethics Committee, Registrar’s Office, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009 (telephone number 6488-3703). All study participants will be provided with a copy of the Information Sheet and Consent Form for their personal records. 194 APPENDIX G- SELECTIVE CONTROL ASSESSMENT OF THE LOWER EXTREMITY (SCALE) APPENDIX H- CANADIAN OCCUPATIONAL PERFORMANCE MEASURE (COPM) 195 196 197 198 APPENDIX I- ASSESSMENT OF LIFE HABITS (LIFE-H) 199 200 201 202 203 204 205 APPENDIX J- CEREBRAL PALSY QUALITY OF LIFE QUESTIONNAIRE (CP-QOL) 206 207 208 209 210 APPENDIX K - EXAMPLE OF A 10 WEEK HOME BASED STRENGTH PROGRAM 1) You are aiming to do this 3 times each week! Perhaps set aside 3 days that you will do every week (e.g. Monday, Wednesday and Friday) 2) Remember to do your stretches before EVERY session! 3) Follow the exercises set out for you for the week that you are up to, if you have trouble doing any of the sets, write down what you did manage to do. 4) At the end of every session, you can put a sticker on your chart to show that you have completed your session. You can see all the hard work you have done by how many stickers your have at the end! 5) Have lots of fun! If you get stuck or need any help at all please call Sîan on ************ 211 211 I aim to improve on …. 1) How fast I can run over short distances (sprinting) 2) How fast I can run for longer distances (endurance running) 3) The distance that I can kick the ball for ruby The main muscles I will be working on are…… The muscles in my legs that will help me run fast. The muscles in my legs that will help me run fast over a long distance. The muscles in my legs that will help me kick a ball further. 212 212 Each week, put a sticker on the days you do your strength exercises Week 1 2 3 4 5 6 7 8 9 10 Sunday June Monday Tuesday Wednesday 27th 28th 29th 30th July 4th 5th 6th July 11th 12th July 18th July Thursday July Friday Saturday 1st 2nd 3rd 7th 8th 9th 10th 13th 14th 15th 16th 17th 19th 20th 21st 22nd 23rd 24th 25th 26th 27th 28th 29th 30th 31st st 2nd 3rd 4th 5th 6th 7th th 9th 10th 11th 12th 13th 14th August 1 August 8 August 15th 16 th 17th 18th 19th 20 August 22nd 23rd 24th 25th 26th 27 August 29th 30th 31st 1st 2nd Sep th 21 st th 28th 3rd 4th 213 213 Stretches: To be done before every session!!! Hips The helper supports the leg at the knee and heel, and brings the knee toward the chest. Hold for 15-20sec. Return the leg to starting position and repeat with the other leg. Hamstrings The person who is helping place one hand above the knee to keep it straight and the other hand under the heel. Keeping the leg straight, slowly raise the leg until a stretch is felt at the back of the thigh. Be sure to keep the other leg flat and hips down during the stretch. Hold for 15-20sec. Return the leg to starting and repeat with the other leg. Quadriceps Lie on your stomach, with legs together bend your knee. Hold your ankle with one hand and pull your heel to your bottom. Hold for 15-20sec. Return the leg to starting and repeat with the other leg. Plantar/Dorsi Sit on the floor with the knee bent and the heel on the floor. Pull up on your toes, or get your helper, to stretch the arch of the foot. Hold for 1520sec. Repeat, with a straight leg. Flexors 214 214 ******* Strength Program Week 1 *Tip* When applying manual resistance, you want him to be able to push all the way through his range, but he has to work for it! Exercise Description Repetitions Resistance/ weight Hip flexion (Hip bends) Performed one leg at a time. Lay on back, with legs out straight. Slowly bring knee up to chest, and lower. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Manual resistance applied against the thigh as they bring the knee up to the chest. Performed one leg at a time. Lying on stomach, bend knee to bring foot up to bottom, then lower back down to ground. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Manual resistance with hand on the back of the lower leg as they push up, and then on the front of the leg (pushing up) as they push down. Hamstring curl Seated Leg Extension Performed one leg at a time. Sit up straight in a chair, with feet flat on the floor. Keeping knees together, straighten out one leg all the way out, tightening your thigh muscles. Slowly lower foot back down to the floor. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Manual resistance with hand pressing down on the leg (at the ankle) as it rises up. ‘Superman’ Performed one leg at a time Lying on stomach, keep legs straight, slowly raise leg of ground, trying to keep the hips square on the ground. Hold for 3sec then lower. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 No resistance. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 No resistance. Side Leg Raises Lay on your side on the floor, with the top leg raised up on a chair/step. Lift the bottom leg off the floor as high as possible, keeping the knee straight. Slowly lower the leg back to the starting position. 215 Lay on your side with legs straight. Lift the top leg completely away from the lower leg. Careful not to roll over onto your front or back. Hold and return to the starting position. 215 **** ****Strength Program Week 2 Exercise Description Repetitions Resistance/ weight Hip flexion (Hip bends) Performed one leg at a time. Lay on back, with legs out straight. Slowly bring knee up to chest, and lower. . Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Attach weights around ankles. 1kg Performed one leg at a time. Lying on stomach, bend knee to bring foot up to bottom, then lower back down to ground. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Attach weights around ankles. 1kg Seated Leg Extension Performed one leg at a time. Sit up straight in a chair, with feet flat on the floor. Keeping knees together, straighten out one leg all the way out, tightening your thigh muscles. Slowly lower foot back down to the floor. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Attach weights around ankles 1kg ‘Superman’ Lying on stomach, keep legs straight, slowly raise one leg of ground, trying to keep the hips square on the ground. Hold for 3sec then lower. 3x12 Hamstring curl Lay on your side on the floor, with the top leg raised up on a chair/step. Lift the bottom leg off the floor as high as possible, keeping the knee straight. Slowly lower the leg back to the starting position. Side Leg Raises 3x10 Lay on your side with legs straight. Lift the top leg completely away from the lower leg. Careful not to roll over onto your front or back. Hold and return to the starting position. 216 216 **** ***** Strength Program Week 3 Exercise Description Repetitions Resistance/ weight Seated Hip flexion (hip bends) Sitting on a chair with feet square on the ground, one leg at a time, slowly raise knee up to chest, hold for 3 sec, lower. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Attach weights around ankles. (1kg) Seated Leg Extension Performed one leg at a time. Sit up straight in a chair, with feet flat on the floor. Keeping knees together, straighten out one leg all the way out, tightening your thigh muscles. Slowly lower foot back down to the floor. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Attach weights around ankles. (1.5kg) Hamstring curl Performed one leg at a time. Lying on stomach, bend knee to bring foot up to bottom, then lower back down to ground. 3x12 Attach weights around ankles. (1kg) Pelvis bridge Lay on back with knees bent up, feet are on the ground. Keeping shoulder blades on the ground. Slowly lift your bottom pushing through your feet, until your knees, hips & shoulders are in a straight line. Tighten your bottom muscles as you do this. Hold for 3 seconds then slowly lower your bottom back down. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 No weights. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 0.5kg Side Leg Raises Lay on your side on the floor, with the top leg raised up on a chair/step. Lift the bottom leg off the floor as high as possible, keeping the knee straight. Slowly lower the leg back to the starting position. Lay on your side with legs straight. Lift the top leg completely away from the lower leg. Careful not to roll over onto your front or back. Hold and return to the starting position. 217 217 **** ***** Strength Program Week 4 Exercise Description Repetitions Resistance/ weight Seated Hip flexion (hip bends) Sitting on a chair with feet square on the ground, one leg at a time, slowly raise knee up to chest, hold for 3 sec, lower. 3x12 Attach weights around ankles. (1kg) 3x15 Low weights (0.5kg) Hamstring curl Performed one leg at a time. Lying on stomach, bend knee to bring foot up to bottom, then lower back down to ground. Seated Leg Extension Sit up straight in a chair, with feet flat on the floor. Keeping knees together, straighten out one leg all the way out, tightening your thigh muscles. Slowly lower foot back down to the floor. 3x15 Low weights (1kg) Pelvis bridge Lay on back with knees bent up, feet are on the ground. Keeping shoulder blades on the ground. Slowly lift your bottom pushing through your feet, until your knees, hips & shoulders are in a straight line. Tighten your bottom muscles as you do this. Hold for 3 seconds then slowly lower your bottom back down. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Weights resting on tummy. 1kg 3x12 0.5kg Side Leg Raises Lay on your side on the floor, with the top leg raised up on a chair/step. Lift the bottom leg off the floor as high as possible, keeping the knee straight. Slowly lower the leg back to the starting position. Lay on your side with legs straight. Lift the top leg completely away from the lower leg. Careful not to roll over onto your front or back. Hold and return to the starting position. 218 218 **** ***** Strength Program Week 5 Exercise Description Repetitions Resistance/ weight Seated hip flexion (Hip bends) Sitting on a ball with feet square on the ground, one leg at a time, slowly raise knee up to chest, hold for 3 sec, lower. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Attach weights around ankles (1kg) Hamstring curl Performed one leg at a time. Lying on stomach, bend knee to bring foot up to bottom, then lower back down to ground 3x6 Heavy weights (1.5kg) Seated leg extension Sit up straight in a chair, with feet flat on the floor. Keeping knees together, straighten out one leg all the way out, tightening your thigh muscles. Slowly lower foot back down to the floor. 3x6 Heavy weights (1.5kg) Pelvic bridge Lay on back with knees bent up, feet are on the ground. Keeping shoulder blades on the ground. Slowly lift your bottom pushing through your feet, until your knees, hips and shoulders are in a straight line. Tighten your bottom muscles as you do this. Hold for 3 seconds then slowly lower your bottom back down. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Lift and extend one leg so that it is straight out, hold, lower and repeat with the other leg. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 1kg Lay on your side on the floor, with the top leg raised up on a chair/step. Lift the bottom leg off the floor as high as possible, keeping the knee straight. Slowly lower the leg back to the starting position. Side leg raises Lay on your side with legs straight. Lift the top leg completely away from the lower leg. Careful not to roll over onto your front or back. Hold and return to the starting position. 219 219 **** ***** Strength Program Week 6 Exercise Description Repetitions Resistance/ weight Seated Hip flexion (Hip bends) Sitting on a ball with feet square on the ground, one leg at a time, slowly raise knee up to chest, hold for 3 sec, lower. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Attach weights around ankles. (1kg) 3x15 Low weights (0.5kg) Hamstring curl Performed one leg at a time. Lying on stomach, bend knee to bring foot up to bottom, then lower back down to ground. Seated Leg Extension Sit up straight in a chair, with feet flat on the floor. Keeping knees together, straighten out one leg all the way out, tightening your thigh muscles. Slowly lower foot back down to the floor. 3x15 Low weights (1kg) Pelvis bridge Lay on back with knees bent up, feet are on the ball. Keeping shoulder blades on the ground. Slowly lift your bottom pushing through your feet, until your knees, hips and shoulders are in a straight line. Tighten your bottom muscles as you do this. Hold for 3 seconds then slowly lower your bottom back down. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 No weights. Standing Theraband hip flexion. Standing at a bench or chair for balance, with Theraband around your ankle so that it is pulling leg back. Keeping your back & knee straight, slowly take your leg forwards, like you are kicking a ball. Hold position &lower back to starting position. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Theraband. Attached around ankle to pull leg backwards. Standing Hip Abduction Begin by standing at a bench or table for balance. Keeping your back & knee straight and foot facing forwards, slowly take your leg to the side tightening the muscles at the side of your thigh. Hold for 3 seconds & lower. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 0.5kg 220 220 **** ***** Strength Program Week 7 221 Exercise Description Repetitions Resistance/ weight Swiss ball squat Standing against a wall with the Swiss ball between back and the wall, and legs slightly in front of the body. Keeping it slow and controlled, lower down to a squat (knees ~90°) and then rise back up to a standing position. Knees should stay in line with the legs. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 No weights. Keep it slow. Standing Hamstring curl Standing at a bench or chair for balance, one leg at a time, bend knee so that foot comes as high as you can up to your bottom. Hold for 3 sec, lower. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 1kg Seated Leg Extension Sit up straight in a chair, with feet flat on the floor. Keeping knees together, straighten out one leg all the way out, tightening your thigh muscles. Slowly lower foot back down to the floor. 3x6 Heavy weights (2kg) Pelvis bridge Lay on back with knees bent up, feet are on the ball. Keeping shoulder blades on the ground. Slowly lift your bottom pushing through your feet, until your knees, hips and shoulders are in a straight line. Tighten your bottom muscles as you do this. Hold for 3 seconds then slowly lower your bottom back down. 3x12 No weights. Standing Theraband hip flexion. Standing at a bench or chair for balance, with Theraband around your ankle so that it is pulling leg back. Keeping your back & knee straight, slowly take your leg forwards, like you are kicking a ball. Hold position &lower back to starting position. 3x12 Theraband. Attached around ankle to pull leg backwards. Standing Hip Abduction Begin by standing at a bench or table for balance. Keeping your back & knee straight and foot facing forwards, slowly take your leg to the side tightening the muscles at the side of your thigh. Hold for 3 seconds & lower. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 1kg 221 **** ***** Strength Program Week 8 Exercise Description Repetitions Resistance/ weight Swiss ball squat Standing against a wall with the Swiss ball between back and the wall, and legs slightly in front of the body. Keeping it slow and controlled, lower down to a squat (knees ~90°) and then rise back up to a standing position. Knees should stay in line with the legs. 3x12 No weights. Keep it slow. Lunges Begin standing with one leg positioned in front & one leg behind as shown in the picture. Slowly lower your body until your front knee is at a right angle. Try to keep your knee in line with your middle toe & your feet facing forward. Keep the movement slow & controlled. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 No weight Standing Hamstring curl Standing at a bench or chair for balance, one leg at a time, bend knee so that foot comes as high as you can up to your bottom. Hold for 3 sec, lower. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 1kg Standing. Leg flexion ‘kicks’ Standing at a bench or chair for balance, with weights attached at the ankle. Standing up as straight as you can, kick as high up as you can. As if you are kicking a big ball as far away as you can. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Attach weights around ankles. 1kg Pelvis bridge Lay on back with knees bent up, feet are on the ball. Keeping shoulder blades on the ground. Slowly lift your bottom pushing through your feet, until your knees, hips and shoulders are in a straight line. Tighten your bottom muscles as you do this. Hold for 3 seconds then slowly lower your bottom back down. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Weights on tummy 1kg Side step Standing up nice and tall with feet facing forwards, take a side step without twisting your body to the side. Repeat side steps in both directions. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 1kg Obstacle course 222 15m x 10m area 1: Sit to stand x3 2: Sprint run 2x 3: Jumps 4: Sprint Run 5: High Knee Walking 6: Run 1 whole lap Sprint run High knee Walking Jumps Sprint run 222 **** ***** Strength Program Week 9 Exercise Description Repetitions Resistance/ weight Swiss ball squat Standing against a wall with the Swiss ball between back and the wall, and legs slightly in front of the body. Keeping it slow and controlled, lower down to a squat (knees ~90°) and then rise back up to a standing position. Knees should stay in line with the legs. Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 Holding on to weights Lunges Begin standing with one leg positioned in front & one leg behind as shown in the picture. Slowly lower your body until your front knee is at a right angle. Try to keep your knee in line with your middle toe & your feet facing forward. Keep the movement slow & controlled. 3x12 No weight Pelvis bridge Lay on back with knees bent up, feet are on the ball. Keeping shoulder blades on the ground. Slowly lift your bottom pushing through your feet, until your knees, hips and shoulders are in a straight line. Tighten your bottom muscles as you do this. Hold for 3 seconds then slowly lower your bottom back down. 3x12 Weights on tummy 1kg Standing. Leg flexion ‘kicks’ Standing at a bench or chair for balance, with weights attached at the ankle. Standing up as straight as you can, kick as high up as you can. As if you are kicking a big ball as far away as you can. 3x12 Attach weights around ankles. 1kg Duradisc Side step with squat Obstacle course Stand with both feet on Duradisc and try to stay balanced for 30 seconds! Standing up nice and tall with feet facing forwards, take a side step without twisting your body to the side and square. Repeat side steps in both directions. 223 15m x 10m area 1: Sit to stand x3 2: Sprint run 3x 3: Jumps 4: Sprint Run 5: High Knee Walking 6: Run 1 whole lap 3 x30sec Day 1: 3x6 Day 2: 3x8 Day 3: 3x10 1kg Sprint run High knee Walking Jumps Sprint run 223 **** ***** Strength Program Week 10 Exercise Description Repetitions Swiss ball squat Standing against a wall with the Swiss ball between back and the wall, and legs slightly in front of the body. Keeping it slow and controlled, lower down to a squat (knees ~90°) and then rise back up to a standing position. Knees should stay in line with the legs. 3x12 Holding on to weights Pelvis bridge Lay on back with knees bent up, feet are on the ball. Keeping shoulder blades on the ground. Slowly lift your bottom pushing through your feet, until your knees, hips and shoulders are in a straight line. Tighten your bottom muscles as you do this. Hold for 3 seconds then slowly lower your bottom back down. 3x12 Weights on tummy 1kg Kicks with Weights Standing at a bench or chair for balance, with weights attached at the ankle. Standing up as straight as you can, kick as high up as you can. As if you are kicking a big ball as far away as you can. Duradisc Stand with both feet on Duradisc and try to stay balanced for 30 seconds! Side step with squat Obstacle course Standing up nice and tall with feet facing forwards, take a side step without twisting your body to the side and square. Repeat side steps in both directions. 15m x 10m area 1: Sit to stand x5 2: Sprint run 4x 3: Jumps 4: Sprint Run 5: High Knee Walking 6: Run 1 whole lap Resistance/ weight 3x 12 Attach weights around ankles. 1kg 3 x30sec 3x12 1kg Sprint run High knee Walking Jumps Sprint run 224 224