Mobility, Stability, Adaptability The challenges of walking for people with Hereditary Spastic Paraplegia Lotte van de Venis
Mobility, Stability, Adaptability The challenges of walking for people with Hereditary Spastic Paraplegia Lotte van de Venis
The studies presented in this thesis were carried out at the Department of Rehabilitation, Donders institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands. The printing and distribution of this thesis was financially supported by: Radboud University Medical Centre | Donders Institute for Brain, Cognition and Behavior | Scientific College Physical Therapy (WCF) of the Royal Dutch Society for Physical Therapy (KNGF) | Motek Medical | Merz Therapeutics | Ipsen Farmaceutica B.V. | OIM Orthopedie XXX ARIAL, TRACKING +200, ALL CAPS Name: 8 pt Arial, tracking +10 ISBN 978-94-6284-322-6 Cover design Anne Thomaes | www.glasatelierthomaes.com Printed by Ipskamp Printing | proefschriften.net Layout and design Daisy Zunnebeld | persoonlijkproefschrift.nl © L. van de Venis, 2024 All rights are reserved. No part of this book may be reproduced, distributed, stored in a retrieval system, or transmitted in any form or by any means, without prior written permission of the author.
Mobility, Stability, Adaptability The challenges of walking for people with Hereditary Spastic Paraplegia Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. dr. J.M. Sanders, volgens besluit van het college voor promoties in het openbaar te verdedigen op vrijdag 7 juni 2024 om 10.30 uur precies door Lotte van de Venis geboren op 11 mei 1993 te Zwolle
Promotoren: Prof. dr. A.C.H. Geurts Prof. dr. B.P.C. van de Warrenburg Prof. dr. V.G.M. Weerdesteyn Copromotor: Dr. J.H. Nonnekes Manuscriptcommissie: Prof. dr. D.H.J. Thijssen Prof. dr. A.I. Buizer (Amsterdam UMC) Prof. dr. C.J.C. Lamoth (Rijksuniversiteit Groningen)
Table of contents Chapter 1 General introduction 7 Chapter 2 Covid-19 reveals influence of physical activity on symptom severity in Hereditary Spastic Paraplegia Journal of Neurology. 2020 Dec;267(12):3462-3464. 21 Chapter 3 Improving gait adaptability in patients with Hereditary Spastic Paraplegia (Move-HSP): study protocol for a randomized clinical trial Trials. 2021 Jan 7;22(1):32 29 Chapter 4 Gait-adaptability training in Hereditary Spastic Paraplegia: a randomized clinical trial Neurorehabilitation and Neural Repair, 2023 Jan;37(1):27-36 49 Chapter 5 Increased trunk movements in people with hereditary spastic paraplegia: do these involve balance correcting strategies? Journal of Neurology. 2022 Aug;269(8):4264-4269 69 Chapter 6 Are clinical tests and biomechanical gait stability measures able to identify fallers in hereditary spastic paraplegia? Submitted 83 Chapter 7 Summary and general discussion 101 Chapter 8 Samenvatting 123 Appendices Dankwoord Curriculum Vitae List of Publications Portfolio Research data management according to FAIR principles Donders Graduate School for Cognitive Neuroscience 133 141 143 145 148 151
Chapter 1 General introduction
8 Chapter 1 General introduction Everyone occasionally stumbles, trips or falls. But what if this starts to occur more frequently? If you start stumbling at work when going for a cup of coffee? Or if you feel as if you trip and fall over the slightest irregularity in the pavement, or it becomes challenging to engage in a conversation while walking. You experience leg stiffness that is becoming more noticeable and fatiguing over time. Even though you value social interactions, at times you decide to skip sports activities, birthdays, and stay inside while groceries and packages are being delivered. Nevertheless, the leg stiffness intensifies, and colleagues start making comments, asking whether you might have an injury, because it looks like you have some trouble walking. In an attempt to describe what you feel, you use the example of walking with a ‘potato bag’ over your legs. You feel as if you are clumsily waddling around with a heavy bag filled with potatoes, slow, off-balance, and bothersome every step you make. Several members of your family (have) experience(d) similar problems, but nobody has yet sought medical care. When consulting a general practitioner, you are referred to a neurologist. After several investigations, it turns out that the leg stiffness you experience is called ‘spasticity’, caused by a condition called ‘hereditary spastic paraplegia’. You are referred to a rehabilitation physician who explains that the leg problems are slowly progressive, but that it is difficult to predict the rate of progression. You learn that spasticity, including muscle stiffness, muscle cramps and restless legs, can be alleviated with medication and exercises, but that additional muscle weakness and loss of deep sensibility will progressively hamper your balance and gait capacity. Hereditary Spastic Paraplegia Hereditary Spastic Paraplegia (HSP) refers to a genetic and clinical heterogenous group of movement disorders.3,4 From a clinical perspective, HSP can be classified into pure or complex forms.5 Pure forms of HSP generally present with progressive bilateral spasticity, muscle weakness, and loss of proprioception of the lower extremities.3 In addition, urinary dysfunctions like incontinence or hesitance are common.6-8 In complex forms of HSP, additional neurological deficits may be present, such as ataxia, cognitive impairments, seizures, peripheral neuropathy, or upper extremity involvement.3 The prevalence of HSP is estimated to be about 2-10 of 100.000 individuals in the general population.9 The first signs and symptoms are often subtle with the development of leg stiffness, which may present at any age between infancy until late adulthood. Insight in the individual prognosis is limited, but disease progression is generally slow.10,11 Yet, a later onset has been associated with a faster disease progression.10-12
9 General introduction The common pathological feature of HSP is a retrograde axonal degeneration of the corticospinal tracts, posterior spinal columns, and, to a lesser extent, the spinocerebellar fibers.4 This degeneration may be due to e.g. abnormal membrane trafficking, axonal development, or mitochondrial functioning.13 To date, up to 87 genetic subtypes associated with HSP have been identified. The different genetic forms are assigned spastic paraplegia loci (SPG) based on sequential numbering in the order of discovery (e.g., SPG4, SPG8). Autosomal dominant, autosomal recessive, X-linked and mitochondrial modes of inheritance have all been reported.14 Of note, it is estimated that a genetic diagnosis can still not be made in 51-71% of all suspected cases, despite the introduction of whole exome sequencing. This is due to the large number of genes involved in HSP and the regular discovery of new genes.14 Gait functioning As illustrated above, the ability to walk is an important part of daily living: it enables us to move around within our home and community, and is, therefore, an important factor promoting independent living, social participation and quality of life.15,16 It requires more than just lifting one foot and placing it in front of the other. In contrast, purposeful walking requires a sufficient level of gait functioning that consists of three aspects: stepping, maintaining dynamic balance, and gait adaptability.17 Stepping First, people have to generate a basic stepping pattern. This relates to the rhythmic and repetitive movements of the legs in interaction with the trunk in order to generate propulsion (i.e., forward movement of the body).17 The description of the stepping pattern is commonly based on distance (i.e., spatial) or time (i.e., temporal) spanned between gait events, referred to as spatiotemporal gait parameters (e.g., step length, step width or step time). Furthermore, position and orientation of body segments is often used, referred to as joint kinematics (e.g., knee flexion or extension). Maintaining dynamic balance Second, people require dynamic balance control, referring to the ability to remain stable and upright while walking, despite the occurrence of both selfinitiated perturbations (e.g., the destabilizing impact of ankle push-off required for forward propulsion) and external perturbations (e.g., bumping into another person or walking over uneven terrain).17 To recover from such perturbations requires sufficient proactive and reactive balance control, depending on a wellfunctioning sensory system to adequately register when dynamic balance is jeopardized, and a good motor system to generate a coordinated response. Then, three strategies can be used to maintain balance while walking. Preferred are 1) the foot placement strategy (i.e., people alter foot placement of the swing leg to adjust 1
10 Chapter 1 the base of support), and 2) ankle strategies (i.e., ankle moments of the stance leg are modulated to make (minor) adjustments to center of mass movements). When both strategies are hindered, 3) hip strategies can be used (i.e., upper body segments are rotated around the center of mass).18 Several methods then exist to objectify dynamic balance. In clinical practice, this is often done as part of clinical tests that assess balance capacity (e.g., with the Mini Balance Evaluations Systems Test). More recently, there is growing interest in the use of biomechanical measures that assess dynamic balance or ‘gait stability’. Gait stability measures often require sophisticated motion capture systems and complex calculations.19 In this thesis, we refer to the following measures of gait stability: gait variability, margin of stability, foot placement deviation, and Lyapunov exponents (for a detailed description – see box 1). Gait adaptability Finally, people require adaptive capabilities during gait, so that the stepping pattern can be altered to meet environmental demands. Nine domains have been identified that necessitate gait adaptability: (1) obstacle negotiation (e.g., alter step length to step over a loose tile), (2) temporal demands (e.g., slowing down in a busy street), (3) cognitive dual-tasking (e.g., engaging in a conversation while walking), (4) terrain demands (e.g., walking over uneven surfaces), (5) ambient demands (e.g., lighting or familiarity with the surroundings), (6) postural transitions (e.g., turning while walking), (7) motor dual-tasking (e.g., manipulating a phone while walking), (8) physical load (e.g., carrying a bag), and (9) maneuvering in traffic.17 It is evident that gait adaptability is of high importance for safe and independent ambulation in the community.17 Gait adaptability can be assessed using clinical tests, such as the obstacle subtask of the Emory Functional Assessment Profile (E-FAP)20,21, or the recently developed Walking Adaptability Ladder test for Kids (WAL-K).22
11 General introduction Box 1. Biomechanical methods to assess dynamic balance Gait variability Gait variability is defined as the fluctuation in spatiotemporal characteristics that occur from step to step during walking.19 Variability is commonly determined for step length, step time, and step width, and expressed in a standard deviation or coefficient of variation (i.e., standard deviation divided by the mean). It is often assumed that a higher spatiotemporal gait variability reflects reduced gait stability.23-25 Margin of Stability In order to maintain balance during quiet stance, one has to be able to maintain one’s center of mass (CoM) within the area encompassed by both feet - the so-called base of support (BoS). In order not to fall in dynamic situations, for example during gait, a similar requirement exists where the so-called “extrapolated center of mass” (XCoM; a variable that takes both position and velocity of the CoM into account) needs to be maintained within the base of support (BoS).26 The distance between the XCoM and the BoS is called the margin of stability (MoS). If the MoS is negative (i.e., the XCoM exceeds the BoS), the person has to make an adjustment – for example take a step – to prevent a fall. A MoS value approaching nill, or an increase in the variability of the MoS are therefore considered to reflect gait instability.27 Foot Placement Deviation The foot placement deviation (FPD) reflects the adherence to the foot placement strategy. This strategy is based on the preposition that CoM position and CoM velocity at midstance can predict the ideal foot placement of the next step.28 To ensure that the actual foot is placed at this predicted ideal location, adjustments in the timing and location of the actual foot placement have to be controlled. The accuracy of the foot placement strategy is reflected in the root mean square error (RMSE) of the actual foot placement compared to the predicted foot placement. A higher RMSE indicates a lower accuracy of the foot placement strategy, which indicates reduced gait stablity.29 Local Dynamic Exponents Local dynamic exponents (LDEs) reflect the ability of a person to attenuate the effects of small perturbations during gait.19 For example, in an optimal condition, the variability of trunk displacements during consecutive steps is nil. However, due to small perturbations that arise during natural gait (e.g., during heel strike or small differences in floor height), trunk displacements will be somewhat different from one step to the other. If these differences are not attenuated, their impact will increase exponentially with time. A higher LDE implies that a person is less able to attenuate small gait perturbations, indicating less gait stability.30 1
12 Chapter 1 The impact of HSP on gait HSP-related signs and symptoms impact on all three requirements of purposeful walking: In general, people with HSP show a reduced gait speed and reduced step length in comparison to healthy controls.31,32 From the early stages of HSP, increased trunk movements during gait can be observed. Previous studies have reported on this phenomenon, though it is not completely clear how these enhanced trunk movements should be interpreted. Presumably, the increased trunk movements are generated to improve foot clearance and step length, but there may be additional explanations.33,34 Step width can initially be increased as a compensation to aid balance. Yet, when HSP progresses, hip adductor spasticity increases, which often causes a narrowing of step width. This can result in scissoring gait; a gait pattern in which the legs cross each other.32,33,35 Furthermore, due to spasticity and progressive shortening of the calf muscles, toe walking can be seen; a gait pattern characterized by the absence of heel-to-floor contact.36 Loss of proprioception results in delayed balance responses, while spasticity of the lower extremities, contractures and subsequent ankle foot deformities (e.g. pes equinovarus) may further hinder adequate balance control. Indeed, both feetin-place responses during unperturbed standing, and the ability to make effective balance correcting steps following perturbations can be hampered.37 With respect to gait adaptability, progressive spasticity, muscle weakness and balance impairments may hinder the ability to alter the gait pattern to changing environmental demands. It is therefore understandable that HSP-related signs and symptoms result in reduced gait functioning.16 Impact of HSP on activities and participation in daily life For people with HSP, balance and gait impairments are among their most disabling symptoms.16 It challenges a variety of daily activities, like standing still, stepping over objects, walking on uneven terrain, or getting in and out of a car. This hinders personal hygiene, employment, housekeeping and participation in leisure activities.15 In addition, activities that require standing or walking generally cost people with HSP more effort and energy compared to their peers.15,38 In order to compensate, intensity of daily physical activities is often reduced, or certain activities are ceased completely. A higher severity of gait impairments – specifically when an aid is required to walk – is associated with a reduced quality of life.35,39 As the severity of balance and gait impairments progresses, the risk of falls and fall-related injuries increases: 67% of people with HSP report to fall at least once a year, and in 51%, a fall has led to an injury at least once. It is well known that the experience of a fall may trigger a vicious cycle40-42: due to the fall, people may develop fear-of-falling. Indeed, in the aforementioned study, 73% of people with HSP stated they were moderately to very afraid of falling.16 A fear of falling can
13 General introduction make people more cautious and make them cease certain activities, even when they are still physically capable of doing them. This can result in physical inactivity and deconditioning, along with a decline in muscle strength and balance capacity, which further increases fall risk.42 To prevent or break this vicious cycle, insight is needed into parameters that can identify people with HSP who are at increased risk of falling in order to tailor fall prevention interventions. Currently, this is a relatively unexplored topic in people with HSP. Clinical management of balance and gait problems in HSP. During consultations with their physician and allied health professionals, people with HSP prioritize the rehabilitation of their balance and gait problems.43 As there are currently no therapies available to prevent, delay or reverse the progressive impairments due to HSP, the clinical management of balance and gait problems in people with HSP must be symptomatic. Possible interventions consist of four domains: (1) exercise therapy (e.g. aimed at maintaining muscle length and functional skills), (2) pharmacological interventions (e.g. to reduce troublesome spasticity), (3) walking aids and orthotic devices, including orthopedic footwear (e.g. to support foot clearance and compensate for foot deformities), and (4) surgical interventions (e.g. to reduce disabling spasticity or contractures). In addition, self-management programs (e.g. directed at fatigue management or attaining adequate levels of physical activity) can be indicated. Some people may require psychosocial support to deal with, for instance, emotional of societal consequences.43,44 A few studies have evaluated the efficacy of gait training interventions.45 The interventions were mainly task-specific, and consisted of functional gait training in combination with intramuscular botulinum toxin46, robotic gait training (e.g., Lokomat® or exoskeleton)47,48, or hydrotherapy49. Following these interventions, promising improvements were reported regarding balance capacity, gait capacity, pain relief, and quality of life.46-49 Although these results are promising, most of the studies used an uncontrolled design comparing pre vs post-training assessments, and included a small number of participants. None of the aforementioned gait training interventions included context-specific tasks that targeted gait adaptability required for walking in the community. Therefore, part of this thesis focuses on the effect of a gait adaptability training in ambulatory people with pure HSP. Gait adaptability training was provided on the C-Mill, a treadmill equipped with augmented reality that provides contextspecific gait adaptability training exercises (for a detailed description of the C-Mill - see Box 2). 1
14 Chapter 1 Box 2. C-MILL The C-Mill1,2 (Motek, Amsterdam, The Netherlands) is a treadmill setup with a walking area of 1x3meters, integrated force plates, a projector, and a safety frame. Visual context (e.g., stepping targets or obstacles) can be projected onto the walking surface to create an augmented reality environment. This is done in an interactive manner. Due to online monitoring of the position and timing of foot placement of the user via the integrated force plates, the visual context can be projected in a gait-dependent manner, and realtime feedback of success or failure can be provided. The C-Mill has specifically been designed to train gait adaptability in a context-specific manner. It offers various tasks, including goal-directed stepping, obstacle negotiation and adaptation to various walking speed. This mimics daily life, as walking in the community requires a person to be able to adapt their gait to meet environmental demands, such as negotiating one’s way through a cluttered terrain, increasing walking speed for a green traffic light, or slowing down speed in a crowded area. The C-Mill provides a safe training environment, given that it has a safety harness for fall protection. As an additional feature, an optional body-weight support system can be installed to unload patients up to 40% of their body weight. Regarding the work presented in this thesis, the body-weight support feature was not used during the gait adaptability training. Training was always supervised by a physical therapist with ample experience in C-Mill training. Figure 1: The C-Mill with various exercises projected onto the treadmill belt.
15 General introduction Outline of the thesis The aim of this thesis is to gain more insight into how balance and gait impairments in people with pure HSP affect their gait capacity. More specifically, we will investigate which factors impact negatively or positively on symptom severity, gait adaptability and fall risk. Furthermore, we will evaluate whether context-specific gait training can improve gait adaptability in people with pure HSP. Based on clinical experience, it is likely that sufficient levels of daily physical activity have a positive impact on the severity of spasticity-related symptoms, whereas psychological stress may impact negatively. In Chapter 2, I investigate this assumption, and report on the results of an online questionnaire that was conducted to evaluate the impact of Covid-19 measures in people with HSP. The Covid-19 measures provided a unique opportunity to evaluate whether changes in levels of physical activity and psychological stress were associated with changes in symptom severity, such as muscle stiffness, pain, or gait impairments. In Chapter 3, I describe the research protocol of a randomized clinical trial with a partial cross-over design that was conducted to evaluate the efficacy of a contextspecific gait adaptability training in ambulatory people with HSP. Chapter 4 presents the results of this randomized clinical trial. I evaluate the efficacy of a five-week gait adaptability training program, added to usual care, to usual care alone on outcome measures related to balance and gait capacity, balance confidence and physical activity. Furthermore, I evaluate potential retention effects of the gait adaptability training after fifteen weeks. In Chapter 5, I take a closer look at increased trunk movements that are observed during gait in people with HSP and investigate whether these trunk movements can (partly) be explained as balance correcting strategies. To this end, I explore whether there is an association between increased trunk movements and reduced balance performance. In Chapter 6, I evaluate whether commonly used clinical tests evaluating balance confidence, balance capacity or gait capacity, and novel biomechanical measures of gait stability differ between people with HSP and healthy controls, and whether these tests may have the potential to differentiate fallers from non-fallers among people with HSP. Finally, in Chapter 7, the main findings of this thesis are summarized and discussed, and implications for clinical practice and future research are provided. 1
16 Chapter 1 Reference list 1. Roerdink, M.B., PJ, Device for displaying target indications for foot movements to persons with a walking disorder. 2009. 2. Roerdink, M., et al., Online gait event detection using a large force platform embedded in a treadmill. J Biomech, 2008. 41(12): p. 2628-32. 3. Shribman, S., et al., Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches. Lancet Neurol, 2019. 18(12): p. 1136-1146. 4. Salinas, S., et al., Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol, 2008. 7(12): p. 1127-38. 5. Harding, A.E., Classification of the hereditary ataxias and paraplegias. Lancet, 1983. 1(8334): p. 1151-5. 6. Braschinsky, M., et al., Bladder dysfunction in hereditary spastic paraplegia: what to expect? J Neurol Neurosurg Psychiatry, 2010. 81(3): p. 263-6. 7. Schneider, S.A., et al., Urinary symptoms, quality of life, and patient satisfaction in genetic and sporadic hereditary spastic paraplegia. J Neurol, 2019. 266(1): p. 207-211. 8. Joussain, C., et al., Urological dysfunction in patients with hereditary spastic paraplegia. Neurourol Urodyn, 2019. 38(4): p. 1081-1085. 9. Ruano, L., et al., The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology, 2014. 42(3): p. 174-83. 10. Harding, A.E., Hereditary “pure” spastic paraplegia: a clinical and genetic study of 22 families. J Neurol Neurosurg Psychiatry, 1981. 44(10): p. 871-83. 11. McDermott, C., et al., Hereditary spastic paraparesis: a review of new developments. J Neurol Neurosurg Psychiatry, 2000. 69(2): p. 150-60. 12. Loureiro, J.L., et al., Autosomal dominant spastic paraplegias: a review of 89 families resulting from a portuguese survey. JAMA Neurol, 2013. 70(4): p. 481-7. 13. Blackstone, C., C.J. O’Kane, and E. Reid, Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci, 2011. 12(1): p. 31-42. 14. Saputra, L. and K.R. Kumar, Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia. Curr Neurol Neurosci Rep, 2021. 21(4): p. 15. 15. Kerstens, H., et al., Stumbling, struggling, and shame due to spasticity: a qualitative study of adult persons with hereditary spastic paraplegia. Disabil Rehabil, 2020. 42(26): p. 3744-3751. 16. van Lith, B.J.H., et al., Experienced complaints, activity limitations and loss of motor capacities in patients with pure hereditary spastic paraplegia: a web-based survey in the Netherlands. Orphanet J Rare Dis, 2020. 15(1): p. 64. 17. Balasubramanian, C.K., D.J. Clark, and E.J. Fox, Walking adaptability after a stroke and its assessment in clinical settings. Stroke Res Treat, 2014. 2014: p. 591013. 18. Reimann, H.J., JJ, Strategies for the Control of Balance During Locomotion. Kinesiology Review, 2017. 7: p. 1. 19. Bruijn, S.M., et al., Assessing the stability of human locomotion: a review of current measures. J R Soc Interface, 2013. 10(83): p. 20120999. 20. Fonteyn, E.M., et al., Gait adaptability training improves obstacle avoidance and dynamic stability in patients with cerebellar degeneration. Gait Posture, 2014. 40(1): p. 247-51.
17 General introduction 21. Heeren, A., et al., Step by step: a proof of concept study of C-Mill gait adaptability training in the chronic phase after stroke. J Rehabil Med, 2013. 45(7): p. 616-22. 22. Kuijpers, R., et al., Reliability and construct validity of the Walking Adaptability Ladder Test for Kids (WAL-K): a new clinical test for measuring walking adaptability in children. Disabil Rehabil, 2022. 44(8): p. 1489-1497. 23. Toebes, M.J., et al., Local dynamic stability and variability of gait are associated with fall history in elderly subjects. Gait Posture, 2012. 36(3): p. 527-31. 24. Ma, L., et al., Gait variability is sensitive to detect Parkinson’s disease patients at high fall risk. Int J Neurosci, 2022. 132(9): p. 888-893. 25. Schniepp, R., et al., Increased gait variability is associated with the history of falls in patients with cerebellar ataxia. J Neurol, 2014. 261(1): p. 213-23. 26. Hof, A.L., M.G. Gazendam, and W.E. Sinke, The condition for dynamic stability. J Biomech, 2005. 38(1): p. 1-8. 27. Fallahtafti, F., et al., Margin of Stability May Be Larger and Less Variable during Treadmill Walking Versus Overground. Biomechanics (Basel), 2021. 1(1): p. 118-130. 28. Wang, Y. and M. Srinivasan, Stepping in the direction of the fall: the next foot placement can be predicted from current upper body state in steady-state walking. Biol Lett, 2014. 10(9). 29. Zwijgers, E., et al., Impaired foot placement strategy during walking in people with incomplete spinal cord injury. J Neuroeng Rehabil, 2022. 19(1): p. 134. 30. Mehdizadeh, S., A robust method to estimate the largest Lyapunov exponent of noisy signals: A revision to the Rosenstein’s algorithm. J Biomech, 2019. 85: p. 84-91. 31. Serrao, M., et al., Dataset on gait patterns in degenerative neurological diseases. Data Brief, 2018. 16: p. 806-816. 32. Klebe, S., et al., Gait analysis of sporadic and hereditary spastic paraplegia. J Neurol, 2004. 251(5): p. 571-8. 33. Serrao, M., et al., Gait Patterns in Patients with Hereditary Spastic Paraparesis. PLoS One, 2016. 11(10): p. e0164623. 34. Adair, B., et al., Kinematic gait deficits at the trunk and pelvis: characteristic features in children with hereditary spastic paraplegia. Dev Med Child Neuro,2016.58(8):p.829-35. 35. Gaßner, H., et al., Functional gait measures correlate to fear of falling, and quality of life in patients with Hereditary Spastic Paraplegia: A cross-sectional study. Clin Neurol Neurosurg, 2021. 209: p. 106888. 36. Nonnekes, J., et al., Improved Gait Capacity after Bilateral Achilles Tendon Lengthening for Irreducible Pes Equinus Due to Hereditary Spastic Paraplegia: a Case Report. J Rehabil Med Clin Commun, 2021. 4: p. 1000059. 37. Nonnekes, J., et al., Pathophysiology, diagnostic work-up and management of balance impairments and falls in patients with hereditary spastic paraplegia. J Rehabil Med, 2017. 49(5): p. 369-377. 38. Rinaldi, M., et al., Increased lower limb muscle coactivation reduces gait performance and increases metabolic cost in patients with hereditary spastic paraparesis. Clin Biomech (Bristol, Avon), 2017. 48: p. 63-72. 39. Klimpe, S., et al., Disease severity affects quality of life of hereditary spastic paraplegia patients. Eur J Neurol, 2012. 19(1): p. 168-71. 1
18 Chapter 1 40. Yardley, L. and H. Smith, A prospective study of the relationship between feared consequences of falling and avoidance of activity in community-living older people. Gerontologist, 2002. 42(1): p. 17-23. 41. Delbaere, K., et al., Fear-related avoidance of activities, falls and physical frailty. A prospective community-based cohort study. Age Ageing, 2004. 33(4): p. 368-73. 42. Scholz, M., et al., Fear of falling and falls in people with multiple sclerosis: A literature review. Mult Scler Relat Disord, 2021. 47: p. 102609. 43. Kerstens, H., et al., Healthcare needs, expectations, utilization, and experienced treatment effects in patients with hereditary spastic paraplegia: a web-based survey in the Netherlands. Orphanet J Rare Dis, 2021. 16(1): p. 283. 44. Veenhuizen, Y., et al., Self-management program improves participation in patients with neuromuscular disease: A randomized controlled trial. Neurology, 2019. 93(18): p. e1720-e1731. 45. Bellofatto, M., et al., Management of Hereditary Spastic Paraplegia: A Systematic Review of the Literature. Front Neurol, 2019. 10: p. 3. 46. Paparella, G., et al., Efficacy of a Combined Treatment of Botulinum Toxin and Intensive Physiotherapy in Hereditary Spastic Paraplegia. Front Neurosci, 2020. 14: p. 111. 47. Bertolucci, F., et al., Robotic gait training improves motor skills and quality of life in hereditary spastic paraplegia. NeuroRehabilitation, 2015. 36(1): p. 93-9. 48. Seo, H.G., B.M. Oh, and K. Kim, Robot-assisted gait training in a patient with hereditary spastic paraplegia. Pm r, 2015. 7(2): p. 210-3. 49. Zhang, Y., et al., The effect of hydrotherapy treatment on gait characteristics of hereditary spastic paraparesis patients. Gait Posture, 2014. 39(4): p. 1074-9.
19 General introduction 1
Chapter 2 Covid-19 reveals influence of physical activity on symptom severity in Hereditary Spastic Paraplegia L. van de Venis B.P.C. van de Warrenburg V.G.M. Weerdesteyn B.J.H. van Lith A.C.H. Geurts J. Nonnekes Published: Journal of Neurology. 2020 Dec;267(12):3462-3464.
22 Chapter 2 Abstract Objective Hereditary spastic paraplegia (HSP) is characterized by progressive spasticity of both lower extremities. Spasticity-related symptoms are common, and thought to be positively influenced by physical activity, and negatively by psychological stress. The lockdown due to the COVID-19 pandemic created an opportunity to explore its impact on symptom severity in HSP. Methods During the fifth week of the partial lockdown in the Netherlands, fifty-eight pure HSP patients rated possible changes in levels of physical activity, psychological stress and symptom severity via a web-based questionnaire. Results The partial lock-down reduced the physical activity in 74% of patients with HSP, whereas 43% reported an increase in psychological stress. Reduced physical activity was associated with increased muscle stiffness, pain, physical fatigue and gait impairments, whereas increase psychological stress was independently associated with increased mental fatigue. Conclusions Our results underscore the potential impact of physical activity on symptom severity in people with HSP.
23 Covid-19 and symptom severity in people with HSP Introduction Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder, characterized by progressive spasticity and muscle weakness of both lower extremities. 1 Spasticity-related symptoms such as muscle stiffness and gait impairments are common and disabling in HSP. 2 Moreover, patients experience a substantial burden from both physical and mental fatigue. 2 Our clinical experience is that physical activity positively impacts on these symptoms, whereas psychological stress may impact negatively. This has, however, not been formally investigated. The (partial) lockdown due to the COVID-19 pandemic has profoundly changed people’s normal routine, assumably reducing levels of physical activity and increasing psychological stress, 3 thereby creating an opportunity to explore the influence of these changes on symptom severity in HSP. Methods We conducted a web-based survey among people with pure HSP2 in the Netherlands. An invitation was sent to participants from our previous survey (n=109), which was approved by our regional medical-ethics committee. Participants were asked to rate possible changes in levels of physical activity, psychological stress, and symptom severity on a 5-point Likert scale. They were invited and completed the questionnaire during the fifth week of the partial lockdown in the Netherlands. Descriptive statistics were used to analyze the primary data. Additionally, chi-square tests (or Fisher-exact-tests if appropriate) were used to test whether changes in physical activity and psychological stress were associated with changes in symptom severity (p<0.05). When both physical activity and psychological stress were associated with a specific change in symptom severity, multivariate logistic forward regression analysis was applied to correct for collinearity of these independent determinants. Results Fifty-eight participants returned a completed survey. Their average age was 57 years (range: 30-77) and 47% was male. A reduction of physical activities was reported by 74% (33% strong decrease, 41% mild decrease), whereas 19% reported no change and 7% mild increase. An increase in psychological stress was reported by 43% (3% strong increase, 40% mild increase), 50% reported no change, and 7% decrease (2% strong, 5% mild). The majority reported a general increase in symptom severity (figure 1). Participants with reduced physical activity more often experienced increased muscle stiffness (p=0.001), pain (p=0.004), physical fatigue (χ2(1)=4.680, p=0.031), and gait impairments (χ2(1)=5.129, p=0.024) compared to those with no change or an increase 2
24 Chapter 2 in physical activity (figure 2). The same trend was seen for balance impairments (χ2(1)=3.291, p=0.070). Those who reported increased levels of psychological stress more often reported an increase in muscle stiffness (χ2(1)=4.612, p=0.032), pain (χ2(1)=3.943, p=0.047), and mental fatigue (χ2(1)=6.234, p=0.013). Forward regression analysis of muscle stiffness and pain revealed that only decreased physical activity was independently associated with an increase in muscle stiffness (R2=0.222 (p<0.001) and pain (R2=0.193 (p=0.003)). Six participants were treated with intramuscular botulinum toxin injections to reduce spasticity-related symptoms. During the lockdown, treatment continued in five participants. Figure 1. The impact of the COVID-19 partial lockdown measures on spasticity-related symptoms in people with pure HSP. Participants reported whether the experienced symptom severity increased (mild or strong), decreased (mild or strong) or did not change. Only participants who experienced a specific symptom (either before or after the lockdown) are included in the figure.
25 Covid-19 and symptom severity in people with HSP Discussion The partial lock-down in the Netherlands due to the COVID-19 pandemic resulted in a reduction of physical activity in the majority of participants with HSP, which proved to be associated with increased muscle stiffness, pain, physical fatigue and gait impairments. This result is coherent with findings in other chronic (neurodegenerative) conditions4 and underscores the potential impact of physical activity on symptom severity in people with HSP. Future studies may investigate whether the present findings can be extended to other conditions resulting in spastic paraparesis (e.g. multiple sclerosis and primary lateral sclerosis). Future studies may also evaluate the effect of interventions targeting daily physical activity in this population, preferably including objective outcomes, which were lacking in the present study. Another limitation is the lack of comparison between current and previous clinical status, which was not possible due to the lockdown restrictions. An additional limitation is the risk of selection bias, which may have resulted in an overestimation of changes in physical activity, psychological stress, and/or symptom severity. The question remains whether people with HSP are able to return to ‘baseline’ levels of functioning after release of the lockdown and expected increase in physical activity. 2
26 Chapter 2 Figure 2. The impact of physical activity and psychological stress on symptom severity in people with pure HSP. Y-axis represents number of people with HSP who experienced the symptom.
27 Covid-19 and symptom severity in people with HSP Reference list 1. Shribman S, Reid E, Crosby AH, Houlden H, Warner TT. Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches. The Lancet Neurology. 2019. 2. van Lith BJH, Kerstens H, van den Bemd LAC, et al. Experienced complaints, activity limitations and loss of motor capacities in patients with pure hereditary spastic paraplegia: a web-based survey in the Netherlands. Orphanet J Rare Dis. 2020;15(1):64. 3. Helmich RC, Bloem BR. The Impact of the COVID-19 Pandemic on Parkinson’s Disease: Hidden Sorrows and Emerging Opportunities. J Parkinsons Dis. 2020;10(2):351-354. 4. van der Kolk NM, de Vries NM, Kessels RPC, et al. Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson’s disease: a double-blind, randomised controlled trial. Lancet Neurol. 2019;18(11):998-1008. 2
Chapter 3 Improving gait adaptability in patients with Hereditary Spastic Paraplegia (Move-HSP): Study protocol for a randomized clinical trial L. van de Venis B.P.C. van de Warrenburg V.G.M. Weerdesteyn B.J.H. van Lith A.C.H. Geurts J. Nonnekes Published: Trials. 2021 Jan 7;22(1):32
30 Chapter 3 Abstract Background People with hereditary spastic paraplegia (HSP) experience difficulties adapting their gait to meet environmental demands, a skill required for safe and independent ambulation. Gait adaptability training is possible on the C-Mill, a treadmill equipped with augmented reality, enabling visual projections to serve as stepping targets or obstacles. It is unknown whether gait adaptability can be trained in people with HSP. The aim of Move-HSP is to study the effects of ten 1-hour sessions of C-Mill training, compared with usual care, on gait adaptability in people with pure HSP. In addition, this study aims to identify key determinants of C-Mill training efficacy in people with pure HSP. Method Move-HSP is a five-week, two-armed, open-label randomized controlled trial with a cross-over design for the control group. Thirty-six participants with pure HSP will be included. After signing informed consent, participants are randomized (1:1) to intervention or control group. All participants register (near) falls for fifteen weeks, followed by the first assessment (week 16), and, thereafter, wear an Activ8 activity monitor for seven days (week 16). The intervention group receives 10 sessions of C-Mill training (twice per week, 1-hour sessions; week 17-21), whereas control group continues with usual care (week 17-21). Afterwards, both groups are re-assessed (week 22). Subsequently, the intervention group enter follow-up, whereas control group receives 10 sessions of C-Mill training (week 23-27), is re-assessed (week 28) and enters follow-up. During follow-up, both groups wear Activ8 activity monitors for seven days (intervention group: week 23, control group: week 29) and register (near) falls for fifteen weeks (intervention group: week 23-37, control group: week 29-43), before the final assessment (intervention group: week 38, control group: week 44). The primary outcome is the obstacle subtask of the Emory Functional Ambulation Profile. Secondary outcomes consist of clinical tests assessing balance and walking capacity, physical activity and fall monitoring. Discussion Move-HSP will be the first RCT to assess the effects of C-Mill gait adaptability training in people with pure HSP. It will provide proof-of-concept for the efficacy of gait adaptability training in people with pure HSP.
31 Protocol: gait-adaptability training in people with HSP Background Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurodegenerative disorders, caused by retrograde axonal degeneration of the corticospinal tracts, fasciculus gracilis fibers and, to a lesser extent, the spinocerebellar fibers.1-3 Pure forms of HSP are clinically characterized by progressive spasticity, muscle weakness and reduced proprioception in the lower extremities, as well as difficulties in making rapid (alternating) leg movements.4-6 Additional symptoms are present in complex forms of HSP, including mental retardation, epilepsy, ataxia, peripheral neuropathy or optic atrophy.1, 4, 7 For people with pure HSP, gait and balance impairments are among the most disabling symptoms. They especially experience difficulties when forced to adapt their gait to meet environmental demands, hampering the ability to walk safely and independently in the community.4, 8-11. A recent study reported that 57% of pure HSP patients fell at least twice a year, and 73% experience fear of falling.11 Incorporating gait adaptability training in rehabilitation programs for people with pure HSP seems, therefore, logical and potentially beneficial.4, 11, 12 A limited number of task-specific gait interventions has shown to improve walking capacity in people with pure HSP. Twenty-five sessions of robot-assisted exoskeleton and overground walking improved walking velocity and balance capacity.13 In addition, eighteen sessions of robotic Lokomat® training increased walking speed, balance capacity and quality of life.9 Even though these results are promising, the interventions lacked tasks that promote gait adaptability. As a consequence, it remains unknown whether people with pure HSP will benefit from gait adaptability training.4 Furthermore, it is unclear how to tailor gait rehabilitation programs to the individual patient with HSP as it is currently unknown which determinants can predict training efficacy. To fill this gap, Move-HSP is the first randomized controlled trial to provide proof of concept for the efficacy of gait adaptability training in people with pure HSP. The training takes place in a safe environment on the C-Mill, a treadmill providing augmented reality via visual projections onto the treadmill. Participants will train obstacle negotiation, precision stepping, and unexpected accelerations and decelerations. Its feasibility and efficacy have been described in multiple neurological populations, including patients with stroke,14 cerebellar ataxia 15 and multiple sclerosis.16 Currently, the clinical experience with gait adaptability C-Mill training for people with pure HSP is positive, but the scientific evidence is lacking.4 3
32 Chapter 3 Objectives This study aims to provide an essential step towards evidence-based and individually tailored gait rehabilitation in people with HSP. The objectives are twofold: 1. To study the effect of ten 1-hour sessions of C-Mill training on gait adaptability in people with pure HSP. 2. To identify key determinants of C-Mill training efficacy in people with pure HSP. Methods Regulation statement Move-HSP will be conducted according to the principles of the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013) and the Medical Research Involving Human Subjects Act. The protocol is written in accordance with the SPIRIT 2013 checklist. Study design and setting Move-HSP is a five-week, single-center, two-armed, open-label, randomized controlled trial (RCT), with a cross-over design for the control group, as they receive the intervention after a waiting list period. The study is conducted at the Radboud University Medical Centre (Radboudumc) within the Centre of Expertise for Parkinson & Movement Disorders; Nijmegen, The Netherlands. C-Mill training can be given at the Radboudumc (Nijmegen, The Netherlands), Paramedisch centrum Rembrandt (Veenendaal, The Netherlands), Stichting Tante Louise (Bergen op Zoom, The Netherlands) and Fysiotherapiepraktijk De Lindehoeve (Voorschoten, The Netherlands). Other training locations may be added while the study is ongoing, depending on the success of participant inclusion. Recruitment and selection Participants will be recruited at the Center of Expertise for Parkinson & Movement Disorders of the Radboudumc (part of the European Reference Network for Rare Neurological Diseases (ERN-RND)). The treating physician informs the patient about Move-HSP and asks for permission whether the investigator (LV) may contact the patient. In addition, a request to participate will be sent to members of the HSP working group of the patient organization “Spierziekte Nederland”. Those who are interested can contact the investigator and will receive an information letter. After two weeks, the investigator (LV) will contact those who expressed their interest and ask for their final decision. If patients agree to participate, eligibility is checked. After inclusion, participants can leave the study at any time without consequences.
33 Protocol: gait-adaptability training in people with HSP Eligibility For inclusion, participants will have to meet the following inclusion criteria: • Diagnosis of pure HSP by a neurologist specialized in inherited movement disorders. Diagnosis is based on inheritance pattern and clinical examination, and when available, molecular diagnosis, • age between 18-70 years old, • ability to walk barefoot on a level ground for 50 meters without a walking aid (use of orthotic devices or orthopedic shoes is allowed). Participants will be excluded if they suffer from other neurological, orthopedic or psychiatric conditions, or if patients underwent an HSP-related surgical procedure of the lower extremities. Group allocation and blinding Participants will be allocated at random to the intervention group or to the (waiting list) control group following a 1:1 ratio. Randomization will be stratified based on disease duration (2 categories: 0-15 years; >15 years) in blocks with a variable size (n=4 or n=6) to prevent an uneven distribution between groups. To determine disease duration, participants are asked for the year of symptom onset. Randomization will be performed in CastorEDC, a web-based data management system for academic studies (www.castoredc.com). Blinding of participants is not possible, as participants will know whether they receive C-Mill training or continue with usual care. The primary investigator (LV) takes part in the training sessions as a physical therapist and, therefore, cannot be blinded either. Participant timeline The outline of this study is shown in Figure 1. Following inclusion, participants are randomly allocated to either the intervention group or the control group (waiting list). During the first fifteen weeks, all participants register (near) falls in a digital fall calendar. Thereafter, participants will have the first assessment at the movement laboratory (Radboudumc; week 16). Following this assessment, participants wear an Activ8 activity monitor for seven consecutive days (week 16). Thereafter, the control group enters a waiting period of five weeks (week 17-21), whereas the intervention group starts with five weeks of gait adaptability training on the C-Mill (Week 17-21). Each session lasts one hour and takes place twice per week. Subsequently, both groups are re-assessed (week 22) Following this second assessment, the intervention group enters the follow-up period, whereas the control group wears the Activ8 activity monitors for seven days (week 22), starts five weeks of gait adaptability training (week 23-27), has the third assessment (week 28), and, thereafter, enters the follow-up period. During follow-up, both groups wear Activ8 activity monitors during the first week (intervention group: week 23, control group: week 29) and, 3
34 Chapter 3 additionally, register (near) falls for fifteen weeks (intervention group: week 23-37, control group: week 29-43). After follow-up, participants have a final assessment in the movement laboratory (intervention group: week 38, control group: week 44). Figure 1. Flowchart of the study protocol During Move-HSP, all participants can continue their usual care. For some participants, this may include local intramuscular injections of botulinum toxin (BTX). To limit the influence of BTX injections on the outcomes, the scheduling of the
35 Protocol: gait-adaptability training in people with HSP assessments will consider the date of the BTX injections. BTX injections induce an effect on muscle spasticity approximately two weeks post-injection. The maximum effect is reached around 6-8 weeks, after which it gradually subsides.17, 18 Participants who receive BTX injections in the lower extremities will have the pre-intervention assessment four weeks post-injection, and the post-intervention assessment ten weeks post-injection. In addition, it will be monitored whether the dosage of oral antispasmodic change during the trial. Control group The eighteen participants attributed to the control group are asked to continue with their daily routine and usual care during the five weeks on the waiting list. If therapy is part of the usual care, participants are requested to continue with the same frequency and composition during the waiting period. Intervention: C-Mill training Gait adaptability training takes place on the C-Mill (Motek Medical, Culemborg, The Netherlands). The C-Mill is a treadmill, providing augmented reality via visual cues projected onto the treadmill. The projections are either stepping targets or obstacles that challenge the participants to adjust their steps accordingly. The training sessions take place during five consecutive weeks, twice per week during 60-minute sessions. In total, participants will train gait adaptability on the C-Mill for 10 hours. The C-Mill protocol is based on clinical experience and finalized after a focus group discussion with expert physical therapists. The training sessions are logged to ensure compatibility and a consistent progression. Each session starts with a tenminute warming-up, followed by five training blocks (figure 2, video). Each training block lasts approximately eight minutes. Block A targets precision stepping by practicing accurate foot placement on the projected stepping tiles. Block B targets obstacle negotiation by avoiding the projected obstacles. Block C elicits changes in the direction of progression by using a variety of slalom trajectories. Block D targets precision acceleration and deceleration, as the participants must walk within a projected square that moves forward and backward on the treadmill. Block E challenges walking at different walking speeds. Block F is the endgame, a five-minute track that combines several gait adaptability components in an interactive way. All sessions end with a cooling-down. To further promote the level of variability, each training block consists of small components (i.e. for block A: Stepping Tiles: belt speed will momentarily increase; width between the stepping stones will momentarily decrease). In addition, different walking speeds are used: 100% is the participant’s comfortable walking speed on the treadmill. This will be determined during the first training session. The belt speed will be manually increased until the participant experiences it as comfortable. The therapist will then increase the belt 3
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