Neurological Rehabilitation_ Spasticity And Contractures In Clinical Practice And Research

Neurological Rehabilitation Spasticity and Contractures in Clinical Practice and Research

Rehabilitation Science in Practice Series Series Editors

Marcia J. Scherer, PhD President, Institute for Matching Person and Technology Professor, Physical Medicine & Rehabilitation, University of Rochester Medical Center Dave Muller, PhD Visiting Professor, University of Suffolk Past and Founding Chair of Chamber of Commerce Editor-in-Chief, Disability and Rehabilitation Director, Ipswich Central Ltd.

Paediatric Rehabilitation Engineering: From Disability to Possibility, edited by Tom Chau and Jillian Fairley Quality of Life Technology Handbook, Richard Schultz Computer Access for People with Disabilities: A Human Factors Approach, Richard C. Simpson Computer Systems Experiences of Users with and Without Disabilities: An Evaluation Guide for Professionals, Simone Borsci, Maria Laura Mele, Masaaki Kurosu, and Stefano Federici Rethinking Rehabilitation: Theory and Practice, edited by Kathryn McPherson, Barbara E. Gibson, and Alain Leplège Human-Computer Interface Technologies for the Motor Impaired, edited by Dinesh K. Kumar and Sridhar Poosapadi Arjunan Rehabilitation: A Post-Critical Approach, Barbara E. Gibson Wheelchair Skills Assessment and Training, R. Lee Kirby Robotic Assistive Technologies: Principles and Practice, edited by Pedro Encarnção and Albert M. Cook Geriatric Rehabilitation: From Bedside to Curbside, edited by K. Rao Poduri, MD, FAAPMR Devices for Mobility and Manipulation for People with Reduced Abilities, Teodiano Bastos-Filho, Dinesh Kumar, and Sridhar Poosapadi Arjunan Multiple Sclerosis Rehabilitation: From Impairment to Participation, edited by Marcia Finlayson Neuroprosthetics: Principles and Applications, edited by Justin Sanchez Ambient Assisted Living, Nuno M. Garcia and Joel J.P.C. Rodrigues Assistive Technology for Blindness and Low Vision, Roberto Manduchi and Sri Kurniawan Rehabilitation Goal Setting: Theory, Practice and Evidence, edited by Richard J. Siegert and William M. M. Levack Assistive Technology Assessment Handbook, Second Edition, edited by Stefano Federici and Marcia Scherer Neurological Rehabilitation: Spasticity and Contractures in Clinical Practice and Research, edited by Anand D. Pandyan, Hermie J. Hermens, Bernard A. Conway

Neurological Rehabilitation Spasticity and Contractures in Clinical Practice and Research

Edited by

Anand D. Pandyan Hermie J. Hermens Bernard A. Conway 

CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2018 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed on acid-free paper International Standard Book Number-13: 978-1-4665-6544-9 (Hardback) International Standard Book Number-13: 978-1-315-37436-9 (eBook) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright​ .com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging‑in‑Publication Data Names: Pandyan, Anand, editor. | Hermens, Hermie J., editor. | Conway, Bernard A., editor. Title: Neurological rehabilitation : spasticity and contractures in clinical practice and research / [edited by] Anand Pandyan, Hermie J. Hermens, and Bernard A. Conway. Other titles: Neurological rehabilitation (Pandyan) | Rehabilitation science in practice series. Description: Boca Raton, FL : CRC Press/Taylor & Francis Group, 2018. | Series: Rehabilitation science in practice series | Includes bibliographical references and index. Identifiers: LCCN 2017058710| ISBN 9781466565449 (hardback : alk. paper) | ISBN 9781315374369 (ebook) Subjects: | MESH: Muscle Spasticity--therapy | Contracture--therapy | Neurological Rehabilitation Classification: LCC RC935.S64 | NLM WE 550 | DDC 616.85/6--dc23 LC record available at https://lccn.loc.gov/2017058710 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

Contents Editors..................................................................................................................... vii Contributors.............................................................................................................ix 1. Definition and Measurement of Spasticity and Contracture.................1 Anand D. Pandyan, Bernard A. Conway, Hermie J. Hermens and Garth R. Johnson 2. Pathophysiology of Spasticity..................................................................... 25 Jens Bo Nielsen, Maria Willerslev-Olsen and Jakob Lorentzen 3. Functional Problems in Spastic Patients Are Not Caused by Spasticity but by Disordered Motor Control..................................... 59 Jakob Lorentzen, Maria Willerslev-Olsen, Thomas Sinkjær and Jens Bo Nielsen 4. The Clinical Management of Spasticity and Contractures in Cerebral Palsy............................................................................................ 79 Andrew Roberts 5. Clinical Management of Spasticity and Contractures in Stroke....... 101 Judith F. M. Fleuren, Jaap H. Buurke and Alexander C. H. Geurts 6. Clinical Management of Spasticity and Contractures in Spinal Cord Injury................................................................................................... 135 Martin Schubert and Volker Dietz 7. Clinical Management of Spasticity and Contractures in Multiple Sclerosis................................................................................... 175 Lorna Paul and Paul Mattison 8. Clinical Assessment and Management of Spasticity and Contractures in Traumatic Brain Injury......................................... 203 Gerard E. Francisco and Sheng Li 9. Hereditary Spastic Paraparesis and Other Hereditary Myelopathies................................................................................................ 235 Jon Marsden, Lisa Bunn, Amanda Denton and Krishnan Padmakumari Sivaraman Nair Index...................................................................................................................... 289 v

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Editors Anand D. Pandyan, PhD, is Professor for Rehabilitation Technology  and Head of the School of Health & Rehabilitation at Keele University. He originally trained as a bioengineer and has a special interest in neurological rehabilitation, clinically usable measurement and applied clinical research. His interest in spasticity started during his PhD study (Bioengineering Unit, University of Strathclyde, Glasgow) and he completed a five-year postdoctoral training period at the Centre for Rehabilitation and Engineering Studies (CREST), Newcastle upon Tyne (with Professors Garth Johnson and Michael [Mike] Barnes) exploring the phenomenon of spasticity in stroke. His current portfolio of research projects, carried out in partnership with therapists and local clinicians, is aimed at: developing a better understanding of the pathophysiological basis of spasticity and its impact on people with upper motor neurone lesions; identifying the therapeutic benefits (and mechanisms of action) associated with treatment involving electrical stimulation; and exploring the effects of early antispasticity treatment and studying their long-term impacts. Much of his current research is focussed on neurological patients with severe levels of disability. Hermie J. Hermens, PhD, earned his master’s in Biomedical Engineering at the University of Twente. His PhD, on surface EMG modelling, processing and clinical applications, was also undertaken at the University of Twente, and he subsequently became Professor of Neuromuscular Control at the same institution. He was the initiator and coordinator of the SENIAM project, which resulted in a broadly accepted worldwide standard on surface EMG electrode properties and their placement on the muscles. He was, together with Anand D. Pandyan, actively involved in the European SPASM project, which resulted in important new insights into the definition of spasticity and procedures and methods for assessing spasticity in a quantitative way. Dr. Hermens was co-founder of Roessingh Research and Development (RRD), originating from the Roessingh Rehabilitation Centre, which has now grown into the largest institute in the area of rehabilitation technology and telemedicine in the Netherlands. He gradually switched his research area from rehabilitation technology towards combining biomedical engineering with ICT to enable remote monitoring and telemedicine. In 2008, he became Professor of Telemedicine and Head of the Telemedicine Research Group, at UTwente; in 2010 Director of Telemedicine at RRD and, in 2012, Director of Technology at the Centre for Care Technology Research (CCTR) and Visiting Professor at the Caledonian University in Glasgow.

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Editors

Bernard A. Conway, PhD, is Professor in Biomedical Engineering at the University of Strathclyde, where he co-directs the Centre for Excellence in Rehabilitation Research. He earned his PhD in Neurophysiology from the University of Glasgow and since then has focussed his research interests on problems related to the loss of control of movement in patients with neurological conditions including spinal cord injury, movement disorders, and limb loss. Over his career he has enjoyed close collaboration with clinical colleagues, giving his research a translational perspective. The multidisciplinary nature of his research has led to its publication in a diversified group of journals. He has also been actively involved in supporting funding agencies in various advisory capacities linked to bioengineering, rehabilitation, health technologies, and ageing. He currently is a trustee of the Institute of Physics and Engineering in Medicine and Medical Research Scotland.

Contributors

Lisa Bunn School of Health Professions Faculty of Health and Human Sciences University of Plymouth Plymouth, United Kingdom Jaap H. Buurke Roessingh Research and Development University of Twente Enschede, Netherlands Bernard A. Conway Department of Biomedical Engineering University of Strathclyde Scotland, United Kingdom Volker Dietz Spinal Cord Injury Center University Hospital Balgrist Zürich, Switzerland Amanda Denton School of Health Professions Faculty of Health and Human Sciences University of Plymouth Plymouth, United Kingdom Judith F. M. Fleuren Roessingh Rehabilitation Centre Roessingh Research and Development Enschede, Netherlands

Gerard E. Francisco Department of Physical Medicine and Rehabilitation University of Texas Health Science Center and NeuroRecovery Research Center TIRR Memorial Hermann Hospital Houston, Texas Alexander C. H. Geurts Radboud University Medical Centre Department of Rehabilitation Nijmegen, Netherlands Hermie J. Hermens Roessingh Research and Development University of Twente Enschede, Netherlands Garth Johnson ADL Smartcare Ltd Newcastle University Newcastle, United Kingdom Sheng Li Department of Physical Medicine and Rehabilitation University of Texas Health Science Center and NeuroRecovery Research Center TIRR Memorial Hermann Hospital Houston, Texas

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Jakob Lorentzen Institute of Neuroscience University of Copenhagen and Elsass Institute Charlottenlund, Denmark Jon Marsden School of Health Professions Faculty of Health and Human Sciences University of Plymouth Plymouth, United Kingdom Paul Mattison Ayrshire Multiple Sclerosis Service Douglas Grant Rehabilitation Centre Ayrshire Central Hospital Irvine, United Kingdom Krishnan Padmakumari Sivaraman Nair Department of Neurology Royal Hallamshire Hospital Sheffield Teaching Hospitals NHS Foundation Trust Sheffield, United Kingdom Jens Bo Nielsen Institute of Neuroscience University of Copenhagen and Elsass Institute Charlottenlund, Denmark

Contributors

Anand D. Pandyan School of Health and Rehabilitation Keele University Keele, United Kingdom Lorna Paul School of Health and Life Sciences Glasgow Caledonian University Glasgow, United Kingdom Andrew Roberts Orthotic Research and Locomotor Assessment Unit Robert Jones and Agnes Hunt Hospital Oswestry United Kingdom Martin Schubert Spinal Cord Injury Center University Hospital Balgrist Zürich, Switzerland Thomas Sinkjær Department of Health Science and Technology Aalborg University Aalborg, Denmark Maria Willerslev-Olsen Elsass Institute Charlottenlund, Denmark

1 Definition and Measurement of Spasticity and Contracture Anand D. Pandyan, Bernard A. Conway, Hermie J. Hermens and Garth R. Johnson CONTENTS 1.1 Introduction.....................................................................................................1 1.2 Definition of Spasticity...................................................................................2 1.2.1 Can the Words Increased Tone/Hypertonia and Spasticity Be Used Interchangeably?.................................................................3 1.2.2 Developing the Framework for Defining Spasticity.......................6 1.2.2.1 Increased (Hyper-Excitable/Exaggerated) Reflexes........8 1.2.2.2 Spasms and Clonus..............................................................8 1.2.2.3 Altered Tone or the Response of a Relaxed Muscle to an Externally Imposed Stretch......................................9 1.2.2.4 Abnormal Movement Patterns and Co-Contraction..... 12 1.2.3 The Classification and Definition of Spasticity in Upper Motoneuron Syndrome.................................................................... 13 1.2.4 Contractures in Patients with Upper Motoneuron Syndrome......14 1.2.5 The Measurement of Spasticity and Contracture........................ 17 1.2.6 Concluding Thoughts....................................................................... 19 References................................................................................................................ 21

1.1 Introduction Spasticity is a clinical condition that is expected to develop following a lesion in the descending tracts of the central nervous system (CNS), at any level (i.e., cortex, internal capsule, brain stem, or spinal cord) (Burke [1988]). It is a common neurological impairment with a reported prevalence of between 20% and 80% (this will depend on the population under study and the method of measurement), which is considered clinically important (see subsequent chapters for disease-specific data). Not all spasticity is considered troublesome to patients; however, a significant number of patients with spasticity will require treatment. Treatment of spasticity is often driven by goals aimed

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at improving function or preventing significant secondary complication such as pain, pressure sores, limb deformities, etc. At a pathophysiological level this condition has been studied in reasonable detail since the 1880s and our current understanding of the pathophysiological basis of this condition and its impact on function has been summarised in Chapters 2 and 3. Unfortunately, the literature related to treatment is scanty and the quality is predominantly poor (and the team found this to be a significant challenge in the compilation of this book). The two main barriers to good science have been the lack of a proper definition of the term spasticity and the use of invalid methods of measurement. Attempting to provide a universally acceptable definition that is both scientifically valid and clinically usable is probably too much of a challenge for now; however, an attempt will be made to present a framework that may help in this process. It may help for readers to have an understanding of this framework before reading the individual disease-specific chapters. The measurement of spasticity is a much easier problem to deal with as there are a range of valid measures that are available. This chapter will, therefore, summarise the state-of-the-art approaches to the measurement of spasticity, both directly or indirectly.

1.2 Definition of Spasticity The observations of Landau (1974) that the term spasticity has become such a habitual part of neurological jargon that no one is expected to define it remains true today in practice (Landau [1974]). What is more challenging is that this behaviour appears also to have permeated the published research! In his editorial, Landau (1974) provides six variations to the definition of spasticity found in the literature. Unfortunately, since then, many more have appeared (e.g. Lance [1980a,b,c]; Sanger et al. [2003]; Pandyan et al. [2005]; Malhotra et al. [2009]). Currently, there is agreement that spasticity is a condition that can develop following an upper motoneuron lesion. Most texts would suggest that the sensory motor problems following an upper motoneuron lesion, of any origin, can be classified as having positive features and negative features (Pandyan et al. [2009]). This particular approach to classification can be traced back to the work of Hughlings Jackson (York and Steinberg [2007]), who considered that the positive features were associated the exposure of activity that was previously inhibited by the nervous system and the negative features result from the loss of higher-level excitatory control. This classification was based on Jackson’s thinking of the nervous system as being hierarchical, with the higher levels having modulatory control over the lower levels. Table 1.1 summarises the features of the upper motor syndrome as commonly

Definition and Measurement of Spasticity and Contracture

3

TABLE 1.1 A Summary of the Positive and Negative Features Associated with the Upper Motoneuron Syndrome, as Commonly Reported in the Literature Positive Features Increased reflexes Spasticity Altered tone Spasm & clonus Abnormal movement patterns & co-contraction

Negative Features Weakness Fatigueability Loss of dexterity (motor control)

reported in the literature and the text, and it is important to note that spasticity was only considered as one feature of the upper motoneuron syndrome. Spasticity is derived from the Greek root word spastikos, which means drawing or tugging. If one reads the literature from the time of 1830 (see Chapter 4), it appears that the term spasticity is often associated with a ‘resistance one feels when passively moving/mobilising a limb segment’ and was also associated with the terms tone and rigidity (Siegel [1988]). Although a variety of descriptions exist in the literature, the first formal definition appears in the works of Denny Brown, where he defines spasticity in capsular hemiplegia as the presence of a soft yielding resistance that appears only towards the end of a passive stretch, and is associated with increased amplitude stretch reflex (Denny-Brown [1966]). Two decades later, in a series of post-conference discussions and a presentation, Lance (1980a,b,c) put forward a series of definitions for the term spasticity. Of the three definitions, the one that is most commonly cited defines spasticity as a motor disorder characterised by a velocity dependent increase in tonic stretch reflexes (muscle tone) and increased tendon jerks resulting from disinhibition of the stretch reflex, as one component of an upper motoneuron lesion (Lance [1980b]). However, the literature still appears not to have any form of consensus with respect to a definition (Pandyan et al. [2005]; Malhotra et al. [2009]). When the literature was last reviewed, approximately a third of the literature equated spasticity with increased or altered muscle tone or hypertonia (and this will be discussed in Section 1.2.1). A third of the literature defined spasticity according to the Lance (1980b) definition (as cited above) or some minor variation. A third of the literature did not define the term spasticity at all, suggesting that not much has been learnt since Landau (1974) or the more recent article from Thilmann (1993). Accordingly, and before we progress to discussing a framework for defining spasticity, it is important to first deal with use of the term (high) tone as a synonym for spasticity. 1.2.1 Can the Words Increased Tone/Hypertonia and Spasticity Be Used Interchangeably? The term tonus was originally introduced in 1838 to describe the slight contractile tension in the muscles when at rest (Rushworth [1960] citing Mueller

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[1838]). It is fascinating to read the summary of Cobb and Wolf (1932) following the First International Congress of Neurology: Confusion of thought has occurred throughout the diverse use of the term tonus. However carefully defined it now carries with an incubus of vague connotation which seems to cloud the issue. Its place as term applied to striated muscle can be more accurately taken over by such specific terms as ‘standing reflex’, ‘postural reflex’, and ‘righting reflex’. The state of the striated muscle at any moment can be described by adjectives such as slack or taut. Better still the amount of tension can be measured and stated in quantitative terms. We make a plea that the term tone be either discarded or returned to its former home in smooth muscle and kept there.

It is frustrating that we appear not to have learnt very much from the precision in the literature of the past. There is now clear evidence that in a state of rest skeletal muscles are electrically silent and that there is good reason to believe that the advice of Cobb and Wolf (1932) is just as appropriate today as it was then. However, asking for people to change entrenched behaviour is unlikely. There are currently two separate definitions of the term tone that are acknowledged: • The first equates tone with the resistance one feels when passively moving a limb segment about a joint. • The second equates tone with the readiness to act. The term hypertonia (or high tone) is related to the first definition of tone (i.e., an increased resistance that one encounters during passive limb displacement). The assumption being made is that any resistance encountered to an externally imposed passive movement is due to an increased activation of muscles (e.g. Sanger et al. [2003]). There is now ample evidence that such an assumption cannot be made (Malhotra et al. [2008]). The resistance that one encounters is often associated with changes in the biomechanical properties of soft tissues and joint structures (Figure 1.1). In certain circumstances, increased muscle activity can contribute to this increased resistance in the absence of any form of soft tissue and joint changes, but this is rare (Figure 1.1). The term hypotonia is often related to both definitions of tone. If one considers the argument in support of a condition of hypotonia against the first definition of tone then the hypothesis one has to consider is that the resistance to passive movement in people with hypotonia is lower than normal. This does make the assumption there is ‘normal tone’. The evidence is clear: in a relaxed state there is no electrical activity in muscles. The stiffness measured in patients with a dense flaccid paralysis is also not very different to people who have no neurological deficits (Barnaby et al. [2002]); Kumar

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Definition and Measurement of Spasticity and Contracture

70

70 Force (N)

100

Force (N)

100

40 10

–20

20 38 56 74 92 110 128 146 164 182 200

10

20 38 56 74 92 110 128 146 164 182 200 –20 –50

–50 Pre Lin. reg pre Post

(a)

40

Angle (degrees)

Linear reg post

Pre Lin. reg pre Post

(b)

Angle (degrees)

Linear reg post

FIGURE 1.1 Recording of stiffness at the elbow (the slope of the force angle curve) measured before and after injection of Botulinum Toxin – A (BoNT-A). The trace in gray is before injections and the trace in black is four weeks after injections. Both patients are responders to treatment of botulinum toxin, i.e., the injections suppressed the stretch-induced activation of muscles. In the patient with no contractures (left-hand pane [a]; discussed in Section 2.3) the stiffness was influenced by the abnormal muscle activity associated with spasticity (stiffness pre-injection was 0.4 N/deg and post-injection was 0.2 N/deg). Note also that in this patient a catch followed by a release can be seen. However, in the patient with the established contractures (b) there was no change in stiffness, suggesting that the spasticity had no contribution to the resistance to passive movement (stiffness pre-injection was 1.1 N/deg and post-injection was 1.0 N/deg). (With permission from Pandyan AD et al. [2009] Spasticity, The New Encyclopedia of Neuroscience. Squire LR, ed. Vol 9. Oxford: Academic Press, pp. 153–163.)

et al. [2006]). In the circumstances, the argument that people with low tone have lower-than-normal resistance to an externally imposed movement is untenable. The other argument links the definition of hypotonia to the second definition of tone (i.e., the muscles can be activated with a smaller-thannormal ­stimulus or the muscle is not in a state of readiness to act). This is a more complex problem to deal with. In some patients with an upper motoneuron lesion there is evidence that a smaller-than-normal stimulus (proprioceptive, cutaneous, etc.) can trigger the activation of an involuntary response of either an isolated muscle or a group of muscles (see Chapter 2). However, such patients are often treated, contradictorily, as hypertonic not hypotonic. One then has to consider whether patients with hypotonia have a lower-thannormal ‘readiness to act’ and the only interpretation left is that such a person does not have an ability to act, i.e., they are paralyzed. It is important to highlight that the original articles on rigidity and spasticity use two specific terms: hypertonic paralysis and hypertonicity in paralysis. The former term is used to describe patients who were unable to voluntarily activate muscles (paralysis) and whose muscles are in a state of contraction. The latter term is used to describe patients who are unable to activate muscles voluntarily (paralysis) but an examiner is able to elicit or observe reflex muscle activation (Bennett [1887]).

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In summary, the words hypertonia and spasticity cannot be used interchangeably. From a first-principles argument, if there was a choice the authors would probably want to support the position taken by Cobb and Wolf (1932) and Rushworth (1960), i.e., not to use these terms within the context of neurological rehabilitation. These terms, however, have been extensively used already and such a recommendation would not be adopted. However, it is important that readers reflect on this discussion when they interpret the term tone, both within this book and in the general literature. Furthermore, for the future, if people choose to use the word tone then it is important that the term is explicitly defined whenever it is used. The challenges of not providing such definitions can be seen with the chapters of this book, in particular the chapters on cerebral palsy and multiple sclerosis (Chapters 4 and 7, respectively), where the authors have struggled to interpret the term tone as the literature has not defined this for them. 1.2.2 Developing the Framework for Defining Spasticity Having accepted that the term spasticity is likely to remain in common use, one then needs to consider a framework that will help with articulating a clinically meaningful definition of this term for routine clinical and research use. More importantly, a valid definition and description is an essential first step in measurement. The remainder of this section will therefore focus on developing a framework for the definition and description of the term spasticity. Two teams, in the early part of 2000, explored ways to develop a universally acceptable definition for spasticity. The first of these teams, the Task Force on Childhood Motor Disorders, took the approach of splitting existing definitions to provide a series of sub-definitions. The second of these teams, A European Thematic Network to Develop Standardised Measures of Spasticity, took a diametrically opposite approach of lumping existing definitions into a universal definition. The two approaches are chronologically described below. Sanger et al. (2003) provide a series of definition linked to both spasticity and hypertonia. Their definition for hypertonia will not be discussed further in this section as the arguments as to why such a definition will not work have already been presented in Section 2.1. Sanger et al. (2003) defined hypertonia as a case in which one or both of the following signs are present: (1) resistance to externally imposed movement increase with increasing speed of stretch and varies with the direction of joint movement and/or (2) resistance to externally imposed movement rises rapidly above a threshold speed or joint angle. Such a definition does not add much clarity to the definition originally proposed by Lance (1980b); in fact, one could argue that it confuses the measurement a lot more. At a fundamental level, there are two major problems with the above definition: (i) a velocity-dependent increase in resistance to passive movement is an inherent viscoelastic behaviour of muscles and tendons (Figure 1.2); and (ii) the threshold speed or joint angle are not defined per se. Under these circumstances one would argue that the approach to splitting lacks adequate precision.

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Definition and Measurement of Spasticity and Contracture

20

–10º PF

10º DF

Torque (N.m)

16 12

Affected limb

8

25º.s–1

5º.s–1

4 0 FIGURE 1.2 Stiffness measured at the knee joint using two different velocities. The authors Singer et al. (2003) have clearly demonstrated that changes in velocity-dependent stiffness can be independent of spasticity. (With permission from Singer B et al. [2003] Velocity dependent passive flexor resistive torque in patients with acquired brain injury. Clinical Biomechanics 18:157–165.)

The SPASM Consortium (Pandyan et al. [2005]), after reviewing the literature came to the conclusion that the term spasticity was being used to refer to a range of signs and symptoms associated with the upper motoneuron lesion. This is probably true of clinical practice too, and anecdotal evidence from discussions with students, researchers and clinical practitioners confirms that this is the case. If one were to ensure that all of the relevant literature associated with the term spasticity was to be reviewed, then there was a need to develop a definition that was sufficiently broad so as to be inclusive of all of the clinical manifestation but adequately specific to focus on the neurological basis of the phenomenon. The consensus definition that was agreed defined spasticity as disordered sensori-motor control, resulting from an upper motoneuron lesion, presenting as intermittent or sustained involuntary activation of muscles. This definition then meant that spasticity was no longer a term used to denote one component of the upper motoneuron syndrome (as described in Table 1.1) but all of the positive features upper motoneuron syndrome (Table 1.2). TABLE 1.2 The Redefining of Spasticity by the Spasm Consortium Resulted in a Definition That Was a Reflection of Both the Literature and Clinical Practice Positive Features Increased reflexes Spasticity Spasm and clonus Altered tone Abnormal movement patterns & co-contraction

Spasticity as Defined by SPASM Consortium Increased reflexes Spasm and clonus Altered tone Abnormal movement patterns and co-contraction

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Whilst such an all-encompassing definition has some benefit, it is of limited clinical and research value as this does not provide an unambiguous framework to inform the measurement process. In order to develop this definition further it is important the lumped definition can be split or stratified in a way that could inform the measurement process. This would require the examination of the individual components and explore if the components could be classified as spasticity. This process is described below. It is important to note that pathophysiology is discussed comprehensively in Chapter 2, so this chapter will not review pathophysiology. 1.2.2.1 Increased (Hyper-Excitable/Exaggerated) Reflexes The term increased reflexes will very specifically be equated to the response observed following a clinical testing of reflexes, i.e., where an examiner taps a tendon to produce a transient stretch of the muscle that then leads to a subsequent contraction. Although not formally studied, the literature seems to suggest that the sensitivity* and specificity† of the stretch reflex response as currently measured is a poor indicator of spasticity in both acute and chronic populations. The literature also remains unclear on what constitutes the signature of an increased reflex: do these terms mean the reflex has a lower threshold, greater magnitude, longer duration or a combination of all. The reflex response, when tested clinically using a tendon tap, normally will involve mono- and­­polysynaptic pathways, meaning that the observation of a change in reflex cannot in itself be a sub-classification of spasticity but rather is a reflection of changed excitability. Furthermore, as this discussion develops (Sections 1.2.2.2 and 1.2.2.3) it will become more apparent that many of the other signs and symptoms that can be classified under the umbrella definition of spasticity is predominantly associated with changes in excitability within a variety of motor pathways. 1.2.2.2 Spasms and Clonus A spasm can be defined as a transient but continuous muscular contraction which can be triggered by a combination of cutaneous and/or visceral triggers and a clonus is defined as a transient but intermittent rhythmic muscle contraction with proprioceptive and/or cutaneous triggers. Both of these signs are commonly reported in patients with spasticity. Both of these phenomena are common in patients with upper motoneuron lesions. Exact prevalence and incidence cannot be reported as these are not systematically documented. Spasms can affect both the flexor and extensor muscle groups of patients and can be influenced by changes in ambient temperature. Anecdotal reports suggest that an increase in spasms is normally associated with a decrease in temperature. Cutaneous stimuli that are noxious can trigger spasms. There * Sensitivity: the ability to accurately identify those with spasticity. † Specificity: the ability to accurately identify those without spasticity.

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9

is some anecdotal evidence that spasms can be influenced by changes in activity within the autonomic nervous system. However, this association has not been systematically studied in any depth. It is important to note that spasms can occur due to reasons other than spasticity, i.e., there is a lack of specificity. Despite this, if a person has spasms subsequent to the upper motoneuron lesion one could conclude that this is an indicator of spasticity. Clonus is also documented to occur, predominantly at the ankle joint, in the later stages following an upper motoneuron lesion. In studies conducted on stroke patients, upper limb clonus is very rarely observed at the elbow joint (<1%) and its prevalence in the lower limb is most likely a consequence of excitability changes facilitating interactions between neurogenic networks, reflex loops, and the biomechanics of the muscle/joint system. At this stage, there is adequate theoretical evidence to consider both spasms and clonus as sub-classifications under the umbrella term of spasticity. 1.2.2.3 Altered Tone or the Response of a Relaxed Muscle to an Externally Imposed Stretch The research underpinning the response of a relaxed muscle to an externally imposed stretch has probably been studied the most extensively in the literature. Some of the earliest clinicians and researchers measured spasticity by studying the muscle response to an externally imposed stretch using either fine wire or surface electromyography (EMG). It is a pity that somewhere along the way this approach to studying spasticity has for all practical purposes disappeared in clinical practice. In neurologically healthy subjects, when a relaxed muscle is passively stretched no EMG responses are normally observed below velocities of 200 deg/s. However, in patients with an upper motoneuron syndrome a range of EMG responses can be seen (Figure 1.3). These can be classified as (a) a velocity-dependent response, (b) a position-dependent response, a combination of (a) and (b), and (c) a clasp-knife-type response. Whilst the muscles of most patients will be in a state of rest prior to the start of the test, there are some patients in whom residual EMG activity at rest is observed. The literature describes these patients as having ‘spastic dystonia’‡ (Figure 1.4). However, what is important to also note in such patients is the phenomenon of position dependency, and possibly a combination of velocity and position dependency can be observed. Recordings such as those above have been widely observed (by, e.g., Tardieu et al. [1954]; Lance [1980a,b,c] and Rymer and Katz [1994]). Readers are encouraged (after reading Chapter 2 of this publication) to explore the literature produced by notable authors such as Sherrington, Matthews, Denny-Brown, Tardieu, Pierrot-Deseilligny, Hultborn, Burke, Lance, etc., ‡

Although we are not comfortable with this term it will be used until a suitable alternative can be found (this is unlikely to happen!).

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Neurological Rehabilitation

Slow vs fast (Vel & EMG) 0.1

Velocity during fast movement

400

EMG during 0.08 fast movement

Velocity (deg/s)

300 S_Vel

0.06

200

F_Vel

Velocity during slow movement

100 0 –1.818

0.04

EMG during slow movement

–100 –80

–60

–64.139

–40

0

–20

F_FEMG

0.02 0 40

20

S_Angle, F_Angle, S_Angle, F_Angle,

S_FEMG

EMG (mV)

500

402.48

4.406 × 10–3

36.153

Angle (deg) Slow velocity Fast velocity Slow_flexor EMG Fast_flexor EMG

(a)

0.29 Velocity during fast movement

60 S_Vel F_Vel

Velocity during slow movement

40

0.2 S_FEMG

EMG during fast movement

F_FEMG

20

0.1

0 –5.31

EMG (mV)

Velocity (deg/s)

99.189

Slow vs fast (Vel & EMG)

100

–20 –100

–80

–97.38

–60

EMG during slow movement –40 –20

S_Angle, F_Angle, S_Angle, F_Angle,

0 0

4.309 × 10–3

–10.003

Angle (deg)

(b)

Slow velocity Fast velocity Slow_flexor EMG Fast_flexor EMG

FIGURE 1.3 Images recorded from the Biceps Brachii muscle of stroke patients. The elbow joint was fully flexed and then extended using a ‘ramp and hold’ method (Rymer and Katz [1994]). The hold was <5 seconds in duration. Two velocities were used to stretch the joint (an uncontrolled slow velocity and an uncontrolled fast velocity as annotated on the respective graphs). The EMG during movement was also collected and the corresponding EMG traces are annotated on the respective graphs. The EMG activity was notch-filtered (50 Hz) and then smoothed using an RMS procedure as described in the source article. (a) This graph shows a velocity-dependent response to an externally imposed movement. There is very little EMG activity during the slow movement; however, there is a large burst of activity during the fast movement. The EMG activity starts to drop off towards zero at the end of the stretching movement. (b) This graph shows a position-dependent response to an externally imposed movement. The EMG activity increase as the muscle is stretched and the activity remains elevated during the hold phase. It is also important to note the EMG activity during the quick stretch starts earlier in the range of movement. (Continued)

11

Definition and Measurement of Spasticity and Contracture

Slow vs fast (Vel & EMG)

294.345

EMG during fast movement Velocity during fast movement

Velocity (deg/s)

200 S_Vel F_Vel

0.269 0.25 0.2

Velocity during slow movement

100

0.15

S_FEMG F_FEMG

EMG (mV)

300

0.1 0 –5.04

–100 –60

0.05

EMG during slow movement –40

–48.161

–20

0

20

S_Angle, F_Angle, S_Angle, F_Angle,

0 60

40

9.557 × 10–3

40.704

Angle (deg) Slow velocity Fast velocity Slow_flexor EMG Fast_flexor EMG

158.085

200

Slow vs fast (Vel & EMG) EMG during fast movement

Velocity (deg/s)

F_Vel

Velocity during fast movement

100

Velocity during slow movement

50

0.06 0.04

S_FEMG F_FEMG

0.02

0 –7.425

0.084

0.08

150

S_Vel

0.1

EMG (mV)

(c)

EMG during fast movement

0 –50 –140 –120 –100 –80 –60 –40 –20 –122.589 S_Angle, F_Angle, S_Angle, F_Angle, –27.948

0.012

Angle (deg)

(d)

Slow velocity Fast velocity Slow_flexor EMG Fast_flexor EMG

FIGURE 1.3 (CONTINUED) Images recorded from the Biceps Brachii muscle of stroke patients. The elbow joint was fully flexed and then extended using a ‘ramp and hold’ method (Rymer and Katz [1994]). The hold was <5 sec­­ onds in duration. Two velocities were used to stretch the joint (a uncontrolled slow velocity and an uncontrolled fast velocity as annotated on the respective graphs). The EMG during the movement was also collected and the corresponding EMG traces are annotated on the respective graphs. The EMG activity was notch-filtered (50 Hz) and then smoothed using an RMS procedure as described in the source article. (c) This graph shows a combination of velocity- and position-dependent responses to an externally imposed movement. The EMG activity increase as the muscle is stretched and the activity remains elevated during the hold phase. It is also important to note the EMG activity during the quick stretch starts earlier in the range of movement and is of a greater magnitude. (d) This graph shows the clasp-knife response to an externally imposed movement. The EMG activity increases rapidly as the muscle is stretched and this slows the movement down. If the examiner continues with the stretch the EMG activity then reduces. This response occurs during both the slow and fast stretch and is triggered at relatively slow velocities.

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Neurological Rehabilitation

150 100

Angle EMG triceps brachii

50 0 –50 0

EMG biceps brachii 2000

4000

6000

Force 8000 1 · 104 1.2 · 104 1.4 · 104

Angle Force EMG(Flexors) EMG(Extensors) FIGURE 1.4 A figure illustrating the phenomenon of spastic dystonia. A patient demonstrating EMG of the Biceps Brachii at rest. When the muscle is stretched the EMG activity increases as the stretch on the muscle is increased and as the stretch is carried out using a quicker speed the magnitude of the activity increases. It is important to note that in this patient stretching of the extensors lead to activation of the Triceps Brachii. When the Triceps were active the activity in the Biceps reduced.

all of whom employed direct measures of muscle electrical activity to gain an understanding of spasticity. What is obvious is that the stretch-induced response (i.e., velocity-dependent response, position-dependent response, the velocity- and position-dependent response and the ‘clasp-knife’ phenomenon) results from an afferent input to the central nervous system. However, the abnormal muscle activity at rest (i.e., spastic dystonia) appears to be independent of an afferent input to the CNS (e.g., loss of cortical inhibition to the brainstem pathways/nuclei). Within the context of a SPASM definition all of these conditions can be considered a sub-classification of spasticity. 1.2.2.4 Abnormal Movement Patterns and Co-Contraction The abnormal movement patterns and co-contractions that are commonly seen after an upper motoneuron lesion are currently classified under the term spasticity. However, it is possible that the abnormal patterns of movement and co-contraction one observes during voluntary movement may result from the compensation to the weakness that co-exists (Chapters 2 and 3 discuss this possibility in greater detail). Furthermore, if one were to test individuals with no known impairments, enhanced tremor-like oscillations and co-contractions can be provoked in cases of fatigue or peripheral

Definition and Measurement of Spasticity and Contracture

13

loading, the latter being the interia-sensitive mechanical-reflex oscillation component of tremor (Elble and Koller [1990]). In normal movement, patterns of co-contraction and the synergetic activation and de-activation of muscles are the norm and are an essential feature of successful movement execution in both simple and complex actions. For example, the ability to grip and transport an object will be severely compromised if one is unable to stabilise the wrist and simultaneously coordinate the co-contraction of muscles of the shoulder and elbow joint during this action. Under these conditions classifying abnormal movement patterns and co-contraction as a sub-classification of spasticity is not appropriate and, collectively, more appropriately reflects a deficit of control. 1.2.3 The Classification and Definition of Spasticity in Upper Motoneuron Syndrome Based on our current understanding, and extending the work of the SPASM consortium, it is possible to first define spasticity as an emergent feature of disordered sensori-motor control, resulting from an upper motoneuron lesion, presenting as intermittent or sustained involuntary activation of muscles. Spasticity can present as: • Spasms (A transient but continuous muscular contraction which can be triggered by a combination of cutaneous and/or visceral triggers). • Clonus (A transient but intermittent rhythmic muscle contraction with proprioceptive and/or cutaneous triggers). • Abnormal activation of muscles to an externally imposed stretch, which can present as a combination of: • velocity-dependent response; • position-dependent response; • ‘clasp-knife’ response. • A continuous activation of muscles even in a state of rest (spastic dystonia). The clinical presentations of spasticity can be modulated by ambient afferent inputs (e.g., touch, temperature, etc.); however, at this stage it is not possible to expand. Further, the time course of the development of spasticity has not been well documented. What is clear is that immediately following a lesion the central nervous system goes into a period of shock and recovery during which time the system will start to present with varying responses and time delays. The time course of development of spasticity is likely to be disease-specific. In stroke, traumatic/hypoxic brain injury, and spinal cord injury the evidence is that spasticity onset can be rapid (i.e., within 48 hours or earlier) but often the onset time course is highly variable. The natural

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Neurological Rehabilitation

history and time course of onset in many disease populations needs to be established. A significant limitation to the proposed definition is the narrow focus on patients with an acquired upper motoneuron lesion. There are large population of patients with acquired/degenerative disease of the nervous system who present with signs that are similar to those described under spasticity or spastic dystonia. In particular, patients with Parkinsonism who present with rigidity and/or cog-wheel rigidity, patients with movement disorders such as Huntington’s disease, Blepharospasm, and Cervical Dystonia, all of whom can present with spasms (often termed dystonia) affecting different parts of the body, and patients with motoneuron disease. Maybe discussion of this is for a second edition; however, there is much work that needs to be done to produce such a unifying framework for definition and measurement. 1.2.4 Contractures in Patients with Upper Motoneuron Syndrome A contracture has been defined as a pathological condition of soft tissues characterised by stiffness and is usually associated with loss of elasticity and fixed shortening of the involved tissues (muscle, tendon, ligament, subcutaneous tissue, skin, blood vessels, and nerves) and results in loss of movement around a joint (Botte et al. [1988]; Lehmann et al. [1989]; Harburn and Potter [1993]; Teasell and Gillen [1993]). Contractures normally occur as a result of a joint being fixed in a shortened position with a lack of loading to the soft tissue structures. In the following paragraphs, we will briefly discuss factors that can contribute to contractures following an upper motoneuron lesion. Following an upper motoneuron lesion a patient will present with paralysis or paresis and as a result the muscle and joint structures of the affected periphery become unloaded. In particular, if a patient does not regain functionally useful movement then the patient will present with muscle atrophy, i.e., a decrease in the size of the muscle fibres and therefore the muscle itself, a decrease in the force generation capacity within the muscle, and an increase in the fatiguability of muscles. The increase in fatiguability probably arises from decreasing glycogen stores and ATP levels within a muscle (Lieber [2009]). The loss of muscle mass could in part be explained by an increase in the catabolic enzyme levels within these muscles that have been paralyzed (Lieber [2009]). The loss of loading, on the soft tissues, may also contribute to an increase in the collagen crosslinks that occur within the tendon and soft tissue structures and this can contribute to an increase in stiffness. However, it is important to note that a patient presenting with no symptoms other than paralysis rarely presents with contractures in the acute and subacute stages following the neurological injury (Figure 1.5). If a patient were to develop contractures, as defined above, in addition to the lack of loading and motion, the joints should also be held in a shortened position. Based on the evidence collected by Pandyan and co-workers there

15

Definition and Measurement of Spasticity and Contracture

0.02

0

(bi)

0.01 –50 0 50 Angle (deg)

0.04

3

0.03

2

0.02

1

0.01 –50 0 50 Angle (deg)

0

4

0.04

0.03

2

0.02

1

0.01

0

(biii)

–50 0 50 Angle (deg)

1

0.01

(aiv)

0

EMG (mV)

0.02

0

0 – 50 0 50 Angle (deg) Angle vs Force (slow) Angle vs Flex or EMG

3

Force (N)

Force (N)

Force (N)

(bii)

EMG (mV)

(aiii)

4

0

0

0

0 – 50 0 50 Angle (deg) Angle vs Force (slow) Angle vs Flex or EMG

2

0 – 50 0 50 Angle (deg) Angle vs Force (slow) Angle vs Flex or EMG

4

0.04

3

0.03

2

0.02

1

0.01

0 –100 –50 0 50 Angle (deg)

0

EMG (mV)

2 1

0.01

Force (N)

0.03

(aii)

0.02

1

EMG (mV)

0.04

3

0.01

1

2

Force (N)

4

2

EMG (mV)

Force (N)

(ai)

0.02

3

0

0 – 50 0 50 Angle (deg) Angle vs Force (slow) Angle vs Flex or EMG

EMG (mV)

0

0.01

EMG (mV)

0.02

1

Force (N)

Force (N)

2

4

EMG (mV)

3

5

(biv)

0 0 50 Angle (deg) Angle vs Force (slow) Angle vs Flex or EMG

0 –100 –50

(ci)

2

0.02

1 0 0 50 100 Angle (deg) Angle vs Force (slow) Angle vs Flex or EMG

0 –100 –50

(cii)

0.03

2

0.02

1

0.01

0 0 –100 –50 0 50 Angle (deg) Angle vs Force (slow) Angle vs Flex or EMG

(ciii)

4

0.04

3 2

0.02

1

EMG (mV)

0.01

0.04

3

Force (N)

0.02

1

4

EMG (mV)

2

3

Force (N)

0.03

EMG (mV)

3

0.04

4

Force (N)

0.04

EMG (mV)

Force (N)

5 4

0 0 0 –100 –50 50 Angle (deg) Angle vs Force (slow) Angle vs Flex or EMG

(civ)

FIGURE 1.5 The relationship between spasticity, contractures, and function. Graphs illustrating the observation that the person most prone to developing a contracture is a patient who has not regained functional movement and who also has concomitant spasticity (graphs ci to civ). Patients who (a) have spasticity and yet recover function (graphs ai to aiv) and (b) have no function and no spasticity (graphs bi to biv) appear not to develop contractures. In all the graphs above, stiffness (a plot of angle vs. force) is indicated in gray and stretch-induced muscle activity from the forearm flexors (a plot of angle vs. EMG activity) is indicated in black. The graphs were plotted for slow movement (ai, aiii, bi, biii, ci, ciii) and the fast movement (aii, aiv, bii, biv, cii, civ) (unpublished observations from Cameron et al. [2014]). Measurements were taken at the forearm flexors of the wrist less than two weeks after the stroke (subscript of I and ii) and repeated six months after stroke (subscripts iii and iv). A patient presenting with velocity-dependent spasticity (ai, aiii, aiii, aiv). This person on admission after stroke, had a NIHSS score of 18 and an action research arm test (ARAT) score of 1. At six months after stroke the patient had a Barthel index of 15 and an ARAT score of 57. Contractures were assessed during slow movement (i.e., the range of movement at the wrist had not changed and the stiffness at baseline and at six months was 0.014 N/deg and at six months was 0.011 N/deg) and there was no evidence that contractures had occurred. A patient presenting with no spasticity (bi, biii, biii, biv). This person, on admission after stroke, had an NIHSS score of 17 and an ARAT score of 0. At six months after stroke the patient had a Barthel index of 18 and an ARAT score of 0. Contractures were assessed during slow movement (i.e., the range of movement at the wrist had not changed and the stiffness at baseline and six months were both 0.009 N/deg) and there was no evidence that contractures had occurred. A patient presenting with a combination of velocity and position-dependent spasticity at the initial measurement (ci, ciii) and position-dependent spasticity, with potential signs of clonus at the second measurement (ciii, civ). This person on admission after stroke had an NIHSS score of 13 and an ARAT score of 0. At six months after stroke the patient had a Barthel index of 3 and an ARAT score of 1. Contractures were assessed during slow movement (i.e., the range of movement at the wrist had reduced by about 50% at the six-month measurement; the stiffness had increased from 0.007 N/deg at baseline to 0.047 N/deg at six-months) and there was unambiguous evidence that contractures were established.

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Neurological Rehabilitation

are three possible factors that can contribute to a person holding a limb in a shortened position: (a) spasticity, (b) pain and (c) reduced cognitive ability. • Does spasticity contribute to contractures? Of the various forms of spasticity presented in Figure 1.3, it can be hypothesised, in patients who have no return of useful function, that any form of position-dependent spasticity, the ‘clasp-knife’ response, and ‘spastic dystonia’ can all contribute to a limb being held in a shortened positon. If one were to extrapolate from the animal models then it is possible that the rate of contracture formation is likely to be quicker in patients with ‘spastic dystonia’ than in patients  with  a  form  of ­position-dependent spasticity or the ‘clasp-knife’ response (Lieber [2009]). A general rule appears to be that joints that are held in a shortened position through muscle activity develop contractures more rapidly than in active muscles held in shortened position. The evidence from clinical studies reinforce these observations, i.e., people who have no function and develop spasticity develop contractures more rapidly than those who do not (Figure 1.4) (Pandyan et al. [2003]; Malhotra et al. [2011]). People who regain limb function and present with signs of spasticity do not develop contractures. A general confounder in the literature is that most people who have studied the relationship between spasticity and contractures have often used invalid clinical scales, making interpretation of the results difficult. • Does pain and cognitive dysfunction contribute to contractures? Anecdotal evidence from data generated form a recently completed study (unpublished observations from Cameron et al. [2014]) suggests that patients with a combination of pain and/or congnitive dysfunction tend to be more prone to contractures. Many of these patients were capable of functional movement but were often unable to use their limbs due the nature of the pain and/or cognitive dysfunction. The most plausible explanation for this is likely to be the individual protecting the limb in a shortened positon in an attempt to alleviate pain. However, these anecdotal associations need to studied more systematically before any firm conclusion can be made. The literature seems to suggest that contractures, when they occur, are more common at the ankle and the wrist when than at other proximal joints (Sackley et al. [2008]). If one were to explore the data from animal models and the few longitudinal data in adult patients with acquired brain injuries, including stroke, it can be found that contractures can develop quiet rapidly, i.e., within 4 to 6 weeks after a stroke (Malhotra et al. [2011]). This is also the time window within which spasticity is expected to develop. This is an important consideration when one has to start measuring or treating patients.

Definition and Measurement of Spasticity and Contracture

17

1.2.5 The Measurement of Spasticity and Contracture When you can measure ... you know something about it – but when you cannot measure ... your knowledge is of a meagre and unsatisfactory kind: it may be the beginning of knowledge but you have scarcely, in your thought, advanced to the stage of science whatever the matter may be (Lord Kelvin, 1889).

Both spasticity and contractures would come under the classification of impairments under the ICF classification. From a first-principle basis one needs to consider spasticity an impairment of the central nervous system and contractures as an impairment of the musculoskeletal system. Both of these impairments are likely to have an impact on activity, societal participation, and possibly carer burden. From a clinical perspective, it may be advantageous to measure spasticity indirectly, i.e., measuring the effects of treatment on activity, societal participation, or carer burden as appropriate to the needs of an individual patient. The disease-specific chapters have discussed approaches to measurement as appropriate. Within the context of this chapter, however, the primary focus will remain on the measurement of the primary impairments of spasticity and contractures. The current methods of measurement or assessment can be classified as clinical scales, biomechanical methods, and neurophysiological methods. The most direct approach to measuring spasticity and the associated pathophysiology is by using neurophysiological methods. The biomechanical methods have the greatest potential to measure contractures. These three approaches are briefly examined in this section and the relative merits are discussed. • Clinical scales to measure spasticity and contractures. There are two scales that can be used to measure spasms: the Penn Spasm Frequency Scale and the Spasm Frequency Score (Penn et al. [1989]; Snow et al. [1990]; Biering-Sørensen et al. [2005]). Both these scales are patient reported scales and quantify the severity of spasms at an ordinal level of measurement. The reliability is limited as this does depend on patient memory of events (Biering-Sørensen et al. [2005]). There are a variety of scales that measure the resistance to an externally imposed passive movement and use these to indirectly quantify spasticity (e.g., the Ashworth Score and its variations – the Tardieu Score, the Composite Spasticity Index, etc.) (Platz et al. [2005]). These scales are the most commonly used measures of spasticity, and are also the measures that are endorsed by many of the regulatory authorities (e.g., FDA). Unfortunately, none of these measures are useful measures of spasticity as these are all significantly confounded. The research evidence proving that these scales,

18

Neurological Rehabilitation

and the general principle of measuring resistance to an externally imposed movement, are not fit for purpose have originated from multiple research groups carrying out work on different continents and will not be rehashed here. If readers are interested, please see the relevant papers (Pandyan et al. [1999]; Haugh et al. [2006]; Fleuren et al. [2010]). It is a source of regret that many of the more direct neurophysiological and relatively simple measures that have underpinned our understanding of spasticity (Rymer and Katz [1994]) have been replaced by inadequate clinical scales for purposes of clinical expediency. • Biomechanical methods to measure spasticity and contractures. A range of biomechanical methods have been described to measure spasticity. These can be classified as manual methods (e.g., Pandyan et al. [2001]); controlled displacement methods using rampand-hold perturbations (Rymer and Katz [1994]), sinusoidal pertur­ bations (Zhang and Rymer [1997]), or random perturbations (Andersen and Sinkjaer [1996]); controlled torque methods (Walshe [1992]); or the gravitational method (Bajd and Bowman [1982]). All of the above methods attempt to measure spasticity by measuring the resistance to an externally imposed perturbation. The evidence would suggest that these biomechanical measures are more often measuring concomitant biomechanical changes in the soft tissue structures as opposed to measuring spasticity. Furthermore, whilst attempting to measure spasticity, most methods measure stiffness eccentrically; under these conditions it is not possible to delineate the components of stiffness (i.e., that arising from muscle activity, the intrinsic stiffness within the muscle due the residual actin and myosin cross bridges, and the contribution from the mechanical properties of the associated soft tissue structures). The biomechanical methods of measurement have been reviewed previously (Wood et al. [2005]; Pandyan et al. [2009]). All of the biomechanical methods have limited clinical applicability when used as measures of spasticity; however, they have a significant role to play in the measurement of contractures. Although not commonly used, accelerometers have the potential to contribute to the measurement of spasms and clonus in a relevant way (Granat and Edmonds [1999]). While in the past such technology was expensive, the size and costs of these sensors have significantly reduced and there is the potential for such technologies to play an important role in the measurement and management of spasms (e.g., 24-hour monitoring systems for patients). In addition, it is also now possible to additionally measure muscle activity data concomitantly. Whilst such technology is available, there is a need for additional research to make it accessible to clinicians.

Definition and Measurement of Spasticity and Contracture

19

• Neurophysiological methods to measure spasticity. A range of neurophysiological methods have been described to measure spasticity or the pathophysiological basis of spasticity. These methods have previously been comprehensively reviewed (Voerman et al. [2005]; Pandyan et al. [2009]). The methods of relevance are as follows: the efferent response to an electrical stimulus (The H-reflex and F-wave); and the efferent response to a mechanical perturbation (tendon tap, manual perturbation, or controlled displacement perturbation – normally a ramp-and-hold stretch). While most of these methods of measurement are relatively easy to perform, in particular the efferent response to a mechanical perturbation, the reliability of these methods of measurement needs to be better understood. Current experimental evidence would suggest that H-reflex and F-wave measurements show a large degree of variability. Furthermore, in patients with an upper motoneuron lesion, developing a method of standardisation in measuring the muscle response to a mechanical perturbation is not possible. Despite the poor levels of reliability, many of these methods of mea­ surement provide far more useful information to inform the management of spasticity than any of the clinical scales or the biomechanical measures used in isolation. For example, when selecting patients for implantation of an intrathecal baclofen pump, an effective way to identify a suitable patient will be to study the H-reflex response to a bolus injection of intrathecal baclofen (Macdonell et al. [1989]). In order to either select patients for treatment with botulinum toxin (or phenol or a motor nerve dissection) or study the response to treatment it would make sense to ensure that the muscle/nerve being treated has an overactive efferent response associated with spasticity (Figures 1.3 and 1.5) as measured using manual neurophysiological methods. 1.2.6 Concluding Thoughts Spasticity appears to be an inevitable sequela following a lesion in the upper motoneuron pathways. Within this chapter we provide a framework to classify spasticity in a way that makes measurement possible. We have also provided an argument to suggest that patients who have spasticity and who do not recover useful functional movement are at risk of contractures. The contractures can develop rapidly and often co-exist with spasticity. The options to treat spasticity are limited: • Reduce the afferent input to the nervous system (selective dorsal rhyzotomy). • Reduce the gain/threshold within the nervous system (pharmacological treatments that tend to depress the nervous system).

20

Neurological Rehabilitation

• Reduce the efferent drive to the muscle (botulinum toxin, phenol, and neurectomies). • Use muscle relaxants. The options to treat contractures are even more limited: • Cyclical Passive Movement (using ergometers or electrical stimulation). • Stretching using splints, serial casts, or progressive stretching devices. • Loading the tendons using electrical stimulation. In order to identify the most useful treatment combination it is essential that not only the right treatment is selected but that the response to the treatment is effectively monitored. This chapter will hopefully give some pointers in ensuring that the right definitions and measurements can inform the methods of treatment. Then there is the issue of linking our understanding of spasticity to the recovery potential of patients. Many of the current first-line treatments for spasticity have the potential to inhibit the learning that is essential for recovering functionally useful movement (e.g., pharmacological agents routinely used in clinical practice) (Cameron et al. [2016]). Current practice will need to be carefully re-examined; however, doing this in the absence of a precise framework is not appropriate. This chapter hopefully provides such a framework to both clinicians and researchers. Finally, one must also consider the possibility that spasticity is an epiphenomenon, although this may not be the case in all patients. The literature and our own work provides evidence that patients who have recovered useful arm function continue to demonstrate signs of spasticity. Identifying such patients is important as it is possible that spasticity may be an inevitable first step in the recovery pathway. The framework may have a role to play in this classification process. This book is the first attempt at bringing together a volume of work from a range of professionals with an interest in spasticity. The framework for the definition was developed in part by the authors reading the chapters that make up this volume. There are likely to be some anomalies between the framework and the summaries within respective chapters. This was expected as the literature that the respective authors have had to draw upon is imprecise. One would hope that the framework within this chapter will help guide the research that follows so that future reviews will be able to coherently summarise the literature with no ambiguity. As pointed out in Section 2.3, this framework has currently been developed for patients with upper motoneuron lesions, as identified within this book. There is a significant volume of work that now needs to be done to provide a framework that will include a range of other disease conditions where patients present with signs and symptoms similar to those described in this chapter (e.g., Parkinsonism, the various forms of dystonia, and other motoneuron diseases).

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21

References Andersen, JB, Sinkjaer T. (1996) An actuator system for investigating electrophysiological and biomechanical features around the human ankle joint during gait. IEEE Transactions on Rehabilitation Engineering 3:299–306. Bajd T, Bowman B. (1982) Testing and modelling of spasticity. Journal of Biomedical Engineering 4(90):90–96. Barnaby B et al. (2002) Ashworth score zero: Normative data estimates for resistance to passive elbow extension obtained from a female non-impaired adult sample. 13th European Congress of Physical and Rehabilitation Medicine. Brighton, UK, May 28 – 31, 2002, p. 209. Bennett AH. (1887) Muscular Hypertonicity in Paralysis: The Opening of a Discussion on the Subject at The Neurological Society of London. London: William Clowes and Sons Ltd. Biering-Sørensen F et al. (2005) Spasticity-assessment: A review. Spinal Cord 44:​ 708–722. Botte MJ et al. (1988) Spasticity & contractures: Physiologic aspects of formation. Clinical Orthopaedics and Related Research 233:7–18. Burke D. (1988) Spasticity as an adaptation to pyramidal tract injury. Advances in Neurology 47:401–422. Cobb S and Wolf HG. (1932) Muscle tonus: A critical review based on work presented at the International Neurological Congress, Bern, Switzerland, 1931. Archives of Neurology and Psychiatry 28:661–678. Denny-Brown D. (1966) The Cerebral Control of Movement. Liverpool: Liverpool University Press. Elbe RJ and Koller WC. (1990) Tremor. Baltimore, MD: Johns Hopkins University Press. Fleuren JF et al. (2010). Stop using the Ashworth Scale for the assessment of spasticity. Journal of Neurology, Neurosurgery and Psychiatry 81(1):46–52. Granat M and Edmonds P. (1999) The application of air bag technology: An objective clinical measure of involuntary muscle spasm. Spinal Cord 37:501–507. Harburn KL and Potter PJ. (1993) Spasticity and contractures. Physical Medicine & Rehabilitation: State of the Art Reviews 7:113–132. Haugh AB et al. (2006) A systematic review of the Tardieu Scale for the measurement of spasticity. Disability and Rehabilitation 28:899–907. Kumar R et al. (2006) Biomechanical measurement of post stroke spasticity. Age & Ageing 35(4):371–375 Lance J. (1980a) Symposium synopsis. In Feldman RJ, Young RR, Koella WP, eds. Spasticity disordered motor control. Chicago: Year Book, pp. 51–55. Lance J. (1980b) Symposium synopsis. In Feldman RJ, Young RR, Koella WP, eds. Spasticity disordered motor control. Chicago: Year Book, pp. 185–204. Lance J. (1980c) Symposium synopsis. In Feldman RJ, Young RR, Koella WP, eds. Spasticity disordered motor control. Chicago: Year Book, pp. 485–494. Landau WM. (1974) Spasticity: The fable of a neurological demon and the emperor’s new therapy. Archives of Neurology 31(4):217–219. Lehmann JF et al. (1989) Spasticity: Quantitative measurements as a basis for assessing effectiveness of therapeutic intervention. Archives of Physical Medicine and Rehabilitation 70:6–15.

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Lieber RL. (2009) Skeletal Muscle Structure, Function, and Plasticity, 3rd edn., Baltimore and Philadelphia: Lippincott Williams and Wilkins. Lindsay C et al. (2014) The early use of botulinum toxin in post-stroke ­spasticity: Study protocol for a randomised controlled trial. Trials 15:12. doi: 10.1186/​1745​ -6215-15-12. Lindsay C et al. (2016) Pharmacological interventions other than botulinum toxin for spasticity after stroke. Cochrane Database of Systematic Reviews, 10: CD010362. doi: 10.1002/14651858.CD010362.pub2. Lord Kelvin. (1889) Electrical Units of Measurement. A lecture delivered at the Institution of Civil Engineers on Mar 3, 1883. Nature Series: Popular lectures and Addresses by Kelvin, William Thomson, Baron, 1824–1907, pp. 73–136 (quote page 73–74). Macdonell RAL et al. (1989) Intrathecal baclofen and the H-reflex. Journal of Neurology, Neurosurgery and Psychiatry 52:1110–1112. Malhotra S et al. (2008) An investigation into the agreement between clinical, biomechanical and neurophysiological measures of spasticity. Clinical Rehabilitation 22(12):1105–1115. Malhotra S et al. (2009) Spasticity, an impairment that is poorly defined and poorly measured. Clinical Rehabilitation 23(7):651–658. Malhotra S et al. (2011) Spasticity and contractures at the wrist after stroke: Time course of development and their association with functional recovery of the upper limb. Clinical Rehabilitation 25(2):184–191. Pandyan AD et al. (1999) A review of the properties and limitations of the Ashworth and modified Ashworth Scales. Clinical Rehabilitation 13:373–383. Pandyan AD et al. (2001) Biomechanical examination of a commonly used measure of spasticity. Clinical Biomechanics 16:859–865. Pandyan AD et al. (2003) Contractures in the post stroke wrist: A pilot study of its time course of development and its association with upper limb recovery. Clinical Rehabilitation 17(1):88–95. Pandyan AD et al. (2005) Spasticity, clinical perceptions and neurological realities and meaningful measurement. Disability and Rehabilitation 27:2–6. Pandyan AD et al. (2009) Spasticity, The New Encyclopedia of Neuroscience. Squire LR, ed. Vol 9. Oxford: Academic Press, pp. 153–163. Penn RD et al. (1989) Intrathecal baclofen for severe spinal spasticity. New England Journal of Medicine 320:1517–1521. Platz T et al. (2005) Clinical scales for the assessment of spasticity, associated phenomena, and function: A systematic review of the literature. Disability and Rehabilitation 27:7–18. Rushworth G. (1960) Spasticity and rigidity: An experimental study and review. Journal of Neurology, Neurosurgery and Psychiatry 23:99–118. Rymer WZ and Katz RT. (1994) Mechanical quantification of spastic hypertonia. Physical Medicine & Rehabilitation: State of the Art Reviews 8:455–464. Sanger T et al. (2003) Classification and definition of disorders causing hypertonia in childhood. Pediatrics 111:e89–e97. Scakley C et al. (2008). The prevalence of joint contractures, pressure sores, painful shoulder, other pain, falls, and depression in the year after a severely disabling stroke. Stroke 39:3329–3334. Siegel IM. (1988) Historical vignette #9. Little big man: The life and genius of William John Little (1810–1894). Orthopaedic Reviews 17(11):1156, 1161–1166.

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Singer B et al. (2003) Velocity dependent passive flexor resistive torque in patients with acquired brain injury. Clinical Biomechanics 18:157–165. Snow BJ et al. (1990) Treatment of spasticity with botulinum toxin: A double blind study. Annals of Neurology 28:512–515. Tardieu G et al. (1954) A la recherche d’une technique de measure de la spasticite. Revenue Neurologique 91:143–144. Teasell RW and Gillen M. (1993) Upper extremity disorders and pain following stroke. Physical Medicine & Rehabilitation: State of the Art Reviews 7:133–146. Thilmann AF. (1993) Spasticity: History, Definitions, and Usage of the Term. In Thilmann AF, Burke DJ, Rymer WZ, eds. Spasticity. Berlin: Springer, pp. 1–5. Voerman G et al. (2005) Neurophysiological methods for the assessment of spasticity: The Hoffman reflex, the tendon reflex and the stretch reflex. Disability and Rehabilitation 27:19–32. Walshe EG. (1992) Muscles, Masses and Motion: The Physiology of Normality, Hypotonicity, Spasticity and Rigidity. Clinics in Developmental Medicine 125. London: Mac Keith Press. Wood D et al. (2005) Biomechanical approaches applied to the lower and upper limb for the measurement of spasticity: A systematic review of the literature. Disability and Rehabilitation 27:19–32. York GK and Steinberg DA. (2007) An introduction to the life and work of Hughlings Jackson. Medical History Supplement 26:3–34. Zhang LQ and Rymer WZ. (1997) Simultaneous and nonlinear identification of mechanical and reflex properties of human elbow joint muscles. IEEE Transactions on Biomedical Engineering 44(12):1192–1209.

http://taylorandfrancis.com

2 Pathophysiology of Spasticity Jens Bo Nielsen, Maria Willerslev-Olsen and Jakob Lorentzen CONTENTS 2.1 How to Measure Spasticity – From Clinical Evaluation to Biomechanical Techniques...................................................................... 26 2.2 The Nature of the Muscle Response to Stretch........................................ 28 2.3 Is Spasticity Caused by Lesion of the Pyramidal Tract?......................... 29 2.4 Spasticity Does Not Appear Immediately after Lesion but Is Caused by Adaptive Changes in Spinal Networks.............................30 2.5 Pathophysiology of Exaggerated Stretch Reflex Activity: Adaptive Changes in Spinal Neural Networks........................................ 31 2.5.1 Pathophysiological Role of Motoneuronal Changes.................... 32 2.5.2 Sprouting, New Synapses................................................................ 35 2.5.3 Regulation at Presynaptic Sites: Increasing the Input from Surviving Fibres...................................................................... 35 2.5.3.1 Presynaptic Inhibition....................................................... 36 2.5.3.2 Post-Activation Depression............................................... 37 2.5.4 Transmission in Group II Pathways............................................... 39 2.5.5 Pathophysiological Role of Changes in Postsynaptic Inhibition of Motoneurons.............................................................. 40 2.5.5.1 Disynaptic Reciprocal Ia Inhibition................................ 40 2.5.5.2 Recurrent Inhibition.......................................................... 41 2.5.5.3 Autogenetic Ib Inhibition..................................................43 2.5.5.4 Fusimotor Drive, Gamma-Spasticity...............................43 2.6 How Is Clonus Related to Spasticity?........................................................44 2.7 What Causes a Spasm?................................................................................. 45 2.8 Spastic Dystonia Is Not Caused by Increased Stretch Reflex Activity.... 45 2.9 Concluding Remarks.................................................................................... 46 References................................................................................................................ 47

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2.1 How to Measure Spasticity – From Clinical Evaluation to Biomechanical Techniques The clinical evaluation of spasticity currently rests on the eyes and hands of the clinician. Clinically, spasticity is often inappropriately equated to muscle tone and is essentially determined by sensing the resistance to passive movement around a joint with the patient in a position that is as relaxed as possible. By making movements at different velocities the clinician may get a feeling of whether the resistance is present at all velocities or only during fastest stretching of the muscles. Sometimes a distinct brief resistance – a catch – may be determined with quick stretches at specific positions of the joint. Backed up by other signs such as large – and especially non-symmetrical – tendon tap reflexes and the presence of clonus, the clinician may perceive that the resistance is velocity-dependent and may possibly be related to hyperexcitable stretch reflexes; i.e., that the muscle resistance is caused by spasticity according to Lance’s definition. In many cases the determination of the presence of spasticity is relatively straightforward and unproblematic (this may especially be the case when the clinician has knowledge of the underlying disorder, e.g., stroke or spinal cord, but may not necessarily be the case without this prior knowledge). However, if the patient is not fully relaxed, if the changes in reflex excitability are not very large, or if other mechanisms also contribute to increased muscle resistance, it may be very difficult to accurately determine the nature of the muscle resistance. The presence of alterations in the elastic properties of the muscle, connective tissue, and/or tendons especially makes it difficult to perform the evaluation sufficiently fast and powerfully and it therefore becomes a challenge to determine the presence of spasticity. The presence of involuntary static muscle activity (spastic dystonia) and an associated inability of the patient to fully relax the muscle also make the evaluation difficult. Clinical evaluation of spasticity has consequently been shown to have variable reproducibility within and between raters (Bhimani et al. 2011, Biering-Sorensen et al. 2006, Haugh et al. 2006, Mutlu et al. 2008) and to be unrelated to objective biomechanical measures of spasticity (Lorentzen et al. 2010, Willerslev-Olsen et al. 2013). The Ashworth scale was introduced in 1964 (Ashworth 1964) as a simple 5-point scale ranging from normal muscle tone (0) to rigidity (4) in order to quantify spasticity in multiple sclerosis before and after treatment. An additional grade (1+) was introduced in 1987 to designate slight resistance with a clear catch (Bohannon and Smith 1987). This modified Ashworth Scale (MAS) is now the most commonly used clinical scale, although it is confounded by the same limitations as the original scale, except for the additional grade. Furthermore, the introduction of this additional grade seems not to have improved the reliability of the scoring (Bhimani et al. 2011, Biering-Sorensen et al. 2006, Burridge et al. 2005) and a conspicuous over-representation of scores 1 and 2 (Fleuren et al. 2010) suggests that what is scored in most patients is ‘some resistance but not

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too much’ (Biering-Sorensen et al. 2006). The scale has consequently shown low validity and sensitivity in studies in which it has been related to biomechanical measures of stiffness (Biering-Sorensen et al. 2006, Burridge et al. 2005, Lorentzen et al. 2010, Malhotra et al. 2008, Sehgal and McGuire 1998). It is surprising given these drawbacks that the scale has become the scale of choice in the clinic, rather than the older Tardieu scale. The Tardieu method was originally introduced in 1954 (Tardieu et al. 1954) and has been modified significantly to become the Tardieu scale that is in use today (Haugh et al. 2006, Held 1969). The essence of the scale is that the examiner has to move the examined limb at three different velocities (slow, moderate, and as fast as possible) in order to estimate range of movement, presence of passive resistance, and presence of spasticity. The scoring of spasticity is based on the presence of a catch and clonus. Although the Tardieu scale theoretically should more adequately distinguish passive and active components of muscle resistance than the Ashworth scale, it has not gained as wide a use in the clinic as the Ashworth scale. Part of the reason for this is that the technique is more demanding for the examiner and is therefore less easy to perform in a similar way for two raters. The scale also lacks sufficient dimensionality to cover patients with very severe spasticity that prevents elicitation of stretch reflexes and clonus. The focus on the presence of clonus is also problematic given the uncertainty regarding the mechanisms of clonus and its relation to spasticity (Mukherjee and Chakravarty 2010). Biomechanical evaluation of spasticity was introduced in the 1950s by Tardieu (Tardieu et al. 1954) and later developed by Knutsson (Knutsson and Martensson 1976). Since then, various devices and techniques have been developed and tested (Mirbagheri et al. 2005, Mirbagheri et al. 2009, Mirbagheri et al. 2004, Sinkjaer 1997, Sinkjaer et al. 1992, Sinkjaer and Magnussen 1994, Sinkjaer et al. 1995, Sinkjaer et al. 1988, Toft et al. 1989b, Toft et al. 1989c, Wood et al. 2005). The main advantage of these techniques is that they provide an objective and quantitative assessment of resistance about a joint. With the addition of EMG measurements from the stretched muscles, they may provide an objective and precise way of distinguishing reflex-mediated from passive muscle resistance (Lorentzen et al. 2010, Sinkjaer et al. 1993, Toft et al. 1989b, Willerslev-Olsen et al. 2013). From this point of view, biomechanical evaluation combined with electrophysiological measures might be considered a ‘gold standard’ for a combined evaluation of spasticity and contractures with which other measures may be compared. However, the expertise and technology involved is too demanding for routine clinical use. Handheld dynamometers and other simplified biomechanical devices may provide sufficiently reliable and consistent measures, but none of the commercially available devices have so far shown sufficiently promising results to be used more widely in the clinic for spasticity evaluation (Barden et al. 2012, Benard et al. 2010, Calota et al. 2008, Kim et al. 2011, Lee et al. 2004, Lorentzen et al. 2012, Waldman et al. 2013). Only few of the existing devices claim to provide a distinction between reflex-mediated and

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passive muscle stiffness and there is therefore a clear need to develop more optimal easy-to-use devices that can help the clinician in the routine clinical diagnosis.

2.2 The Nature of the Muscle Response to Stretch In order to understand the pathophysiology of spasticity it is useful initially to consider the responses of a muscle to stretch (1). At velocities below the threshold of the stretch reflex the resistance against the movement is caused solely by the passive elastic properties of the muscle, connective tissue, tendon, and joint (Lorentzen et al. 2010, Mirbagheri et al. 2005, Mirbagheri et al. 2004, Toft et al. 1989a, Toft et al. 1989b). This resistance is usually called passive stiffness (Toft et al. 1989a, Toft et al. 1989b) and is far less sensitive to the velocity of the stretch than the stretch reflex-mediated resistance (Lorentzen et al. 2010). However, the resistance varies with the position of the joint and thus the degree of stretch of the muscle (Mirbagheri et al. 2005, Mirbagheri et al. 2009, Mirbagheri et al. 2004). If the subject is not fully relaxed, neural activation of the muscle will result in formation of cross-bridges between myosin and actin filaments that will impede the stretch and add very significantly to the stiffness (Figure 2.1). This stiffness is usually called intrinsic stiffness, to distinguish it from passive and reflex-mediated stiffness

Normal

Adaptation (spasticity)

Lesion

Descending drive

Descending drive

Descending drive

Sensory input

Sensory input

Sensory input Motoneurone

Output from spinal cord

Motoneurone

Output from spinal cord

Motoneurone

Output from spinal cord

FIGURE 2.1 Theoretical changes in sensory and descending input to spinal motoneurons in the acute and chronic phase following central motor lesion. The figure illustrates sensory and descending input to spinal motor neurons in the intact state (Normal), and following a central motor lesion in both the acute state (Lesion), and in the chronic phase (Adaptation, spasticity). The numbers and thickness of the arrows represent the power and intensity of the input and outputs.

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(Sinkjaer et al. 1993), but it should be emphasised that it is caused by an (extrinsic) neural signal and may be very difficult to distinguish in practice from reflex-mediated stiffness given the integration between descending motor commands and reflexes (Nielsen 2004). When stretches above a certain threshold (which is determined individually by the sensitivity of muscle spindles, transmitter release from central synapses, and the excitability of motoneurons) are applied, a stretch reflex response will be evoked and add to the resistance against the movement (Figure 2.1). This reflex-­mediated stiffness is, at least in theory, equivalent to the catch that is assessed as part of the clinical evaluation of spasticity. The mechanical response evoked by the stretch conceals that there are at least two separate reflex responses in most muscles (Christensen et al. 2000). These responses may be demonstrated by EMG measurement from the muscle (Toft et al. 1989b, Toft et al. 1991). The initial (short-latency or M1) response is mediated by the spinal monosynaptic Ia pathway and is equivalent to the reflex response elicited by a tendon tap (Morita et al. 1998). The response is generally strongly exaggerated in spastic patients (Ibrahim et al. 1993, Sinkjaer and Magnussen 1994, Sinkjaer et al. 1993). In lower limb muscles the initial response is followed by a second (medium-latency or M2) and sometimes a third (long-latency or M3) response (Christensen et al. 2000). The M2 response has been shown in all likelihood to be mediated by gr. II afferents from the muscle spindles (Christensen et al. 2000, Grey et al. 2001). Similar to the M1 response, it is generally exaggerated in spastic patients (Sinkjaer and Magnussen 1994, Sinkjaer et al. 1993, Willerslev-Olsen et al. 2014). The third response, on the other hand, is generally reduced or abolished in spastic patients consistent with the idea that it is mediated by a transcortical pathway that is involved in the lesion (Christensen et al. 2000). Similar mechanisms probably also contribute to the stretch response observed at longer latency than the M1 response (generally called long-latency or M2 response) in upper limb muscles, but due to the short difference in conduction time for spinal and transcortical responses, the responses appear to be difficult to separate (Christensen et al. 2000). These later responses in upper limb muscles may therefore be reduced, unchanged, or exaggerated in the individual patient. Since the mechanical resistance sensed either by a clinical examiner or a biomechanical device is the sum of these different reflex responses, transmission in all the involved pathways should be taken into account when considering the cause of an exaggeration of the muscle resistance.

2.3 Is Spasticity Caused by Lesion of the Pyramidal Tract? Spasticity is observed following both spinal and cortical lesions and is in the clinic commonly associated to lesion of the corticospinal tract, but studies in

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animals suggest that this is wrong. Tower (1940) was the first to observe in monkeys that selective lesion of the pyramidal tract produced flaccid paresis without any signs of spasticity (Tower 1940). This was investigated in more detail in the seminal studies by Lawrence and Kuypers (1968a, 1968b). They reported that complete unilateral or bilateral pyramidal tract lesion in monkeys produced severe paresis, whereas lesion of brainstem tracts left the monkeys with increased reflex excitability and little paresis (1968a, 1968b). These observations have been confirmed in several subsequent studies in both monkeys and other animals (Aoki et al. 1976, Metz et al. 1998). The evidence that the pyramidal tract is not involved in the development of spasticity in animals is thus convincing. The most convincing evidence from human subjects is that of Nathan (1994), who reported the effect of surgical incision in the spinal cord to relieve chronic pain. His findings are well in line with the studies in monkeys. In subjects in whom lateral incisions severing the corticospinal tract were made, no spasticity was observed, whereas this was the case for more ventral lesions, which severed descending tracts from the brain stem (Nathan 1994). Other studies on the topic have only involved observations from single subjects. Sherman et al. (2000), somewhat confusingly, reported increased biceps brachii tendon jerk without clinical signs of spasticity in a single patient with selective unilateral lesion of the pyramidal tract (Sherman et al. 2000). In all likelihood, this finding says more about the clinical examination than anything else. The same may be the case for the study of Paulson et al. (1986), who reported development of spasticity in a single patient with selective lesion of the medullary pyramids. On balance, the human studies thus point in the same direction as the animal studies in suggesting that spasticity is caused by lesion of brain stem pathways or their cortical control rather than lesion of the corticospinal tract. The low occurrence of spasticity in stroke survivors with severe paresis or paralysis as sign of corticospinal lesion is well in line with this (Wissel et al. 2013). These findings suggest that lesion of the corticospinal tract alone is insufficient to start the range of spinal adaptations that result in spasticity. Apparently, additional affection of the vast innervation of spinal motoneurons and interneurons by reticulospinal pathways and other descending tracts from the brain stem is required in order to set the adaptive changes in motion, but we have little understanding of why this is, or of the physiology or pharmacology of these systems.

2.4 Spasticity Does Not Appear Immediately after Lesion but Is Caused by Adaptive Changes in Spinal Networks The excitability of spinal circuitries is depressed during a variable period in both animals and humans following a spinal lesion, due to what is called

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‘spinal shock’ (Ditunno et al. 2004). The mechanisms responsible for spinal shock are not fully clarified but seem to involve loss of descending excitation, increased spinal inhibition, reduction of persistent inward currents in the spinal motoneurons due to loss of serotonergic innervation, reduced neuronal metabolism, and retraction of dendrites and synapses (Ditunno et al. 2004). The time course of development of spasticity following spinal lesion is likely related both to the gradual relief of spinal shock and the gradual development of an hyperexcitable state leading to spasticity. In the clinic, spasticity usually becomes manifest in spinal cord-injured subjects 1–12 months after the lesion, whereas reflex hyperexcitability is observed in animals within 1–2 months (Aoki et al. 1976, Ditunno et al. 2004). Spinal shock is not observed following stroke or supraspinal lesions and it is therefore possible to follow the development of spasticity without the interference from spinal shock in such cases. In both animals and humans, it takes several weeks for spasticity to develop following stroke (Wissel et al. 2013). The importance of this is that spasticity is not caused by simple release of the spinal circuitries from a tonic supraspinal inhibition, as believed some years ago (Burke 1988). This idea ties into another old belief, which has also been proven wrong: That spinal reflexes are primitive reflexes which in humans are only seen in the first year of life, but are then suppressed as the corticospinal tract develops and achieves functional connections with the spinal circuitries. With this mindset, it follows that, in adults, reflexes, and exaggerated reflexes in particular, are seen as abnormal and require treatment because they are thought of as being caused by the release of a normal inhibitory descending influence. However, what really happens during development is that the corticospinal tract and spinal circuitries become functionally integrated and learn to collaborate to ensure motor reactions are appropriate for the conditions that exist at any particular moment in time and the task being undertaken (Clowry 2007, Nielsen 2004). Moreover, the gradual development of spasticity puts emphasis on plastic changes in the spinal circuitries as adaptations to the loss of descending supraspinal drive (Burke 1988).

2.5 Pathophysiology of Exaggerated Stretch Reflex Activity: Adaptive Changes in Spinal Neural Networks It may seem self-evident to point out that the task of a spinal motoneuron is to activate the muscle fibres that it innervates and thereby contribute to posture and movement. However, this simple notion provides an intuitive way of understanding the adaptive changes that occur in the spinal networks in response to lesion of descending pathways. When descending excitation of the motoneuron is lost, regulatory mechanisms that aim to restore an

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efficient output to the muscle set in. A simplified version of this point is illustrated in Figure 2.1. In the normal situation, sensory input and descending drive both contribute to the activation of the motoneurons. Following lesion of central motor fibres, the descending drive is reduced and the sensory input is insufficient to maintain a normal output from the spinal cord to the muscles. As spasticity develops plastic mechanisms that could be considered compensatory set in. These involve increased descending drive in surviving motor tract fibres and alteration of intrinsic properties in spinal motoneurons. These changes help to increase the output from the spinal cord to the muscles, albeit not necessarily to the level before lesion, and they do not necessarily normalise motor control. In the motoneuron these plastic changes involve up-regulation of membrane channels and receptors that increase the excitability of the membrane and reduction of the threshold for action potential generation (Figure 2.2). It also involves the sprouting of nearby fibres (descending fibres as well as sensory afferents and fibres from local interneurons), growth of motoneuronal dendrites, and establishment of new synaptic sites. Mechanisms that regulate transmitter release from sensory afferents (and in all likelihood also central motor fibres), such as presynaptic inhibition, ensure that the efficiency of the synapses that contribute to the motoneuronal drive is increased (Figure 2.2). A general up-regulation of excitation and down-regulation of inhibitory influences from various interneuronal populations on the motoneurons is seen. All these mechanisms work in concert with the common aim to maintain a functional output from the spinal cord to the muscles. Spasticity thus reflects an adaptive change in the spinal cord aimed at maintaining a functional output when a significant part of the normal descending excitatory drive to the motoneurons is lost. It is difficult to see this as a maladaptation. It is essentially a very sensible adaptation. 2.5.1 Pathophysiological Role of Motoneuronal Changes The neuronal membrane is packed with receptors and channels that contribute to the regulation of the excitability of the cell. The number, density, type, and state of these receptors and channels is regulated by a large number of intracellular messenger systems. These mediate changes in the receptors and channels themselves and regulate gene transcription and production of the proteins necessary for new receptors. The excitability of the cell is thus, in essence, a dynamic property, which is continuously regulated according to the immediate and more distant experience of the cell. Dramatic changes such as loss of a major part of the excitatory drive to the cell therefore have significant immediate and long-term impact on the trafficking of molecules and molecular signaling within and between the individual cells. Voltage-dependent Ca2+ and Na+ persistent inward currents (PICs) play a central role in this regulation of motoneuronal (as well as interneuronal) excitability (Heckman et al. 2003, Hultborn et al. 2004, Powers and Binder 2001,

m. Soleus

mn mn mn

(a) Motoneuronal properties (PICs)

(b) Sprouting, new synapses

(c) Regulation of transmitter release (Post-activation depression, presynaptic inhibition)

FIGURE 2.2 The stretch reflex circuitry and spinal pathophysiological mechanisms in spasticity. The figure illustrates the stretch reflex circuitry. Red neurons indicate motor neurons and green neurons indicate 1a afferents. The circuitry is superimposed on the right side of the figure. The motorneurons, located in the ventral horn, are regulated by different properties: (a) changes of intricic properties of the motor neuron; (b) sprouting; (c) neurotransmitter release (post-activation depression, presynaptic inhibition); and (d) postsynaptic inhibition (reciprocal, autogenic Ib, recurrent).

m. Tibialis anterior

Motoneurons

m. Quadriceps

la afferents

(d) Postsynaptic inhibition (Reciprocal, autogenic lb, recurrent)

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Rekling et al. 2000). Inward currents produce prolonged depolarisations (plateau potentials) when opposing outward currents are reduced or the Ca2+ channels are facilitated by, e.g., serotonergic and noradrenergic innervation of the motoneurons (Heckman et al. 2003, Hultborn et al. 2004, Powers and Binder 2001, Rekling et al. 2000). Under normal circumstances the function of PICs is, however, much more dynamic and subtle. Although not fully clarified, one important functional role of PICs seems to be to enhance the synaptic effect of excitatory inputs to the motoneurons. EPSPs in motoneurons produced by pyramidal tract activation are thus boosted by PICs to an extent that it has been argued that physiological descending drive to the motoneurons would be insufficient to drive the motoneurons at the firing frequencies observed during movement without them (Binder 2002, Hultborn et al. 2004, Hultborn et al. 2003). It has also been argued that EPSPs generated at dendritic sites distant from the cell soma would be unable to reach the spike initiation zone without the existence of PICs in the membrane to increase the gain of the EPSPs (Binder 2002). As already mentioned, PICs cannot be evoked during the period of spinal shock following spinal cord lesions unless specifically increased by monoaminergic agonists (Ditunno et al. 2004, Hultborn et al. 2004). However, plateau potentials may be induced again at least in some cases in the chronic spinal state without adding any neurotransmitter precursors or agonists (Hultborn et al. 2004). Bennett et al. (1999, 2001) developed a rat preparation in which a very low chronic spinal lesion causes pronounced hyperreflexia of the tail without interfering with normal hind limb or bladder function. PICs were regularly seen in the chronic test state, but never in the acute post-lesion situation (Bennett et al. 1999, Bennett et al. 2001). This appears to be linked to upregulation of monoaminergic receptors, in particular 5-HT(2B) and 5-HT(2C) receptors in the motoneuronal membrane (Murray et al. 2010, Murray et al. 2011a, Rank et al. 2011, Ren et al. 2013, Wienecke et al. 2010). It is likely that similar plastic changes occur also at interneuronal level, although this has not been shown. Little is known about a possible contribution of PICs to the development of spasticity in human subjects because of the difficulty in demonstrating the existence of such intrinsic membrane properties in the intact organism. However, Nickolls et al. (2004) found that muscle stimulation, which provided an excitatory sensory drive to the spinal motoneurons, did not induce plateau-like behavior of motor unit activity in patients with spinal cord injury as easily as in healthy subjects, but nevertheless argued that plateau potentials might contribute to the clinical manifestations of the patients, such as spasticity (Nickolls et al. 2004). From observations of motor unit behavior during spasms in spinal cordinjured patients, Gorassini et al. (2004) inferred that motor units required significantly less synaptic drive in order to be de-recruited at the end of spasms as compared to the synaptic drive required to recruit them in the beginning of the spasm. From this they argued that persistent inward currents were activated during the spasm and appeared to contribute to the occurrence

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of the spasms (Gorassini et al. 2004). In line with animal experiments this appears to depend on upregulation of serotonergic receptors (D’Amico et al. 2013a, D’Amico et al. 2013b). These findings from both animals and humans are certainly of relevance for the pathophysiology of spasms, but given the mechanisms involved, upregulation of PICs is unlikely to be a universal explanation of spasticity. Loss of serotonergic innervation and subsequent upregulation of 5-HT receptors likely only occurs to any significant extent following spinal cord injury, but not following supraspinal lesions. This likely also explains why spasms are rare in spastic patients following stroke. This in turn undermines the idea that PICs should be causally involved in the pathophysiology of spasticity. Further work in this area is warranted, but will require some innovative experimental design. 2.5.2 Sprouting, New Synapses Following lesions in the central nervous system, several m ­ orphological changes are usually seen, including outgrowth of dendrites, ‘collateral sprouting’ from remaining/surviving neurons as a result of partial denervation, and establishment of new synapses (Bareyre et al. 2004, Fouad et al. 2001, Raineteau and Schwab 2001, Raisman 1969, Weidner et al. 2001). Such adaptations are well documented for terminations of descending fibres on the spinal motoneurons, especially in spinal cord injury (Fouad et al. 2001, Raineteau and Schwab 2001). They probably contribute to ‘overactivity’ phenomena such as spastic dystonia (see later) and lack of specificity of voluntary motor control following central lesions. They may thus contribute to the inability of patients in performing precise movement, the tendency to perform involuntary associated movements, and the development of ‘spastic’ postures involving involuntary excessive activation of postural muscles during movement. However, to what extent these mechanisms also contribute to stretch reflex exaggeration is unclear. Muscle afferents likely also sprout and innervate vacant synaptic sites from descending fibres on spinal motoneurons, but there is little direct evidence of this. 2.5.3 Regulation at Presynaptic Sites: Increasing the Input from Surviving Fibres Although the majority of interest has naturally been devoted to alterations in transmitter release from sensory afferents in relation to the development of spasticity, it should be emphasised that it is likely that synapses of surviving descending fibres and spinal interneurons are also upregulated in order to facilitate activation of the motoneurons following the lesion, as already mentioned above. However, such changes have, to the best of our knowledge, not been thoroughly investigated. Presynaptic inhibition elicited by sensory afferents (see below) has been shown not to be distributed to descending motor fibres (Nielsen and Petersen 1994, Rudomin et al. 1991).

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Post-activation depression (see below) also does not seem to affect transmission from descending pathways (Hultborn et al. 1996). However, synapses of descending fibres are, in all likelihood, subjected to some other kind of regulation and are therefore also likely to be amenable to plastic adaptive changes following lesion. 2.5.3.1 Presynaptic Inhibition Presynaptic inhibition of sensory afferent terminals was described originally in the cat spinal cord by Frank and Fuortes in 1957 (Frank 1957) and subsequently investigated in more detail by John Eccles and his co-workers (Eccles et al. 1962a, Eccles et al. 1962b, Eccles et al. 1963; and see reviews by Rudomin and Schmidt 1999, Willis 2006). The interneurons responsible for presynaptic inhibition receive considerable input from a range of sensory afferents of different modality throughout the leg, as well as descending control from the corticospinal tract and brainstem nuclei (Burke 2012, Jankowska 1992, Rudomin and Schmidt 1999, Willis 2006). The interneurons in turn project widely in the spinal cord to suppress transmitter release from sensory afferent terminals on motoneurons by releasing GABA which binds to receptors located on the presynaptic terminals of the sensory afferents (Burke 2012, Rudomin and Schmidt 1999). Activation of GABA-A receptors result in opening of Cl channels, which causes an outward Cl current and thereby a depolarisation of the terminals (primary afferent depolarisation; PAD – although other mechanisms may also contribute to this phenomenon [Hochman et al. 2010]). PAD inactivates some of the voltage-sensitive sodium channels and thereby reduces the amplitude of any subsequent action potentials. As a consequence, fewer voltage-sensitive Ca channels are opened and transmitter release from the terminals is reduced (Burke 2012, Rudomin and Schmidt 1999). In both human and animal experiments, presynaptic inhibition has been found to be strongly regulated by supraspinal control centres (Burke 2012, Meunier 1999, Rudomin et al. 2004). During voluntary movement including locomotion presynaptic inhibition is turned into a highly focused modulatory mechanism that shapes the sensory inflow to spinal motoneurons and interneurons according to the needs of the given task and the central command (Dietz et al. 1990, Faist et al. 1996). Activation of some muscles may thereby be facilitated by removing presynaptic inhibition of the sensory afferents, while ensuring that unwanted activation of other muscles (such as antagonists) does not take place (Crone and Nielsen 1989b, Hultborn et al. 1987, Nielsen and Kagamihara 1993). This regulation of presynaptic inhibition in relation to voluntary movement is of significance for the functional relevance of spasticity and will be further described in Chapter 3. Following spinal cord lesion in cats, presynaptic inhibition of sensory afferents is reduced and this reduction seems to follow the development of spasticity (Naftchi et al. 1979).

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In humans, presynaptic inhibition of Ia afferents on spinal motoneurons supplying leg muscles has been found to be reduced in multiple sclerosis and spinal cord-injured subjects with spasticity as compared to a population of able-bodied individuals (Faist et al. 1994, Nielsen et al. 1995b). This is also the case in cerebral palsy individuals with clinical signs of spasticity (Achache et al. 2010). Presynaptic inhibition of Ia afferents from upper limb muscles is also reduced in spastic stroke survivors (Aymard et al. 2000, Lamy et al. 2009), but this is not the case for presynaptic inhibition of Ia afferents from leg muscles (Aymard et al. 2000, Faist et al. 1994, Lamy et al. 2009). It has therefore been argued that reduced presynaptic inhibition is unlikely to be involved in the pathophysiology of spasticity, but is more likely an epiphenomenon (Lamy et al. 2009), possibly in relation to the disuse of the limb (Lundbye-Jensen and Nielsen 2008). The observation that there is no correlation between reduced presynaptic inhibition and the degree of spasticity evaluated by the Ashworth scale is in line with this (Aymard et al. 2000, Lamy et al. 2009, Nielsen et al. 1995b). However, as mentioned above the Ashworth scale has been shown to be a poor measure of the extent of spasticity and this finding may therefore rather be related to shortcomings of the clinical evaluation of spasticity. The success of GABAergic drugs, such as diazepam and baclofen, in reducing reflexes and diminishing spasticity (Abbruzzese 2002, Macdonell et al. 1989, Verrier et al. 1975) should not be taken as support that presynaptic inhibition plays an important role for the development of spasticity. Any drug that reduces transmitter release from sensory afferent terminals on spinal motoneurons or suppress motoneuronal excitability would have a similar effect and, contrary to what is sometimes claimed, a specific effect on an important pathophysiological mechanism would make little difference (Murray et al. 2011b). 2.5.3.2 Post-Activation Depression It was originally described by Curtis and Eccles (1960) that Ia EPSPs are frequency-dependent, with a relative facilitation at short intervals, and a depression with longer intervals (Curtis and Eccles 1960). Naturally, this also influences the size of stretch reflexes and it is therefore not surprising that a similar pattern of facilitation and suppression of the Soleus H-reflex and stretch reflex may be demonstrated in humans (Crone and Nielsen 1989a, Grey et al. 2008, Hultborn et al. 1996, Taborikova and Sax 1968). Following a single elicitation of a stretch reflex or an H-reflex, subsequent reflexes are strongly depressed for up to 10–15 seconds (Figure 2.3). This depression has been called post-activation depression since it is seen following a previous activation of homonymous Ia afferents and is not (or only to a limited extent) seen for afferents that have not been activated (Hultborn et al. 1996). It is therefore assumed that the depression results primarily from mechanisms operating within the presynaptic terminals (Lev-Tov and Pinco 1992, Li and

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Healthy subjects (n = 30) Multiple sclerosis patients (n = 17) Patients with spinal cord injury (n = 16)

Size of H-reflex (% of control reflex)

120

100 80 60 40 20

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0 120

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FIGURE 2.3 Post-activation depression and spasticity. The graph illustrates the size of the H-reflex as a percentage of the control reflex (y-axes) at different intervals after the stretch (x-axes). Black dots indicate healthy subjects (n = 30), orange dots indicate multiple scleroses patients (n = 17), and yellow triangles indicate patients with a spinal cord injury (n = 16).

Burke 2001, Pinco and Lev-Tov 1993). It is unclear whether similar mechanisms are involved but post-activation depression shares many features with the short-term homosynaptic plasticity described for synapses in the hippocampus (Andersson and Hanse 2011). Post-activation depression is reduced in spastic patients with spinal cord injury (Nielsen et al. 1993, Nielsen et al. 1995b), multiple sclerosis (Nielsen et al. 1995; Grey et al. 2008), stroke (Aymard et al. 2000, Grey et al. 2008, Lamy et al. 2009, Schindler-Ivens and Shields 2000), and cerebral palsy (Achache et al. 2010), thus ensuring that transmitter release is not significantly reduced with discharges of Ia afferents at rates above 0.1 Hz (Figure 2.3). This is well within the physiological range of the firing rate of Ia afferents and normal activity of Ia afferents must therefore be expected to be influenced by this. It is also within the range of frequencies used during the neurological examination of spasticity and the reduction in post-activation depression thus directly contributes to the exaggeration of the stretch reflex and the increased reflexmediated muscle stiffness determined during the examination (Grey et al. 2008). In fact, the data from Grey et al. (2008) indicates that if the neurological examiner made sure to test reflexes and muscle stiffness at intervals of longer than 10 s, no significant reflex alteration as compared to healthy subjects would be detected. In other words, it is only because the neurological

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examination usually involves multiple attempts at moving the limb or evoking the reflex, which then causes post-activation depression to be elicited, that reflex exaggeration is determined in spastic patients. This may also explain the close correlation between reduced post-activation depression and the clinical assessment of spasticity (Grey et al. 2008; Lamy et al. 2009; Achache et al. 2010), although the limitations in this assessment should be kept in mind. Post-activation depression is also the only mechanism that has been shown to be affected in both the lower and upper limb in spastic subjects regardless of the etiology of spasticity (Achache et al. 2010, Lamy et al. 2009). This may indicate a key role of reduced post-activation depression in the string of events leading to spasticity. The simple regulation of the contribution of sensory inputs to the activation of the motoneurons that it provides is an attractively simple means of upgrading sensory input when descending drive is lost. However, it should be pointed out that we still have no clear understanding of the functional significance of post-activation depression, as will be further discussed in Chapter 3. It is not known how a spinal lesion could affect Ia terminals, but an impressive array of mechanisms have been identified that contribute to short-term synaptic plasticity in general (both the initial facilitation and the following depression; recently reviewed by Zucker and Regehr 2002). Although post-activation depression appears to be a mechanism intrinsic to the synapses, several studies have provided evidence that it may be regulated by descending motor commands and is thus a highly regulated mechanism (Nielsen et al. 2007, Raoul et al. 2012). It is certainly a possibility that loss of this descending regulation leads to alterations in the mechanisms responsible for the depression, possibly secondary to alterations in monoaminergic neurotransmitters and their receptors, similar to what has been described for motoneurons (D’Amico et al. 2013b, Murray et al. 2011b, Rank et al. 2011). It has also been suggested that reduced post-activation depression may be related to lack of sensory activity secondary to disuse of the limb (Lundbye-Jensen and Nielsen 2008). 2.5.4 Transmission in Group II Pathways As already mentioned, muscle stretch and passive manipulation of a limb as part of clinical and biomechanical evaluation of spasticity also generates activity in group II pathways that probably contribute to the muscle resistance sensed during the clinical examination. The interneurons mediating these effects appear to be primarily located in Rexeds laminae IV and VIII, whereas another group of interneurons located in Rexeds laminae V–VII integrate input from group II afferents and group Ib afferents from Golgi tendon organs (Jankowska and Edgley 2010). Some of these interneurons are inhibitory, whereas others are excitatory and the effect on a given set of spinal motoneurons by activation of the afferents thus depends heavily on central regulation of the interneurons (Jankowska 1989, Jankowska and Edgley 2010). Notably, monoaminergic neurotransmitters effectively suppress transmission

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in group II pathways and may thereby produce a selective suppression of the medium-latency (M2) reflex responses in lower limb muscles (Corna et al. 1995, Grey et al. 2001). The antispastic effect of Tizanidine (Kamen et al. 2008) may be related to this selective depression. Most studies have reported exaggerated group II reflexes in spastic subjects and there is evidence to suggest that transmission in excitatory group II pathways are released from descending monoaminergic suppression in patients with central motor lesions (Nardone and Schieppati 2005). However, it is not clarified to what extent group II interneurons play a pathophysiological role in spasticity. 2.5.5 Pathophysiological Role of Changes in Postsynaptic Inhibition of Motoneurons Motoneurons are under close inhibitory control from a number of spinal interneuronal populations. The most well-studied are the interneurons mediating reciprocal Ia inhibition, recurrent inhibition, Ib autogenetic inhibition, and non-reciprocal Group I inhibition (Figure 2.2). 2.5.5.1 Disynaptic Reciprocal Ia Inhibition It was Charles Sherrington who provided the first evidence of a spinal pathway that could elicit suppression of antagonist muscles (his reciprocal innervation [Sherrington 1906]), but it was work by John Eccles that demonstrated the disynaptic nature of the reciprocal Ia inhibitory pathway (Hultborn 2006). Work by Hans Hultborn in the late 1960s and 1970s clarified the organisation of the interneurons interposed in the pathway and especially the parallel activation of descending fibres and sensory afferents on common motoneurons and Ia inhibitory interneurons (Hultborn 1976, Hultborn et al. 1976a, Hultborn et al. 1976b, Hultborn et al. 1976c, Hultborn et al. 1971, Hultborn and Udo 1972). This laid the basis for an understanding of the central control of reciprocal inhibition in relation to voluntary movements in the 1980s and 1990s (Crone et al. 1985, Crone et al. 1987, Iles 1986, Kagamihara and Tanaka 1985, Nielsen and Kagamihara 1992, Nielsen et al. 1992, Shindo et al. 1984, Tanaka 1976). This control is generally impaired in patients with spasticity, as will be further discussed in Chapter 3. For reciprocal inhibition to be of any pathophysiological relevance for spasticity, it is essential that there is evidence that the interneurones interposed at least in the pathway from ankle dorsiflexors to plantarflexors are tonically active in healthy subjects at rest (Nielsen et al. 1995a). The pathway thus contributes to maintaining the excitability of soleus motoneurons low in resting subjects. The reduction of reciprocal inhibition between ankle dorsiflexors and plantarflexors that has been observed in spastic patients with multiple sclerosis (Crone et al. 1994), stroke (Bhagchandani and Schindler-Ivens 2012,

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Crone et al. 2003, Crone et al. 2000, Okuma and Lee 1996, Okuma et al. 2002, Okuma et al. 1999), spinal cord injury (Crone et al. 2003), and hereditary spastic paraparesis (Crone et al. 2004) may therefore potentially contribute to hyperreflexia and increased reflex-mediated muscle stiffness in the ankle plantarflexors. Achache et al. (2010) reported that reciprocal inhibition was similar in healthy subjects and adults with CP, but since there was hardly any inhibition in healthy subjects, a possible reduction of reciprocal inhibition in CP subjects may have gone unnoticed. Reciprocal inhibition from ankle plantarflexors to dorsiflexors is, in contrast, usually found to be increased in spastic patients (Mailis and Ashby 1990, Yanagisawa et al. 1976). As dorsiflexor muscles seldom show any spasticity, this may not be too surprising. Reciprocal inhibition has also been found to be deficient in wrist muscles (Artieda et al. 1991), but since newer studies have put doubt on the origin and nature of the inhibition observed between wrist muscles, the significance of this finding is unclear (Wargon et al. 2006). It has generally not been possible to find any correlation between reduced reciprocal inhibition and the degree of spasticity evaluated by the Ashworth scale, but, given the lack of reliability of the Ashworth scale and the small size of reciprocal inhibition in many subjects, this is not surprising. On the other hand, a positive correlation has been found between reduced reciprocal inhibition and functional deficits in stroke patients and, regardless of its pathophysiological role in spasticity, reciprocal inhibition thus appears to be of clinical importance for at least gait function in spastic patients (Bhagchandani and Schindler-Ivens 2012, Okuma and Lee 1996). 2.5.5.2 Recurrent Inhibition Recurrent inhibition is mediated by Renshaw cells, which are located in the ventral horn of the spinal cord, where they receive excitatory collaterals from the motor axons and project back to the motoneurons as well as Ia inhibitory interneurones (Figure 2.4). Recurrent inhibition is not easy to study in human subjects, but Pierrot-Deseilligny and Bussel (1975) have developed a complex H-reflex technique by which this is possible (Pierrot-Deseilligny and Bussel 1975). The basis of the technique is to use a previous reflex discharge to activate the Renshaw cells and study the effect of this activation on a subsequently evoked test reflex. With this technique it has been demonstrated that recurrent inhibition at rest appears to be normal in most patients with spasticity (Katz and Pierrot-Deseilligny 1999, Katz et al. 1982). Only in patients with progressive paraparesis or ALS is a reduction found at rest and it is doubtful that this reduction contributes to the spasticity observed in these patients (Mazzocchio and Rossi 1989, Raynor and Shefner 1994). Changes in recurrent inhibition thus probably play no major role in the pathophysiology of spasticity.

m. Soleus

motoneuroner mn mn mn

la

Size of conditioned reflex (% of control reflex) 70

80

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Healthy subjects (n = 25) Hemiplegic patients (n = 11) Paraplegic patients (n = 11) MS patients (n = 30)

12

FIGURE 2.4 Disynaptic reciprocal inhibition and spasticity. The figure on the left illustrates the circuitry of disynaptic reciprocal inhibition. Red neurons indicate motorneurons and greenneurons indicate 1a afferents. Descending drive is represented by the purple line. The graph on the right shows the size of the conditioned reflex (% of control reflex) at different conditioning-test intervals (0–10 ms). Healthy subjects are indicated as black dots, hemiplegic (stroke) patients as red dots, paraplegic (SCI) patients as green triangles, and MS patients as yellow triangles. The horizontal dotted line illustrates the size of the control reflex.

m. Tibialis anterior

m. Quadriceps

la afferenter

descenderende drive fra bla corticospinale nervebane

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Pathophysiology of Spasticity

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2.5.5.3 Autogenetic Ib Inhibition Autogenetic Ib inhibition was described originally in the cat spinal cord in the 1950s (Laporte and Lloyd 1952). The inhibition is caused by activation of Ib afferents coming from Golgi tendon organs and is mediated by segmental inhibitory interneurons projecting to the motoneurons of the same muscle. Ib inhibition may also be demonstrated in human subjects by stimulating the branch from the tibial nerve that innervates the medial gastrocnemius muscle and measuring the subsequent depression of the soleus H-reflex (Pierrot-Deseilligny et al. 1979). Whereas this inhibition is easily demonstrated in healthy subjects, Delwaide and Olivier (1988) failed to produce any inhibition on the paretic side in 6 out of 6 hemiplegic patients, but instead observed a facilitatory effect in many subjects (Delwaide and Oliver 1988). This may relate to the pronounced facilitatory effect on the soleus H-reflex following stimulation of the peroneal nerve, which was observed by Crone et al. (2003) in their study of patients with stroke and spinal cord injury (Crone et al. 2003). One possible explanation of the occurrence of this facilitation, which paralleled the development of hyperreflexia, is increased excitability of excitatory Ib afferent pathways, similar to those described in the cat spinal cord (Gossard et al. 1994, McCrea et al. 1995). Furthermore, it has been argued that reciprocal inhibition at wrist level is mediated by Ib inhibitory pathways (Wargon et al. 2006). If so, the observation that reciprocal inhibition at the wrist level is reduced in hemiplegic patients (Nakashima et al. 1989) may provide further evidence that alteration of Ib inhibition/excitation plays a role in the pathophysiology of spasticity. It thus seems likely that changes in the balance between inhibitory and excitatory Ib pathways play an important role in the development of spasticity and further studies in this area are certainly needed. 2.5.5.4 Fusimotor Drive, Gamma-Spasticity Increased fusimotor drive leading to increased sensitivity of the muscle spindles to muscle stretch was a popular explanation of spasticity some 20 to 30 years ago (so-called gamma-spasticity). It was found during the 1960s and 1970s that stretch reflexes, which are influenced by the sensitivity of the muscle spindles, tended to be increased more in spastic patients than the H-reflex, which is evoked by electrical stimulation of the peripheral nerve and is therefore not influenced by the sensitivity of the muscle spindles (Ashby and Verrier 1976). However, subsequent studies have demonstrated that H-reflexes and stretch reflexes differ in many other ways than their sensitivity to changes in fusimotor drive and a comparison of the two reflexes therefore cannot be used to make any conclusions regarding changes in muscle spindle sensitivity (Burke et al. 1983, Burke et al. 1984, Morita et al. 1998). Importantly, microneurography studies have also failed to demonstrate any changes in the discharge of muscle spindle afferents in spastic

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patients, making it unlikely that any significant changes in fusimotor drive exists (Hagbarth et al. 1973, Wilson et al. 1999a, Wilson et al. 1999b).

2.6 How Is Clonus Related to Spasticity? Clonus is characterised by rhythmic alternating oscillation at relatively low frequency (3–8 Hz) at distal joints, in particular the ankle joint, following muscle stretch that is sufficiently fast to elicit a stretch reflex (or catch). Clonus is primarily seen in spastic patients and exaggerated stretch reflexes are usually present when clonus is observed (Mukherjee and Chakravarty 2010). Clonus is therefore also often considered to be an integrated part of spasticity, as also witnessed by the focus on clonus in the Tardieu scale (Haugh et al. 2006). However, many patients with severe spasticity fail to show clonus and especially when muscle stiffness is very pronounced clonus is seldom seen (Mukherjee and Chakravarty 2010). One possible explanation of this is that at least partly different pathophysiological mechanisms may be involved in the development of spasticity and clonus. Clonus has traditionally been thought to be caused by alternating elicitation of stretch reflexes in antagonist muscles (Hidler and Rymer 1999). The observation that the frequency of clonus depends on the length of the limb segment in which clonus is observed is consistent with this idea (Hidler and Rymer 1999). Furthermore, clonus has been observed to be reset by stimulation of peripheral nerves and to disappear when sensory afferent activity is blocked by ischemia (Rossi et al. 1990). Modeling studies also show that increased stretch reflex excitability with appropriate conduction delays may adequately explain the occurrence of clonus (Hidler and Rymer 1999). If this is correct, inclusion of clonus in the definition of spasticity and its use in the Tardieu scale would be justified. However, several studies have suggested that other mechanisms may at least contribute to the occurrence of clonus (Beres-Jones et al. 2003, Dimitrijevic et al. 1980, Walsh and Wright 1987). Dimitrijevic et al. (1980), contrary to Rossi et al. (1990), failed to interfere with clonus by sensory inputs and demonstrated examples where clonus was elicited by cutaneous input rather than muscle stretch. Walsh and Wright (1987) also failed to interfere with clonus by mechanical loading of the limb. Beres-Jones et al. (2003) observed that EMG patterns in antagonistic ankle joint muscles during clonus in spinal cord-injured subjects were often synchronised and unrelated to mechanical stretch of the muscles (Beres-Jones et al. 2003). These studies, thus, suggest that central oscillator networks may at least contribute to the occurrence of clonus. Their central idea is that sensory input to the spinal cord may activate the rhythmic locomotor network in the cord. This network has been shown to be capable of oscillating for prolonged periods of time following sensory input in animals and to some extent also in humans (Calancie et  al.  1994,

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Dietz et al. 1997, Pinter and Dimitrijevic 1999). Due to the contradictory findings in the various studies it seems at least possible that both mechanisms may be involved, possibly to varying extents in different patients and may manifest differently at joints with different loading/stretch conditions. Regardless of this, caution should be made when relating clonus too closely to spasticity.

2.7 What Causes a Spasm? Spasms are involuntary muscle contractions, which last from seconds to minutes and are usually provoked by a sensory stimulus, although in some cases no clear sensory stimulus can be determined. Spasms are differentiated from spasticity by the longer duration and strength of the contraction, which can sometimes be so severe that it becomes painful. Spasms are also differentiated from spasticity by being elicited preferentially by cutaneous rather than muscle afferent inputs. Spasms are mainly seen following spinal cord injury, whereas they are rarely seen in stroke patients, even with very significant exaggeration of stretch reflexes and severe muscle stiffness (Malik et al. 2014). Spasms are thus clearly pathophysiologically distinct from exaggerated stretch reflexes. The occurrence of spasms is closely related to increased withdrawal reflexes following injury and it is generally accepted that spasms are caused by pathologically increased transmission in flexor reflex afferent (FRA) circuitries in the spinal cord (Barolat and Maiman 1987). As already discussed, studies in both animal and human have suggested a significant role of upregulation of 5-HT receptors, secondary to loss of serotonergic innervation and resulting in increased persistent inward currents (PICs) in motoneurons and possibly also in interneurons in the FRA circuitries (Bennett et al. 1999, Bennett et al. 2001, D’Amico et al. 2013b, Gorassini et al. 2004, Murray et al. 2011a). This would explain why spasms are mainly seen in spinal cord-injured subjects and rarely following stroke or in cerebral palsy.

2.8 Spastic Dystonia Is Not Caused by Increased Stretch Reflex Activity Spastic dystonia is a term that was introduced by Denny-Brown to designate tonic muscle activity in arm muscles in monkeys following central motor lesion (Denny-Brown 1966). He observed that the activity persisted when dorsal roots were cut and concluded that stretch reflex activity was not involved.

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In humans it is seen in the upper limb, where it contributes to the hemiplegic posture primarily in subjects with stroke or cerebral palsy (Gracies 2005, Sheean 2002, Sheean and McGuire 2009). In humans a dynamic form of spastic dystonia is also seen during standing and gait where the subject may adopt a posture with plantarflexion at the ankle, pronounced extension at the knee, and associated flexion at the elbow (Gracies 2005, Sheean 2002, Sheean and McGuire 2009). These features resemble the overflow phenomena observed in patients with extrapyramidal (basal ganglia) lesions, hence the term dystonia. We have at present no clear indication of what causes spastic dystonia except for the findings in monkeys by Denny-Brown (and which need to be confirmed in humans). Plastic changes at a spinal level involving upregulation and sprouting of surviving descending fibres may explain both the tonic and dynamic form, whereas upregulation of PICs in motoneurons may possibly explain the tonic form (Gorassini et al. 2004). However, changes at a cortical level may also play a role and it should also be kept in mind that stroke often involves other structures than the descending pathways and that basal ganglia affection is not uncommon in stroke patients. Spastic dystonia may thus be the end-result of reduced voluntary control of muscles due to (partial) corticospinal lesion and increased involuntary activation due to basal ganglia lesion.

2.9 Concluding Remarks This chapter has emphasised that there is a range of adaptations in spinal circuitries following lesion of central motor fibres. These adaptations should be seen as an attempt to ensure a functional output from the spinal cord following loss of some of the normal supraspinal drive to the spinal motoneurons. We have the possibility of testing part of the circuitries that show adaptation following lesion by imposing muscle stretch and eliciting a sensory input to the spinal cord. The increased muscle resistance that we may sense in this way thus provides information of only some of the adaptations that occur, and it is therefore not surprising that spasticity; i.e., hyperactive stretch reflexes, only provide a partial insight into the full range of clinical manifestations of the adaptations to central lesions. In a broader sense, these adaptations are also responsible for such manifestations as spasms, clonus, and spastic dystonia, as well as the movement disabilities encountered by patients following central motor lesions. These may, to some extent, be related to spasticity but may also be seen separately. Treatment of patients with central motor lesions should take the different underlying pathophysiological mechanisms responsible for the various manifestations of spinal cord adaptations into account. The realisation that sensory feedback is closely integrated with descending motor commands as a basis of all movements

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and that spasticity is a reflection of an upgrading of sensory feedback as a compensation for loss of descending drive should also warrant caution when prescribing antispastic medication to patients with some functional ability. Given the integrated nature of sensory feedback and descending motor commands involved in all voluntary movements, the practice of dorsal rhizotomy must also cause some worry (Tedroff et al. 2011).

References Abbruzzese G. 2002. The medical management of spasticity. European Journal of Neurology: the official journal of the European Federation of Neurological Societies 9 Suppl 1: 30–4; discussion 53–61 Achache V, Roche N, Lamy JC, Boakye M, Lackmy A et al. 2010. Transmission within several spinal pathways in adults with cerebral palsy. Brain: A Journal of Neurology 133: 1470–83 Andersson MS, Hanse E. 2011. Astrocyte-mediated short-term synaptic depression in the rat hippocampal CA1 area: two modes of decreasing release probability. BMC Neuroscience 12: 87 Aoki M, Mori S, Fujimori B. 1976. Exaggeration of knee-jerk following spinal hemisection in monkeys. Brain Research 107: 471–85 Artieda J, Quesada P, Obeso JA. 1991. Reciprocal inhibition between forearm muscles in spastic hemiplegia. Neurology 41: 286–9 Ashby P, Verrier M. 1976. Neurophysiologic changes in hemiplegia. Possible explanation for the initial disparity between muscle tone and tendon reflexes. Neurology 26: 1145–51 Ashworth B. 1964. Preliminary Trial of Carisoprodol in Multiple Sclerosis. Practitioner 192: 540–2 Aymard C, Katz R, Lafitte C, Lo E, Penicaud A et al. 2000. Presynaptic inhibition and homosynaptic depression: a comparison between lower and upper limbs in normal human subjects and patients with hemiplegia. Brain: A Journal of Neurology 123 (Pt 8): 1688–702 Barden HL, Nott MT, Baguley IJ, Heard R, Chapparo C. 2012. Test-retest reliability of computerised hand dynamometry in adults with acquired brain injury. Australian Occupational Therapy Journal 59: 319–27 Bareyre FM, Kerschensteiner M, Raineteau O, Mettenleiter TC, Weinmann O, Schwab ME. 2004. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nature neuroscience 7: 269–77 Barolat G, Maiman DJ. 1987. Spasms in spinal cord injury: a study of 72 subjects. Journal of the American Paraplegia Society 10: 35–9 Benard MR, Jaspers RT, Huijing PA, Becher JG, Harlaar J. 2010. Reproducibility of hand-held ankle dynamometry to measure altered ankle moment-angle characteristics in children with spastic cerebral palsy. Clinical Biomechanics 25: 802–8 Bennett DJ, Gorassini M, Fouad K, Sanelli L, Han Y, Cheng J. 1999. Spasticity in rats with sacral spinal cord injury. Journal of Neurotrauma 16: 69–84

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3 Functional Problems in Spastic Patients Are Not Caused by Spasticity but by Disordered Motor Control Jakob Lorentzen, Maria Willerslev-Olsen, Thomas Sinkjær and Jens Bo Nielsen CONTENTS 3.1 Reflexes Are an Integrated Part of Voluntary Movement....................... 59 3.2 Stretch Reflex Modulation in Spastic Subjects.......................................... 60 3.2.1 Reflex Modulation during Simple Contraction of Agonist Muscle................................................................................................. 60 3.2.2 Hyperexcitable Stretch Reflexes in the Stance Phase of Gait...... 62 3.2.3 Control of Reflexes in the Antagonist............................................63 3.2.4 Suppression of Reflexes in Swing Phase.......................................63 3.3 Sensory Feedback Contribution to Movement.........................................64 3.4 Long-Latency Stretch Reflexes and Coordination of Movement........... 66 3.5 Interjoint Coordination................................................................................ 67 3.6 Interlimb Coordination................................................................................ 68 3.7 Co-Contraction as a Strategy to Maintain Joint Stiffness....................... 69 3.8 Over-Activity as a General Adaptation to Central Lesion Causing Disordered Motor Control........................................................................... 70 3.9 Training to Learn New Strategies and Thereby Make Use of Spasticity.................................................................................................... 70 References................................................................................................................ 71

3.1 Reflexes Are an Integrated Part of Voluntary Movement The name of Charles Scott Sherrington is, more than anything, linked to the concept of simple reflexes, although he himself warned against putting too much emphasis on simple reflex mechanisms without realising the much more complex integrative function of the nervous system. In 1906 he wrote: A simple reflex is probably a purely abstract conception, because all parts of the nervous system are connected together and no part of it is probably ever capable of reaction without affecting and being affected by various other parts, and it is a

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system certainly never absolutely at rest. But the simple reflex is a convenient, if not a probable, fiction. Reflexes are of various degrees of complexity, and it is helpful in analyzing complex reflexes to separate from them reflex components which we may consider apart and therefore treat as though they were simple reflexes.

Sherrington’s student John Eccles (1903–1997), and his student in turn, Anders Lundberg (1920–2009), investigated many of these complexities of the spinal reflex networks, emphasising the vast convergence on common interneurons and motoneurons from sensory afferents and descending motor fibres (Alstermark et al. 2010, Hultborn 2006). Their findings effectively confirmed Sherrington’s view of the integrated nature of reflexes. However, it was not until the 1980s and onwards that human experiments demonstrated unequivocally that reflexes are modulated during movement and integrated into the central motor programmes underlying voluntary movement (Burke 2012, Nielsen 2004). Given the knowledge of the integrative nature of reflexes going back to Sherrington’s work, it is not surprising that hyperexcitable reflex excitability in patients at rest during neurological examination has been shown to have little relevance for the functional capabilities of those patients. William Landau expressed this with characteristic bluntness in 1980: However useful to clinical diagnosis may be the increase of excitability at anterior horn cells and, to some extent muscle spindles, these phenomena have little more relation to the patients disability than does insertion of the rectal thermometer in pneumonia (Landau [1980]; p. 20).

3.2 Stretch Reflex Modulation in Spastic Subjects 3.2.1 Reflex Modulation during Simple Contraction of Agonist Muscle Direct demonstration that evaluation of spasticity at rest has little relevance for the situation during movement was originally provided by Ibrahim et al. (1993). They measured stretch reflexes in elbow flexors of healthy subjects and on the lesioned and non-lesioned sides in hemiplegic stroke patients at rest and during voluntary elbow flexion. Whereas stretch reflexes were strongly exaggerated on the lesioned side when measurements were made at rest, no significant difference on the two sides or with respect to healthy subjects was found during the elbow flexion. Sinkjaer et al. (1993) and Sinkjaer and Magnussen (1994) at the same time demonstrated that the reflex-mediated stiffness of the ankle plantarflexor muscles was similar during ankle plantarflexion in spastic patients suffering from stroke or multiple sclerosis as compared to healthy subjects (Ibrahim et al. 1993, Sinkjaer and Magnussen 1994, Sinkjaer et al. 1993).

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The lack of difference in reflex excitability during contraction is not surprising given the well-established understanding of the convergence of descending motor commands and sensory feedback signals on common spinal neurons (Burke 2012, Nielsen 2004). In healthy subjects stretch reflex excitability is increased during contraction of the muscle in which the reflex is evoked through regulation of a number of different mechanisms that have been investigated during the past 20 to 30 years (Figure 3.1). First, the depolarisation necessary to activate the motoneurons during a contraction naturally also makes them more excitable to the input from stretch reflex afferents. There is no reason why this should be different in spastic patients. Indeed, making measurements at matched contraction levels, as in the studies by Ibrahim et al. (1993) and Sinkjaer et al. (1993), ensures that the motoneuronal excitability will be matched also and that any difference between healthy and spastic motoneurons will be taken out of the equation. Healthy subject, at rest

Presynaptic inhibition Postactivation depression

Healthy subject, during contraction

Reciprocal inhibition Gr I/II excitation

Gr I/II inhibition

m. Tibialis anterior m. Tibialis anterior m. Soleus

Spastic subject, at rest

Gr I/II excitation

m. Soleus

Spastic subject, during contraction

Gr I/II excitation

m. Tibialis anterior m. Soleus

m. Tibialis anterior m. Soleus

FIGURE 3.1 Modulation of reflex pathways at rest and during contraction in healthy and spastic subjects. The figure illustrates the spinal reflex circuitry in healthy subjects at rest and during contraction (top left and right, respectively) and in spastic subjects at rest and during contraction (bottom left and right, respectively). Presynaptic inhibition and postactivation depression is illustrated by a yellow neuron, reciprocal inhibition is illustrated by a blue neuron, and group Ib/II inhibition (healthy at rest) and excitation (healthy during contraction, spastic at rest and during contraction) is illustrated with a green neuron. The two muscles represent the soleus muscle and tibialis anterior.

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Another  way  of  saying this is that the neural adaptations that cause the motoneurons to be more excitable in the resting state cannot be demonstrated during contraction because it is ensured by the very design of the measurement that the excitability levels are matched. Since neural adaptations have lowered the threshold of the motorneurons, the spastic subject with a hyper-excitable motoneuron will have to use relatively less descending activity during rest to reach a given contraction level as compared to a healthy subject (note, however, that this may be perceived as a far bigger effort given the primary lesion of the descending command); i.e., without the hyper-excitability in the resting state the ability of spastic patients to voluntarily activate the muscle would likely have required a much larger effort. A contributing factor to the depolarisation of the motoneurons is the removal of inhibitory inputs to the motoneurons. Inhibition of motoneurons from reciprocal inhibitory interneurons and other classes of interneurons is thus reduced when a muscle is voluntarily activated (Crone et al. 1987, Nielsen and Kagamihara 1992). In spastic patients, these inhibitory influences are already scaled down in the resting state and there is thus no need for the patient to remove them as part of the central command during movement. Second, the gain of the stretch reflexes is also increased in healthy human subjects by increased release of transmitter substances from the sensory afferent synapses on the motoneurons. At least two mechanisms contribute to this: post-activation depression, which effectively depresses the reflex in the resting state, is switched off during contraction (Hultborn and Nielsen 1998) and presynaptic inhibition is greatly reduced for Ia afferents projecting to the active motoneurons (Hultborn et al. 1987, Nielsen and Kagamihara 1993). Since both mechanisms are already reduced when at rest in spastic subjects, little additional change is seen during contraction. Finally, group Ib/II inhibition is prominent at rest in healthy subjects, but replaced by excitation during movement (Faist et al. 2006, Stephens and Yang 1996). This is, in all likelihood, related to gating of transmission in the pathways, replacing inhibition, which would hinder the activation of the muscle, by excitation, which will instead help the supraspinal structures in maintaining muscle activation (Gossard et al. 1994, Jankowska et al. 1993). In spastic subjects, group Ib/II inhibition is reduced and replaced even in the resting state by excitation (Achache et al. 2010b, Crone et al. 2003, Delwaide and Oliver 1988), which persists during voluntary contraction, analogous with observations made in voluntary movements made by healthy subjects. 3.2.2 Hyperexcitable Stretch Reflexes in the Stance Phase of Gait In contrast to what is observed in relation to simple static contractions of a muscle, soleus H-reflexes and stretch reflexes are generally found to be exaggerated when elicited during the stance phase of gait in spastic patients suffering from stroke (Cho and Lee 2013, Mazzaro et al. 2006, Mazzaro et al. 2007, Sinkjaer et al. 1996b) or cerebral palsy (Hodapp et al. 2007a, Hodapp

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et al. 2007b, Willerslev-Olsen et al. 2014). In healthy subjects, presynaptic inhibition helps to diminish the size of the H-reflex in the stance phase of walking as compared to matched levels of EMG activity during standing (Capaday and Stein 1986, Capaday and Stein 1987, Ethier et al. 2003, Faist et al. 1996, Ferris et al. 2001, Simonsen and Dyhre-Poulsen 1999, Simonsen et al. 1995). There is good reason to assume that the spastic patients are unable to adequately increase presynaptic inhibition and depress the reflex in the same way as in healthy subjects. In healthy children, this depression appears to depend on development of the corticospinal tract and is not seen to the same extent as in adults until the age of 12 to 14 years (Hodapp et al. 2007a, Hodapp et al. 2007b, Willerslev-Olsen et al. 2014). In children with hemiplegic CP, the depression of the reflex does not appear on the affected side at least before the age of 15 (Hodapp et al. 2007a, Hodapp et al. 2007b, WillerslevOlsen et al. 2014). 3.2.3 Control of Reflexes in the Antagonist At the onset of certain contractions, reciprocal inhibition is greatly increased in order to prevent unwanted activation of the antagonists (Crone et al. 1987, Crone and Nielsen 1989, Kagamihara and Tanaka 1985, Morita et al. 2001, Nielsen and Kagamihara 1992). At the same time, presynaptic inhibition of Ia afferents projecting to antagonist motoneurones is also increased to further reduce the risk of eliciting stretch reflexes in the antagonist muscles when they are stretched at the onset of movement (Morita et al. 2001, Nielsen and Kagamihara 1992, Nielsen and Kagamihara 1993). This regulation of antagonist muscles is impaired in patients with spasticity and they therefore fail to prevent the elicitation of stretch reflexes at the onset of movement (Morita et al. 2001). It is likely that one strategy adapted by patients in this situation is to move slower in order to prevent elicitation of reflexes with too-fast movements (Morita et al. 2001, Okuma and Lee 1996). 3.2.4 Suppression of Reflexes in Swing Phase In healthy subjects, a very profound suppression of soleus H-reflexes and stretch reflexes is seen in the swing phase of walking (Capaday and Stein 1986, Ethier et al. 2003, Simonsen and Dyhre-Poulsen 1999, Sinkjaer et al. 1996a, Willerslev-Olsen et al. 2014). This likely relates to increased reciprocal inhibition from ankle dorsiflexors to plantarflexors when the dorsiflexors are activated to lift the foot above the ground (Petersen et al. 1999). A similar modulation of the H-reflex has been described during bicycling with a very profound suppression (likely due to increased reciprocal inhibition from dorsiflexors to plantarflexors) during upstroke (Pyndt et al. 2003, Pyndt and Nielsen 2003). In patients with stroke, multiple sclerosis, and cerebral palsy, a much-less-pronounced suppression of reflexes in swing during gait is observed (Mazzaro et al. 2007, Sinkjaer et al. 1996b, Willerslev-Olsen et al. 2014).

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A similar tendency has also been observed for stroke patients during bicycling, although a significant effect was not observed except for patients with the most reduced function (Schindler-Ivens et al. 2008). Although it has not been specifically tested, it seems likely that the inability to adequately suppress reflexes in the swing phase relates to impaired control of reciprocal inhibition as demonstrated for dynamic movements in sitting subjects by Morita et al. (2001). It may be argued that the relative hyperexcitability of the reflex in the swing phase prevents the patients from performing fast movements and thereby from walking as quickly as would otherwise have been possible. To what extent this is really a functional problem is not fully clarified. At some point it has also been assumed that inappropriate control of the reflex in the swing phase could contribute to premature activation of the plantarflexors prior to heel strike and cause co-activation of the antagonistic muscles. A large part of the rationale for using botulinum neurotoxin as a treatment of toe-walking in children with CP has thus been to prevent premature activation of plantarflexors. However, premature activation of plantarflexors is often seen in healthy children and there is no clear evidence that co-activation around the ankle joint prior to ground contact should be more common in children with CP than in healthy children (Willerslev-Olsen et al. 2014). Also, the larger stretch reflexes in children with CP in the swing phase than in healthy children do not seem to contribute to any inadvertent EMG activity. Similar to what has been found in the stance phase of walking, sudden shortening of the co-activated plantarflexors in the swing phase does not result in a drop in EMG activity at the latency of the stretch reflex (Willerslev-Olsen et al. 2014). Since this muscle shortening will result in cessation of activity in force- and length-sensitive afferents from the plantarflexors, the lack of drop in EMG activity at stretch reflex latency suggests that there is no contribution of muscle spindle afferent activity to plantarflexor muscle activity in children with CP during the swing phase of walking. It is therefore a likely possibility that spasticity does not lead to co-activation and premature activation of plantarflexors in children with CP and that it does not contribute to toe-walking in these children.

3.3 Sensory Feedback Contribution to Movement In healthy subjects, presynaptic inhibition appears to prevent the monosynaptic Ia input to the motoneuornes from contributing substantially to the activation of the muscles during gait (Capaday and Stein 1986, Donelan et al. 2009, Grey et al. 2007, Pearson 2004, Pearson 2008, Sinkjaer et al. 2000). During locomotion in the cat, stimulation of extensor muscle afferents does not produce any substantial monosynaptic EPSPs in triceps surae motoneurones (Brownstone et al. 1994, Gossard et al. 1994, McCrea et al. 1995), but

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rather EPSPs with an at-least-disynaptic latency (McCrea et al. 1995). There is good evidence to suggest that these EPSPs involve multimodal afferent convergence (group Ia, Ib, and II) to interneurons that are components of a locomotor rhythm generator in the cat lumbar spinal cord (Gossard et al. 1994, McCrea et al. 1995). In intact cats it has also been shown that transmission in load-sensitive rather than length-sensitive afferents are of dominant importance for the maintenance of extensor muscle activity in the stance phase of real and fictive gait (Conway et al. 1987, Donelan et al. 2009, Pearson 2004, Pearson 2008). Sudden unloading of the limb thus initiates the flexor phase, whereas maintenance of load on the muscles during stance – and thus activity in Ia afferents – provides a continuous excitatory drive to the motoneurons. This suggests that interneurons mediating load-sensitive inputs to the motoneurones rather than the Ia monosynaptic pathway are of major importance for the muscle activation during gait. This is likely also the case in human subjects (Sinkjaer et al. 2000). Unloading of the ankle plantarflexor muscles thus produces a depression of soleus EMG activity with a latency compatible with transmission in a similar pathway as what has been described in the cat (Donelan et al. 2009, Pearson 2004, Pearson 2008, Sinkjaer et al. 2000). Furthermore, this depression is not sensitive to a block of Ia afferents (Sinkjaer et al. 2000). In healthy human subjects, the monosynaptic Ia afferent pathway thus seems to make only a minor or no contribution to the triceps surae muscle activity in the stance phase of walking. However, with the exaggeration of stretch reflexes in spastic patients it could be expected that they would show some contribution of the pathway to the maintenance of EMG activity, but this does not seem to be the case. In both adults with stroke and children with CP, unloading of the ankle plantarflexors in the stance phase of gait thus produces a depression of soleus EMG activity with a latency similar to that observed in healthy subjects. If anything, this depression is smaller in spastic patients than in healthy subjects (Mazzaro et al. 2007, WillerslevOlsen et al. 2014), indicating a reduced transmission in the pathway and a reduced contribution of sensory afferent feedback to the activity of the soleus muscle. The clinical significance of this finding is that it is not possible to conclude that sensory input to the spinal cord is exaggerated under functional conditions based on observations of exaggerated reflex responses either at rest or under those functional conditions. It should again be remembered, as pointed out by Sherrington, that reflexes are (fictive) simplified concepts (something that we evoke under very unnatural conditions to serve our diagnostic purposes) that have little relevance to normal physiological integration of sensory feedback. If sensory feedback from the active plantar flexor muscles in the stance phase is of importance in maintaining the muscle activity, as the data from cat and human laboratory experiments suggest (Donelan et al. 2009, Pearson 2004, Pearson 2008), suppression of this feedback by antispastic medication may be disadvantageous. This is also supported from over-ground human

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experiments. Subjects who are asked to walk without visual feedback across a platform that is tilted slightly to emulate irregularities in the ground thus adjust the EMG activity in the plantarflexor muscles according to the platform within a short time after making contact with the platform (af Klint et al. 2008). It could be shown that this is likely to be caused by load-sensitive afferents from the plantarflexors and this illustrates that one important function of this feedback is to provide automatic adjustments to irregularities in the ground (af Klint et al. 2010, af Klint et al. 2008, Af Klint et al. 2009). If this feedback is suppressed by antispastic medication or surgical intervention, the ability of the subjects to adjust their gait according to the ground conditions and limb loading would be assumed to be lost and they would be forced to pay much more conscious attention to their gait. This is exactly what is observed when subjects are given antispastic medication such as baclofen and diazepam (Orsnes et al. 2000, Laurent Bouyer, Jakob Lorentzen, Maria Willerslev-Olsen, Jens Bo Nielsen, personal observation).

3.4 Long-Latency Stretch Reflexes and Coordination of Movement As also described in Chapter 2, several additional reflex components are observed at latencies longer than the monosynaptic stretch reflex, especially during contraction. The M2 reflex response in leg muscles is caused by the activation of spinal interneurons through activation of group II afferents (Corna et al. 1995, Grey et al. 2001, Nardone and Schieppati 2005) and is generally found to be exaggerated in spastic subjects similar to the monosynaptic reflex components (Ibrahim et al. 1993, Sinkjaer and Magnussen 1994, Willerslev-Olsen et al. 2014). The significance of these responses for the functional ability of spastic subjects is unclear, but since the responses mostly behave similarly to the monosynaptic M1 component, it seems likely that the above discussion of the M1 component also applies to the M2 component. The later-occurring M3 responses have a latency that is sufficiently long for them to be mediated through a transcortical reflex pathway (Christensen et al. 2000). Animal experiments have unequivocally demonstrated the existence of such transcortical pathways and indirect evidence from human experiments support that a transcortical pathway also contributes at least to the long-latency reflex responses in some muscles in humans (Christensen et al. 2001, Christensen et al. 2000, Petersen et al. 1998). Most convincingly, TMS over the primary motor cortex at an intensity sufficiently low to activate only local inhibitory interneurons efficiently suppresses the long-latency stretch reflex components in finger muscles (Taylor et al. 1995) and the tibialis anterior muscle (Zuur et al. 2009). For the TA, this is also the case during gait (Zuur et al. 2009). For other muscles such as the soleus muscle and the

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proximal arm muscles the evidence is less convincing and it appears likely that other pathways, possibly involving brain stem nuclei, also contribute to the long-latency reflex responses. Similar long-latency responses may also be observed following cutaneous stimulation of both the fingers and the foot and, similar to what has been observed for muscle afferents, transcortical reflex pathways appear to contribute to these responses (Christensen et al. 2000). Given the transcortical nature of long-latency reflexes, it is not surprising that they are generally found to be absent or greatly reduced in patients with central motor lesions, including cortical stroke (Christensen et al. 2000, Trumbower et al. 2013, Zehr et al. 1998). The functional significance of these long-latency responses and thus the functional significance of their absence in patients with central motor lesions is not fully clarified, although suggestions for their possible importance has been put forward (Dietz and Sinkjaer 2007). The responses are generally rather stereotyped and appear in a predictable fashion, but at the same time their latency makes them almost indistinguishable from a voluntary reaction to a sensory stimulus that occurs only a few milliseconds later. To an even greater extent than the monosynaptic spinal stretch reflex, these responses should, therefore, be seen as an integrated part of voluntary movements rather than as simple stereotypic reflex responses. The sensory feedback from both muscles and skin provides the cortex with important information about the supporting ground as well as obstacles encountered during gait, which permits that functionally relevant adaptations of gait may be executed (Christensen et al. 2001, Christensen et al. 2000, Zuur et al. 2009). Such adaptations will depend on the time in the gait cycle, the particular context, and the intentions of the subject, to name only a few factors. Integration at a cortical level may help to ensure that these different constraints are taken into account before the particular reaction to the sensory input is executed. The reduction and even absence of the responses in patients with central lesions in all likelihood provides an important contribution to their functional inability. Without sufficient adjustment and updating of the central commands according to the sensory information, the central control of movement will be deficient. This will involve, in particular, the reactions that are necessary to maintain balance and adjust gait according to external challenges. It should again be pointed out that antispastic medication is likely to diminish further the information carried by the sensory feedback important for these reactions.

3.5 Interjoint Coordination Sensory afferents from skin, muscles, tendons, and joints project to spinal interneurons that influence the activity not only of motoneuroes innervating

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muscles acting at the joint from where the afferents originate, but also of motoneurons innervating muscles acting at other joints in the same limb (Burke 2012, Jankowska 1992). Relatively little is known about the modulation of transmission in these reflex pathways during movement in healthy subjects and patients with spasticity. Ia afferents from muscle spindles thus project monosynaptically to synergistic motoneurons throughout the same limb (Burke 2012). Failure of presynaptic inhibition of these projections likely also contributes to some of the gait disturbances in spastic patients. O’Dyer et al. (2009, 2011) described that exaggerated excitation of soleus muscles from femoral nerve afferents was directly correlated to increased co-activation of ankle extensors and knee extensors in stroke survivors (O’Dyer et al. 2009, O’Dyer et al. 2011). This co-activation was also shown to be well correlated to functional impairment in the patients (O’Dyer et al. 2011). Group I and group II afferents from ankle plantarflexors and dorsiflexors also project to knee extensors and flexors (Burke 2012). The reflex pathway from ankle dorsiflexors to the knee muscles is relatively suppressed during static conditions in sitting or standing subjects, but transmission in the pathway is greatly facilitated just prior to and just after heel strike during gait (Iglesias et al. 2008, Marchand-Pauvert and Nielsen 2002a, MarchandPauvert and Nielsen 2002b). The functional importance of this gating of transmission in the pathway is probably to ensure the stability of the knee joint when the load of the body is moved onto the supporting limb early in stance (Iglesias et al. 2008, Marchand-Pauvert and Nielsen 2002b). A similar modulation is also seen in stroke patients, but with pronounced exaggeration of the later components of the reflex excitation (Achache et al. 2010a). This may be a compensation to ensure the stability of the knee joint in light of muscle weakness (paresis) and may possibly also contribute to the stiffness of gait in spastic patients.

3.6 Interlimb Coordination In animals, commissural interneurons that project from one side of the spinal cord to interneurons and motoneurons on the other side are involved in coordinating activation of the muscles to ensure the occurrence of appropriately timed activity in flexors and extensors (Bannatyne et al. 2009, Butt et al. 2002, Dietz and Michel 2009, Jankowska et al. 2009). These interneurons receive in animal models significant input from both sensory afferents (in particular, group II afferents) and descending fibres (in particular, vestibulospinal fibres) (Bannatyne et al. 2009, Jankowska et al. 2009). It is unclear to what an extent these spinal pathways influence gait in human subjects and potentially contribute to the gait deficit in spastic subjects. Following nerve stimulation or muscle stretch, short-latency inhibitory

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responses are observed contralaterally, whereas excitatory responses are generally of such long latency that it cannot be excluded that supraspinal pathways are involved (Berger et al. 1984, Dietz et al. 1984, Stubbs et al. 2011a, Stubbs et al. 2011b, Stubbs et al. 2012). In complete spinal cord-injured subjects, sensory input also does not influence the activity of the opposite leg during treadmill-generated locomotion, suggesting that interlimb coordination requires supraspinal control (Dietz et al. 2002). Lesion of descending pathways either in the spinal cord or at cortical level is therefore likely to interrupt the connections that are essential for coordination of the two legs (Sousa et al. 2013). Treadmill training where the two legs may be trained individually or together may thus also depend on re-establishment of supraspinal control of the spinal networks rather than training of the spinal networks themselves, although evidence to support this possibility has also been presented (Barbeau et al. 2006, Colombo et al. 2000, Reisman et al. 2010a, Reisman et al. 2010b).

3.7 Co-Contraction as a Strategy to Maintain Joint Stiffness For decades it has been assumed that the co-activation of antagonistic muscles is undesirable and the observation of increased co-activation around a number of joints during functional movements in patients has therefore been seen as disadvantageous (el-Abd et al. 1993, Poon and Hui-Chan 2009). The logic in this is that co-activation costs more energy as it requires the agonist to overcome the force of the antagonists. Activation of muscles becomes more fractionated with fewer groups contributing to successful movement as motor learning and rehabilitation progress (Nielsen 1998, Smith 1981). This is also the case in relation to rehabilitation of function in patients following central lesions (Miyoshi et al. 2010, Ohn et al. 2013, Okuma and Lee 1996). Activation of muscles becomes gradually more focused and involves increasingly fewer muscles, which are activated less as motor learning and rehabilitation progress (Miyoshi et al. 2010, Ohn et al. 2013, Okuma and Lee 1996). This does not signify, however, that co-activation is necessarily disadvantageous for the patient. On the contrary, co-activation may be the only viable strategy for the patient to maintain stability around a joint when muscles are weak due to paresis and paralysis. As demonstrated by Nielsen et al. (1994), co-activation of muscles around the ankle joint is the most efficient way of increasing joint stiffness and ensuring stability of the joint (Nielsen et al. 1994). A co-contraction strategy is adapted also in healthy human subjects whenever steady control of the joint position and maintenance of balance is a requirement (Nielsen and Kagamihara 1992, Nielsen 1998). That co-activation may be an efficient functional strategy is witnessed by the fact that ballet dancers use co-activation around the ankle joint to ensure balance

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during various postures and jumps (Nielsen et al. 1993). The co-activation of knee extensors and ankle plantar- and dorsiflexors may also be examples of a similar compensatory strategy aimed at ensuring the stability of especially the knee joint, due to partly paretic and weak muscles (Achache et al. 2010a, Dyer et al. 2009, Dyer et al. 2011).

3.8 Over-Activity as a General Adaptation to Central Lesion Causing Disordered Motor Control As pointed out in several review papers (Gracies 2005a, Gracies 2005b, Sheean 2002, Sheean and McGuire 2009, Yelnik et al. 2010), as well as in Chapter 2, spasticity may be seen as part of a more general spinal adaptation to the loss of descending drive resulting not only in exaggerated stretch responses (at least at rest), but also an upregulation of the synaptic efficacy of surviving descending fibres. In addition, supraspinal adaptations may result in an exaggerated and insufficiently focused descending drive to spinal motoneurones that are not normally activated as part of the generated movement. This inadvertent ‘over-flow’ or ‘over-activity’ is likely the cause of the ‘spastic dystonia’ seen in many patients with stroke and other central lesions. The associated postural disturbances, affection of joint position, and compromised movement control are clearly of great functional significance for patients. It is therefore unfortunate that we have little knowledge of the underlying causes, except for the original observations in monkeys that stretch reflex activity is not responsible and that these disturbances therefore should be seen as separate from spasticity (Denny-Brown 1966). There is clearly a need for more research to determine the pathophysiological changes leading to spastic dystonia and how these changes contribute to the movement disorder in patients with central lesions in order to optimise future treatment.

3.9 Training to Learn New Strategies and Thereby Make Use of Spasticity It is often reported as a clinical observation that patients with spasticity may use the muscle activity provided by the exaggerated stretch reflex activity to stand and maybe even walk (Dietz 2003, Dietz 2008, Dietz and Sinkjaer 2007, Dietz and Sinkjaer 2012). Although this idea is attractive, there is little direct evidence to support that it is correct. There is, however, convincing evidence that spasticity does not become more pronounced with training

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(Damiano 2014, Dodd et al. 2002, Kirk et al. 2016, Lorentzen et al. 2017, Schram Christensen et al. 2017) and it is also likely a possibility that a large part of the beneficial effect of functional training in subjects with spastic movement disorder may be related to a more optimal integration and interpretation of sensory feedback signals (Frisk et al. 2017, Willerslev-Olsen et al. 2015). With our current understanding of the role of sensory feedback in generation of voluntary muscle activity and as error signals for the updating of central motor commands (Nielsen 2016), it would make sense to design future interventions to make use of spasticity to facilitate functional recovery rather than to diminish it at all cost. If spasticity is seen as a plastic response to reduced descending input to the spinal cord with the overall aim of maintaining a functional drive to the muscles, a treatment goal might be to train patients to adapt new movement strategies where they can more easily make use of the possibilities provided by the altered sensory feedback.

References Achache V, Mazevet D, Iglesias C, Lackmy A, Nielsen JB et al. 2010a. Enhanced spinal excitation from ankle flexors to knee extensors during walking in stroke patients. Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology 121: 930–8. Achache V, Roche N, Lamy JC, Boakye M, Lackmy A et al. 2010b. Transmission within several spinal pathways in adults with cerebral palsy. Brain: A Journal of Neurology 133: 1470–83. af Klint R, Mazzaro N, Nielsen JB, Sinkjaer T, Grey MJ. 2010. Load rather than length sensitive feedback contributes to soleus muscle activity during human treadmill walking. Journal of Neurophysiology 103: 2747–56. af Klint R, Nielsen JB, Cole J, Sinkjaer T, Grey MJ. 2008. Within-step modulation of leg muscle activity by afferent feedback in human walking. The Journal of Physiology 586: 4643–8. Af Klint R, Nielsen JB, Sinkjaer T, Grey MJ. 2009. Sudden drop in ground support produces force-related unload response in human overground walking. Journal of Neurophysiology 101: 1705–12. Alstermark B, Hultborn H, Jankowska E, Pettersson LG. 2010. Anders Lundberg (1920-2009). Experimental Brain Research 200: 193–5. Bannatyne BA, Liu TT, Hammar I, Stecina K, Jankowska E, Maxwell DJ. 2009. Excitatory and inhibitory intermediate zone interneurons in pathways from feline group I and II afferents: differences in axonal projections and input. The Journal of Physiology 587: 379–99. Barbeau H, Basso M, Behrman A, Harkema S. 2006. Treadmill training after spinal cord injury: good but not better. Neurology 67: 1900–1; author reply 1–2. Berger W, Dietz V, Quintern J. 1984. Corrective reactions to stumbling in man: Neuronal co-ordination of bilateral leg muscle activity during gait. The Journal of Physiology 357: 109–25.

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Brownstone RM, Gossard JP, Hultborn H. 1994. Voltage-dependent excitation of motoneurones from spinal locomotor centres in the cat. Experimental Brain Research 102: 34–44. Burke D, Pierrot-Deseilligny, E. 2012. The Circuitry of the Human Spinal Cord: Spinal and Corticospinal Mechanisms of Movement. Cambridge: Cambridge University Press. Butt SJ, Lebret JM, Kiehn O. 2002. Organization of left-right coordination in the mammalian locomotor network. Brain Research. Brain Research Reviews 40: 107–17. Capaday C, Stein RB. 1986. Amplitude modulation of the soleus H-reflex in the human during walking and standing. The Journal of Neuroscience: Official Journal of the Society for Neuroscience 6: 1308–13. Capaday C, Stein RB. 1987. Difference in the amplitude of the human soleus H reflex during walking and running. The Journal of Physiology 392: 513–22. Cho SH, Lee JH. 2013. Comparison of the Amplitudes of the H-reflex of Post-stroke Hemiplegia Patients and Normal Adults during Walking. Journal of Physical Therapy Science 25: 729–32. Christensen LO, Andersen JB, Sinkjaer T, Nielsen J. 2001. Transcranial magnetic stimulation and stretch reflexes in the tibialis anterior muscle during human walking. The Journal of Physiology 531: 545–57. Christensen LO, Petersen N, Andersen JB, Sinkjaer T, Nielsen JB. 2000. Evidence for transcortical reflex pathways in the lower limb of man. Progress in Neurobiology 62: 251–72. Colombo G, Joerg M, Schreier R, Dietz V. 2000. Treadmill training of paraplegic patients using a robotic orthosis. Journal of Rehabilitation Research and Development 37: 693–700. Conway BA, Hultborn H, Kiehn O. 1987. Proprioceptive input resets central locomotor rhythm in the spinal cat. Experimental Brain Research 68: 643–56. Corna S, Grasso M, Nardone A, Schieppati M. 1995. Selective depression of mediumlatency leg and foot muscle responses to stretch by an alpha 2-agonist in humans. The Journal of Physiology 484 (Pt 3): 803–9. Crone C, Hultborn H, Jespersen B, Nielsen J. 1987. Reciprocal Ia inhibition between ankle flexors and extensors in man. The Journal of Physiology 389: 163–85. Crone C, Johnsen LL, Biering-Sorensen F, Nielsen JB. 2003. Appearance of reciprocal facilitation of ankle extensors from ankle flexors in patients with stroke or spinal cord injury. Brain: A Journal of Neurology 126: 495-507. Crone C, Nielsen J. 1989. Spinal mechanisms in man contributing to reciprocal inhibition during voluntary dorsiflexion of the foot. The Journal of Physiology 416: 255–72. Damiano DL. 2014. Progressive resistance exercise increases strength but does not improve objective measures of mobility in young people with cerebral palsy. Journal of Physiotherapy 60: 58. Delwaide PJ, Oliver E. 1988. Short-latency autogenic inhibition (IB inhibition) in human spasticity. Journal of Neurology, Neurosurgery, and Psychiatry 51: 1546–50. Denny-Brown D. 1966. The cerebral control of movement. Liverpool: University Press. Dietz V. 2003. Spastic movement disorder: what is the impact of research on clinical practice? Journal of Neurology, Neurosurgery, and Psychiatry 74: 820–1. Dietz V. 2008. Spasticity-spastic movement disorder. Spinal Cord 46: 588. Dietz V, Michel J. 2009. Human bipeds use quadrupedal coordination during locomotion. Annals of the New York Academy of Sciences 1164: 97–103.

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Dietz V, Muller R, Colombo G. 2002. Locomotor activity in spinal man: significance of afferent input from joint and load receptors. Brain: A Journal of Neurology 125: 2626–34. Dietz V, Quintern J, Berger W. 1984. Corrective reactions to stumbling in man: functional significance of spinal and transcortical reflexes. Neuroscience Letters 44: 131-5. Dietz V, Sinkjaer T. 2007. Spastic movement disorder: impaired reflex function and altered muscle mechanics. Lancet Neurology 6: 725–33. Dietz V, Sinkjaer T. 2012. Spasticity. Handbook of Clinical Neurology 109: 197–211. Dodd KJ, Taylor NF, Damiano DL. 2002. A systematic review of the effectiveness of strength-training programs for people with cerebral palsy. Archives of Physical Medicine and Rehabilitation 83: 1157–64. Donelan JM, McVea DA, Pearson KG. 2009. Force regulation of ankle extensor muscle activity in freely walking cats. Journal of Neurophysiology 101: 360–71. Dyer JO, Maupas E, de Andrade Melo S, Bourbonnais D, Fleury J, Forget R. 2009. Transmission in heteronymous spinal pathways is modified after stroke and related to motor incoordination. PloS One 4: e4123. Dyer JO, Maupas E, Melo Sde A, Bourbonnais D, Forget R. 2011. Abnormal coactivation of knee and ankle extensors is related to changes in heteronymous spinal pathways after stroke. Journal of Neuroengineering and Rehabilitation 8: 41. el-Abd MA, Ibrahim IK, Dietz V. 1993. Impaired activation pattern in antagonistic elbow muscles of patients with spastic hemiparesis: contribution to movement disorder. Electromyography and Clinical Neurophysiology 33: 247–55. Ethier C, Imbeault MA, Ung V, Capaday C. 2003. On the soleus H-reflex modulation pattern during walking. Experimental Brain Research 151: 420–5. Faist M, Dietz V, Pierrot-Deseilligny E. 1996. Modulation, probably presynaptic in origin, of monosynaptic Ia excitation during human gait. Experimental Brain Research 109: 441–9. Faist M, Hoefer C, Hodapp M, Dietz V, Berger W, Duysens J. 2006. In humans Ib facilitation depends on locomotion while suppression of Ib inhibition requires loading. Brain Research 1076: 87–92. Ferris DP, Aagaard P, Simonsen EB, Farley CT, Dyhre-Poulsen P. 2001. Soleus H-reflex gain in humans walking and running under simulated reduced gravity. The Journal of Physiology 530: 167–80. Frisk RF, Jensen P, Kirk H, Bouyer LJ, Lorentzen J, Nielsen JB. 2017. Contribution of sensory feedback to plantar flexor muscle activation during push-off in adults with cerebral palsy. Journal of Neurophysiology: jn.00508.2017. Gossard JP, Brownstone RM, Barajon I, Hultborn H. 1994. Transmission in a locomotorrelated group Ib pathway from hindlimb extensor muscles in the cat. Experimental Brain Research 98: 213–28. Gracies JM. 2005a. Pathophysiology of spastic paresis. I: Paresis and soft tissue changes. Muscle and Nerve 31: 535–51. Gracies JM. 2005b. Pathophysiology of spastic paresis. II: Emergence of muscle overactivity. Muscle and Nerve 31: 552–71. Grey MJ, Ladouceur M, Andersen JB, Nielsen JB, Sinkjaer T. 2001. Group II muscle afferents probably contribute to the medium latency soleus stretch reflex during walking in humans. The Journal of Physiology 534: 925–33. Grey MJ, Nielsen JB, Mazzaro N, Sinkjaer T. 2007. Positive force feedback in human walking. The Journal of Physiology 581: 99–105.

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Hodapp M, Klisch C, Berger W, Mall V, Faist M. 2007a. Modulation of soleus H-reflexes during gait in healthy children. Experimental Brain Research 178: 252–60. Hodapp M, Klisch C, Mall V, Vry J, Berger W, Faist M. 2007b. Modulation of soleus H-reflexes during gait in children with cerebral palsy. Journal of Neurophysiology 98: 3263–8. Hultborn H. 2006. Spinal reflexes, mechanisms and concepts: from Eccles to Lundberg and beyond. Progress in Neurobiology 78: 215–32. Hultborn H, Meunier S, Pierrot-Deseilligny E, Shindo M. 1987. Changes in presynaptic inhibition of Ia fibres at the onset of voluntary contraction in man. The Journal of Physiology 389: 757–72. Hultborn H, Nielsen JB. 1998. Modulation of transmitter release from Ia afferents by their preceding activity – post-activation depression In Presynaptic Inhibition and neuronal control, ed. P Rudomin, R Romo, L Mendell, pp. 178–91. Oxford: Oxford University Press. Ibrahim IK, Berger W, Trippel M, Dietz V. 1993. Stretch-induced electromyographic activity and torque in spastic elbow muscles. Differential modulation of reflex activity in passive and active motor tasks. Brain: A Journal of Neurology 116 (Pt 4): 971–89. Iglesias C, Nielsen JB, Marchand-Pauvert V. 2008. Speed-related spinal excitation from ankle dorsiflexors to knee extensors during human walking. Experimental Brain Research 188: 101–10. Jankowska E. 1992. Interneuronal relay in spinal pathways from proprioceptors. Progress in Neurobiology 38: 335–78. Jankowska E, Bannatyne BA, Stecina K, Hammar I, Cabaj A, Maxwell DJ. 2009. Commissural interneurons with input from group I and II muscle afferents in feline lumbar segments: neurotransmitters, projections and target cells. The Journal of Physiology 587: 401–18. Jankowska E, Riddell JS, Skoog B, Noga BR. 1993. Gating of transmission to motoneurones by stimuli applied in the locus coeruleus and raphe nuclei of the cat. The Journal of Physiology 461: 705–22. Kagamihara Y, Tanaka R. 1985. Reciprocal inhibition upon initiation of voluntary movement. Neuroscience Letters 55: 23–7. Kirk H, Geertsen SS, Lorentzen J, Krarup KB, Bandholm T, Nielsen JB. 2016. Explosive Resistance Training Increases Rate of Force Development in Ankle Dorsiflexors and Gait Function in Adults With Cerebral Palsy. Journal of Strength and Conditioning Research 30: 2749–60. Landau WM. 1980. Spasticity: What is it? What is it not? In Spasticity: Disordered motor control, ed. RG Feldman, WP Koella, pp. 17–25. Chicago: Ciba-geigy Coporation. Lorentzen J, Kirk H, Fernandez-Lago H, Frisk R, Scharff Nielsen N et al. 2017. Treadmill training with an incline reduces ankle joint stiffness and improves active range of movement during gait in adults with cerebral palsy. Disability and Rehabilitation 39: 987–93. Marchand-Pauvert V, Nielsen JB. 2002a. Modulation of heteronymous reflexes from ankle dorsiflexors to hamstring muscles during human walking. Experimental Brain Research 142: 402–8. Marchand-Pauvert V, Nielsen JB. 2002b. Modulation of non-monosynaptic excitation from ankle dorsiflexor afferents to quadriceps motoneurones during human walking. The Journal of Physiology 538: 647–57.

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Mazzaro N, Grey MJ, do Nascimento OF, Sinkjaer T. 2006. Afferent-mediated modulation of the soleus muscle activity during the stance phase of human walking. Experimental Brain Research 173: 713–23. Mazzaro N, Nielsen JF, Grey MJ, Sinkjaer T. 2007. Decreased contribution from afferent feedback to the soleus muscle during walking in patients with spastic stroke. Journal of Stroke and Cerebrovascular Diseases: Official Journal of National Stroke Association 16: 135–44. McCrea DA, Shefchyk SJ, Stephens MJ, Pearson KG. 1995. Disynaptic group I excitation of synergist ankle extensor motoneurones during fictive locomotion in the cat. The Journal of Physiology 487 (Pt 2): 527–39. Miyoshi T, Takahashi Y, Lee H, Suzuki T, Komeda T. 2010. Upper limb neurorehabilitation in patients with stroke using haptic device system: reciprocal bi-articular muscle activities reflect as a result of improved circle-drawing smoothness. Disability and Rehabilitation. Assistive Technology 5: 370–5. Morita H, Crone C, Christenhuis D, Petersen NT, Nielsen JB. 2001. Modulation of presynaptic inhibition and disynaptic reciprocal Ia inhibition during voluntary movement in spasticity. Brain: A Journal of Neurology 124: 826–37. Nardone A, Schieppati M. 2005. Reflex contribution of spindle group Ia and II afferent input to leg muscle spasticity as revealed by tendon vibration in hemiparesis. Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology 116: 1370–81. Nielsen J, Crone C, Hultborn H. 1993. H-reflexes are smaller in dancers from The Royal Danish Ballet than in well-trained athletes. European Journal of Applied Physiology and Occupational Physiology 66: 116–21. Nielsen J, Kagamihara Y. 1992. The regulation of disynaptic reciprocal Ia inhibition during co-contraction of antagonistic muscles in man. The Journal of Physiology 456: 373–91. Nielsen J, Kagamihara Y. 1993. The regulation of presynaptic inhibition during cocontraction of antagonistic muscles in man. The Journal of Physiology 464: 575–93. Nielsen J, Sinkjaer T, Toft E, Kagamihara Y. 1994. Segmental reflexes and ankle joint stiffness during co-contraction of antagonistic ankle muscles in man. Experimental Brain Research 102: 350–8. Nielsen JB. 1998. Co-contraction of antagonistic muscles in man. Danish Medical Bulletin 45: 423–35. Nielsen JB. 2004. Sensorimotor integration at spinal level as a basis for muscle coordination during voluntary movement in humans. Journal of Applied Physiology 96: 1961–7. Nielsen JB. 2016. Human Spinal Motor Control. Annual Review of Neuroscience 39: 81–101. Ohn SH, Yoo WK, Kim DY, Ahn S, Jung B et al. 2013. Measurement of synergy and spasticity during functional movement of the post-stoke hemiplegic upper limb. Journal of Electromyography and Kinesiology: Official Journal of the International Society of Electrophysiological Kinesiology 23: 501–7. Okuma Y, Lee RG. 1996. Reciprocal inhibition in hemiplegia: Correlation with clinical features and recovery. The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques 23: 15–23. Orsnes GB, Sorensen PS, Larsen TK, Ravnborg M. 2000. Effect of baclofen on gait in spastic MS patients. Acta Neurologica Scandinavica 101: 244–8.

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Pearson KG. 2004. Generating the walking gait: role of sensory feedback. Progress in Brain Research 143: 123–9. Pearson KG. 2008. Role of sensory feedback in the control of stance duration in walking cats. Brain Research Reviews 57: 222–7. Petersen N, Christensen LO, Morita H, Sinkjaer T, Nielsen J. 1998. Evidence that a transcortical pathway contributes to stretch reflexes in the tibialis anterior muscle in man. The Journal of Physiology 512 (Pt 1): 267–76. Petersen N, Morita H, Nielsen J. 1999. Modulation of reciprocal inhibition between ankle extensors and flexors during walking in man. The Journal of Physiology 520 Pt 2: 605–19. Poon DM, Hui-Chan CW. 2009. Hyperactive stretch reflexes, co-contraction, and muscle weakness in children with cerebral palsy. Developmental Medicine and Child Neurology 51: 128–35. Pyndt HS, Laursen M, Nielsen JB. 2003. Changes in reciprocal inhibition across the ankle joint with changes in external load and pedaling rate during bicycling. Journal of Neurophysiology 90: 3168–77. Pyndt HS, Nielsen JB. 2003. Modulation of transmission in the corticospinal and group ia afferent pathways to soleus motoneurons during bicycling. Journal of Neurophysiology 89: 304–14. Reisman DS, Bastian AJ, Morton SM. 2010a. Neurophysiologic and rehabilitation insights from the split-belt and other locomotor adaptation paradigms. Physical Therapy 90: 187–95. Reisman DS, McLean H, Bastian AJ. 2010b. Split-belt treadmill training poststroke: a case study. Journal of Neurology Physical Therapy 34: 202–7. Schindler-Ivens S, Brown DA, Lewis GN, Nielsen JB, Ondishko KL, Wieser J. 2008. Soleus H-reflex excitability during pedaling post-stroke. Experimental Brain Research 188: 465–74. Schram Christensen M, Jensen T, Voigt CB, Nielsen JB, Lorentzen J. 2017. To be active through indoor-climbing: an exploratory feasibility study in a group of children with cerebral palsy and typically developing children. BMC Neurology 17: 112. Sheean G. 2002. The pathophysiology of spasticity. European Journal of Neurology: Official Journal of the European Federation of Neurological Societies 9 Suppl 1: 3–9; dicussion 53–61. Sheean G, McGuire JR. 2009. Spastic hypertonia and movement disorders: pathophysiology, clinical presentation, and quantification. PM R 1: 827–33. Simonsen EB, Dyhre-Poulsen P. 1999. Amplitude of the human soleus H reflex during walking and running. The Journal of Physiology 515 (Pt 3): 929–39. Simonsen EB, Dyhre-Poulsen P, Voigt M. 1995. Excitability of the soleus H reflex during graded walking in humans. Acta Physiologica Scandinavica 153: 2–32. Sinkjaer T, Andersen JB, Ladouceur M, Christensen LO, Nielsen JB. 2000. Major role for sensory feedback in soleus EMG activity in the stance phase of walking in man. The Journal of Physiology 523 Pt 3: 817–27. Sinkjaer T, Andersen JB, Larsen B. 1996a. Soleus stretch reflex modulation during gait in humans. Journal of Neurophysiology 76: 1112–20. Sinkjaer T, Andersen JB, Nielsen JF. 1996b. Impaired stretch reflex and joint torque modulation during spastic gait in multiple sclerosis patients. Journal of Neurology 243: 566–74.

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Sinkjaer T, Magnussen I. 1994. Passive, intrinsic and reflex-mediated stiffness in the ankle extensors of hemiparetic patients. Brain: A Journal of Neurology 117 (Pt 2): 355–63. Sinkjaer T, Toft E, Larsen K, Andreassen S, Hansen HJ. 1993. Non-reflex and reflex mediated ankle joint stiffness in multiple sclerosis patients with spasticity. Muscle and Nerve 16: 69–76. Smith AM. 1981. The coactivation of antagonist muscles. Canadian Journal of Physiology and Pharmacology 59: 733–47. Sousa AS, Silva A, Santos R, Sousa F, Tavares JM. 2013. Interlimb coordination during the stance phase of gait in subjects with stroke. Archives of Physical Medicine and Rehabilitation 94: 2515–22. Stephens MJ, Yang JF. 1996. Short latency, non-reciprocal group I inhibition is reduced during the stance phase of walking in humans. Brain Research 743: 24–31. Stubbs PW, Nielsen JF, Sinkjaer T, Mrachacz-Kersting N. 2011a. Crossed spinal soleus muscle communication demonstrated by H-reflex conditioning. Muscle and Nerve 43: 845–50. Stubbs PW, Nielsen JF, Sinkjaer T, Mrachacz-Kersting N. 2011b. Phase modulation of the short-latency crossed spinal response in the human soleus muscle. Journal of Neurophysiology 105: 503–11. Stubbs PW, Nielsen JF, Sinkjaer T, Mrachacz-Kersting N. 2012. Short-latency crossed spinal responses are impaired differently in sub-acute and chronic stroke patients. Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology 123: 541–9. Taylor JL, Fogel W, Day BL, Rothwell JC. 1995. Ipsilateral cortical stimulation inhibited the long-latency response to stretch in the long finger flexors in humans. The Journal of Physiology 488 (Pt 3): 821–31. Trumbower RD, Finley JM, Shemmell JB, Honeycutt CF, Perreault EJ. 2013. Bilateral impairments in task-dependent modulation of the long-latency stretch reflex following stroke. Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology 124: 1373–80. Willerslev-Olsen M, Andersen JB, Sinkjaer T, Nielsen JB. 2014. Sensory feedback to ankle plantar flexors is not exaggerated during gait in spastic hemiplegic children with cerebral palsy. Journal of Neurophysiology 111: 746–54. Willerslev-Olsen M, Petersen TH, Farmer SF, Nielsen JB. 2015. Gait training facilitates central drive to ankle dorsiflexors in children with cerebral palsy. Brain: A Journal of Neurology 138: 589–603. Yelnik AP, Simon O, Parratte B, Gracies JM. 2010. How to clinically assess and treat muscle overactivity in spastic paresis. Journal of Rehabilitation Medicine 42: 801–7. Zehr EP, Fujita K, Stein RB. 1998. Reflexes from the superficial peroneal nerve during walking in stroke subjects. Journal of Neurophysiology 79: 848–58. Zuur AT, Christensen MS, Sinkjaer T, Grey MJ, Nielsen JB. 2009. Tibialis anterior stretch reflex in early stance is suppressed by repetitive transcranial magnetic stimulation. The Journal of Physiology 587: 1669–76.

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4 The Clinical Management of Spasticity and Contractures in Cerebral Palsy Andrew Roberts CONTENTS 4.1 Introduction................................................................................................... 79 4.2 Cerebral Palsy................................................................................................80 4.3 Treatment Objectives.................................................................................... 82 4.4 Medical Treatment........................................................................................85 4.4.1 Oral Medication................................................................................85 4.4.1.1 Benzodiazepines................................................................85 4.4.1.2 Oral Baclofen....................................................................... 86 4.4.1.3 Gabapentin and Pregabalin.............................................. 86 4.4.2 Injection Therapies........................................................................... 86 4.4.2.1 Botulinum Toxin................................................................ 86 4.4.2.2 Phenol.................................................................................. 87 4.5 Therapy........................................................................................................... 88 4.5.1 Stretching........................................................................................... 88 4.5.2 Strengthening.................................................................................... 88 4.6 Surgical Treatment........................................................................................ 89 4.6.1 Neurotomy......................................................................................... 89 4.6.2 Intrathecal Baclofen.......................................................................... 89 4.6.3 Selective Dorsal Rhizotomy............................................................ 91 4.6.3.1 Case Study........................................................................... 94 4.7 Conclusion..................................................................................................... 96 References................................................................................................................ 96

4.1 Introduction For the past century, clinicians have had to treat the consequences of injury to the developing nervous system in the absence of a sound understanding of the underlying pathology. Louis Stromeyer was the first to undertake surgical treatment of a contracture secondary to an upper motoneuron injury in 1831. Little in England, who suffered from poliomyelitis, had his heel cord contracture released by Stromeyer and subsequently practised 79

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the orthopaedic management of neurological conditions, including cerebral palsy, which came to be known as Little’s disease [1]. A lack of non-invasive investigational techniques meant that an understanding of the motor consequences of injury to the developing nervous system was restricted to animals. The cat and rat are not ideal models for the human and our knowledge of spasticity, as it affects man, has been deficient until the last two decades. Experiments in man have not always had encouraging clinical results, as demonstrated by Foerster’s use of total dorsal rhizotomy for spasticity leading to deafferentation [2]. Not surprisingly given the complexity of the condition, progress in the clinical management of spasticity has been slow.

4.2 Cerebral Palsy Cerebral palsy is a common disabling condition in childhood that encompasses a large spectrum of conditions. A key characteristic of the cerebral palsies is that they occur around the time of birth or soon after, injuring the nervous system at a time when rapid change is occurring during typical development. At birth, the cortical spinal tracts have not formed. Projections from the motor cortex develop to infiltrate the ipsilateral and contralateral spinal cord. In the absence of injury, the ipsilateral projections are selectively removed and the contralateral projections gradually mature over the first two years of life [3]. Whilst the understanding and characterisation of an individual’s condition has  been aided greatly by the advent of cross-sectional imaging, specifically magnetic resonance imaging, the correlation between changes seen by the neuroradiologist and the problems encountered by the patient is often rather tenuous [4]. Increasingly, it is appreciated that the precise time of the injury and the environment shortly after injury have a significant influence on the effect of a discrete lesion [5]. The gap between neuro-imaging and reality has been bridged by the treating clinician often with a degree of imprecision. Fundamental differences between patients, for example, the presence or absence of ipsilateral corticospinal drive, are not appreciable without sophisticated diagnostic techniques [6]. As obstetric practice has improved over the last 30 years, the spectrum of motor disorders resulting from injury has changed. Difficult delivery resulting in oxygen deprivation and consequent hypoxic ischaemic encephalopathy is now an uncommon event, producing fewer children with total-body cerebral palsy. The management of neonatal jaundice has also led to a reduction in kernicterus that was associated with athetoid* cerebral palsy and dystonia.† * Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture [7]. † Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both [8].

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Premature birth leads to a haemorrhagic injury adjacent to the internal capsule as the foetal brain undergoes a rapid reduction in pressure on emerging from the intrauterine environment. Immature cerebral blood vessels are weaker than those at full term and rupture leads to haemorrhage to varying degrees. Severe haemorrhage may be sufficiently extensive to cause bleeding into the ventricles and subsequent clot organisation with obstruction of the cerebral aqueduct, leading to hydrocephalus. Characteristically, the cortico-reticular tracts adjacent to the pyramidal tracts are involved, reducing the inhibitory drive delivered by the reticular system to the cord. Whilst cerebral palsy following premature birth is characterised by spasticity and kernicterus leads to basal ganglia involvement producing athetosis or dystonia, more generalised hypoxic insults produce a mixture of motor disorders as a result of multiple lesions distributed through the hemispheres. Often, hypoxic brain injury will lead to a significant degree of cognitive impairment with learning difficulties during childhood. The surgical treatment of contractures and bony deformity in spastic cerebral palsy is well-established in the treatment of mobility and postural impairment, but consensus has formed that dystonia is both hard to treat and unpredictable with regards to outcome. First, dystonia is an abnormality of pattern rather than a resetting of the length-tension relationship of muscle seen in spasticity. It is possible through surgery to change a patient from one dystonic pattern to a completely different pattern, leading to a new but equally disabling posture. Because dystonia often results in an end-of-range posture at a joint, uncontrolled muscle force in the post-operative period has the potential for interfering with tendon transfers and bony procedures with suboptimal results. No reliable preventative strategy has been agreed on with respect to surgery in dystonia but good prolonged pain control and local neuromuscular blockade with botulinum toxin to cover the post-­ operative period seemed to help. Unfortunately, dystonia is all too often a post-­operative diagnosis, following a presumed procedure for the consequences of spasticity. The commonest form of cerebral palsy encountered in Western clinical practice is that associated with premature birth with unilateral or bilateral internal capsule bleeding leading to periventricular leucomalacia. Some children with unilateral involvement have a neronal migration disorder that is often accompanied by spastic dystonia as a result of a more diffuse problem. Where periventricular leucomalacia is encountered, the cortex is initially intact. Depending on the lesion distally the motor area for the lower limb may migrate laterally out of the inter-hemispheric sulcus towards the motor area for the upper limb. The resulting reduction in available pyramidal cells and thus eventual potential motor units, as well as a blurring of the distinction between upper and lower limb motor maps, will lead to weakness and imperfect control in addition to distal effects of cord reorganisation in response to reduced reticulo spinal drive. Current clinical practice remains focused on intervention to modify the reflex arc. The conceptual model in the author’s mind is that spasticity is: ‘the pathological effect of a failure of hierarchical control of the threshold of the tonic stretch

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reflex in support of posture and movement’ [9]. This gross simplification of the positive and negative effects of the upper motoneuron lesion on the developing brain is reflected in the simplistic nature of our current treatment strategies. Clinical experience with adults affected by cerebral palsy confirms that spasticity is usually a long-term phenomenon. One study suggesting that spasticity wanes during childhood based its assessment on the calf; however, it is likely that contracture of gastrocnemius later in childhood masks persistent spasticity in soleus, giving the impression of a reduction in spasticity [10]. Clonus can commonly be elicited in a spastic calf with the knee flexed, where it is not evident when the same rate and range of motion are used with the knee in extension.

4.3 Treatment Objectives Spasticity and contracture are not necessarily problems that require treatment. The establishment of achievable objectives aligned to the wishes of the child and family is essential. Often, unrealistic expectations need to be explored and rationalised before an agreed way forward can be found. A hierarchy of objectives can be generally agreed, with distressing symptoms taking priority over function and cosmesis. In the multicentre SPARCLE study of children between the age of 8 and 12 years living with cerebral palsy across the European Union, pain was found to be the dominant factor that impinged upon quality of life [11]. Previously, pain was not sought as a symptom when managing children with cerebral palsy because children often considered the pain to be ‘normal’ and did not mention it to their parents or their clinical carers. The majority of children in the SPARCLE study had sufficient cognitive function that they were able to use the Child Health Questionnaire and Paediatric Pain Questionnaire [12,13]. In children with very significant cerebral palsy, their ability to vocalise their discomfort is often restricted; as a result, there are pain scores that have been developed for total-body-involved children [14]. An enquiry about pain should be the first step in identifying possible objectives for treatment in cerebral palsy. Spasticity may lead to pain by producing abnormal forces on a particular structure, such as capsule and synovium, as a result of prolonged posture at the end of the joint’s range. Prolonged function with abnormal posture may lead to a failure of the integrity of the foot as a lever of progression, with high pressures over the navicular or base of the fifth metatarsal leading to pain. Crouch gait may lead to unacceptable loads on the extensor mechanism of the knee, with a failure of the distal pole of the patella or the tibial tuberosity leading to discomfort. Orthotic management, typically with ankle-foot orthoses, can often be complicated by discomfort when deformity or spasticity lead to

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high interface pressures between the device and the child’s skin. Where cerebral palsy is associated with muscle weakness and high levels of spasticity, prolonged activation of weak muscles can lead to pain. Whether pain in spastic muscle is the result of lactic acidosis or mechanical stretch is uncertain. The inability of the child to suppress muscle activation may lead to discomfort during therapeutic stretching. Function is impaired as a result of the complex interaction of spasticity, weakness, and control impairment. Some typical patterns are seen but the wide variety of defects leads to variability of functional impairment. In the child affected by periventricular leucomalacia who has sufficient strength to establish early walking, spasticity affecting the calf leads to the development of an equinus gait pattern. Once the child is in equinus, the origin of the ground reaction vector is advanced and a persistent extending moment during stance develops around the knee. A persistent extending moment around the knee negates the need for learning the control of the knee flexors and extensors that occurs in the typically developing child. Furthermore, the advanced ground reaction vector requires the hip to remain in flexion. The secondary contracture of the hip develops and the absence of end-stance hip extension removes the effect of the ilio-inguinal ligament on the anterior femoral neck leading to persistent femoral anteversion (Figure 4.1, left-hand frame). At the time of the adolescent growth spurt, failure of the foot as a lever often occurs as a result of rapid gain in weight, and the sudden return

FIGURE 4.1 The effect of calf spasticity on ground reaction vector alignment leads to excessive knee extension and hip flexion during stance. The application of an ankle-foot orthosis makes this worse until corrections applied to the shoes normalise the ground reaction vector with respect to the knee joint centre.

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30

Ankle dorsiflexion

3.0

Ankle dorsiflexing moment

5.0

Dors

Dors

Gen

Deg

Nm/kg

W/kg

Plan

Plan

Abs

–90

–1.0

–2.0

Ankle power

FIGURE 4.2 The effect of calf spasticity on ankle posture produces a pathologically increased moment in the first half of stance, giving a ‘double bump’ in the moment graph (centre) leading to abnormal generation and absorption of power in the power graph (right). Gray band = normal values.

of the ground reaction vector towards the ankle joint centre causes the child to walk with trunk upright and the thigh anteriorly inclined, producing a crouch gait pattern with progressive deterioration in walking ability. Spasticity impedes gait at several points in a gait cycle. In the calf, soleus is typically more hyper-reflexic than gastrocnemius and frequently causes the child to vault in mid-stance, expending energy without producing propulsion (Figure 4.2). On examination, gastrocnemius is often less obviously involved with the features of the upper motoneuron syndrome than soleus, but appears to have a very ready propensity to become contracted in response to the posture imposed by its near neighbour. The hamstrings are often significantly spastic and may limit knee extension in terminal swing, producing an excessively flexed posture at initial contact. Rectus femoris requires precise control because of its rôle at the knee and hip. A burst of activity is normally seen in the rectus femoris at pre-swing, terminating quickly once the foot is off the ground to allow inertial forces to flex the knee and shorten the limb. A lack of useful activity in the calf during stance makes forward propulsion of the leg difficult in pre-swing and excessive activity in rectus femoris is required in swing phase as a compensation leading to a stiff knee gait pattern with a significant increase in energy expenditure as a result of the higher moment of angular momentum associated with the extended limb (Figure 4.3). Bone growth in the presence of spasticity and abnormal posture may result in torsional deformity in the tibia, uncoupling the ankle plantar ­flexion-knee extension couple, or in the proximal femur leading to a defunctioning of the hip abductor mechanism necessary to stabilise the trunk during stance. Femoral anteversion in the newborn is much higher than in the adult, with the reduction resulting from hip extension in terminal stance producing pressure between the anterior femoral neck and the ilio-­ femoral ­ligament. The orientation of the femoral neck alters in response to

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Rectus femoris

1.2

0.0

85

0

20

40

60

80

100

FIGURE 4.3 Rectus femoris surface EMG normal values (gray bars = 1 standard deviation) with a comparison trace from a patient exhibiting swing phase spasticity (black trace).

the posteriorly directed pressure by means of Wolff’s law.* Where function is near-normal, improving the appearance of gait may be of benefit to the child necessitating de-rotation procedures to align the knee and foot in the direction of progression.

4.4 Medical Treatment 4.4.1 Oral Medication 4.4.1.1 Benzodiazepines Benzodiazepines, most notably diazepam, have been investigated for spasticity management in cerebral palsy. In general, benzodiazepines act by binding to the GABAα receptor found extensively throughout the central nervous system [15]. Whether the anti-spasticity action of benzodiazepines is predominantly at cord level, or also at a higher level, is uncertain. A recent American Academy of Neurology review suggested that the role of diazepam is as a short-term spasticity treatment. Owing to the sedative and dependency effects of benzodiazepines, medium- or long-term treatment * Wolff’s law relates to the absorption of bone in areas of low strain and deposition of bone in areas of high strain. Inhibition of bone resorption by osteoclasts underpins this adaptive mechanism to load exhibited by the vertebrate skeleton.

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should be avoided. Current practice is frequently to use diazepam as a rescue medicine for painful spasms, particularly after surgical procedures, but not to use it on a long-term basis [16]. 4.4.1.2 Oral Baclofen Oral baclofen acts as an agonist on the metabotropic GABAβ receptor, which, in turn, activates the G-protein K+ channel. In spite of its relatively modest molecular weight, baclofen penetrates the blood–brain barrier rather poorly. As a long-term oral medication, progressive increases in dosage are required until the therapeutic effect is obtained. Nausea, drowsiness, or hypotonia limit the oral dose of baclofen and often the therapeutic benefit is not seen before unwanted effects are encountered. Sudden cessation of oral baclofen may be associated with hallucinations [17]. However, withdrawal of the oral form is a less severe problem than that encountered during intrathecal use of the same agent. One clinical trial of oral baclofen showed a favourable response in 70% of patients in terms of spasticity reduction and passive and active limb movement, with a 25% incidence of adverse effects, all of which resolved on withdrawal of medication [18]. The treatment effect is sufficiently modest that oral baclofen is not widely used in children with spastic cerebral palsy [16]. 4.4.1.3 Gabapentin and Pregabalin Gabapentin and pregabalin, whilst pharmacologically different, have a similar spectrum of action against neuropathic pain. Both agents have been evaluated for the management of spasticity in general, but neither agent has been specifically used in cerebral palsy or spasticity management [19,20]. Where neuropathic pain complicates cerebral palsy, there may be a role for the use of these agents, but a wide variety of side-effects often limit their usefulness [19,21]. 4.4.2 Injection Therapies 4.4.2.1 Botulinum Toxin Botulinum toxin type A has been widely used in the management of spasticity in cerebral palsy. Early experiments in spastic mice suggested that the effect of toxin was temporary [22]. The concept of botulinum toxin as ‘bridging treatment’ whilst the patient grew, allowing definitive treatments towards the end of growth, became established. It remains common practice for children to have regular cycles of botulinum toxin injections to maintain range of movement. Boyd has identified a consensus that after three injections, the effect of botulinum toxin in any particular muscle diminishes [23]. While this lessening of efficacy was originally considered to be due to antibody formation, it is probably related to dystrophic change with muscle.

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Anecdotal reports of muscles becoming inelastic and unresponsive to physiotherapy stretching come from physiotherapists treating children who have had repeated botulinum toxin injections. Two studies have examined ­placebo-controlled botulinum toxin injections to be calf muscle combined with serial casting. Both studies showed better length either by measuring muscle length or joint angle at 6 weeks after administration, but marginally shorter muscles after botulinum toxin, compared with saline, at 12 months [24,25]. Muscle fibrosis following toxin injection may be the mechanism underlying this long-term effect of botulinum on muscle length. The dose of botulinum toxin used depends upon the commercial product, with the leading suppliers having assays that give different units for preparations delivering similar effects. Initially, cautious dosing regimes were employed. Higher doses of toxin were gradually introduced until very high doses per kilogram of body weight were used in a multilevel fashion [26]. The role of botulinum toxin in managing spasticity in cerebral palsy is licensed in the calf, but other uses are ‘off-licence’. This is not an impediment to the widespread use of toxin therapy in the upper and lower limbs, as well as in the management of the spastic bladder. As a trial therapy to evaluate the effect of muscle lengthening or as a rebalancing treatment, botulinum toxin remains an extremely useful therapeutic agent in spite of concerns about dystrophic change after multiple uses. The use of botulinum toxin should be restricted to muscle where shortening is dynamic rather than structural. The distinction between structural and dynamic shortening is that slow stretching or anaesthesia leads to a lengthening of muscle that exhibits dynamic shortening, but structural shortening is unaffected by anaesthesia. Differentiating between contracture and spasticity is usually straightforward in cerebral palsy because spastic dystonia and other velocity-independent motor disorders are relatively uncommon. A slow stretching of muscle and joint will usually allow the distinction between structural and dynamic contracture. Where muscle is inappropriately short during activity, either kinematics or dynamic EMG can be used to identify that activity in a specific muscle or muscle group is inappropriate when compared with normal. 4.4.2.2 Phenol Phenol as a 7% aqueous preparation may be used for local nerve blockade. The corrosive nature of phenol is such that small quantities have to be used, requiring the careful location of nerves with a nerve stimulator. Typically, in a child, 0.25 mL of 7% aqueous phenol is injected directly onto the nerve. The most frequent target for these blocks is the obturator nerve by medial approach behind the origin of the tendon of adductor longus. Because the injection has to be precisely targeted on the surface of the nerve, a general anaesthetic is necessary. The nerve stimulator is gradually turned down until a response occurs as a very low current and also disappears with only a slight movement of the needle. The clonic twitching of the adductors in

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response to the nerve stimulator can be seen to fade over a period of 1 to 2 minutes after the injection. It then takes between 6 and 9 months for the nerve to regrow through the lesion following the Wallerian degeneration induced by the chemical insult.

4.5 Therapy 4.5.1 Stretching Stretching forms an essential component of maintenance therapy for children with spastic cerebral palsy [27]. During sleep, postures of flexion are often adopted in the trunk and limbs. Whether this flexion is behavioural or neural in origin, the flexed posture allows the development of contractures with a progressive deterioration of function both of the hip and at the knee. Stretching emulates the physiological response of muscle as mechanically sensitive tissue challenged by a combination of physical play and skeletal growth. Evidence for this assertion is available in cats, but not in developing humans [28]. Where control and weakness limit the ability to play and be active, therapeutic input from therapists, family members, and the patient to stretch up muscles is important. The duration and intensity of stretch are important determinants of efficacy. Various animal models have been used to evaluate effective stretching, suggesting that a 60-minute stretch is likely to produce a maximum effect and will not be bettered by more prolonged stretching. Orthotic devices such as standing frames or contracture-­ correction devices can be used to deliver therapeutic stretching in a consistent fashion, provided compliance is maintained [29]. 4.5.2 Strengthening Strengthening spastic muscles was traditionally viewed as a hazardous practice, but evidence in the last decade suggests that improvements in strength can be obtained through resistive strength training, although there are limits to the extent to which this can be achieved [30]. A concern that strengthening spastic muscles can lead to an increase in spasticity has been refuted by clinical studies [31]. Because of the injury to the central nervous system, the number of alpha motoneurons (which have a one-to-one mapping with pyramidal cells) will be restricted and therefore there will be a limit imposed on maximal strength. Furthermore, spastic muscle is stiffer as a result of increased connective tissue and longer, less-compliant sarcomeres [32]. Finally, children with cerebral palsy have a very limited ability to recruit motor units, further reducing the force they are able to produce [33].

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4.6 Surgical Treatment 4.6.1 Neurotomy It is possible to reduce muscle action by partial or total division of the motor nerve. Unfortunately, this has only a limited application because of either mixed motor and sensory components within the nerve or lack of a suitable target. One instance where a single muscle might beneficially be degraded in its action is soleus, which is often particularly spastic in cerebral palsy. The motor nerve can be found in the popliteal fossa and its identity confirmed with electrical testing. An approximately 50% division of the motor nerve leads to a reduction in strength and, consequently, a reduction in equinus. It is less commonly practised in the English-speaking community than in continental Europe [34,35]. The motor branch to soleus is, in an adult, approximately 1 mm in diameter, making accurate division difficult. The decrement in action is permanent. Multiple neurotomies in the lower limb may be useful in removing the unwanted effects of spastic dystonia in stroke [36]. Neurotomy may also be useful in the upper limb, where function is not the prime objective. 4.6.2 Intrathecal Baclofen Baclofen, when given by mouth, has a weak effect as a result of poor penetration of the blood-brain barrier. To overcome this in patients with extensive spasticity, implantable pumps of increasing levels of sophistication have been developed.* Daily doses of intrathecal baclofen are typically three orders of magnitude smaller than that those required to achieve a modest effect when given orally. In heavily involved individuals, postural problems secondary to spasticity, structural problems such as scoliosis, and lack of control and weakness particularly in the trunk and neck muscles can make seating and care difficult. Intrathecal baclofen treatment has the advantage of being adjustable so that unwanted excessive reduction of spasticity unmasking weakness and lack of control can be reversed. In addition, the ability to vary the pattern of baclofen infusion throughout the day allows further refinement. Clearly, invasive and expensive treatments such as intrathecal baclofen require multidisciplinary assessment and a test dose given by lumbar-­ puncture injection into the thecal space. Because of the profound agonistic effect of baclofen on GABA receptors, withdrawal and overdose are significant potential hazards. Combined with the cost of the pump and a programme for refilling the device on a regular basis, the side-effects and complications necessitate careful patient selection. * Medtronic, 20 Lower Hatch Street, Dublin 2, Ireland Flowonix Medical, 500 International Drive, Suite 200, Mt. Olive, New Jersey 07828, USA.

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In general, patients who are non-ambulant or patients with very precarious postural control with total-body involvement are potentially suitable for intrathecal baclofen treatment. Because of the ability to vary the profile of drug delivery and the overall dose by means of an external programmer held over the pump, fine adjustments can be made to optimise spasticity reduction, while avoiding excessive loss of trunk muscle activation. Furthermore, if spasticity results from a progressive condition, the overall dose of baclofen can be increased to account for the increasing levels of spasticity. The pumps vary in size, with miniature drives, control systems, and a reservoir for the baclofen. Pumps now tend to be placed in an intermuscular plane beneath the external oblique muscle in the right iliac fossa. Movement of the pump within its pocket can lead to discomfort and the need for revision. In smaller children, even the smallest pumps can lead to discomfort from impingement on the costal margin, particularly where there is a scoliosis or truncal instability secondary to impaired control. The catheter connection with the pump represents one of the potential weaknesses of the system, with the occasional occurrence of kinks and disconnections. Pump disconnection or failures can lead to a life-threatening neuroleptic malignant syndrome requiring prompt identification, intensive-care support, and revision of the catheter or device [37]. The full syndrome includes rhabdomyolysis, headache, autonomic dysfunction, fever, coma, and death. A strategy for diagnosing problems with pumps includes plain radiography, contrast injection via a diagnostic port, and the use of rapid infusion rates of saline to enable fluoroscopic visualisation of the rotor moving within the device. Specific supportive measures and guidelines to manage acute withdrawal have not been established, with case reports providing some evidence of effective strategies [38]. Whilst the catheter has a very fine bore, the dead space (volume of baclofen solution) contained within the length of the catheter is sufficient, where concentrated solutions of baclofen are used, to present an overdose hazard if the line is flushed through in an antegrade direction [39,40]. The catheter is tunneled subcutaneously from the pump and passes into the thecal sac through a low lumbar entry point. The height of the intrathecal catheter tip has a bearing on the distribution of drug within the thecal sac, with relatively high catheters having more effect on trunk tone and lower catheters less of an effect. Although not primarily intended to affect the upper limbs, patients and families often report an improvement in upper limb function and some aspects of speech and swallowing after the establishment of intrathecal baclofen [41]. In addition to spasticity, intrathecal baclofen infused through a trial catheter over five days can have a significant effect on dystonia [42]. In patients with a mixture of motor disorder types, the anti-dystonic effects of baclofen can be a very valuable feature, particularly when compared with selective dorsal rhizotomy, which may reveal unwanted dystonic postures uninhibited by the restraint of spasticity. Intrathecal baclofen treatment is expensive because of the cost of the pump and the refill programme. Savings in total care costs for children treated with intrathecal baclofen have been reported

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as a result of the reduction in whole-body spasticity secondary to the pump [43]. Compared with intrathecal baclofen, selective dorsal rhizotomy has a one-off cost but is permanent, is much more confined to the lower limb, and is unsuitable for motor disorders other than pure spasticity. 4.6.3 Selective Dorsal Rhizotomy For more than 100 years, disruption of the reflex arc in an attempt to reduce spasticity has been attempted. Initially, the German neurosurgeon Otfrid Foroester performed complete rhizotomy with rather poor outcomes, leading to him abandoning the technique. In the 1960s, the Italian neurosurgeon Vincenzo Fasano used neurophysiology monitoring to guide partial division of the dorsal roots, selecting those components of the root that were most provocative of spasticity when stimulated [44]. Dr Warwick Peacock in South Africa used Fasano’s technique to manage patients with spastic cerebral palsy diplegia. After moving to the West Coast of America, Peacock’s technique spread widely among North American neurosurgeons. The selection criteria employed by Dr Peacock required high levels of spasticity; a diagnosis of spastic diplegia and adequate muscle strength. An emphasis was placed on the careful selection of patients. As with any technique, a wave of enthusiasm was followed by a period of retrenchment, with many North American clinicians associated with the management of cerebral palsy regarding the technique as unhelpful. A wave of enthusiasm for selective dorsal rhizotomy in Scandinavia has been documented by the CPUP National Surveillance Program, with an interesting decline in the number of patients operated on in recent years. Dr Peacock’s technique consisted of an extensive laminectomy from L1 down to L5, enabling visualisation of the whole of the cauda equine [45] (Figure 4.4). The ability to confirm the level of exit of a particular root and the lack of tension on the root at the time of sectioning is set against the extensive incision required by the original procedure practiced by Peacock. More recently, a limited approach to the conus where the dorsal roots are sequentially arranged (until disturbed by the surgeon) has been popularised in North America [46]. The majority of centres now undertake the conus procedure, with only a few persisting with Dr Peacock’s original cauda equina procedure. Sectioning of L1 is deemed as important because of the effect of spasticity on the psoas muscle. A degree of debate exists regarding sectioning of the second sacral nerve. It is claimed that a more durable result arises from sectioning S2, but concerns over alteration in sphincter function as well as sexual function in the long term caused some centres to avoid intervening at S2 [47,48]. Our programme of selective dorsal rhizotomy strictly avoided S2 and we have noted normal sexual function and sphincter function in our patients at skeletal maturity. The proportion of root sectioned varies among series. Dr Peacock advised no more than 50% of the root be sectioned but the trend has emerged for 75% section. In terms of sensory function,

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FIGURE 4.4 Traditional exposure of the cauda equina during selective dorsal rhizotomy.

loss of afferent fibres is often not remarked upon by the patient, but clearly the difference between a 50% and 75% root section is leaving 50% or 25% of the sensory fibres. It is not possible to identify which portions of the root contain cutaneous sensation and which contain joint, fusimotor, and tendon afferent returns. Neurophysiological monitoring during sectioning is standard practice, both to confirm the sensory nature of the root and to triage portions of the root that produce most aberrant spread of motor response after rootlet stimulation. It is generally possible to split roots into 4 or 5 sections, which can subsequently be tested. Identifying the sensory root anatomically is relatively straightforward as it is slightly more mobile than the motor root. The first sacral root is often somewhat homogeneous and a formal motor test is invaluable when sectioning this root, certainly with the cauda equina method. Some debate has centred around whether neurophysiological monitoring is of benefit. It is certainly important to handle rootlets gently, avoiding traction, as this very often leads to erroneous responses. Likewise, repeated testing of rootlets can often result in fatigue and rather variable findings. A degree of proprioceptive loss results from rhizotomy even with 50% root section. Some patients demonstrate features of de-afferentation (Figure 4.5). A particular marker of this is excessive knee flexion in swing phase, as seen on sagittal plane knee kinematic recordings.

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Knee flexion

90

Flex

80 70

Angle (degrees)

60 50 40 30

Ext

20 10 0 –10

0

10

20

30 40 50 60 70 Normalized (percent) Ankle dorsiflexion

80

90

100

0

10

20

30

80

90

100

30 Dors

20 10 0 Angle (degrees)

–10 –20 –30 –40 –50

Plan

–60 –70 –80 –90

40

50

60

70

FIGURE 4.5 Deafferentation following SDR is manifested by exaggerated movement particularly at the knee where excessive flexion occurs in swing phase as a primary abnormality rather than as a coping mechanism for poor clearance (gray band = normal range).

Selective dorsal rhizotomy, when applied to patients with minimal weakness and significant spasticity (a rather exclusive group), will produce a lasting improvement in function, as shown by three-dimensional gait analysis [49]. Antigravity strength equivalent to MRC grade 4 in the hip and knee extensors is needed for sustained successful walking function after SDR.

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The magnitude of the benefit delivered by rhizotomy is in proportion to the extent of the spasticity present, as shown on manual testing using the modified Ashworth scale and the effect on knee kinematics and ankle kinematics and kinetics. Dynamic surface EMG showing prolonged activation throughout the gait cycle provides qualitative support for the presence of spasticity that may benefit from surgical management. Typically, contractures at the hip and ankle improve over 6 months following the surgery, with knee flexion contractures proving more resistant, probably because of the presence of extensor weakness either at the hip or the knee. Where contractures have resolved in children who had been walking in crouch, improvement in inner range strength often takes 12 months of focused strengthening with the hip and knee positioned in extension coupled with accurate orthotic management. The use of ankle-foot orthoses in footwear that is mechanically designed to encourage knee and hip extension in stance facilitates the process of translating an improvement in range of movement into one that can be used as a result of strength developing in that new range. Our experience has been that children with a slow walking speed prior to rhizotomy have a strong tendency to increase in weight, crossing centiles as weight increases more rapidly than growth would require [50]. Presumably, children who walk slowly have a reduced ability to capitalise on their spasticity reduction because of their underlying weakness and, with a reduction in the presumed calorieburning effect of spasticity, convert their excess calories into weight [50]. The reduction in spasticity appears to be permanent and the long-term results of the procedure, again in a carefully selected series, are encouraging [51,52]). 4.6.3.1 Case Study An 8.5-year-old boy with GMFCS 2 bilateral cerebral palsy following a premature birth was noted to have crouch gait with a lack of end stance hip extension. He had bilateral 10° hip flexion contractures with marginally tight hamstrings and knees that extended fully. At the ankle, he could be brought to plantigrade with the knee in extension but during gait was on his toes throughout the gait cycle. He was noted to have good strength, with grade 5 power of hip extension and knee extension. His hips demonstrated high levels of femoral neck anteversion. He underwent a selective dorsal rhizotomy From L1 to S1 at the age of 9 with maximal root section of 40% at S1 and between 20 and 30% root section elsewhere. Post-operatively he had intensive inpatient physiotherapy with ankle-foot orthoses tuned to control the ground reaction vector. During the remainder of childhood, he continued in orthoses and had no orthopaedic surgery. At most recent follow-up 10 years afterwards he was noted to be active, taking part in badminton and other sports. He mentioned that he had lower back pain after sitting for long periods of time but otherwise he was free of any symptoms. Cadence and step length had increased in line with growth, as shown in Table 4.1. Sagittal kinematics at the knee and ankle showed a significant improvement, as shown in Figure 4.6.

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TABLE 4.1 Parameter Changes Pre- and 10 Years Post-SDR

Units Pre-SDR Post-SDR 10 Years Post-SDR

Cadence

Speed

Steps/min 67.2 99.8 124

M/sec 1.18 1.21 1.26

50

Normalised Speed

Stride Length

Normalised Stride Length

Leg Length/sec 1.84 1.27

M 1.06 1.47 1.2

Leg Length 1.66 1.55

Pelvic tilt

90

Ant

Flex

deg

deg

Post

Ext

–10

–10

80

Hip flexion/extension

30

Flex

Dors

deg

deg

Ext

Plan

–20

–90

Knee flexion/extension

Ankle dorsi/plantar

FIGURE 4.6 Sagittal kinematics before and 10 years after SDR (green = right and red = left, dark colors are pre op with gray band indicating normal range).

By reducing spasticity in the hamstrings and quadriceps the position of the knee and the rate of knee flexion in pre-swing are improved respectively. In keeping with other reports of the effect of SDR on gait, pelvic alignment became more sacrum-up. Interestingly, his right ankle kinetics deteriorated in adolescence after his 6-year post-op gait assessment as he abandoned his AFOs and developed some tightness of the right ankle (Figure 4.7).

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2.0

Ankle dors/plan moment

4.7

Dors

Gen

Nm/kg

W/kg

Plan

Abs

–1.0

–3.8

Ankle power

FIGURE 4.7 Ankle kinetics before and 6 years after SDR (green = right and red = left, dark colors are pre op with gray band indicating normal range).

4.7 Conclusion Cerebral palsy produces a complex pattern of histological, physiological, and structural changes in muscles with weakness, shortening, and spasticity. The wide variety of treatments available for contractures and spasticity in cerebral palsy partly relates to the lack of a single target as well as the evolving nature of the condition during growth. Future opportunities for managing the effects of spasticity on the growing child include the use of biological agents to improve muscle strength and increasing understanding of the heterogeneity of receptors within the central nervous system.

References 1. Siegel IM. Historical vignette 9. Little big man: The life and genius of William John Little (1810–1894). Orthop Rev. 1988 Nov;17(11):1156, 1161–1156, 1166. 2. Tan TC, Black PM. The contributions of Otfrid Foerster (1873–1941) to neurology and neurosurgery. Neurosurgery. 2001 Nov;49(5):1231–5; discussion 1235–6. 3. Eyre JA, Taylor JP, Villagra F, Smith M, Miller S. Evidence of activity-dependent withdrawal of corticospinal projections during human development. Neurology. 2001 Nov;57(9):1543–1554. 4. Bax M, Tydeman C, Flodmark O. Clinical and MRI correlates of cerebral palsy: The European Cerebral Palsy Study. JAMA. 2006 Oct;296(13):1602–1608. doi: 10.1001/jama.296.13.1602. 5. Eyre JA. Corticospinal tract development and its plasticity after perinatal injury. Neurosci Biobehav Rev. 2007;31(8):1136–1149. doi: 10.1016/j.neubiorev.2007.05.011.

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6. Kesar TM, Sawaki L, Burdette JH, Cabrera MN, Kolaski K, Smith BP et al. Motor cortical functional geometry in cerebral palsy and its relationship to disability. Clin Neurophysiol. 2012 Jul;123(7):1383–1390. doi: 10.1016/j.clinph.2011.11.005. 7. Sanger TD, Chen D, Fehlings DL, Hallett M, Lang AE, Mink JW et al. Definition and classification of hyperkinetic movements in childhood. Mov Disord. 2010 Aug;25(11):1538–1549. doi: 10.1002/mds.23088. 8. Sanger TD, Delgado MR, Gaebler-Spira D, Hallett M, Mink JW, TFoCMD. Classification and definition of disorders causing hypertonia in childhood. Pediatrics. 2003 Jan;111(1):e89–e97. 9. Feldman AG, Orlovsky GN. The influence of different descending systems on the tonic stretch reflex in the cat. Exp Neurol. 1972;37:481–494. 10. Hägglund G, Wagner P. Development of spasticity with age in a total population of children with cerebral palsy. BMC Musculoskelet Disord. 2008;9:150. doi: 10.1186/1471-2474-9-150. 11. Parkinson KN, Dickinson HO, Arnaud C, Lyons A, Colver AT. Pain in young people aged 13 to 17 years with cerebral palsy: Cross-sectional, multicentre European study. Arch Dis Child. 2013 Jun;98(6):434–440. doi: 10.1136​ /archdischild-2012-303482. 12. Landgraf J, Abetz L, Ware JE.  Child Health Questionnaire (CHQ): A User’s Manual, Second Printing. Boston, MA: HealthAct; 1999. 13. Varni JW.  Book Pediatric Pain Questionnaire – Teen Form.  City: LICENSOR Mapi Research Trust; 1998. Pediatric Pain Questionnaire – Teen Form. 14. Breau LM. Non-communicating children’s pain checklist: Better pain assessment for severely disabled children. Expert Rev Pharmacoecon Outcomes Res. 2003 Jun;3(3):327–339. doi: 10.1586/14737167.3.3.327. 15. Nutt D. GABAA receptors: Subtypes, regional distribution, and function. J Clin Sleep Med. 2006 Apr;2(2):S7–11. 16. Whelan MA, Delgado MR. Practice parameter: Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): Report of the quality standards subcommittee of the american academy of neurology and the practice committee of the child neurology society. Neurology. 2010 Aug;75(7):669. doi: 10.1212/WNL.0b013e3181ec670b. 17. D’Aleo G, Cammaroto S, Rifici C, Marra G, Sessa E, Bramanti P et al. Hallucinations after abrupt withdrawal of oral and intrathecal baclofen. Funct Neurol. 2007;22(2):81–88. 18. Milla PJ, Jackson AD. A controlled trial of baclofen in children with cerebral palsy. J Int Med Res. 1977;5(6):398–404. 19. Bradley LJ, Kirker SGB. Pregabalin in the treatment of spasticity: A retrospective case series. Disabil Rehabil. 2008;30(16):1230–1232. doi: 10.1080/09638280701602392. 20. Formica A, Verger K, Sol JM, Morralla C. Gabapentin for spasticity: A randomized, double-blind, placebo-controlled trial. Med Clin (Barc). 2005 Jan;​ 124(3):81–85. 21. Krach LE. Pharmacotherapy of spasticity: Oral medications and intrathecal baclofen. J Child Neurol. 2001 Jan;16(1):31–36. 22. Cosgrove AP, Corry IS, Graham HK. Botulinum toxin in the management of the lower limb in cerebral palsy. Dev Med Child Neurol. 1994 May;36(5):386–396. 23. Boyd RN, Hays RM. Outcome measurement of effectiveness of botulinum toxin type A in children with cerebral palsy: An ICIDH-2 approach. Eur J Neurol. 2001 Nov;8 Suppl 5:167–177.

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24. Kay RM, Rethlefsen SA, Fern-Buneo A, Wren TAL, Skaggs DL. Botulinum toxin as an adjunct to serial casting treatment in children with cerebral palsy. J Bone Joint Surg Am. 2004 Nov;86–A(11):2377–2384. 25. Ackman JD, Russman BS, Thomas SS, Buckon CE, Sussman MD, Masso P et al. Comparing botulinum toxin A with casting for treatment of dynamic equinus in children with cerebral palsy. Dev Med Child Neurol. 2005 Sep;47(9):620–627. 26. Molenaers G, Desloovere K, Cat JD, Jonkers I, Borre LD, Pauwels P et al. Single event multilevel botulinum toxin type A treatment and surgery: Similarities and differences. Eur J Neurol. 2001 Nov;8 Suppl 5:88–97. 27. Farmer SE, James M. Contractures in orthopaedic and neurological conditions: A review of causes and treatment. Disabil Rehabil. 2001 Sep;23(13):549–558. 28. Williams PE, Goldspink G. The effect of immobilization on the longitudinal growth of striated muscle fibres. J Anat. 1973 Oct;116(Pt 1):45–55. 29. Furia JP, Buck Willis F, Shanmugam R, Curran SA. Systematic review of contracture reduction in the lower extremity with dynamic splinting. Adv Ther. 2013 Aug;30(8):763–70. doi: 10.1007/s12325-013-0052-1. Epub Sep 10, 2013. 30. McNee AE, Gough M, Morrissey MC, Shortland AP. Increases in muscle volume after plantarflexor strength training in children with spastic cerebral palsy. Dev Med Child Neurol. 2009 Jun;51(6):429–435. doi: 10.1111/j.1469-8749.2008.03230.x. 31. Miller GJ, Light KE. Strength training in spastic hemiparesis: Should it be avoided? NeuroRehabilitation. 1997;9(1):17–28. doi: 10.3233/NRE-1997-9103. 32. Smith LR, Lee KS, Ward SR, Chambers HG, Lieber RL. Hamstring contractures in children with spastic cerebral palsy result from a stiffer extracellular matrix and increased in vivo sarcomere length. J Physiol. 2011 May;589(Pt 10):2625– 2639. doi: 10.1113/jphysiol.2010.203364. 33. Stackhouse SK, Binder-Macleod SA, Lee SCK. Voluntary muscle activation, contractile properties, and fatigability in children with and without cerebral palsy. Muscle Nerve. 2005 May;31(5):594–601. doi: 10.1002/mus.20302. 34. Decq P, Filipetti P, Cubillos A, Slavov V, Lefaucheur JP, Nguyen JP. Soleus neurotomy for treatment of the spastic equinus foot. Groupe d’Evaluation et de Traitement de la Spasticité et de la Dystonie. Neurosurgery. 2000 Nov;47(5):1154– 60; discussion 1160–1. 35. Hong Mu X, Xu L, gang Xu S, Cao X, Zhang P, Ying Zheng C et al. Treatment of equinovarus caused by cerebral palsy with neurotomy of muscular branch of tibial nerve. Zhongguo Gu Shang. 2009 Jan;22(1):31–32. 36. Bollens B, Gustin T, Stoquart G, Detrembleur C, Lejeune T, Deltombe T. A randomized controlled trial of selective neurotomy versus botulinum toxin for spastic equinovarus foot after stroke. Neurorehabil Neural Repair. 2013 Oct;27(8):695–703. doi: 10.1177/1545968313491002. 37. Samson-Fang LJ, Stevenson RD. Identification of malnutrition in children with cerebral palsy: Poor performance of weight-for-height centiles. Dev Med Child Neurol. 2000 Mar;42(3):162–168. 38. Meythaler JM, Roper JF, Brunner RC. Cyproheptadine for intrathecal baclofen withdrawal. Arch Phys Med Rehabil. 2003 May;84(5):638–642. 39. Yeh RN, Nypaver MM, Deegan TJ, Ayyangar R. Baclofen toxicity in an 8-yearold with an intrathecal baclofen pump. J Emerg Med. 2004 Feb;26(2):163–167. doi: 10.1016/j.jemermed.2003.07.009.

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40. Darbari FP, Melvin JJ, Piatt JH, Adirim TA, Kothare SV. Intrathecal baclofen overdose followed by withdrawal: Clinical and EEG features. Pediatr Neurol. 2005 Nov;33(5):373–377. doi: 10.1016/j.pediatrneurol.2005.05.017. 41. Leary SM, Gilpin P, Lockley L, Rodriguez L, Jarrett L, Stevenson VL. Intrathecal baclofen therapy improves functional intelligibility of speech in cerebral palsy. Clin Rehabil. 2006 Mar;20(3):228–231. 42. Albright AL, Barry MJ, Shafton DH, Ferson SS. Intrathecal baclofen for generalized dystonia. Dev Med Child Neurol. 2001 Oct;43(10):652–657. 43. Saulino M, Guillemette S, Leier J, Hinnenthal J. Medical Cost Impact of Intrathecal Baclofen Therapy for Severe Spasticity. Neuromodulation. 2014 Aug. doi: 10.1111/ner.12220. 44. Fasano VA, Barolat-Romana G, Ivaldi A, Sguazzi A. Functional posterior radiculotomy, in the treatment of cerebral spasticity. peroperative electric stimulation of posterior roots and its use in the choice of the roots to be sectioned. Neurochirurgie. 1976;22(1):23–34. 45. Peacock WJ, Eastman RW. The neurosurgical management of spasticity. S Afr Med J. 1981 Nov;60(22):849–850. 46. Park TS, Gaffney PE, Kaufman BA, Molleston MC. Selective lumbosacral dorsal rhizotomy immediately caudal to the conus medullaris for cerebral palsy spasticity. Neurosurgery. 1993 Nov;33(5):929–33; discussion 933–4. 47. Lang FF, Deletis V, Cohen HW, Velasquez L, Abbott R. Inclusion of the S2 dorsal rootlets in functional posterior rhizotomy for spasticity in children with cerebral palsy. Neurosurgery. 1994 May;34(5):847–53; discussion 853. 48. Huang JC, Deletis V, Vodusek DB, Abbott R. Preservation of pudendal afferents in sacral rhizotomies. Neurosurgery. 1997 Aug;41(2):411–415. 49. Cole GF, Farmer SE, Roberts A, Stewart C, Patrick JH. Selective dorsal rhizotomy for children with cerebral palsy: The Oswestry experience. Arch Dis Child. 2007 Sep;92(9):781–785. doi: 10.1136/adc.2006.111559. 50. Roberts A, Stewart C, Cole G, Farmer S, Patrick J. Energy consumption in spasticity. Dev Med Child Neurol. 2002 Apr;44(4):284. 51. Langerak NG, Tam N, Vaughan CL, Fieggen AG, Schwartz MH. Gait status 17–26 years after selective dorsal rhizotomy. Gait Posture. 2012 Feb;35(2):244–249. doi: 10.1016/j.gaitpost.2011.09.014. 52. McFall J, Stewart C, Kidgell V, Jarvis NPS, Freeman R, Roberts A. Changes in gait which occur before and during the adolescent growth spurt in children treated by selective dorsal rhizotomy. Gait Posture. 2015 June electronic publication.

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5 Clinical Management of Spasticity and Contractures in Stroke Judith F. M. Fleuren, Jaap H. Buurke and Alexander C. H. Geurts CONTENTS 5.1 Introduction................................................................................................. 101 5.2 Pathophysiology of Spasticity after Stroke.............................................. 102 5.3 Motor Recovery and Motor Control after Stroke................................... 105 5.4 The Role of Spasticity in the Control of Posture and Gait.................... 108 5.4.1 Muscle Overactivity during the Stance Phase............................ 111 5.4.2 Muscle Overactivity during the Swing Phase............................ 113 5.5 The Role of Spasticity in Arm and Hand Function............................... 115 5.5.1 Spasticity in Patients with a Severely Affected Upper Limb (UAT 0–1)............................................................................... 117 5.5.2 Spasticity in Patients with a Moderately Affected Upper Limb (UAT 2–3)............................................................................... 117 5.5.3 Spasticity in Patients with a Mildly Affected Upper Limb (UAT 4–7)......................................................................................... 118 5.6 Assessment of Spasticity in Stroke Patients............................................ 118 5.6.1 Assessment of Spasticity: Body Function and Structure.......... 119 5.6.2 Assessment of Spasticity: Activity and Participation................ 121 5.7 Management of Spasticity after Stroke.................................................... 122 5.7.1 Noninvasive Methods.................................................................... 123 5.7.2 Invasive, Reversible Methods........................................................ 124 5.7.3 Invasive, Permanent Methods....................................................... 126 5.7.4 Management Strategy for Stroke Patients with Spasticity........ 128 References.............................................................................................................. 128

5.1 Introduction Stroke, or cerebrovascular accident, is an acquired brain injury due to an acute disturbance of blood supply to the brain, leading to ischemia. Blood flow interruption can be caused by thrombotic or embolic occlusion (ischemic stroke) or by rupture of a cerebral artery (hemorrhagic stroke). Approximately 110,000 strokes occur in England every year and 800,000 in 101

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the United States of America (National Audit Office, 2010; Mozzafarian et al., 2015). It is one of the top five causes of death and the largest cause of adult disability in Western countries. The World Health Organization has predicted that disability-adjusted life years (DALYs) lost to stroke will rise from 38 million in 1990 to 61 million in 2020 (WHO, 2004). Spasticity after stroke is relatively common. A number of clinical studies have been performed in the last decade, presenting prevalence figures between 4 and 46% (Watkins et al., 2002; Sommerfeld et al., 2012; Wissel et al., 2013; Opheim et al., 2014). The outcomes depend on the used definition of spasticity, the measurement methods, the time after stroke, and the population studied. Most studies included patients with a first-time stroke and spasticity was defined as 1 point or higher on the Modified Ashworth Scale (MAS). Watkins et al. (2002) also included patients with recurrent stroke and used two measurement scales for spasticity, the MAS and the Tone Assessment Scale. The Tone Assessment Scale is a broader scale assessing resistance in response to passive movement at more joints and including the constructs “posturing at rest” and “associated reactions” as well. The prevalence of spasticity found in this study, 38% measured 12 months after the onset in a general stroke population, may still be an underestimate, given the methods of measurement and definition used. In the field of Rehabilitation Medicine spasticity is an important topic. Not the presence of spasticity per se, but the impact of spasticity on daily life, requires attention in affected individuals. Although some beneficial effects of spasticity have been reported in the literature (Mahoney et al., 2007), the presence of post-stroke spasticity is generally associated with negative consequences. Patients report sensations of stiffness, heaviness, or pain in the affected limb. Spasms or cramp-like sensations are common, e.g., during the night. Limb deformities or skin lesions might develop and spasticity can increase carer burden, due to problems in moving, handling, and positioning in routine daily care. In addition, spasticity can decrease the functional ability of the affected limb. From the literature, it can be estimated that in the group of chronic stroke patients with spasticity, 20–30% will have disabling spasticity, for which treatment is needed (Lundström et al., 2008).

5.2 Pathophysiology of Spasticity after Stroke The pathophysiology of spasticity is discussed in Chapter 2 and its potential impact on function in Chapter 3. In cerebral lesions, pathological increase in muscle activity is explained by the loss of supraspinal control on spinal reflex activity, which is mainly controlled in the brain stem. For the maintenance of normal muscle activity, muscle spindles have a key role, transmitting

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signals regarding muscle length and rate of change in muscle length via group Ia and group II sensory fibres. Sensitivity of the muscle spindles’ dynamic and static responsiveness is under central control, exerted through alpha and gamma motoneuron coactivation. Together with the Golgi tendon organs, which supply feedback to the central nervous system on changes in muscle-generated and applied tension via type Ib afferents, muscle proprioceptive afferent feedback participates in shaping muscle activity patterns. Interneurons integrate multi-sensory afferent information through excitatory Ia and inhibitory Ib pathways from a variety of muscles. They receive a wide range of inputs from several different sources, both peripheral and central (supraspinal), and each interneuron forms widespread synapses with both homonymous and heteronymous alpha motoneurons. As a consequence, spinal cord reflex responses are highly adaptable and shaped by the convergence of inputs that inform on proprioceptive and exteroceptive conditions. Spasticity is probably the result of an imbalance of inputs from central motor pathways, such as the (cortico-)reticulospinal and other descending pathways, to the interneuronal circuits of the spinal cord. Via corticobulbar tracts, motor areas of the cortex project on the ventromedial reticular formation, the brain stem area where sensory information is being processed (Sheean, 2002). The main supraspinal inhibitory tract arising from the ventromedial reticular formation is the lateral reticulospinal tract, which runs very close to the lateral corticospinal (pyramidal) tract with overlap of their spinal targets (Lemon, 2008). The lateral reticulospinal tract is under facilitatory control of corticobulbar tracts, thereby augmenting the inhibitory drive to the upper and lower limbs in healthy subjects. The main excitatory pathway, also arising in the brainstem, is the medial reticulospinal tract, which facilitates the maintenance of anti-gravity tone in muscles situated around the longitudinal axis of the body. The medial reticulospinal system is, however, not under cortical control. Damage to the corticobulbar fibres – in the cortex or lower down the tract – will thus primarily lead to decreased facilitation of inhibition of limb reflexes at brain stem level. Consequently, (sub) cortical lesions involving the corticobulbar tracts give rise to a net loss of inhibitory control at brain stem level, leading to increased alpha motoneuron excitability at the cervical and lumbar spinal cord levels and, subsequently, increase in limb muscle tone. The overall clinical picture of motor symptoms after stroke depends on the location and extent of the lesion. Whether spasticity will appear and to what extent is hard to predict, although generally it is more often present in patients with severe paresis. Probably associated, spasticity is found to be more common and more severe in the upper than in the lower limbs (Sommerfeld et al., 2012). If present, spasticity usually appears in the first few days to weeks after the cerebral damage, possibly related to the dissolving diaschisis at cerebral level and a process of plastic rearrangement of interneurons at brainstem and spinal levels.

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After stroke, common patterns of motor dysfunction can be recognised (Mayer et al., 1997), given the fact that the middle cerebral artery territory is the most frequently affected site. In the upper limb, the typical distribution of potentially affected muscle groups includes the shoulder adductors, shoulder internal rotators, elbow flexors, forearm pronators, wrist flexors, finger flexors, thumb flexors, and thumb adductor. In the lower limb the hip flexors, thigh adductors, knee flexors and extensors, ankle plantar flexors, ankle invertors, and toe flexors are often involved. Affected muscles, both paretic and/or spastic, often follow a so-called anti-gravity distribution, a term used for muscle groups that help to maintain trunk and head posture by counteracting gravity. There is an increased appearance of stereotyped multi-joint movement patterns (“pathological limb synergies”) and decreased ability to uncouple these. It is sometimes considered a regression to phylogenetically older movement patterns, based on limb synergies and primitive reflexes, arising from more basic systems in the brainstem, basal ganglia, and cerebellum. Stereotyped movement patterns can be observed in abnormal posture at rest (Kline et al., 2007), but also as “rigid patterns” during active movement. There are indications that the lower motor networks originating from the brainstem have more diffuse projections onto alpha motoneurons at the spinal level, explaining the less-selective activation and abnormal co-contractions of muscle groups (Dewald et al., 1995). It is very likely that the above-mentioned lateral reticulospinal tracts play an important role in subserving these stereotyped movement patterns in an attempt to compensate for the loss of direct corticospinal connections to the cervical and lumbar motor neuron pools. For example, strengthening of the normally weak activation of hand muscles by the reticulospinal tract could lead to a certain degree of functional recovery (Baker, 2011). As such, “spastic” muscular overactivity may be a useful functional compensation rather than a phenomenon that must be eliminated (van Kordelaar et al., 2012). Both positive motor symptoms, i.e., the increased (stretch) reflex activity in the antigravity muscles (afferent-mediated) and the more pronounced presence of rigid synergy patterns (efferent-driven) co-exist post stroke and therefore are hard to disentangle in clinical practice. Strictly following the umbrella definition for spasticity used in this book, the efferent-driven rigid synergy patterns are not included, which complicates the assessment of whether “true” spasticity is present. However, in clinical practice the exact pathophysiology and semantics with regard to the definition seem to be less relevant, because the clinical focus is primarily on whether treatment for “muscle overactivity” is required and – if yes – on its goal. In both cases, careful reflection on the negative impact versus the positive contribution of “muscle overactivity” is needed. In case treatment is indicated, therapeutic options do not basically differ between the two. Other clinical phenomena such as clonus, flexor and extensor spasms can also be included in the used definition (see Chapter 1). Clonus, which may

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be the presentation of intrinsic oscillating spinal neuronal networks (after chronic loss of supraspinal input and diminution of load-related sensory input [Beres-Jones et al., 2003]), is frequently observed in stroke patients, mainly in the ankle plantar flexors, but sometimes in other muscle groups as well (wrist flexors, finger flexors). Typical flexor and extensor spasms, as observed, for example, in spinal cord-injured patients, are less common after stroke. The multi-joint flexor or extensor reactions seen after stroke are probably related to manifestations of pathological limb synergies and primitive reflexes. However, overlap in pathophysiology is unclear. Early after a cerebral lesion, changes in mechanical, visco-elastic properties of muscle fibres and other soft tissues occur as a result of paresis and immobility. Histological transformations in the muscles, such as muscle fibre atrophy and loss of sarcomeres, have been shown to contribute to muscle stiffness, leading to increased tension development upon passive muscle lengthening and enhanced reflex sensitivity (Dietz, 2000; O’Dwyer et al., 1996; Gracies, 2005 [I]). Accumulation of intramuscular connective tissue, increased fat content, and degenerative changes at the musculotendinous junction also cause reduced muscle compliance. Structural alterations in other soft tissues, including joints, ligaments, vessels, and skin, also contribute to reduced range of motion (see Chapter 1).

5.3 Motor Recovery and Motor Control after Stroke In the first weeks after stroke, neurological recovery shows a nonlinear pattern. Early improvements in functioning are assumed to reflect intrinsic recovery processes such as restitution of penumbral tissue, dissolving diaschisis, and reorganisation of cortical and cortico-spinal neurons (Kwakkel et al., 2004; van Kordelaar et al., 2014). The degree of recovery after stroke is largely defined within the first days after stroke onset. The extent of improvement observed in the first days or weeks post-stroke and the initial severity of disability are important indicators of the outcome at 6 months after stroke. In patients with first-ever ischemic anterior or middle cerebral artery strokes, motor recovery is almost completed within 4 to 10 weeks (Kwakkel et al., 2006; van Kordelaar et al., 2014), independent of the severity of the initial stroke. Theoretically, enhanced neuroplasticity could also allow for faster learning of compensatory strategies while performing tasks during this time window. In terms of functional recovery, most patients reach a plateau 3 to 6 months after onset (Kwakkel and Kollen, 2013). Restoration of motor function tends to follow a stepwise sequence up to the degree of recovery that an individual patient can reach (Twitchell, 1951; Brunnstrom, 1970). Areflexic flaccid paresis or paralysis is followed by return of reflexes, increase in muscle activity, and development of spasticity.

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Stages

Description

Stage 1

Flaccidity is present and no movements of the limbs can be initiated. The basic limb synergies or some of their components may appear as associated reactions or minimal voluntary movement responses may be present. Spasticity begins to develop. The patient gains voluntary control of the movement synergies, although full range of all synergy components doest not necessarily develop. Spasticity is severe. Some movement combinations that do not follow the synergies are mastered and spasticity begins to decline. More difficult movement combinations are possible as the basic limb synergies lose their dominance over motor acts. Spasticity disappears and individual joint movements become possible.

Stage 2

Stage 3 Stage 4 Stage 5 Stage 6

FIGURE 5.1 Brunnstrom stages. (With permission from Brunnstrom, S [1970]. Movement Therapy in Hemiplegia: A Neurophysiological Approach. New York: Harper & Row.)

Subsequently, voluntary movements can appear as part of rigid flexion and/ or extension synergies, followed by movements outside such synergies, to the final stage, in which muscle activation is normalised and occurrence of normal movement is possible (Figure 5.1). For many stroke patients, regaining independent gait is an important goal in the rehabilitation process. In general, the prognosis for regaining some lower limb function after middle cerebral artery stroke is fairly good. At 6  months post-stroke, 60 to 80% of all surviving patients are able to walk independently, yet with very different levels of ambulation (Perry et al., 1995) and, in association, notable weight-bearing asymmetry (Buurke et al., 2005; Kamphuis et al., 2012). A number of studies have shown that not only the muscle strength of the hemiparetic leg, but particularly the compensatory ability of the unaffected leg, is significantly associated with achieving independent gait. Although it used to be common practice to pursue returning to “normal” motor behavior in rehabilitation training after stroke, it has become clear in the last decade that movement patterns on the affected side are characterised by more or less fixed synergies observable early after stroke, especially in relatively severely affected patients. Balance and gait recovery in these patients is closely related to learning compensatory movement strategies (de Haart et al., 2004; Buurke et al., 2005; Den Otter et al., 2006; Buurke et al., 2008). For the upper limb, the prognosis after middle cerebral artery stroke is much less favorable. Prospective cohort studies suggest that 33 to 66% of stroke patients with an initially paralytic upper limb do not show any recovery in upper limb function 6 months after stroke. Depending on which

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outcome measure was used, 5 to 20% of these patients achieve full recovery of the upper limb at 6 months (Kwakkel and Kollen, 2013). It was found that only patients with some movement in the upper limb within 4 weeks post-stroke had a 94% chance to improve their Action Research Arm Test (ARAT) scores at 6 months post-stroke (Kwakkel et al., 2003). The presence of shoulder abduction and voluntary finger extension within 3 days after stroke appeared to be essential for regaining some dexterity: patients with some finger extension and shoulder abduction at day 2 after stroke onset had a 98% probability of achieving an ARAT-score ≥ 10 at 6 months. Patients without this voluntary motor control had a probability of only 25%. Sixty percent of the patients with some finger extension within the first three days reached maximum scores on the ARAT at 6 months (Nijland et al., 2010). Spasticity is just one component in disordered motor function after stroke. Careful assessment of all signs and symptoms that might contribute to impaired motor function in the individual patient with stroke is essential to understand the full clinical picture and selecting the appropriate intervention. Movement dysfunction after stroke arises from a complex interaction between “negative” motor features (such as paresis, fatigability, and slowness), “positive” motor features (reflex hyperexcitability, emergence of primitive reflexes, and spasticity), and changes in the mechanical properties of muscles and other soft tissues. The decreased voluntary motor unit recruitment to generate muscle force on the one hand and the increased involuntary motor unit recruitment on the other hand, in varying combinations and to differing extents, lead to less fluent and less effective motor output (Gracies, 2005 [II]). Impairment of selective muscle control might be misinterpreted as simple weakness, but it is primarily characterised by inadequate timing and selective activation of individual muscles. This loss of control is usually more severe distally than proximally, related to the high dependency of the distal limbs on direct corticospinal tracts. More “primitive” locomotor patterns commonly become a substitute source of control. As a result, smooth movement patterns are limited due to the inability to modulate direction, speed, and intensity of movements. As pointed out earlier, changes in mechanical properties of the muscles and other soft tissues lead to reduced tissue compliance and secondarily increased reflex sensitivity, thereby contributing to inadequate motor control. Besides motor symptoms, sensory and cognitive functions play an important role in normal motor control as well. Purposeful action is possible because movement control is continuously supported by an ongoing stream of sensory information. Proprioceptive feedback is needed for fast adjustments of ongoing movements (feedback control), but also for long-term maintenance of internal body representation, on which anticipatory movements can be programmed (feedforward control). Thus, somatosensory impairments may underlie disturbances in both feedback-mediated and feedforward-mediated motor processes. Cognitive dysfunctions, such as disturbed visuospatial perception or apraxia, can also hinder performance of a

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motor task. Other psychological factors associated with confidence, such as fear of falling, may also have a negative impact on motor performance.

5.4 The Role of Spasticity in the Control of Posture and Gait Postural control, i.e., maintaining posture under different circumstances, is achieved by different strategies. It is influenced by motor, sensory, and cognitive processes, which can be disturbed after stroke. Posture must be controlled in both static and dynamic situations. While sitting or standing still, adequate trunk control is demanded when support or assistance is absent. Adequate trunk control is required to perform activities of daily living. Numerous studies have shown that trunk control, or sitting balance, at an early stage after stroke, can predict outcomes for activities of daily living at a later stage (e.g., Hsieh et al., 2002). Decreased trunk control can lead to problems with positioning in a chair or in bed. Paresis, sensation loss, disturbed body orientation in space, and/or visuospatial neglect are primarily responsible. During voluntary movement, the postural balance is continuously adapting to perturbations. Knowledge of these perturbations is integrated into motor programmes and used in anticipatory motor planning (feed-forward). These responses are refined or learned throughout life and eventually operate automatically. Postural readjustment on unexpected perturbations is based on stereotyped response patterns. Some of these are innate, but others have to be acquired by motor learning, dependent on feedback of visual, vestibular, and somatosensory information (Kandel et al., 2000). In healthy adults, routine walking is considered an automatic and rhythmic motor act that does not require a high level of conscious effort or attention. There is evidence from many vertebrate species and humans that the basic locomotor patterns are generated in the spinal cord. These networks, called central pattern generators (CPGs), are considered to play a key role in regulating both the pattern, magnitude, and timing of muscle activations that make up the gait cycle (Duysens et al., 1998; Kandel et al., 2000; Kiehn et  al., 2010). In addition, these networks utilise proprioceptive feedback related to limb posture, loading, and foot contact in order to refine and tune the step cycle to prevailing conditions and preserve postural integrity. Close interaction with the reflex networks and supraspinal descending control mechanisms (cortical and sub-cortical) further refine walking patterns and assist in the initiation and cessation of stepping, obstacle avoidance, and changes in direction and speed. A large part of the stroke population regains walking capacity (Functional Ambulation Categories ≥ 3). However, postural control often remains compromised, resulting in a higher incidence of falls and a great impact on

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independence in activities of daily living and gait (Kamphuis et al., 2013). Unsupported standing requires more motor skill of the hemiparetic patient. Weight-bearing asymmetry, in favor of the non-paretic leg, and increased postural sway are characteristic in these patients (Geurts et al., 2005). Training of weight-bearing symmetry used to be main focus in balance rehabilitation. As pointed out earlier, evidence for the assumption that restoration of more symmetrical weight distribution leads to improved postural stability after stroke is lacking. In fact, weight-bearing asymmetry has recently been suggested to be a compensatory strategy, for instance, to enhance the kinetic contribution of the non-paretic leg to balance in quiet standing (Kamphuis et al., 2013), rather than being the cause of postural instability. Another theory suggests that weight-bearing asymmetry compensates for the contra­ lesional tilt of the postural and visual vertical by adjustment of body posture via increased loading of the ipsilesional side (Barra et al., 2009). The decreased ability to stabilise the distal segments of the paretic lower limb is the main contributing factor to the postural instability in stance. Although the role of spasticity in maintaining standing posture might not be principal, spasticity can threaten stability biomechanically, as a result of dysfunctional joint posture due to the muscular imbalance, particularly at the level of the affected ankle and foot. The walking pattern after stroke shows typical abnormalities, both clinically and electromyographically, which is directly reflected in a decrease in walking velocity. Clinically, hemiplegic gait is typically characterised by the affected leg in extension, sometimes with circumduction in swing phase, and equinovarus deformity of the foot. Muscle activation patterns in the leg during gait, measured with surface electromyography, show large differences in timing compared with healthy persons, but appear not to change significantly in time after stroke (Den Otter et al., 2006; Buurke et al., 2008). Although large inter-individual differences are found, some common characteristics can be observed in the timing of muscle activity associated with hemiparetic gait. Increased muscle activity is observed in several muscle groups, but is not necessarily problematic. Conversely, increased co-­activation might be a valuable compensation strategy to enhance stability of the affected, but also of the unaffected, limb. This theory is illustrated by two studies, in which increased co-activation was found in the upper and lower leg muscles during stance phase (Den Otter et al., 2007; Buurke et al., 2008). Den Otter et al. (2007) found increased co-activation of biceps femoris and rectus femoris in the affected leg during single support phase and the first double support phase. In the lower leg, longer total durations of gastrocnemius activity were found during the first double support phase. In the tibialis anterior, longer durations of activity were observed during swing phase, whereas smaller total durations of activity were found during single support. Remarkably, similar patterns were found for the non-affected leg, except for the mean total duration of tibialis anterior activity during the first double stance phase of the paretic leg (Figure 5.2).

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*

1

0

DS1

Rectus femoris

*

SS

Proportion of time active

Proportion of time active

Biceps femoris

DS2

SW

0

0

*

DS1

*

*

SS

DS2

DS1

*

SS

DS2

SW

Gastroenemius medialis

SW

Proportion of time active

Proportion of time active

Tibialis anterior 1

*

1

1

0

Control Unaffected log Affected log

*

DS1

SS

DS2

SW

FIGURE 5.2 Mean (+SD) duration of muscle activity of Biceps femoris (top-left panel), Rectus femoris (topright panel), Tibialis anterior (bottom-left panel), and Gastrocnemius medialis (bottom-right panel), for each of the four subphases of the gait cycle (DS1, first double support phase; SS, single support phase; DS2, second double support phase; SW, swing phase). (With permission from Den Otter AR, Geurts AC, Mulder T, Duysens J. Abnormalities in the temporal patterning of lower extremity muscle activity in hemiparetic gait. Gait Posture. 2007 Mar;25[3]:342–52.)

Compensation strategies for decreased stability in the trunk and affected upper leg were also suggested in the study of Buurke et al. (2008), in which delayed “off”-times in erector spinae, gluteal muscles, rectus femoris, vastus lateralis, and semitendinosus were found on the affected side. In this study, the unaffected leg showed abnormalities as well, of which the extra burst in semitendinosus during stance was most prominent (Figure 5.3). This was explained as compensation strategy for the diminished push-off of the affected leg, causing extension of the unaffected hip, thereby facilitating the swing of the affected leg. Compensation strategies for decreased stability in the trunk were also suggested, as delayed “off”-times in erector spinae and gluteal muscles were found on the affected side. Both studies illustrate that increased muscle activity does not necessarily indicate “problematic spasticity”. Only when muscle activity timing errors interfere with one of the prerequisites of gait (in particular stability in stance phase, foot clearance in swing phase, and/or prepositioning of the foot for initial contact) (Gage, 1993), risk of falling increases and treatment must be considered.

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Semitendinosus (unaffected side)

Week 3

50 0 50

Week 6

0 Week 9 50 0 Week 12 50 0 Week 24

50 0

0

% of gait cycle

100

FIGURE 5.3 The extra and consistent burst of the semitendinosus muscle of the unaffected leg during stance, measured at 3, 6, 9, 12 and 24 weeks post-stroke. Along the y-axis the amplitude of the normalised smooth rectified EMG (SRE) in microvolts is presented. The x-axis shows the normalised time of the stride. The horizontal black bars represent the windows from median on to median off times. The smaller gray bars indicate the 25 and 75 percentiles of the median on and off times. (From Buurke et al., 2008.)

5.4.1 Muscle Overactivity during the Stance Phase Stability is the main prerequisite of gait during the stance phase. Decreased stability in stance usually leads to reduction of step length and reduced walking velocity. A frequently observed clinical characteristic is equinovarus of the ankle and foot, a functional deformity leading to inadequate ankle control. In the sagittal plane, excessive plantar flexion is a result of paresis of dorsal flexors in combination with involuntary muscle activity of the plantar flexors. During stance phase, soleus and/or gastrocnemius

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(a)

(b) FIGURE 5.4 Stroke patient with clonus of gastrocnemius (a) and soleus (b) in stance phase of the left leg.

overactivity can lead to persistent ankle plantar flexion and to disabling anterior-posterior instability (Figure 5.4). The ankle rocker is decreased and the torque to reach the forefoot rocker is increased, usually leading to a higher knee extension torque (the so-called “ankle plantar flexion knee extension couple”). In the coronal plane, muscular imbalance between evertors and invertors is often seen. When activity of the lateral foot elevators, i.e., the long toe extensors and peroneus tertius, is decreased during swing phase, excessive varus of the hindfoot will occur (Perry and Burnfield, 2010). In mild cases, a slight (lateral) foot clearance deficit occurs during swing and initial contact is made at the lateral side of the foot, but a fast return to

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plantigrade support is seen during the loading response. In these cases, the anterior tibialis muscle is activated based on selective control or as part of a flexor synergy. Extensor muscle synergy takes over as soon as weight is loaded onto the affected foot, leading to tibialis anterior relaxation. In more severe cases, varus may persist throughout the stance phase as a result of prolonged anterior tibialis activity, which is often accompanied by (excessive) posterior tibialis muscle activity. When the  dysfunctional  equinovarus posture persists during the stance phase, the supporting surface of the foot will decrease, by increased loading of the forefoot and/or lateral foot, thereby decreasing stability in stance. When more proximal control (knee extension, hip extension) is reduced as well, stance stability, step length, and walking velocity are compromised even more. As a result, these patients experience an increased risk of falling and are frequently unable to walk either unassisted or without orthotic devices (Weerdensteyn et al., 2008). Other types of muscle overactivity that might emerge during stance phase include extensor hallucis longus muscle overactivity, leading to hyper­ extension of the hallux (“striatal toe”), which may interfere with comfort of footwear. Inappropriate activity of intrinsic foot muscles and long toe flexors may result in painful forefoot and toe flexion and difficulty with the forefoot rocker. 5.4.2 Muscle Overactivity during the Swing Phase In the swing phase, equinovarus of the ankle interferes with foot clearance and with appropriate prepositioning of the foot for initial contact and loading (Renzenbrink et al., 2012). In the sagittal plane, paresis of ankle dorsiflexors is the most prominent cause. It can be aggravated by pathological activity of the plantar flexor muscles (Figure 5.5). In the coronal plane, paresis of the lateral foot elevators and overactivity of the invertors constitute the main cause of the varus deformity. Adequate foot clearance can also be at risk due to “stiff knee gait,” the phenomenon of reduced knee flexion in early swing. Normal peak knee flexion in this phase is 60–65 degrees and is induced by ankle plantar flexion force during push-off in pre-swing, in combination with hip flexion. Knee extensor muscles are normally relaxed in early swing, although rectus femoris has a short period of action during stance to swing transition (Nene et al., 2004). An exact definition of stiff knee gait for stroke patients is not available. For children with cerebral palsy a cut-off value below 45 degrees of peak knee flexion or a delayed knee peak flexion is generally used (Sutherland and Davids, 1993). Whether overactivity of rectus femoris or pathological activity

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FIGURE 5.5 Stroke patient with premature soleus activity contributing to disturbed prepositioning of the left foot in terminal swing.

of vastus muscles is the underlying cause should be assessed with surface electromyography (Figure 5.6). In almost all cases decreased plantar flexion power is an important contributing factor. Sometimes the extensor hallucis longus shows overactivity during the swing phase as well. This can be a part of the dystonic “striatal toe” phenomenon. However, when the overactivity is restricted to the swing phase and shows a phasic pattern, it is much more likely a compensation for reduced tibialis anterior muscle strength.

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FIGURE 5.6 Stroke patient with stiff knee gait. Rectus femoris muscle (yellow) is (over)active during initial/ mid-swing phase.

5.5 The Role of Spasticity in Arm and Hand Function After stroke, upper extremity weakness is the most common impairment, occurring in about 80% of patients (Langhorne et al., 2009). Only 5 to 20% fully recover (Nakayama et al., 1994; Kwakkel and Kollen, 2013). It was found that the prevalence of spasticity in the upper limb one year after stroke, in a group of patients with initially impaired upper limb function, was 46% (Opheim et al., 2014).The severity of spasticity, measured with the Modified Ashworth Scale, increased during the first year. Presence of spasticity after 1 year was associated with poorer sensorimotor function, more pain, reduced range of motion, and reduced sensibility.

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In the upper limb spasticity rarely has functional benefit. To describe the role of spasticity and the degree of additional disability due to spasticity, post-stroke arm-hand function can be subdivided into three groups, based on the Utrecht Arm/Hand Test (UAT), an ordinal measurement scale. The UAT is a bedside 8-point scale for the evaluation of upper extremity impairment after stroke (Kruitwagen-van Reenen et al., 2009), based on the recovery stages according to Twitchell (1951) (Figure 5.7):

1. UAT 0-1: severely affected, no arm-hand function. 2. UAT 2-3: moderately affected, some arm-hand function. 3. UAT 4-7: mildly affected, useful arm-hand function. Score 0: A-functional arm. Observation: Shoulder movement only exists through movement of the torso; retraction/elevation of the shoulder is not possible. Score 1: Flexion-synergy of the arm. Observation: In an attempt to wilful action the arm always moves in flexion pattern of elbow, wrist and fingers. Score 2: First distal selectivity. Observation: The flexion pattern occurs predominantly, however when extending the elbow palmair flexion of the wrist is possible. Score 3: Dorsal flexion wrist and fist. Observation: When extending the elbow palmair flexion and dorsal flexion of the wrist is possible. The patient can open and close the fist. Score 4: ‘Carrying a suitcase’. Observation: MCP2 to 5 extension; IP flexion is possible. The patient can grasp and let go of a suitcase handle; can abduct and adduct the fingers. Cylinder grasp and tweezers grasp are not possible. Score 5: ‘Cylinder grasp’. Observation: The patient can grasp a mug and release willfully. Score 6: ‘Tweezers grasp’. Observation: The patient can fixate a pen in tweezers grasp and release the pen. Score 7: Clumsy hand. Observation: The patient can perform all tasks, but slower and clumsier.

FIGURE 5.7 The Utrecht Arm/Hand Test . (With permission from Kruitwagen-van Reenen ET, Post MW, Mulder-Bouwens K, Visser-Meily JM. A simple bedside test for upper extremity impairment after stroke: validation of the Utrecht Arm/Hand Test. Disabil Rehabil. 2009;31[16]:1338–43.)

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5.5.1 Spasticity in Patients with a Severely Affected Upper Limb (UAT 0–1) A recent study, exploring the relationship between MRI outcomes and upper limb spasticity after stroke (defined as Modified Ashworth score of 1 or higher), suggests that a higher lesion volume was associated with more severe spasticity (Cheung et al., 2016). A longitudinal study explored the time course of development of both spasticity and contractures at the wrist in 30 stroke patients without arm function within 6 weeks of a first stroke (Malhotra et al., 2011). Spasticity was measured by quantifying the muscle activity during passively imposed stretch at two velocities. The authors found that 28 patients (92%) showed signs of spasticity throughout the study period of 36 weeks. Participants who recovered arm function (n = 5) showed signs of spasticity at all assessment points, but did not develop contractures. Patients who did not regain arm function (n = 25) had signs of spasticity and changes associated with contracture formation at every time point tested. Besides the development of contractures, spasticity in arm and hand can have other adverse consequences, like pain, skin lesions, and interference with daily care. 5.5.2 Spasticity in Patients with a Moderately Affected Upper Limb (UAT 2–3) During motor recovery, basic limb synergies emerge and, when recovery proceeds, eventually diminish in time. After stroke, particularly strong coupling was found between shoulder abduction and elbow flexion (Dewald et al., 1995; Beer et al., 1999). This hinders the execution of functional movement, since voluntary lifting the arm for reaching induces simultaneous involuntary elbow flexion, thereby diminishing the reaching distance. When elbow extensors are paretic and not strong enough to overcome this antagonist force (“reduced output paresis”), functional use of the arm is limited. A kinematic study into the influence of gravity compensation on arm movement after stroke showed that the active range of elbow extension increases during 2-dimensional planar reaching movements with arm support when compared with similar unsupported movements (Beer et al., 2004). Similar results were found during 3-dimensional reaching tasks, reaching upward to a target at shoulder height. Reaching distance appeared to be slightly larger when gravity compensation was applied (Prange et al., 2011), but muscle activity patterns did not change (Prange et al., 2009). On the other hand, synergy patterns seem to increase in strength in more complex tasks, an observation which is well-known by clinicians. This supports the hypothesis that patients with moderate upper-limb paresis suffer from a lack of automaticity of motor control, which is challenged in a dual-task situation (Houwink et al., 2013). It remains a point of discussion whether this phenomenon of inappropriate co-contraction should be regarded as decreased reflex inhibition

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(“spasticity”) or as resultant of abnormal efferent drive originating from brainstem areas. An alternative hypothesis is that these different patterns of joint coupling serve as a compensation strategy, allowing the performance of functional tasks despite the presence of motor deficits in the paretic upper limb (Levin et al., 2009). The number of degrees of freedom to be controlled is reduced by fixating the joints in the arm, while using the trunk to move the arm and hand to the target (Van Kordelaar et al., 2012). 5.5.3 Spasticity in Patients with a Mildly Affected Upper Limb (UAT 4–7) In mildly affected stroke patients, daily activities that do not require nearmaximal effort do not elicit abnormal coupling between shoulder and elbow movements (Prange et al., 2010). However, in this group of patients with functional capacity of the arm and hand, smooth movement patterns may still be impaired to a certain degree (Chae et al., 2002). Spasticity or “muscle overactivity” might play a role in terms of increased co-contraction. Again, it can be debated whether this activation pattern hinders or enables functional use. Clinically, movement patterns are characterised by the ability to use a joint outside a basic synergy pattern, i.e., the capacity to uncouple multijoint activation patterns, particularly active wrist extension, finger extension, and finger spreading. However, this capacity may still be limited, due to the amount of attention that is needed to perform the task. In the mildest cases only subtle deficits in the ability to perform rapidly alternating movements (dysdiadochokinesis) is seen.

5.6 Assessment of Spasticity in Stroke Patients Assessment of spasticity post-stroke is mainly relevant when problematic spasticity is present, i.e., when it leads to secondary complaints or complications, or when it hinders functional ability. In that case, treatment must be considered. In the literature, consensus on which measurement tool should be used is lacking, partly due to the unsatisfactory validity and reliability of the available instruments. In addition, practical limitations play a role, as many clinicians prefer quick, easy-to-use, and cheap methods (Burridge et al., 2005). Several characteristics of spasticity itself make meaningful measurement difficult as well: spasticity tends to vary during the day and behaves differently in dynamic versus static situations (Dietz and Sinkjaer, 2007; Fleuren et al., 2008). This implies that the degree of spasticity measured at rest, e.g., with a passive stretch test, does not necessarily correlate with the degree of spasticity during active movement, such as walking or reaching. In addition, a discrepancy between the clinicians’ and patients’ perception can exist (Voerman et al., 2009). In patients

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with spinal cord injury, their perception of spasticity appeared to be influenced by personal factors such as pain, coping strategy, and by environmental factors (Voerman et al., 2011). It seems reasonable to assume that in the early phase after stroke, the manifestation of spasticity will be an unknown phenomenon for most patients, requiring education to put it in the right perspective. 5.6.1 Assessment of Spasticity: Body Function and Structure The available instruments for spasticity can be categorised into three groups: clinical, biomechanical, and neurophysiological methods (Johnson, 2005). They mainly address spasticity at the level of “Body function and structure”, the first domain in the ICF classification (WHO, 2001). The biomechanical and neurophysiological measurement methods are mostly used in laboratory settings, although neurophysiological methods are increasingly applied in advanced clinical diagnostics as well, mostly during gait analysis. Clinical methods include several instruments with different measurement characteristics and assessing different constructs (see Table 5.1). TABLE 5.1 Illustrations of Clinical Methods to Assess Spasticity Group

Measurement Tool

A. Measurement of Muscle Tone Ashworth Scale Modified Ashworth Scale Tardieu Scale Visual Analogue Scale

Construct

Performed By

Resistance to passive movement Resistance to passive movement Resistance to passive movement; angle of catch E.g., resistance to passive movement E.g., perceived muscle tone during certain activity

Clinician

B. Measurement of Joint Posture/Range of Motion (ROM) ROM by visual estimation ROM ROM with goniometer ROM Maximum interknee distance ROM Ankle posture at rest Angle C. Measurement of Other Clinical Phenomena Spasm Frequency Scale Frequency of spasms Clonus Score Number of cycles during clonus

Clinician Clinician Clinician Patient

Clinician Clinician Clinician Clinician Patient Clinician

Source: Derived with permission from Platz T, Eickhof C, Nuyens G, Vuadens P. Clinical scales for the assessment of spasticity, associated phenomena, and function: a systematic review of the literature. Disabil Rehabil. 2005;27(1–2):7–18.

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The Ashworth Scale and its modified version are still common practice in the clinical setting and are widely used in scientific research as well. They are both ordinal scales that aim to score spasticity. However, to be a measure of spasticity, a scale can only be valid when the increase in resistance to passive movement is caused by an increase in neural, stretch-related reflex activity (Vattanasilp and Ada, 1999; Pandyan et al., 2003). This is probably not the case, as the resistance to passive movement is a sum total of reflex muscle activity and non-neural mechanical characteristics (Pandyan et  al., 1999; Fleuren et al., 2010). Therefore, adjusting the measured construct into the resistance  to passive movement of a limb, as perceived by the clinician, would be more consistent with what is actually being rated (Table 5.2). Although the methodological value of the adapted scale might be questioned, it completes the clinical examination without the misconception of measuring true spasticity. Biomechanical measurement methods assess muscle activation indirectly, by calculation of the applied force (or moment) needed for passive rotation of a joint over a certain range. This rotation can be performed manually, by instrumented displacement, or by gravity, like in the pendulum test for the knee (Vodovnik et al., 1984). Obviously, the complexity to discriminate the contributions of neural and non-neural components to the resistance to passive movement is one of the main limitations of these methods. Although new techniques with application of haptic robots and advanced modelling techniques are in progress to discriminate more accurately between neural and mechanical components of velocity-dependent stiffness (De Gooijer et al., 2013, Sloot et al., 2015), these are not yet accessible for clinical use. Second, agreed protocols for the tests and normative data of age-matched controls are lacking in the current literature (Wood et al., 2005). TABLE 5.2 Perceived Resistance to Passive Movement (PRPM) Test Perceived Resistance to Passive Movement 0

No increased resistance

1 Slightly increased resistance (a catch) when the limb is moved in flexion or extension 2 More marked increase in resistance, but limb easily moved 3 Considerable increase in resistance, passive movement is difficult 4 Limb is rigid in flexion or extension Technique: Patient in relaxed position (document position of the patient). Instruct the patient not to assist or oppose the movement. First, test the passive range of motion of the joint by slow flexion or extension. Subsequently, perceived resistance is assessed within the entire range with a faster movement, covering the whole range within 1 second. The movement can be repeated maximally 2 times (note the lowest score). Source: With permission from Fleuren J, Voerman G, Nene A, Snoek G, Hermens H. Protocol for spasticity assessment in patients with complex spasticity. Roessingh Rehabilitation Centre and Roessingh Research and Development, Enschede, 2012 (not published).

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With neurophysiological measurement methods, electrical activity of involved muscles is measured. The use of the Hoffmann reflex, the electrical equivalent of the mechanical tendon reflex, has been studied extensively (Voerman et al., 2005). The same accounts for some other electrically elicited reflexes. However, their clinical relevance is limited. The use of surface electromyography (sEMG) for the recording of (reflex) muscle activity during functional tasks or during passive movement can be a valuable addition, when applied in a standardised way. The construct validity is potentially good, as it comes close to the definition of spasticity. However, due to large inter- and intra-subject variability, parameters related to intensity of muscle activity cannot be used reliably. Interpretation of data is mainly dependent on timing parameters, which can be compared to available datasets of healthy subjects during a standardised task, such as walking. Timing errors represent any inappropriate phasing of muscle activity. The activity of any muscle may be prolonged or shortened, continuous or absent. Its onset and cessation may be premature or delayed. Each of these phasing errors may alter the pattern of sequential movements during gait (Perry and Burnsfield, 2010). In the case of “overactivity,” the inappropriate timing may be related to altered reflex threshold values, but it can also be related to abnormal efferent drive (De Niet et al., 2011). 5.6.2 Assessment of Spasticity: Activity and Participation When the goal of treatment is to improve daily functioning, other methods should be considered to assess (the functional consequences of) spasticity. In general, the association between a decrease in spasticity and an improvement of functioning is rather weak (Ada et al., 1998). However, an individual patient may benefit from spasticity treatment when it allows less effort for the performance of a specific activity. For example, a decrease in spasticity of the elbow flexor muscles can increase the reaching distance and, consequently, improve the utility of the hand. In general, detailed history-taking of the patients’ perception and needs is an essential first step. Self-report instruments, such as the Canadian Occupational Performance Measure, the Goal Attainment Scale, or Visual Analogue Scaling (using a well-defined construct), may be helpful in this process. When treatment aims to improve arm or hand capacity in a stroke patient, the Action Research Arm Test (Lyle, 1981) or the Stroke Upper Limb Capacity Scale (Houwink et al., 2011) can be chosen to evaluate the effects of treatment. For the improvement of gait, timed walking tests, e.g., the 10-meter Walking Test (Collen et al., 1990), 6-minute Walking Test (Eng et al., 2002), and Timed Up and Go Test (Podsiadlo et al., 1991) are easily applicable. For more accurate diagnostics of spasticity during gait, for example, when neuromuscular blocks or ankle-foot surgery is considered, instrumented gait analysis with kinematic recording and dynamic EMG is required.

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Example: Patient W Mrs W is a 57-year-old patient who suffered a left-sided stroke 4 years ago, which led to right-sided hemiplegia and mild cognitive impairments. She can walk approximately 100 meters outside with a wheeled walker, but starts toe-dragging when walking longer distances. Because of hyperextension of the right knee during stance phase she underwent phenol blocks of the right tibial nerve several times, with fairly good results. However, during swing phase stiff knee gait is observed. Mrs W hopes to be able to walk longer distances without tripping. Her physiatrist suggests instrumented gait analysis. The clinical question is whether the reduced foot clearance is related to decreased knee flexion in swing phase and – if so – to assess the cause. Is the stiff knee a result of a lack of propulsion force from the calf muscles, is it caused by overactivity of the rectus femoris muscle during swing, or both? For this analysis measurement of joint angles, ground reaction force and dynamic electromyography of gastrocnemius and/or soleus muscle, rectus femoris, and vastii is needed.

5.7 Management of Spasticity after Stroke As emphasised in earlier paragraphs, spasticity treatment is indicated only when its presence is considered problematic. Decision-making is based on the patients’ needs and characteristics, such as the distribution of spasticity, the perceived degree of discomfort, and the secondary risks of spasticity. On the other hand, clinical decisions depend on the available treatment options, their invasiveness and reversibility (Table 5.3). It can be helpful to distinguish between focal, regional, multifocal, or generalised spasticity. Focal spasticity is limited to one or a few muscles TABLE 5.3 Overview of Treatment Methods in Terms of Invasiveness and Reversibility I Noninvasive methods • Elimination of provocative factors • Physical therapy • Oral medication II Invasive, reversible methods • Nerve blocks • Neuromuscular blocks • Intrathecal medication III Invasive, permanent methods • Neurosurgical procedures • Orthopedic procedures

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acting at the same joint, e.g., elbow flexors. Regional spasticity includes a group of muscles innervated by the same (e.g., the tibial) nerve. Generalised spasticity is seen when spasticity is not limited to a muscle group of muscle synergy. 5.7.1 Noninvasive Methods Noninvasive treatment options with temporary effect are usually a first step in spasticity treatment. A decrease in spasticity provides new information about the actual impact of spasticity and its contribution to the clinical problem. First, spasticity-provoking factors need to be identified and eliminated. Suddenly increasing spasticity can be a response to a certain internal or external stimulus. A variety of factors can provoke this increase (Phadke et al., 2013). Any physical stimulus is a possible provoking factor, such as pressure sores, infection, constipation, or pain. Clinicians should routinely examine for spasticity-triggering factors, e.g., by evaluation of proper positioning, by regular skin inspection, and adequate management of bladder and bowel function. In addition, psychological factors may affect the degree of spasticity. Emotional stress, anxiety, and being rushed to perform an activity are described to increase self-reported spasticity (Phadke et al., 2013). Education of the patient and their carers is highly relevant in this respect. Physical therapy is not primarily aimed at spasticity reduction. In stroke patients, physical therapy is commonly applied to facilitate active muscle control and to maintain the joints’ range of motion and muscle length. There are some techniques that can reduce spasticity, but only for a short time period, such as application of heat, stretching of the muscles, and hippotherapy. Surface neuromuscular electrical stimulation is used, but spasticity treatment is usually not the main goal. Although the intervention may have a short-term inhibiting effect on spasticity, possibly via reciprocal inhibition by stimulation of the (non-spastic) antagonist or by exhausting the stimulated spastic muscle, a long-term effect on upper limb spasticity in stroke patients without functional arm movement has not been shown (Malhotra et al., 2013). Post-stroke, orthotic devices are often applied to the wrist and hand. Although it is controversial as to whether orthotic treatment is effective in the reduction of muscular contracture (Tyson and Kent, 2011), it is suggested that in combination with botulinum toxin treatment, prescription of an orthotic device may aid in the preservation of muscle length. Oral spasmolytic drugs are usually considered in more generalised spasticity. Baclofen, a gamma-aminobutyric acid (GABA) agonist, is often used as the first-choice drug in patients with spasticity. It reduces the motor output of spastic muscles, as GABA is one of the main inhibiting neurotransmitters in the central nervous system, leading to hyperpolarisation of the post-synaptic membrane of the 1a afferent. The optimal dosage must be individually evaluated. Sedation is a common side effect in stroke patients, potentially leading to (increase in) attention and memory deficits, ataxia,

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and confusion. Benzodiazepines enhance the inhibiting effect of GABA, but obviously a sedative effect may be present. Tizanidine, an alpha-2-adrenerge agonist, has an indirectly inhibiting effect on polysynaptic reflexes, probably via facilitation of glycine, another important inhibitory neurotransmitter in the central nervous system. Dantrolene sodium is a postsynaptic muscle relaxant that lessens excitation-contraction coupling in muscle cells, probably by interfering with the calcium release from the sarcoplasmic reticulum. An advantage of this peripherally acting drug is a lower risk of central side effects. However, both dantrolene sodium and tizanidine have a potential for hepatotoxicity, so liver function examination should be performed at regular intervals. Despite the widespread use, the evidence for the efficacy of orally administered antispastic agents is scarse and weak (Montane et al., 2004). In placebo-​ controlled trials with dantrolene, tizanidine, baclofen, or diazepam, the experimental drug was significantly better than placebo in patients with stroke, but the therapeutic effect was modest. Adverse effects were generally more frequent in the active treatment groups than in the placebo groups, up to 64% in a dantrolene group (Ketel and Kolb, 1984; Katrak et al., 1992). Drowsiness, weakness, and fatigue were most often reported. Therefore, generally speaking, these drugs should be applied cautiously for spasticity treatment after stroke. Particularly when the aim is to improve function, their effect is often disappointing. Nonetheless, specific indications such as symptom reduction, especially during the night, or presence of otherwiseintractable spasticity may justify their use. 5.7.2 Invasive, Reversible Methods For the treatment of focal or regional spasticity, different types of neuromodulation can be useful options. Neurolysis of well-accessible motor branches of peripheral nerves impairs the conduction along that nerve. The most frequently used agents for this procedure are phenol and alcohol. The effect is not permanent and the duration is highly variable, on average about 6 months. In stroke patients, a nerve block of the tibial nerve, a mixed motor and sensory nerve to the calf muscles, tibialis posterior, and toe flexors, with phenol 5–7% solution is the most commonly applied. The proper indication is the presence of hindering clonus of the ankle plantar flexors, interfering with stance stability. Other well-accessible nerves are the musculocutaneous nerve (which innervates a.o. elbow flexors) and obturator nerve (for disabling hip adductor spasticity). However, blocks of mixed nerves with phenol, such as the tibial nerve, carry the risk of neuropathic pain in the sensory region of the nerve. Since botulinum toxin has appeared on the market and was licensed for spasticity treatment, the use of nerve blocks has decreased. In particular the more difficult procedures have become less popular. Nevertheless, some clinicians claim greater clinical efficacy of phenol for specific indications (Manca et al., 2010).

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Nowadays, intramuscular injection of botulinum toxin is an established, well-tolerated, but relatively expensive treatment for focal spasticity. Botulinum toxin prevents the release of acetylcholine from the pre-synaptic nerve terminals, thus blocking the peripheral cholinergic transmission at the neuromuscular junction. This results in reduced muscle contraction. The clinical effects are dose-dependent and temporary. Usually, the effects taper off after 3 to 4 months. Botulinum toxin is injected in the muscle belly of specifically selected muscles. As it diffuses within the muscles, the injections do not have to be placed precisely in the region of motor endplate (of which the exact location is usually unknown), which makes the procedure fairly easy. Nevertheless, ultrasound guided injections are recommended for proper muscle targeting. Adequate dosages and concentrations for spasticity treatment with intramuscular injections of botulinum toxin are extensively described in different guidelines. There is a substantial body of evidence for the effectiveness of botulinum toxin in the management of upper and lower limb spasticity in stroke patients. However, its contribution to the improvement of upper limb function has not been clearly established (Shaw et al., 2011). In general, the focus of botulinum toxin treatment in the upper limb is on improving posture and passive function of the non-functional arm and hand, with the aim to support hygiene and the independent performance of various activities of daily life, such as grooming, dressing, etc. The effects of botulinum toxin injections on active function of the upper limb are less strongly supported by the literature. As for the lower limb, focal spasticity interfering with the prerequisites of gait, as described in paragraphs 5.4.1 and 5.4.2, can effectively be treated with botulinum toxin. Particularly the triceps surae, posterior tibial, rectus femoris, extensor hallucis and toe flexor muscles are fairly easily accessible with ultrasound guidance or electrical stimulation. If spasticity causes multifocal problems, e.g., both in the affected upper and lower limb, botulinum toxin can be helpful as well, but dose limitations may reduce its applicability. Therefore, additional strategies must be considered. Due to its reversibility, repeated treatment may be required over several years. Botulinum toxin has shown sustained activity with repeated use. However, a lack of response can occur, possibly due to inaccurate selection of the correct muscle, inadequate injection technique, increasing non-neural contribution to the muscle stiffness, or – rarely – the presence of neutralising antibodies (Wissel et al., 2009). For some patients, repeated injections may be undesirable. Therefore, an alternative approach is to use botulinum toxin treatment as a diagnostic procedure prior to surgical techniques (see next paragraph). The reversibility gives the opportunity to evaluate the effect without permanent consequences. Intrathecal baclofen (ITB) might be an attractive option in case of more generalised spasticity. Unlike oral baclofen, the intrathecal route bypasses the blood-brain barrier, thereby dramatically reducing the required dose and minimising the occurrence of side effects. In the literature on ITB in stroke,

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significant reduction of spastic hypertonia in upper and lower limbs has been described (Meythaler et al., 2001; Ivanhoe et al., 2006) without affecting the strength of the unaffected side. In addition, improvement of hemiplegic gait was reported. Catheter tip placement and dose adjustments after ITB pump implantation have a significant influence on clinical outcomes. ITB distribution can be influenced by the location of the catheter tip and by changing the infusion mode. When only spasticity in the leg is aimed to treat, catheter tip location in the lower thoracic region will suffice. It is subject of discussion whether, in case spasticity in the upper limb must be reduced as well, the catheter tip should be located more cranially in the high thoracic region or at the cervical level (Heetla et al., 2014). In ambulatory stroke patients, a test phase with an external pump, prior to definitive pump implantation, is highly recommended, to make sure that walking ability is preserved during treatment (Bleyenheuft et al., 2007). 5.7.3 Invasive, Permanent Methods Nonsurgical management of spasticity provides temporary relief of symptoms and does not interfere with spontaneous recovery after stroke. Surgical intervention should be avoided during this time. In the chronic phase of stroke, roughly starting after 6 months when the clinical condition has stabilised, surgical management can be valuable. In the nonfunctional upper limb, problems with cosmetics and hygiene are addressed mostly. Persistent stiffness in the arm or a clenched fist may be difficult and painful to handle during washing and dressing. In addition, patients may have objections against repeated botulinum toxin injections. In a functional hand, surgeons tend to hold back due to the risk of loss of active function. In the lower limb, functional goals are easier to pursue. When the aim is to improve gait, surgical intervention should be based on instrumented gait analysis. Neurosurgical procedures are uncommon in stroke patients. Selective neurotomy of the tibial nerve is described in a Belgian study (Bollens et al., 2013) as an alternative treatment for overactivity of the calf muscles. In this study, triceps surae, tibialis posterior, and flexor hallucis longus muscles were denervated selectively and permanently, which resulted in a long-lasting effect. On gait parameters, such as ankle kinematics during stance and swing phase, tibial nerve neurotomy and botulinum toxin treatment showed similar effect. Orthopedic or plastic surgery (tendon lengthening and/or transfer) is indicated in the case of fixed muscle contracture or to adjust imbalanced muscle activity. Treatment of spasticity is usually not the primary goal, although reduction of spasticity may be a desired secondary effect, considered a result of an altered threshold for stretch reflex activity due to the increased length. In the spastic lower limb, several surgical techniques can be performed for correction of deformities (Kamath et al., 2009). Some procedures do address the negative consequences of spasticity on gait. In general, these options should be preserved for patients with at least a fair prognosis with respect to regaining

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walking ability. For example, a commonly performed procedure is the percutaneous Achilles tendon lengthening, during which three small incisions are made at the back of the ankle along the Achilles tendon, one laterally and two medially. The tendon stretches as the fibres are cut and the ankle is dorsiflexed to the desired angle (Canale and Beaty, 2008). In the case of a structural pes equinovarus, lengthening of spastic soleus and/or gastrocnemius can be performed in combination with release of posterior tibial muscle to improve ankle-foot stability during the stance phase as well as to provide proper prepositioning of the foot for loading. Prior to surgery, the effect of weakening of the muscles can be evaluated by performing a neuromuscular block. If a dynamic pes varus deformity is present during swing phase, a split anterior tibial tendon transfer can be performed, provided that the tibialis anterior shows sufficient muscle strength. The lateral half of the anterior tibial tendon is released from its insertion and transferred to the cuboid bone (Canale and Beaty, 2008). If the tibialis anterior is too weak, an alternative may be to transfer the tendon of an overactive posterior tibial muscle to the cuboid bone to support a balanced dorsiflexion of the foot. An arthrodesis of the talonavicular joint may also support a balanced ankle dorsiflexion when the lateral foot elevators (long toe extensors and peroneus tertius) are paretic. Extensor hallucis longus transfer to the mid-dorsum of the foot can be performed to treat a troubling striatal toe, but may also provide additional dorsiflexion force for the ankle. Spasticity of the long toe flexor muscles often leads to clawing of the toes and contributes to equinus deformity of the foot. Particularly after Achilles tendon lengthening, as the foot is brought into a more plantigrade position, shortening of the long toe flexors might be revealed. In that case, concomitant correction of claw toes is advised, e.g. by tenotomy of the long toe flexors. In the case of forefoot equinus, release of the short toe flexors (intrinsics) should be considered as well (Canale and Beaty, 2008). In the thigh, tendon transfer of rectus femoris can be considered in a patient with stiff knee gait. When dynamic EMG analysis reveals a rectus femoris muscle that is abnormally active during swing phase, a diagnostic neuromuscular block of the rectus femoris can be performed, to assess whether it leads to improvement on peak knee flexion during swing (Tenniglo et al., 2014). For a medial transfer, the rectus femoris is separated from the vastii. The rectus tendon is then dissected and transferred through the medial intermuscular septum to the semimembranosus (Canale and Beaty, 2008). In the upper extremity, spasticity reduction is observed after release of elbow flexors (brachioradialis, biceps brachii, and/or brachialis muscles), pronator teres, and wrist flexors (flexor carpi ulnaris and radialis, and the palmaris longus). Muscles that contribute to finger flexion deformities are flexor digitorum superficialis and profundus, which can be fractionally lengthened by incising the tendon fibres obliquely at the musculotendinous junction. However, superficialis to profundus transfer will provide more lengthening and opening of the hand. After release of the extrinsic finger flexors, persisting intrinsic muscle spasticity may be revealed, leading to an intrinsic-plus

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deformity. In that case, surgical tendon release of the intrinsic muscles must be performed as well. Tendon transfers, for example, transfer of the flexor carpi ulnaris tendon to the extensor carpi radialis brevis tendon to provide for stronger wrist extension, are uncommon in stroke patients. Generally, patients lack active wrist extension, and – if present – wrist flexor lengthening is believed to provide sufficient wrist extension (Tafti et al., 2008). 5.7.4 Management Strategy for Stroke Patients with Spasticity When an indication for treatment of problematic spasticity is assessed, a stepwise approach is recommended. Potential provoking factors of spasticity must always be identified and eliminated if present. In the early phase after stroke reversible treatment options are preferred. Depending on the distribution of spasticity, focal spasmolysis is often the first choice, because of its effectiveness and reversibility. Focal injections have the drawback of being invasive, but debilitating side effects, as observed frequently after oral medication, are much less common. Oral medication can be prescribed when more generalised spasticity is present, but its use is mostly restricted to symptom reduction, especially during the night. More permanent treatment options become relevant in the chronic phase, roughly from 6 months post-stroke onwards, as an alternative to repeated focal injections. Selective neurotomy of the tibial nerve may be an effective substitute, but it is rarely performed to treat spastic pes equinovarus up till now. Otherwise, tendon lengthening and release procedures, possibly in combination with tendon transfer to enhance active function, are available treatment options for both upper and lower limb spasticity. However, much more adequately conducted research is necessary to build on sufficient evidence and to support treatment algorithms.

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6 Clinical Management of Spasticity and Contractures in Spinal Cord Injury Martin Schubert and Volker Dietz CONTENTS 6.1 Introduction................................................................................................. 136 6.1.1 Epidemiology and Specific Aspects of Spasticity in SCI.......... 137 6.1.2 Spinal Shock, Recovery of Spinal Excitability, and Development of Spastic Movement Disorder..................... 139 6.1.3 Pattern of Spastic Movement Disorder Depends on Patho-Anatomy.......................................................................... 141 6.2 Pathophysiology-Based Treatment of Spasticity.................................... 143 6.2.1 Clinical Signs of Spasticity............................................................ 144 6.2.2 Spastic Movement Disorder.......................................................... 144 6.2.3 Therapeutic Consequences............................................................ 145 6.3 Patient Selection and Therapeutic Approach......................................... 147 6.3.1 Indication for Treatment of Spasticity in SCI.............................. 147 6.3.2 Clinical Assessment of Spasticity in SCI..................................... 148 6.3.3 Clinical Presentation and Anatomical Distribution of Spasticity...................................................................................... 149 6.3.4 Physiological Effects of Training.................................................. 150 6.3.5 The Mainstay of Spasticity Treatment in SCI Is Physical Therapy............................................................................................. 150 6.3.6 Oral Systemic Anti-Spastic Pharmacotherapy........................... 152 6.3.7 Intrathecal Anti-Spastic Pharmacotherapy................................. 155 6.3.8 Focal Anti-Spastic Pharmacotherapy: Chemodenervation....... 157 6.3.9 Surgical Correction of Contractures............................................ 160 6.3.10 Focal Anti-Spastic Surgical Treatment: Selective Dorsal Rhizotomy........................................................................................ 161 6.4 The Complex Spastic SCI Patient: Selection of Therapeutic Approach...................................................................................................... 162 6.4.1 Case 1: Combination Therapies: Oral Systemic and Focal........ 163 6.4.2 Case 2: Combination Therapies: Intrathecal Systemic and Focal.......................................................................................... 164 References.............................................................................................................. 164

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6.1 Introduction As in other pathologies involving lesions of the central motor system, spasticity in SCI can be defined as disordered sensorimotor control, resulting from an upper motor neuron lesion and presenting as intermittent or sustained involuntary activation of muscles by sensory input. Activation is independent of the type and location of triggering sensory input. It can be touch, pain, temperature, or proprioceptive stimuli, or it can be mediated by vegetative stimuli. As in other types of central nervous system (CNS) lesion, spasticity per se is a pathological condition that is part of a motor syndrome related to loss of voluntary motor control and related changes in sensory-motor integration and adaptation within the motor system. These changes and adaptations may include adverse as much as beneficial effects for patients’ level of function and subjective well-being. For instance, it can contribute to muscle strength and thus function where voluntary strength is lost, thereby supporting stance or gait in incomplete SCI. Hence, spasticity in SCI as much as in other CNS pathologies may be seen as a compensatory state of a deficit of sensory-motor control that is usually associated with a lower level of functional CNS organisation. This potentially leads to more disability if negative effects prevail and balance between voluntary and involuntary activation is lost. Only in this case is treatment needed. In any case, treatment should be focused only on these negative effects and should be done with a specific aim. Such aims can be function, pain control, reducing of care burden, or prevention of complication such as impending contractures. It must always involve an interdisciplinary consideration of the patient’s special situation of impairment. Thus, treatment will usually require that medical staff, patient, and his/her relatives discuss the treatment aim and agree upon a treatment concept. This chapter will first deal with the manifestation of spasticity in SCI and how it can be beneficial or detrimental to function. It will then describe particular features of SCI spasticity based on spinal syndromes and their pathophysiology. While there is good understanding of changing excitability of spinal motoneurons below the level of lesion as derived from animal models [1–3], these are not deemed representative of the spastic motor disorder in human SCI and thus have little meaning in the context of clinical practice. Although there is some experimental work in the human that supports the notion of changing excitability of infra-lesional spinal motoneurons as a basis for the generation of muscle spasms [4], models derived from this work rely on several assumptions of analogy with animal models and have no significance for practical treatment of spasticity in human SCI. This is mainly due to the fact that the anatomy of the spinal lesion is more relevant for clinical presentation than modeled excitability changes at the cellular level. The anatomy of a human spinal lesion results in phenotypes with implications for functional deficits that have more effect on spasticity treatment than underlying pathophysiology of presumed neural interaction

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at the spinal segmental level. Therefore, the effects of spasticity in SCI will be discussed in terms of phenotypes and their implications for function and need for treatment. 6.1.1 Epidemiology and Specific Aspects of Spasticity in SCI Spasticity is seen as a major health problem by many patients with SCI [5,6]. Although spasticity can be seen as a compensatory adaptation to the loss of voluntary motor control, it may also severely limit patients’ mobility when overshooting and thus can negatively affect independence in activities of daily living (ADL) and work. Prevalence of spasticity in SCI is reportedly as frequent as 40–74%, depending on the type of survey and whether external or self-reported outcomes were drawn upon [1,5–9]. In most surveys, spasticity is rated as the most disabling complication, followed by pain, sexual, bowel, and bladder dysfunction and pressure ulcers. There is an interrelation of spasticity, pain, reduced mobility, contractures, and pressure sores [5,6,10]. Many patients report pain as a consequence of spasticity. In fact, spastic and neuropathic pain can be inseparable in the clinical condition. Independent of geographic region, the prevalence of secondary health conditions such as spasticity is known to vary across demographic and SCI characteristics. Spasticity was more often reported in SCI with incomplete lesions or tetraplegia [5,7,8,10]. SCI as a unique form of CNS damage comes with certain features that are characteristic to its patho-anatomy. As the lesion is a focused one, severing the infra-lesional part of the cord from the supralesional CNS, characteristics of SCI will influence the manifestation and the distribution of spasticity. Neural mechanisms are discussed to be the primary contributors to spasticity following SCI by some authors [9], whereas others emphasise the relevance of mechanisms underlying muscle hypertonia that are unrelated to increased stretch reflex activity. Intrinsic changes in the muscle tissue itself, e.g. loss of sarcomeres, histochemical changes, and composition of muscle fibres, ultrastructure and proportion of extracellular matrix, have been suggested to have a significant impact on spastic hypertonia [11–16]. From a clinical viewpoint, the original definition by Lance [17] is not sufficient to understand resulting functional impairment. It is also not helpful in delineating indication for treatment as it does not explain the syndrome of spastic motor disorder. Clinical signs of spasticity are not related to spastic movement disorder. The functional impairment that follows a central motor lesion will be influenced and modified by spasticity. However, it is not a direct consequence of the clinical syndrome that was clinically defined by Lance as ‘a velocity-dependent increase in tonic stretch reflex with exaggerated tendon jerks, clonus, and spasms, resulting from hyper-excitability of the stretch reflex’ [2,18]. This is due to several aspects. On the one hand, the definition by Lance does not capture the signs and symptoms of what is usually referred to as spastic motor disorder. It does not include the impending secondary

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changes within muscle and connective tissue leading to contractures as an unwanted final point of missed treatment. On the other hand, it overemphasises the significance of the hyperexcitability of the stretch reflex while negating the functional significance of loss of polysynaptic reflex activity [19]. Spasticity in SCI evolves with time after lesion. It varies with location of lesion level and other SCI characteristics such as central cord damage and completeness of the lesion. Clinical aspects of spasticity are diverse, including muscle hypertonia, flexor or adductor spasms, clonus, and dyssynergic patterns of contraction. Muscle hypertonia, an abnormal increase in muscle stiffness, can be regarded as a defining feature of spasticity. Other than exaggerated reflexes, it has both diagnostic and therapeutic significance [16]. This heterogeneity in clinical presentation cannot be explained by exaggeration of the stretch reflex alone. There is abundance of clinical and experimental neurophysiological work extending on the suspected mechanisms of spasticity in SCI and the reader is referred to the respective chapter. However, it should be mentioned that there is controversy about the putative role of hyper-excitability of spinal motoneurons as a major cause in the emergence of spinal spasticity. This was put forward based on the observation of low-frequency invariant spontaneous self-sustained firing in motor units from 5 out of 15 SCI patients [4]. It was explained as a consequence of altered intrinsic voltage-dependent persistent inward currents (PICs; e.g., persistent inward calcium currents) [1]. The hypothesis was primarily derived from animal work and then indirectly tested in human SCI [4]. Under normal circumstances, PICs are assumed to have physiological roles at the MN level in amplifying synaptic inputs to provide a sustained excitatory drive that allows motoneurons to fire repetitively following a brief synaptic excitation. In SCI patients in whom involuntary muscle spasms could be elicited by various types of afferent stimulation, a self-sustained firing of motoneurons was observed which would last for seconds at unusually low and regular discharge frequency. Based on several assumptions derived from animal experiments it was suggested, that this slow spontaneous firing likely occurs without appreciable synaptic noise and is driven to a substantial degree by PICs intrinsic to the motoneuron [4]. This would not necessarily be in contradiction with observations of reduced motor unit action potentials [20] and reduced overall activity of the motor units during functional movement [12,21–23] as well as a reduction of functional long-latency reflexes on the one, and enhanced short latency reflex excitability and spontaneous muscle spasms on the other side [19,24]. However, self-sustained firing of motoneurons was only observed and described following induced muscle spasms and not during functional movement. It is unclear whether it could commonly be observed in chronic spinal injury or if it is only present during induced spasms. Long-term intramuscular single-motor unit recordings in the human, which could substantiate the finding, are lacking. It remains to be determined if there is a relation with functional impairment or if there is a significant role of the phenomenon in the development of contractures.

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There is more human experimental data supporting the idea that spasticity involves synaptic mechanisms such as recurrent inhibition [25], reduction in Ia-reciprocal inhibition [26,27], and reciprocal inhibition of flexor reflex afferents [28]. In summary, changes of motoneuron and interneuron plasticity are assumed to play a significant role in spinal spasticity, which early after an SCI are thought related to postsynaptic mechanisms such as receptor upregulation, and later during the recovery phase would be associated primarily with pre-synaptic mechanisms [1,9,29]. However, these changes are not observed immediately after spinal trauma. They evolve with time, suggesting gradual changes of neural adaptation following SCI. 6.1.2 Spinal Shock, Recovery of Spinal Excitability, and Development of Spastic Movement Disorder When describing the natural course of disease following SCI it must be distinguished between pathologies with acute onset and those that result in slow alteration of the cord, e.g., due to tumor or other etiology with increasing compression. Following an acute onset there will be a phenomenon of a sudden loss of reflexes and muscle tone, commonly referred to as ‘spinal shock’. The term was introduced by Hall in 1841, who, in describing the sudden loss and recovery of reflexes, for the first time linked it with the term ‘reflex arc’ [30]. Our present idea is that a flaccid motor paresis is observed immediately after acute onset of a complete SCI when there are no motor responses to external stimuli below the level of lesion. During the subsequent days and weeks, motor reactions to external stimuli and reflex activity gradually reappear in a more or less systematic manner [24]. The phenomenon of spinal shock remains an issue of debate and controversy. Due to involvement of the autonomous system in acute SCI, there is some overlap with cardiovascular symptoms, i.e., arterial hypotension and cardiac compensatory response. The question of duration of spinal shock can be seen as a matter of definition of the delimiting type of motor reaction or reflex [31]. Depending on what is chosen as the distinguishing motor criterion, cessation of spinal shock may be assumed with the appearance of a ‘delayed plantar response’ (DPR), which occurs within hours after SCI and persists for hours to a few days [32,33]. If deep tendon reflexes (DTR) are chosen as the criterion, then duration of spinal shock is longer and will comprise several weeks. DTR return in the majority of patients but the Babinski sign may or may not be present, which seems to be related to the presence of spasticity [34]. Appearance of interlimb reflexes indicates late changes reflecting increased polysegmental spinal reflex excitability 6–12 months after SCI [35]. Competitive synapse growth originating from preserved long descending motor input [36] and segmental reflex inputs [29] are postulated as underlying the individual outcome and clinical presentation of recovery of voluntary motor control and spastic motor disorder [35].

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Complete and incomplete SCI were claimed to be distinguishable by the extent and duration of spinal shock in several studies lasting only minutes to hours in ‘slight’ injuries [32,37]. Furthermore, response amplitude to tendon tap and reflex spread to adjacent segments are sensitive indicators of preserved supraspinal control over lower limb musculature in subjects with acute SCI and may thus be helpful for prediction of recovery [32]. Conversely, this would be well in line with the clinical observation of long-lasting flaccidity as an indicator of complete SCI. Within this spectrum of motor responses and gradually increasing motor activity following spinal shock it is difficult to distinguish spasticity as a single and clearly defined motor phenomenon. Spreading reflex activity and clonus is regarded a clinical sign of evolving spasticity. Muscle hypertonia and polysegmental reflexes may appear as involuntary contractions and spasms, thus adding to the picture of spastic motor syndrome of SCI [35]. In the clinical view, the transition from spinal shock to spasticity is a continuum of an initially gradual increase in motor excitability [24] with characteristic changes in muscle stiffness, spasms, and subsequent reduction of short- and increase in long-latency reflex excitability. In contrast to tetraplegic patients, paraplegia resulted in M-wave and flexor reflex amplitudes that were found to decrease, indicating that spastic motor disorder eventually is not associated with increased excitability of motoneurons and premotoneuronal network [12,24]. Neurophysiological methods have deepened our understanding of underlying excitability changes in spinal circuits and peripheral nerves during this transition [20,24,29,38,39]. During spinal shock, the loss of tendon tap reflexes and flaccid muscle tone is associated with low excitability of spinal motor neurons, as tested by neurographic methods (F-waves) and with a loss of flexor reflexes, whereas only H-reflexes can be elicited because the unexcitable intrafusal gamma fibre system is bypassed by direct electrical stimulation of 1a afferents. Reduced excitability of peripheral mixed nerves was shown to be based on high threshold stimulus–response relationships that were apparent from the early phase of spinal shock. This coincided with depolarisation-like features reaching a peak after 12 and 17 days for the median and common peroneal nerves, respectively [20,38,40]. Between Days 68 and 215 after SCI at the end of rehabilitation Boland and coworkers (2011) found that excitability for upper and lower limbs had returned towards normative values, but not for all parameters. These reductions of excitability of the peripheral motor axon were described to be paralleled by the development of spasticity despite reduced excitability of the motor axon. This supports the notion that spasticity occurs without overactivity of the motoneurons and their axons. During the transition to spasticity, the reappearance of tendon tap reflexes and muscle tone can parallel the occurrence of spasms and is associated with the recovery of excitability of spinal motoneurons as indicated by increasing F-wave persistence and flexor reflex excitability [24] but there is no excess activity of the motor system causing spasticity. Little change in spinal excitability can be shown after

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this transition phase as the decrease in compound muscle action potentials (CMAP/M-wave) and reduced flexor reflex amplitude suggest a secondary degeneration of spinal circuits and motoneurons subsequent to severe spinal trauma [20,24,41]. Furthermore, flexor reflex excitability depends on the level of lesion, indicating that spinal interneurons and pre-motoneuronal circuits may depend on the extent of infra-lesional intact spinal network [24,32]. As an overall conclusion of these neurophysiological observations during transition from spinal shock to spasticity, it must be emphasised that spasticity in SCI develops without a net increase in spinal excitability. 6.1.3 Pattern of Spastic Movement Disorder Depends on Patho-Anatomy Traumatic SCI usually results in a diffuse damage zone of the spinal cord extending for 2–3 segments, clinically reflected by a ‘zone of partial preservation’. In incomplete SCI, the distribution and extent of segmental damage is of great relevance for recovery. Contusion injuries inherently represent the combined damage of both segmental central and peripheral neural structures [42]. Preserved function of neuronal circuits below the level of the lesion is the target of rehabilitation training. Spasticity develops only in this zone. Next to severity and completeness of the injury, clinical spinal syndromes are relevant as they can show distinct patterns of recovery and spastic motor disturbance due to specific epidemiology and anatomical distribution of lesion in the spinal cord [43]. The anterior cord syndrome (ACS), due to a flexion injury of the spine, results in predominant damage of the ventral cord, the segmental ventral horn cells, and spinothalamic and long motor tracts. This is also possible when a minor mechanical impact triggers a disturbance of the blood supply from the anterior spinal artery [44]. In patients with diffuse non-penetrating spinal injuries, the clinical syndrome is characterised by segmental flaccid paresis and spastic paresis with disturbance of pain and temperature sensation caudal to the lesion level but sparing of light touch and proprioception, which are mediated in the dorsal tracts of the cord. Incidence is low, accounting for only 2.7% of all traumatic spinal injuries [45] and less than 1% of all spinal syndromes [43]. Traumatic ACS as defined by Schneider [46] affects the anterior two-thirds of the cord and hence involves damage of the lateral corticospinal tracts. This is associated with a poor prognosis and minor recovery rates of muscle force and poor coordination. Traumatic central cord syndrome (CCS) is the most common acute incomplete cervical spinal cord injury, accounting for 44% of all spinal syndromes and for 9% of all SCI in a recent study of 839 spinal cord injuries [43,47]. About 20% of patients with cervical spinal cord injuries present a clinical CCS [47]. The syndrome is characterised by predominant upper extremity weakness and clumsy hands, and less severe lower extremity dysfunction and sensory and bladder dysfunction. Spasticity will be generalised with a focus on the hands as paresis and loss of motor function is most pronounced

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here unless lesion level is within the range of the motoneurons supplying the hand muscles, as this will result in peripheral-type lesion with atrophy and flaccid paresis. However, most cervical lesions occur at cervical levels C4 to C6, maximum at C5, while very few affect C7 or C8 segmental levels [43,48], thus mostly sparing motoneurons of the hand muscles, which are localised below. CSS represents the oldest age group, with the lowest admission functional level of all SCI clinical syndromes, which is a cofactor in determining relatively poor recovery of hand function in this group, despite its favorable outcome compared to traumatic incomplete cervical SCI in general [43], which is in the range of the group of Brown-Sequard [49]. Hand spasticity in these patients can add to their functional impairment in activities of daily life due to loss of manual dexterity. However, walking ability can also be severely impaired by spasticity of the trunk and legs. CCS was originally thought to result from post-traumatic centro-medullary hemorrhage and edema [50], or from a Wallerian degeneration, as a consequence of spinal cord compression in a narrowed canal [47]. The central focus of spinal damage in combination with the special somatotopic organisation of the corticospinal tract, where motor tracts for the upper are localised more centrally than those for the lower extremities, were assumed to be responsible for the predominance of motor deficits in the hands in CSS. However, more recent anatomical analysis and primate animal studies suggest that the syndrome is due to the specific effects of a cervical spinal lesion on direct corticomotor (pyramidal) tracts given their significant role in manual motor control [51]. This would be in line with the seminal findings of these direct cortico-motoneuronal projections by Bernhard and Bohm [52] and with these authors’ appreciation and consideration of this anatomical feature, which is unique in primates and humans. A loss of the capacity for ‘fractionation’ of movements and control of small groups of muscles in a highly selective manner [53] is as much characteristic of CCS as an impairment of the acquisition of new motor skills [54]. Therefore, when considering the significance of direct cortico-motoneuronal control in human manual dexterity [51], CSS may be considered a prototypical condition where spinal cervical lesion inflicts damage predominantly on pyramidal tract axons affecting fine motor control and coordination of the hand. Loss of fine motor control in general and, hence, particularly in the condition of CSS is associated with spastic motor disorder, which can lead to contracture and pain, predominantly in the upper extremity. This mostly concerns the flexor muscles of the hands. A hemisection of the cord leads to Brown-Séquard Syndrome (BSS), which was first described in 1851 by the neurologist Charles Edouard Brown-Séquard [55] as ipsilateral ataxia and spastic paresis due to proprioceptive and motor loss in association with contralateral loss of pain and temperature sensation below the level of lesion. A surgical unilateral lesion dividing most of the ipsilateral tracts of the spinal cord resulted in complete flaccid paresis of the ipsilateral limbs only for a few hours, after

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which voluntary movements began to reappear [56]. Within days after such a sharp lesion, patients were able to exert slow digital movements, and walking ability was attained within 2 weeks. Slow and feeble manual function recovered within less than 3 weeks of the operation. This indicates that recovery and redundancy in corticospinal control is strong in human SCI. However, this syndrome is rare in traumatic SCI and its recovery is generally less favorable than in the cases with a sharp penetrating spinal lesion, as described by Nathan, indicating that there must be more extensive and diffuse lesion of spinal tracts in lateralised traumatic SCI [57]. Although BSS-like syndromes with more or less lateralisation of lesion are relatively rare in Europe and account for less than 4% of all traumatic SCI [43], they are nevertheless relevant as prognosis is known to be most favorable among incomplete traumatic SCI [43,57,58], particularly with regard to ambulation. Physiologically, recovery occurs in a rather characteristic order, with proximal extensors prior to distal flexors on the more affected side and vice versa on the less affected side [58]). This is attributed to the unilateral (distal flexors) and bilateral (proximal extensors) distribution of preserved fibres and their recovery due to sprouting and formation of collaterals. The recovery is most likely owed to lumbar midline crossing fibres [59,60]. Spasticity usually is present, but does not pose a problem in these patients. Conus medullaris syndromes amount to 1.7% and posterior cord syndrome to less than 1% in the analysis of McKinley and coworkers [43]. Data on these groups are sparse. In general, spinal syndromes tend to need shorter rehabilitation length of stay, indicating that sufficient functional outcome is reached after shorter duration of rehabilitation, which is likely secondary to an in-complete pattern of lesion and high proportion of preserved spinal nerve fibres [43]. Spasticity usually only occurs in the plantar-flexors and digital muscles where there is an epi-conus lesion leaving intact ventral horn motoneuron cells that are disconnected from supraspinal input.

6.2 Pathophysiology-Based Treatment of Spasticity Spasticity even today is frequently thought to be reflected in an ‘extraactivity’ in limb muscles mediated by exaggerated reflexes leading to muscle overactivity. Also, most articles in this volume are focused on these phenomena. The consequence of this thinking is that spasticity should be treated by attenuating reflex and muscle activity by antispastic drugs or botulinum toxin injections. However, for over 40 years convincing evidence has been available indicating that these assumptions hold only partially for ‘clinical spasticity’ but not for spastic movement disorder, which hampers the patient (for review [61]).

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In contrast to clinical signs of spasticity, it is characterised by a reduced limb muscle activation. According to the studies on spastic movement disorder, secondary to a CNS lesion, alterations of mechanical muscle fibre properties occur in association with low tonic muscle activity, which allows the development of spastic muscle activity to compensate the reduced dynamic muscle activation during functional movements after, e.g., a stroke. This enables the patient, for example, to support the body during stepping. The consequence of this compensatory mechanism in mobile patients is that anti-spastic drugs can accentuate paresis. In the following paragraphs, we will discuss the multiple aspects of evidence in more detail. 6.2.1 Clinical Signs of Spasticity The diagnosis of a spastic paresis is based on the examination of tendon tap reflexes and muscle stiffness in the passive subject. Early after an acute damage of the CNS, tendon tap reflexes are exaggerated, but muscle stiffness develops only after some weeks. When stretching a limb muscle of a spastic patient (Ashworth Test) during the clinical examination a tonic muscle, activation occurs in this muscle, leading to an increased resistance [62]. This observation has led to the assumption that exaggerated reflexes result in an increased muscle activity and, consequently, are responsible for the movement disorder. However, electrophysiological investigations on the neuronal adaptations after a complete spinal cord injury indicate a divergent course of increasing clinical signs of spasticity but decreasing or stable values of their potential neuronal correlates (M-wave, F-wave, H-reflex, and flexor reflex) [24]. Consequently, non-neuronal mechanisms were assumed to contribute to spastic muscle stiffness. In addition, according to all investigations of natural, complex movements in patients with spasticity, the assumption of a relevant ‘extra-activity’ contributing to spastic muscle stiffness could not be confirmed [19]. 6.2.2 Spastic Movement Disorder For a patient with spasticity, the impaired performance of hand or leg/ stepping movements and their treatment are of importance, not the clinical signs found during examination. During active movements such as gait a low amplitude, tonic activation of upper and lower limb muscles can be observed, i.e., a normal modulation of EMG activity is lacking while a normal timing of muscle activity is largely preserved [12,63]. The reduction of limb muscle activity is suggested to be due to a diminished excitatory drive from supraspinal centers and an attenuated activity of certain polysynaptic (or long-latency) reflexes [64,65]. Polysynaptic reflexes are known to modulate limb muscle activity [64] and thereby adapt the movement pattern to the environmental requirements.

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In contrast, short latency reflexes neither in healthy subjects nor in patients with spasticity contribute significantly to muscle activity during natural movements [19]. These observations indicate that the muscle activity required during movement performance (e.g., to support the body during the stance phase of stepping) develops on a lower level of organisation after a CNS damage [19,61,66]. Consequently, the muscle tone required is not achieved by a modulated muscle activation as it is the case in healthy subjects. Instead, muscle hypertonus develops with the stretching of the tonically activated muscle. This represents a more simple mode of muscle tone generation, which is also based on structural alterations of a muscle secondary to a CNS lesion, i.e., a loss of sarcomeres [66], muscle fibre changes and increase of structurally deteriorated extracellular matrix [14–16]. Increased passive tension in the muscle is unrelated to stretch reflex activation. At the single-fibre level, elevated passive tension was found in muscle cells expressing fast myosin heavy chain isoforms, especially MyHC-IIx, but not in those expressing slow MyHC. Type IIx fibres were present in higher-than-normal proportions in spastic muscles, whereas type I fibres were proportionately reduced [16]. This is equivalent to an alteration of the contractile properties toward tonic muscle characteristics. According to these authors, ultrastructural changes of the extracellular matrix such as expanded connective tissue, but also decreased mitochondrial volume fraction and appearance of intracellular amorphous material, suggest that the global passive muscle stiffening in SCI spasticity is caused by structural and functional adaptations outside and inside the muscle cells, which alter their passive mechanical properties. This change compensates in part for the loss of neurogenic muscle activation and allows, for example, for support of the body during the stance phase of stepping. However, the performance of quick/fast movements becomes impossible by this mode of regulation of muscle stiffness. Muscle spasms do not play a role in this. Patients with spasticity do not only suffer from an impaired motor output but a defective control and processing of afferent signals contribute to the movement performance [65]. Thus, in patients with spasticity, in comparison with healthy subjects, muscle activity is enhanced in the passive state, i.e., during the clinical examination, but is reduced during active natural movements. The spastic signs observed during the clinical examination can therefore hardly be translated to the movement disorder. Clinically, spastic signs are more pronounced in damage of the spinal cord compared to a cerebral lesion. However, from a pathophysiological point of view there exist only quantitative but no qualitative differences. 6.2.3 Therapeutic Consequences Exaggerated reflexes do little to contribute to the movement disorder that impairs the patient. Nevertheless, most anti-spastic drugs are directed to reduce the activity of short-latency reflexes mediated by group Ia fibres in

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order to reduce muscle stiffness. However, mobile patients require spastic muscle stiffness to support their body during stepping to compensate for paresis [61]. Therefore, anti-spastic drugs can accentuate paresis and consequently can lead to a worsening of function. Similarly, some authors argue that botulinum toxin type A is assumed to result in a largely cosmetic effect on spastic signs without functional improvement [67,68], although this toxin might reduce the activity of the intrafusal fibres [69,70]. Intrathecal baclofen might also reduce hyperactive reflexes without producing significant weakness [71–73]. In conclusion, therapeutic interventions in patients with spastic paresis due to an incomplete SCI should be focused on the training, relearning, and activation of residual motor function [74,75], and the prevention of secondary complications, such as muscle contractures [76]. Anti-spastic drug therapy might predominantly benefit immobilised patients by reducing muscle stiffness and relieving muscle spasms [77], which might in turn improve nursing care for these patients. In cases where function is hampered by a focal imbalance of specific muscle groups resulting in movement impairment or contracture, focal botulinum toxin is known to be effective in improving pain, helping to avoid or to reduce contractures, and facilitating function. Its action is by a weakening and relaxation of muscle activity resulting in a biomechanical change in the muscle’s function. It makes the muscle amenable to stretching and lengthening in order to restore to some extent the interaction of antagonists. Thus, in addition, the weakening of the agonist allows to some extent a strengthening of the antagonist muscles and thereby it is possible to restore some of the disturbed antagonistic balance [78]. This is independent of mobility of the patient but will require at least some mobility of the affected limb when targeting functional improvement. In contrast, mobile patients can benefit from a functional arm and leg (locomotor-) training, which is associated with a recovery of function [19,61]. In animal experiments it could be shown that afferent signals induced by the functional training to spinal cord neurons below the lesion lead to a directed neuroplasticity [79] that is associated with a physiological mode of limb muscle activation. In contrast, according to this study, a lack of training of natural movements leads to a chaotic sprouting associated with a neuronal dysfunction, which might hamper a successful regeneration in the future in chronic SCI subjects [80]. The clinical consequence of a functional training in mobile patients is that with the improvement of function during the course of training less spastic muscle stiffness is required for movement performance, i.e., a new equilibrium between improved mobility and less pronounced signs of spasticity becomes established [61]. As a consequence it follows that, in mobile patients, anti-spastic medication can impede recovery of natural movements, as the performance of natural movements requires some spastic muscle stiffness for compensation of the paresis, i.e., lack of sufficient muscle activation [81]. Robotic devices can support this repetitive training. They allow longer training times and can provide useful feedback information to the patient about the course of

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functional recovery [82]. In immobilised patients a neuronal dysfunction develops about 1 year after injury [21,83] likely as a consequence of the loss of afferent feedback signals due to the immobility. This is reflected in rodent experiments by an undirected sprouting of tract fibres below the level of lesion [79].

6.3 Patient Selection and Therapeutic Approach A consideration of treatment of spasticity is made when the patient or the attending medical team observes persistent or pending signs of impairment or harm associated with spasticity. As spasticity evolves with time after SCI (due to spinal shock in severely affected patients), this is more likely to occur some weeks after the injury during rehabilitation. It is important to follow a strategy ruling out possible external triggers and after analyzing the exact circumstance of the phenomenon before initiating a treatment. Thus, it is important to obtain the view of the other members in the medical team and inquire about the observations of the patient and their relatives prior to the decision to treat. Management of these patients is teamwork, as is the entire rehabilitation of SCI. Initial questions will pertain to the level of independence and mobility of the patient. While there are exceptions, ambulatory function mostly may preclude or limit treatment approaches with intrathecal application of baclofen, which is mostly reserved for immobilised patients with severe incapacitating spasticity leading to contractures. 6.3.1 Indication for Treatment of Spasticity in SCI Despite the complex theoretical and pathophysiological knowledge of underlying mechanisms associated with alteration of stiffness and reflex function, the management of spasticity in SCI is to a large extent empirical. An indication for treatment of spasticity in SCI exists when it may cause harm and interference with function, nursing, or subjective well-being [78]. This may be expressed by the patient or by the nursing staff and treating therapist and physician [84]. A consensus should be reached as to the reason to treat and treatment aim [78,84]. The most common treatment goals in spastic SCI are enhancement of mobility and speed, increase of endurance and speed of ambulation or wheelchair propulsion, improvement of transfers, improvement of reaching, grasping, grooming and dressing, relief from pain, and painful muscle spasms, improvement of tolerance to wear splints and orthosis, which in turn will be needed to improve mobilisation of limbs and secure therapy effects aimed at prevention of contractures, prevention of contractures, promotion of hygiene, improve positioning, and facilitate mobilisation and other therapies [78].

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Depending on distribution of spastic symptoms and their interference with function, mobility for nursing aims, or subjective well-being of the patient, a treatment regimen can be chosen [78,84]. Management of spasticity is always a multidisciplinary and polymodal process, which includes physical and pharmacological measures. It has to be considered that the effects of spasticity might not always be negative. Spasticity can stabilise weakened legs, allowing a patient to stand or transfer and have improved mobility. Spasticity can also be a functionally helpful factor by being protective against skeletal muscle atrophy, decreasing the incidence of fracture. Moreover, spasticity has been reported to increase glucose uptake and will improve metabolism, thereby reducing the risk for diabetes in SCI [85] as well as augmenting cardiovascular function and energy consumption. The goal of treatment of spasticity must therefore consider the balance of functional benefits from spasticity and its adverse effects in allowing and facilitating motor function and nursing in immobilised patients. 6.3.2 Clinical Assessment of Spasticity in SCI Prior to any initiation of treatment, it is essential to have a thorough description of the extent and degree of the spasticity. Furthermore, the patient’s day-to-day functioning should be known. Spasticity can prevent simple maneuvers essential in daily life, such as transfer and the placing of hands and arms to control an electric wheelchair, rendering manual hygiene or catheterisation difficult. Personal accounts of the patient as well as information from those who know the patient should be obtained. This is particularly relevant when planning treatment of focal spasticity with chemo-denervation, as it must be determined after first injection of botulinum b toxin whether the dosage and pattern of application is optimal. When evaluating and discussing treatment options, a clear goal should be determined for what is to be achieved by the treatment. In the clinical examination, it is important to assess the range of active and passive movements as well as painful limitations of movement or abnormal limb positions. While not functionally relevant, as it is not strongly related to loss of function, the most widely used assessment scales are the Ashworth Scale and the Modified Ashworth Scale [86,87]. It is therefore not recommendable to assess treatment effects, except in testing response to intrathecal baclofen (see below). Other scales come with the same limitations [88–90] and are therefore of limited clinical value. Assessment can be done with the aid of video clips from before and after treatment [84]. Electromyography (EMG) can be useful to identify and inject spastic muscles in focal treatment by chemo-denervation. However, EMG cannot be used to assess degree of spasticity. Individual patient history, with an emphasis on functional limitations of specific activities in daily life, are more helpful to determine, if treatment is effective and satisfactory. There are established and validated scales and scores in SCI to assess and quantify activities of daily life (ADL), e.g., the Spinal Cord Independence

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Measure [91–93]. SCIM and other scores cover the main ADL domains relevant to SCI, such as mobility (6 minute walking test, 10 m walking test, walking index in SCI: WISCI) [94,95], self-care (SCIM), unilateral hand function (Graded Redefined Assessment of Strength, Sensibility, and Prehension: GRASSP) [96,97], and bladder and bowel management (SCIM) [98]. Most of these scores have been validated and shown to be responsive to change and can serve as a tool to evaluate effects of anti-spastic treatment if function is a treatment aim [93,99]. In any case, it is recommendable to include patientreported outcomes relating to quality of life and participation when defining treatment outcomes in any individual case and in clinical trials. Assessment prior to and after treatment should then include both patient-reported and externally rated functions in the activity of daily life. These are functionally relevant and can contribute to a patient’s well-being, while scores for the rating of clinical spasticity are not suited, and will likely not contribute to, a patient’s benefit from treatment. 6.3.3 Clinical Presentation and Anatomical Distribution of Spasticity Patho-anatomical distribution and severity of spinal lesion, among other factors, determine localisation of spasticity. Spastic symptoms may be more or less focal or regional, e.g., most prominent in the upper extremity in a central cord syndrome or pronounced in the legs in a thoracic complete spinal lesion. Generalised spasticity may affect the trunk and abdominal muscles, leading to pain or respiratory constraints. Spasticitiy of the upper extremity after SCI typically presents with shoulder adduction and inward rotation, elbow, wrist, and finger and thumb flexion, and pronation. Typically, patients’ hands tend to be fixed with closed fists, resulting in an impairment of reaching, grasping, and releasing. Spastic hypertonus of the pelvic striate muscles can impede micturition and defecation. Distribution and localisation of symptoms will guide the choice and form of application of anti-spastic treatment. A sudden increase in spasticity should prompt the attending physician to screen for underlying pathology that can be completely independent of the spastic motor disorder. The first step in the management of all problematic spasticity is to identify, address, and treat any remediable causes and factors [100] such as an over-filled bladder, obstipation, acute infections, syringomyelia, or bone fractures may substantially influence the degree of, or suddenly initiate, spasticity and must be determined [84]. An assessment of the clinical and functional consequences for the patient is decisive before management. If such measures are ineffective then it is appropriate to pursue or increase medical treatment until a therapeutic response is obtained. It is important to notice and attribute sudden changes in spasticity especially in SCI because infection of the urinary tract, fever, constipation, skin lesions, and local bone or joint injuries may not present in the usual way and go unnoticed below the level of lesion. In fact, increase of spasticity may be the leading and only symptom. Consequently, worsening of spastic symptoms

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should prompt search for the most common and likely ailments of SCI and spastic symptoms may immediately be alleviated by appropriate (and causal) treatment of bladder infection or skin sores. Therefore, a thorough check of patient history (e.g., for recent falls or injuries) as well as a thorough examination should be initiated in cases of sudden change of spasticity. If triggers are found their causal treatment may be prior and effective to also treat harmful spasticity. 6.3.4 Physiological Effects of Training A slowing of peak velocity of plantar-flexor muscles was shown to be related to loss of strength and spasticity in SCI patients [101]. Spasticity and injury level determine the pattern of abnormality in gait after spinal cord injury [102]. Spasticity and paresis may thus be seen as directly related to the extent of functional motor impairment. There are few systematic studies on this issue [103–105] and recent work shows that functional improvement can be induced by different types of functional motor training while simultaneously affecting volitional control and spasticity [106]. Endurance and precision training were shown to facilitate descending excitatory as well as spinal inhibitory networks in patients with incomplete SCI in parallel with improvement of walking function and reduction of the cutaneo-muscular reflex excitability. The latter involves excitatory and spinal inhibitory components. Training-induced parallel increase of volitional control and spinal inhibitory components of the cutaneo-motor reflex suggests that spared descending pathways originating from the motor cortex can be strengthened by the intervention, hence increase of motor control will parallel a decreased susceptibility for involuntary muscle spasms [106,107]. Thus, various types of functional motor training and physiotherapy may, in addition to strengthening the descending excitation of the spinal cord, also increase the strength of inhibitory spinal networks activated by both descending and peripheral afferent pathways. These neurophysiological changes may then lead to improvement of volitional control of movement as well as reductions in involuntary muscle spasticity, such as reflected in the reduced spasm-like cutaneo-muscular reflex. 6.3.5 The Mainstay of Spasticity Treatment in SCI Is Physical Therapy As was argued earlier, all patients with spasticity should be urged to exercise. If this is not sufficiently effective, the patient should have physiotherapy with guidelines for exercises that counteract the spasticity. Physical therapy does not have to be costly and can be performed by any caregiver who supports and guides a patient in his activity. For an immobile patient who is able to move with help, regular transfers and mobilisation twice a day may be critical to prevent contractures. For someone who can barely stand or walk, such a help for active mobilisation twice a day may be crucial for

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him in order not to lose his remaining capacities. We have often seen spastic patients who, once bed-ridden, never regained their former ambulatory capacity without any other cause than transient immobilisation. The most important factor is regular activation in short bouts that do not exhaust the patient. Systematically increasing training intensity in order to keep stress levels low is likely recommendable as a basic principle of physical therapy and may improve any outcome [108]. If no treatable causes triggering spasticity can be found, the team should decide whether focal or general signs of spasticity prevail and require treatment. In focusing on functional deficits, the first level of treatment and the basis for any further escalation should be physical therapy. This recommendation is based on the notion of the ambivalent role of spasticity in central paresis and impaired motor control. In a systematic analysis of the disturbed motor control following SCI [19,109] it was suggested that replacing lost patterned activation of the spinal cord by activating synaptic inputs via assisted movements and/or electrical stimulation may help to recover lost spinal inhibition, thus leading to a reduction of uncontrolled activation of the spinal cord to improve its function [109]. Increasing the excitation of the spinal cord with spared descending and/or peripheral inputs by facilitating movement, instead of suppressing it pharmacologically is therefore the primarily suggested approach to improve residual motor function and manage spasticity after SCI. Any treatment of spasticity will then be a combination of physiotherapy passively mobilising the spastic limb or body part and increasing active movement within the limits of residual motor function. Physiotherapy can be administered whether the patient is mobile or immobilised. Therapy can be tailored to the patient’s needs and capabilities. It is associated with the welcome effect of personal attention. Water therapy in itself can help to reduce muscle stiffness and will, as a side effect, reduce tension-inducing load as it eliminates gravity and thereby reduces defensive hypertonus and alleviates mobilisation. Recently, treatment concepts such as those described by Bobath and Vojta (for review see [110]) have not been pursued very rigorously. While primarily used in pediatric facilities in the past for treatment of spastic cerebral palsy, they are not common concepts in SCI treatment. They are worth mentioning as systematic approach with the scheme to activate complex stereotyped movement patterns that are believed to reside in the network of the spinal cord (Vojta) or to inhibit spastic symptoms in flexor muscles of the upper and extensors in the lower extremities (Bobath). However, there are no validated studies to support this notion. Locomotor training (LT) has become a standard of treatment of leg muscle function for ambulation and stance balance control in SCI [110–112]. The observation that LT can ameliorate spasticity is based on observations made in cats with complete spinal lesions [113]. LT on a treadmill is combined with bodyweight support, reducing gravitational forces by 20–50% by means of mechanical support by an overhead harness. As subjects walk on the

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treadmill with a reduced load on their lower extremities, coordinated stepping movements and patterned muscle activation can be facilitated by the moving treadmill. In a recent review evaluating the current LT approaches for gait rehabilitation in a total of 384 individuals with incomplete SCI, it was shown that evidence on the effectiveness of locomotor therapy is still limited [114]. While all approaches showed some potential for improvement of ambulatory capacity there is no superior method and effects were limited. Main effects in the included studies were shown for gait velocity and distance, hence a functional improvement which may be assumed to be associated with an indirect improvement of muscle tone and its regulation. However, only a subgroup of studies included measures of spasticity and this outcome was neither systematically analyzed nor reported in the review. 6.3.6 Oral Systemic Anti-Spastic Pharmacotherapy If necessary, generalised spasticity can be treated with oral medication. Several drugs with antispastic effect are available with various mechanisms of action. Baclofen, tizanidine, benzodiazepines, gabapentin, clonidine, and cannabinoids are centrally acting drugs. Gabapentin, clonidine, and cannabinoids are not officially approved for the treatment of spasticity in SCI. They are well-established drugs with known risk profiles and some lowlevel evidence for antispastic activity and may therefore be considered as second- or third-line treatment options in SCI spasticity on an individual basis. Dantrolene and botulinum toxin type A have peripheral action. The latter will be discussed in a separate paragraph. A synopsis of available oral pharmaceutics, their main effect of action and metabolism, and side effects is given in Table 6.1. Some of these drugs were especially developed to treat spasticity after SCI. For instance, baclofen was first introduced in 1964 for this use. Baclofen is structurally similar to g-aminobutyric acid (GABA). It binds to GABA-B receptors in the brainstem and dorsal horn of the spinal cord. By suppressing the release of excitatory neurotransmitters involved in monosynaptic and polysynaptic reflexes, it is assumed to reduce muscle stiffness and spasms [115]. Treatment effects of oral anti-spastic drugs are not well-documented. Most of the studies upon which anti-spastic pharmacological treatment has so far been based date from the 1970s, 1980s, and 1990s of the last century. While still being cited in modern work, these early studies lack modern standards of good scientific and clinical practice and the paucity of newer work may, at best, indicate that there is little interest to build a better base of evidence in pharmacological treatment of spasticity in SCI. New literature often appears in the form of reviews of the same poorly controlled original studies. Such systematic reviews repeatedly show that there is insufficient evidence to assist clinicians in a rational approach to anti-spastic treatment for SCI [85,116]. These reviews, as well as several others, showed that study quality is low. Thus, therapy is mostly empirically guided, and randomised controlled

24–48

2 × 25–5 × 50

2 × 0.075–3 × 0.15 3 × 100–3 × 800

THC and CBD* (Sativex)

Dantrolene (Dantamacrin)

Clonidine (Catapresan) Gabapentine (Neurontin)

Alpha 2 GABA (indirect)

Formatio reticularis, polysynaptic reflexes ECS (CB1, CB2 receptors) Striated muscle

GABA-A (spinal and cerebral) Alpha 2

GABA-A (spinal)

Mechanism

Hepatic Renal

Hepatic

Hepatic

Hepatic

Hepatic

Hepatic

Hepatic

Metabolism

Dizziness, sleepiness, nausea, mood disorder Hepatopathia, sleepiness, nausea, weakness, Hypotonus, bradycardia Dizziness, sleepiness

Sleepiness, nausea, weakness, hypotonus, respiratory depression (IT) Sleepiness, nausea, weakness, hypotonus Sleepiness, nausea, weakness, hypotonus, dry mouth (Rare) gastro-intestinal symptoms, hypotonus

Side Effects

Second line due to side effects Second line Second line, for spastic pain

Aerosol

Acts primarily on trunk muscles

Slow dose increase!

Caution: withdrawal; intrathecal dose 1/100 to 1/1000 of oral dose Caution: withdrawal

Specials

a

Baclofen, clonazepam, tizanidine, and tolperisone are first-choice drugs; THC and CBD, dantrolene, clonidine, and gabapentine are second-choice drugs. * Oral spray, mix of: THC = Delta-9-Tetrahydrocannabinol; CBD = Cannabidiol, maximum dosage 12 × 100 ul.

3 × 150

3 × 2–4 × 6

Tizanidine (Sirdalud)

Tolperisone (Mydocalm)

0.5–3 × 2

3 × 5–3 × 30

Baclofen (Lioresal)

Clonazepam (Rivotril)

Dosage (mg)

Drug (Trade Name)

Common Oral Antispastic Medicationa

TABLE 6.1

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trials (RCT) are rare and done only in very limited numbers of patients. A large systematic review with specific focus on SCI [116] returned a yield of 262 references, of which only eight met the inclusion criteria of cross-over RCT, with 100 patients (80 males) enrolled in these 8 cross-over studies, 14 of which were spinal forms of multiple sclerosis. Three of these studies tested efficacy of intrathecal application of baclofen (ITB; see paragraph below). One parallel multi-center trial compared tizanidine with placebo [117] among 118 patients (104 males), all of whom had an SCI (traumatic etiology in 108 patients) at cervical and thoracic level, proving efficacy without additional loss of strength. However, there was no improvement of ADL [117,118]. Outcomes in most studies were measured in terms of spasticity scales (MAS or other), while only one study assessed the performance of activities of daily life, showing no improvement [117,118]. The poor quality of included studies, and the marked differences in study designs, outcome assessments, and methods of reporting, did not allow for the performance of a quantitative combination (meta-analysis) of the results. The same applies to other similar reviews [85,116]. While efficacy is low, adverse drug reactions were reported to be common. Within the scope of these reviews, only a couple of studies were of direct comparisons of antispastic drugs (e.g., tizanidine vs diazepam or baclofen), where no significant differences were found clinically [85,116], whereas differential effects on flexor and extensor leg muscles were observed in a direct comparison of baclofen and tizanidine, while neither drug caused weakness at low dosage [119]. However, in the latter study on 10 chronic SCI patients, no clinical or functional data were presented. The general methodological quality of most studies was poor according to the systematic review by Taricco et al. [116] was poor, impeding meta-analysis or firm conclusions regarding the clinical management of spasticity. Poor efficacy of anti-spastic drugs on muscle hypertonus was attributed to the fact that most anti-spastic drugs reduce reflex activity. In contrast, as pointed out earlier, recent pathophysiologic evidence has suggested that exaggerated reflexes contribute little to spastic muscle hypertonia [61]. In the majority of mobile patients, impairment of functional movements is clinically more relevant than impairment of muscle tone. Functional movements were only assessed in half of the trials. Daily living activities and the overall patients’ status were also rarely assessed, which contrasts with the therapeutic objective of routine clinical practice. In conclusion, for various reasons, there was not enough evidence from available clinical trials to assess, and compare, the effects of drugs commonly used to relieve spasticity after spinal cord injury. Hence, the overall perception on oral anti-spastic treatment in SCI is today one of obfuscation, best expressed by the following quote from one recent review: ‘published reports depict a […] gloomy panorama on the treatment of chronic spasticity by oral route’ [85]. Based on empirical recommendations, a combination of pharmacological agents at low dosage is assumed to help reduce side effects while

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increasing efficiency. The choice of the drug or combination thereof will be made based upon the individual response of the patient, age group, prior experience, price, and profile of side effects and potential interaction with other medication (e.g., tizanidine must not be combined with gyrase inhibitors such as ciprofloxazine, as this would cause relevant interaction with the toxic effects of the anti-spastic drug). Any of these systemic treatments should be amended with focal physiotherapy, but can also be combined with focal chemodenervation (botulinum toxin or phenol, see below). This is more relevant, as adherence to anti-spastic medication is problematic, hence dosage should be kept minimal when combined with non-pharmacological treatment. In a large study of 2840 subjects with various types of central motor syndrome (including stroke, spinal cord injury, traumatic brain injury, cerebral palsy, and multiple sclerosis), adherence to anti-spastic medication was at best 50% of treatment periods [120]. This may indicate an unmet need for better anti-spastic medication and better guidance with treatment. In a recent systematic pharmacological approach, efficacy of spasticity treatment with tetrahydrocannabinol (THC) was assessed in a placebocontrolled trial in 25 SCI patients [121]. A major reason for drop-out was the increase of pain and psychological side effects. The latter should be reduced when using a combination of THC and cannabidiol, a partial antagonist that is now commercially available as an aerosol for the treatment of spasticity in multiple sclerosis [122,123]. However, when compared to established drugs, the cost of this preparation is high. 6.3.7 Intrathecal Anti-Spastic Pharmacotherapy The effective treatment of generalised spasticity is achieved by intrathecal application of baclofen (ITB), first introduced by Penn and Kroin in 1984 [89]. Studies on outcome measures such as the Ashworth Scale and spasm score as well as studies assessing quality of life have suggested the superiority of ITB over oral baclofen [124,125]. Despite a lack of trials directly comparing oral administration of baclofen and ITB, it is commonly agreed that ITB is indicated when spasticity continues to produce a clinical disability, despite trials of high dosages of oral treatments in patients who have functional goals and/or significant pain and disability. ITB allows for flexible dosing patterns to suit an individual patient’s lifestyle [100]. Thus, whenever generalised spasticity cannot be adequately controlled with oral medication, i.e., due to insufficient effects on muscle hypertonus despite maximum dosage or due to intolerable side effects at sufficient dosage with a combination of oral drugs, reversion to ITB should be considered. Severe sequelae of spasticity, such as contractures or progressive neurogenic scoliosis, may be among the conditions that should prompt consideration of ITB where applicable. Despite the considerable cost of the device and the effort required to test efficacy for each patient prior to implantation, this route of application

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has clear advantages over oral administration. Efficacy is empirically superior to that of oral therapy and can be achieved with little or no side effects. The effect of ITB is estimated to be 100 times greater than with oral administration. Due to the much-enhanced pharmacological effect, patients do not experience drowsiness or dizziness, while muscle hypertonus can be effectively reduced in the lower extremities and in the trunk. Patients with high degree of functional impairment due to immobilisation are most likely to benefit from this therapy. There is some limitation of efficacy in the arms and shoulders because with ITB the concentration of baclofen diminishes in the cranial direction [126]. Furthermore, effects in the upper extremity will be weaker due to the recommended position of the intrathecal catheter no more cranially than the level of Th1, to avoid central effects of the drug, such as depression of respiratory function and vigilance. It is assumed that a more cranial position of the catheter may lead to toxic concentrations of the drug at the brain stem level and thereby significantly increase the risk of critical side effects associated with depression of respiratory and rhythmregulating midbrain centers. Furthermore, positioning of the catheter tip should be optimised with respect to the main focus of spasticity. If it is in both the upper and lower extremities then one should attempt to place the catheter tip as high as T1; if the spasticity only affects the lower extremities, it can be placed between T6 and T10 [100]. It is recommended to evaluate the patients and their caretakers to determine whether they and caregiving teams meet the demands required to ascertain pump management and maintenance. It must be explained to the patient and their caregivers that it is crucial to make follow-up appointments to keep track of effects and adverse events. Relative contraindications are anticoagulant therapy with coagulation disorders, anatomic abnormality of the spine, and localised or systemic infection. It is generally agreed to only implant ITB pumps in non-ambulatory patients. This is due to the fact that the effect of baclofen on muscle hypertonus is non-specific and will also pertain to volitional muscle activation. In fact, in spastic patients it may be impossible to distinguish spastic tone from volitional strength directed to main posture. Therefore, postural control and endurance of ambulation can be deteriorated with ITB due to impaired gait and balance control. There may be few cases where spastic muscle hypertonus or muscle spasms interfere with volitional control, thus impeding or reducing gait performance. Under these conditions it may be worth considering ITB in ambulatory patients. However, it is strongly recommended to implant the subdermal pump only after an extended test period with ITB administered by external pump via temporary lumbar catheter. This is necessary in order to familiarise the patient with the effects that are to be expected and in order to test if ambulation can be maintained despite ITB doses that are sufficient to control spasticity. At the same time this may be a first step towards finding of the individual optimal dose and patient’s expectations can be adjusted prior to more invasive steps and costly implantation.

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Irrespective of the issue of ambulation, intrathecal test doses should be applied in all cases where ITB is considered in order to ensure treatment efficacy prior to implantation. Usually a test dose of 50 ug is applied as an intrathecal bolus via spinal tap and the patient must be monitored for respiratory depression or arrythmia during the following 6 hours. If no effect is seen the procedure will be repeated on the following days, increasing the dose in 25-ug steps up to 75 ug (second day) and if necessary to 100 ug (third day). This scheme relies on experience from a large multi-center study when ITB was first introduced [115]. If there is no clear or beneficial effect at a dose of 100 ug it is unlikely that the treatment with ITB will be successful. While highly effective, ITB bears a risk of various complications. Implantation and management of ITB should therefore be confined to dedicated centers with experienced teams. There should be an emergency service available or accessible round the clock, as malfunction of ITB can be associated with sudden baclofen withdrawal, putting patients at vital risk if untreated. There are early as well as recent reports indicating a considerable complication rate of 0.011 per month, or 12–13% per year. Of these complications, the majority (78%) were related to catheter malfunction [115,127]. Another more recent and prospective study presented an even higher frequency of adverse events, distinguishing surgical (53%), device-related (29%, predominantly catheter dysfunctions), and drug-related events (18%) [128]. Drug-related side effects and complications usually comprise drowsiness, nausea, hypotension, and respiratory depression. They occur mostly during testing of ITB when bolus is applied or when adjustments are made to the pump settings. There are reports about development of tolerance [129]. Another severe complication may arise in malfunction of the pump or, more frequently, in dislocation or disconnection of the catheter. In these cases, withdrawal reactions can lead to malignant muscle hypertonia with hyperthermia, hyperreflexia, potential autonomic instability, seizures, and hallucinations. Patients should be taken under surveillance and treated by oral administration of the drug. There is slow development of drug tolerance even with ITB, as was shown in an early prospective long-term studies [115] and in more recent studies [115,127] where the authors of this retrospective analysis found an initial development of tolerance during 5 years but that the mean applied dosage of baclofen stabilised after 5 years at a dosage of ca. 500 ug/day. No significant increase in dosage was found thereafter. For a good overview of ITB management, technical details and complications, side effects, and special considerations the reader is referred to the recent publication by Khurana [100]. 6.3.8 Focal Anti-Spastic Pharmacotherapy: Chemodenervation An indication for chemodenervation exists in focal spasticity causing harm or showing progression. Physical management as part of good nursing care,

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physiotherapy, occupational therapy, exercise, stretching and strengthening of limbs, splinting, and pain relief are the basis of spasticity management [78]. Therefore, this should be provided as a basis of any additional treatment with more invasive techniques, such as chemodenervation. Local spasticity may benefit from oral anti-spastic medication but should preferrably be treated with focal therapy of the spastic muscle(s), thereby avoiding systemic side effects. The most common measures are botulinum toxin A (botulinum neuro toxin, BoNT) and motor point and nerve block by phenol/alcohol as a cheaper alternative, though potentially at the cost of more local side effects and pain. Early RCT have proven efficacy of BoNT in the treatment of spasticity in etiologies other than SCI [130,131]. In a RCT comparing BoNT to phenol blockade of the tibial nerve to treat spastic foot after stroke, BoNT was superior to phenol [132]. This and the other controlled trials together with the potential local damage that can be inflicted by the injection of alcohol or phenol has nowadays also led to primary use of BoNT in the treatment of focal spasticity in SCI. Despite its recognition and acceptance in the management of local spasticity in SCI [78], there is a lack of high-quality evidence for its efficiency in SCI spasticity, as is revealed by recent systematic review [133]. Although this literature search, looking at management of spasticity in a sample population with a majority of SCI patients, identified 9 studies on BoNT and 10 on phenol/ethanol, none of them were RCT and none of them were adequately powered. This is true for many studies on the treatment of spasticity, often due to poor study design, low numbers, a variable management approach, and diverse, non-standardised treatment schemes. As in other etiologies, improvement of function is difficult to show or achieve [134], which is, among other reasons, due to the fact that reduction of spastic muscle hypertonus, as often used as a primary outcome, does not directly translate to an improvement in function. Furthermore, motor dysfunction in spastic paresis is usually mainly caused by weakness and the other ‘negative’ features of upper motoneuron syndrome, and not by muscle overactivity [19]. The effect of local treatment with BoNT injected into spastic muscles causes local weakness via blockade of the neuromuscular junction. The toxin is internalised by the presynaptic motoneuron, where it inhibits the release of acetylcholine [135]. The effect of injections is time-limited due to collateral sprouting and regrowth of nerve endings and formation of synapses, thus the treatment must usually be repeated after 2–6 months. International guidelines recommend a combination of botulinum toxin injections and physiotherapy. Phenol and ethanol produce neurolysis when injected close to the nerve endings that supply spastic muscles. Injection of these agents causes denaturation, which disrupts neural transmission and subsequently diminishes muscle activity resulting from central disinhibition. Adverse events are directly related to the mechanism of action, i.e., muscle weakness reducing or disturbing functional abilities with both drugs and, additionally, dysesthesia or denervation pain in treatment with ethanol/phenol.

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Specific indications and aims for anti-spastic treatment with focal chemodenervation include: functional improvement (enhanced speed and mobility, quality, or endurance of gait or wheelchair propulsion, transfers, dexterity and reaching, and sexual functioning), symptom relief (pain and muscle spasms, allow wearing of splints, improved hygiene, prevention of contractures), postural improvement (enhanced body image), decreased care burden (alleviation of dressing and hygiene processes, positioning for feeding, etc.), enhanced service responses (prevention of need for unnecessary medication and other treatments, facilitation of therapy, delay or prevention of surgery) [78]. It must be remembered that the treatment of spasticity is physical primarily in order to influence and control consecutive biomechanical changes. A programme of physical treatment should be established before and continued during and after pharmacological intervention. Muscle stretching improves the therapeutic effect of BoNT and vice versa [136], but, as in other areas of the field, RCT to produce high-level evidence are lacking. Selection of injection points, dosage, and injection of BoNT should be done by trained and experienced physicians. Gaining the skills requires time and commitment. The placing of the injection should be guided by ultrasound or EMG, which is recorded from the injection needle or by electrical stimulation of the muscle at the intended target position. The aim of EMG guidance is to record muscle action potentials at the intended injection site and assess their interference pattern on muscular activation [78]. Activation can be difficult to interpret in view of mass synergies in spasticity. Nevertheless, this will help to detect and distinguish spastic activity from contracture as has mainly been shown in the upper extremity in children with cerebral palsy [137–139] but is commonly used in SCI [133]. It can thereby also serve to focus injections to the endplate [140,141]. Local muscle stimulation by electric pulses that run through the injection needle can be used to localise the motor point and thereby likely improve efficacy of BoNT treatment, as is indicated by the growing body of studies elaborating on improved injection techniques [140,142–144]. In order to get good results, careful thought and planning is required. BoNT has a good propensity to seek neuromuscular junctions but placing the toxin as close as possible may best be achieved by electric stimuli at the lowest intensities to achieve better results. A high-volume dilution and an endplate-targeted injection are apparently superior to a low volume and endplate non-targeted injection, when injecting biceps brachii with BoNT in patients with spastic hemiparesis [140]. It may be assumed that these results can be extended to SCI but experimental or clinical data are missing. A number of articles are available to guide the treatment of spasticity with BoNT-A in particular [145,146]. These highlight the principles of treatment and the need for patients with spasticity to be managed by a multi-disciplinary team. They present checklists and extend on the right conditions to obtain optimal outcomes and, importantly, they assist in patient selection and the organisation of services [78].

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Contractures cannot be treated with BoNT as they indicate an inactive muscle. However, in our experience contract muscle fibres in a spastic muscle may be localised next to muscle fibres that are still active. Therefore, it may be reasonable to attempt injection even when a muscle is significantly shortened in contracture due to spasticity. The criterion for focal treatment should then be electrical activity in the EMG and intensive stretching and possibly splinting should follow the injection. Next to the surgical lengthening of muscles and tendons these measures are to our knowledge the only ones to treat states where contractures have already occurred. In conclusion, BoNT and ethanol/phenol are used in the SCI population to manage limb spasticity. BoNT is nowadays the prevailing drug in use, with good results, good therapeutic safety, and empirical as well as some scientific evidence of success. However, these interventions have not been rigorously studied in individuals with SCI. 6.3.9 Surgical Correction of Contractures A significant association between spasticity and contractures, i.e., reduced range of motion (ROM), is known in relation to spasticity in traumatic SCI [10]. In spastic paraplegia, this can typically affect the ankle plantarflexion, flexion of the knee, or flexion-adduction of the hip, where it will lead to impairment of positioning, gait, and transfers. If not sufficiently treatable pharmacologically, peripheral surgeries to release joints, muscles, and tendons can be satisfactory in selected cases, some of which may regain ambulatory capacity [147–149]. In tetraplegia, spasticity in the upper limb is generally more incapacitating because it has potentially negative effects on hand function as well as on transfers and mobility [150]. It typically involves shoulder adduction/internal rotators, together with elbow, wrist, finger and thumb flexors, and forearm pronators, and long-standing spasticity can cause soft-tissue structures to adapt to the shortened flexed and pronated position, subsequently leading to contractures. Hand spasticity typically results in difficulties related to reaching, grasping, and releasing items [150]. Surgery aims to improve the ability to grasp, release, and open the hand by lengthening or releasing tendons. These procedures have been developed for the past 20 years and nowadays provide a reliable decrease in tension in the spastic agonists. They may allow for an improvement of remaining functioning of antagonists when overpowering agonists are released, thereby reestablishing a better balance and synergy [150–152]. Furthermore, surgical transposition of the muscle-tendon unit can improve or reestablish joint stability in the spastic hand and it can help to reduce pain and the risk of developing contractures [150,153]. Surgical lengthening of tendons or release of contractures may be part of a concept of reconstruction of arm and hand function in tetraplegia; however, tendon transfers are not performed at the same time as lengthenings and releases to avoid poor balance of the hand. Restoration of elbow and wrist extension or handgrip has high potential to

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improve autonomy and mobility, and abilities such as eating, personal care, and self-catheterisation and productive work in at least 70% of tetraplegic patients [154]. An indication for surgical treatment can be seen if pharmacological treatment is insufficient or causes intolerable side effects. Another reason for focal surgery may be proof of antibodies against BoNT, rendering this drug ineffective as a treatment alternative in dynamic focal spasticity. Hypertonus should be stable over time and must have a limiting effect on daily activities. The patient should be well-informed and motivated to sustain and support post-operative treatment. Surgical treatment of contractures should be part of an entire treatment concept in first defining targeted improvements, allowing early mobilisation within 24 h by use of special suture techniques providing sufficient stability, splinting, and maintenance of activities of daily living, and subsequent systematic coordination and endurance training [150]. Given these prerequisites, post-operative improvement of hand function and patient reported benefit can be substantial and may be expected during a time period up to one year [155]. 6.3.10 Focal Anti-Spastic Surgical Treatment: Selective Dorsal Rhizotomy Selective dorsal rhizotomy (SDR) is an invasive therapeutic approach taken in selected children with spastic diplegia from cerebral palsy (CP), which is well-established for its positive effects on muscle tone and strength [156], range of motion, and ambulatory function [157–159]. In the CP population improvement in motor function after SPR was shown to be more than could be explained by the associated with intensive physiotherapy [158]. However, standardised assessment of gross motor function after one year led to controversial findings indicating that effects of SDR on function are modest and hard to extrapolate [160,161]. Long-term follow-up of CP patients for 5–15 years indicates that spasticity is effectively treated by SDR, while functional benefit is minor and depends on severity of the lesion [162–164]. However, other long-term follow-up studies, including patient-reported outcomes, show that the spasticity-reducing effect of SDR, although pronounced, did not seem to improve long-term functioning and contractures reoccurred in a significant number, indicating that contracture development in CP is not mediated by spasticity alone [165,166]. Spinal side effects, increase of pain, and hip luxation were seen, which, together with a gradual loss of the initial improvement [165,167,168], suggests caution for the indication of this invasive procedure. The role of this operation in the treatment of other spasticity causes is less well defined. A recent literature review to survey outcomes from SDRs performed outside the CP population showed that SDR have also been reported in patients with SCI and myelopathy with severe spasticity [169]. In this series, a total of 35 SCI patients, including patients with transverse myelitis and myelomeningocele, were reported. In a subgroup of traumatic SCI,

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spasticity and pain could be improved in the majority of cases and ambulatory performance was unchanged or also improved after the surgery in a case of spasticity following transverse myelitis [170]. Another early report on a small number of MS patients suffering from myelitis or myelopathy as well as one case of traumatic SCI claimed similarly favorable outcomes with respect to spasticity and ambulation [171]. The presumed mechanism by which SDR reduces spasticity and improves remaining motor function is by modulation (reduction) of afferent inputs to lower motor neurons to compensate for a loss of upper motor neuron regulation (inhibition), although the details of this mechanism are poorly understood [169]. The fact that the surgical intervention of SDR is effective independent of the level of lesion of the descending first-order motoneurons (i.e., CP or SCI) would support this notion. This is also supported by the observation of largely reduced spasticity following other surgical interventions involving SDR in SCI, e.g., with anterior sacral root stimulation for treatment of neurogenic bladder dysfunction following SCI [172]. Although these outcomes from SDR surgery are described as favorable and the use of SDR is suggested to be expanded to include pathologies such as spinal lesion [170], post-operative assessments and follow-up times are not standardised across reports and there are no systematic long-term observations in SCI. The example in CP children demonstrates that rigorous assessment standards must be applied to validate long-term outcomes given the fact that the intervention induces permanent changes within the nervous system. In conclusion, although the few reports on SDR in SCI may be promising, there is insufficient evidence to consider SCI diagnosis to be an indication for SDR. SDR may have a role in otherwise treatment-resistant spasticity in SCI, as could be shown in three pediatric patients with SCI [173]. However, it must be kept in mind that SDR, as an irreversible neuroablative procedure, should be performed with great caution and in selected cases only [169].

6.4 The Complex Spastic SCI Patient: Selection of Therapeutic Approach In this concluding section, two case reports will be presented illustrating difficulties that may specifically arise in the treatment of spasticity in SCI. They show how single pharmacological treatment may not be satisfactory due to systemic side effects or insufficient improvement of hypertonus and spasms. While a systematic approach and planning of treatment should include informed consenting and active cooperation of the medical team with the patient and their caregiver, it is important to also acknowledge

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patient history and observations on treatment effects, since the clinical exam can only test conditions during a very short time period, which is often not representative of the majority of daily life. In this description, subtle details may be relevant. 6.4.1 Case 1: Combination Therapies: Oral Systemic and Focal A 60-year-old female suffered spinal ischemia with incomplete Brown Sequard Syndrome at the Th8 level ASIA impairment scale C. She recovered walking ability using 2 canes within 5 months of rehabilitation and was released, returning to work as a part-time teacher. Within the following 6 months she developed increasing spasticity of the legs, which was treated orally with 5 mg of baclofen twice a day. Spasticity was not liming ambulatory capacity or other leg motor function and therefore this dose was not increased in order to allow the patient to continue to drive. However, repeated falls were noted, starting during rehabilitation and continuing during the following months. A first fall-related intra-articular fracture of the first phalanx of the left foot was documented by the orthopedic surgeons 2.5 years after the spinal injury, which was treated by casting. Within 5 years of SCI sudden unexpected falls resulted in 3 other fractures, e.g., a left malleolar fracture treated surgically after 3.5 years, a right metatarsale III/IV fracture after 4.5 years, and a right tri-malleolar fracture with dislocation after 5 years. A more detailed history-taking revealed that she had had unexpected flexing spasms of the hip and knee in every of these instances. Usually these spasms were triggered by episodes of back pain or bowel movements. As in other falls the flexion spasms resulted in sudden instability of stance and repeated uncontrollable movements of the legs. On several occasions, these movements had resulted in fractures when the uncontrollably moving leg had hit the floor or another object. Treatment of the instable intra-articular tri-malleolar fracture was initiated with external fixation. This resulted in exacerbation of hip flexion spasms and massive increase of hypertonus in triceps surae, posterior and anterior tibial muscles of the affected side, which could not be sufficiently treated orally or by BoNT injections. As exacerbation of spasticity lead to further dislocation of the fracture including the fixateur externe, the external fixation had to be removed and was replaced with an internal fixation. Oral medication was intensified, combining a daily dose of tizanidine 12 mg and baclofen 55 mg. The patient was discharged with this medication after consolidation of the fracture and rehabilitation of walking function during 3 months after the fracture. During subsequent controls, she reported side-effects in the form of dizziness and sleepiness, impeding her driving. This lead to a dose reduction to 40 mg baclofen but, subsequently, flexion spasms increased again. Focal treatment of hip flexors with BoNT was initiated, resulting in a satisfying control of frequency and intensity of the spasms.

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6.4.2 Case 2: Combination Therapies: Intrathecal Systemic and Focal A 21-year-old male suffered traumatic SCI with incomplete tetraplegia at the C3 level ASIA impairment scale C in a severe farming vehicle accident. After decompression surgery, the spine was internally stabilised from cervical 3 to thoracic 2 in several operations. During rehabilitation, he required early repeated BoNT injections in his overactive elbow flexors to allow continued arm training with sufficient elbow extension. Additional oral antispastic medication amounting to 75 mg of baclofen and 6 mg of tizanidine did not sufficiently reduce abdominal spasms and leg spasticity. A further increase of medication was followed by central side effects such as sleepiness and reduced alertness. Intrathecal testing with baclofen resulted in excellent response regarding lower body spasticity. Therefore, intrathecal baclofen was initiated following implantation of a permanent intrathecal catheter connected to a subcutaneous programmable pump 4 months after SCI. This improved lower body spasticity significantly at a final intrathecal dose of 130 ug baclofen at a concentration of 500 ug/ml. Oral anti-spastic medication could subsequently be tapered and alertness and participation in rehabilitation training improved substantially. Rehabilitation over a period  of 6 months resulted in partial independence for activities of daily life and the patient achieved mobility in an electric wheelchair, which he operates with his better right hand. Intermittent BoNT injections continued to help control his overactive elbow flexors to allow maintenance of sufficient elbow extension, which is also a prerequisite for correct positioning of the arm used to control the electric wheelchair. Recently, focal chemodenervation had to be extended because increasing wrist flexion spasticity had led to significant deterioration of the hand position, almost rendering his proper control of the wheelchair impossible. Additional injections in his right flexor carpi ulnaris resulted in efficient reduction of hypertonus in this muscle, reestablishing proper manual control. Further opportunity for improved hand control was evaluated recently by planning reconstructive hand surgery, as the neurological level had lowered to functionally C5 following chemodenervation of hyperactive wrist flexors, improving poor balance of wrist control and allowing active training of the antagonists for better wrist extension.

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88. Mehrholz, J. et al., Reliability of the Modified Tardieu Scale and the Modified Ashworth Scale in adult patients with severe brain injury: A comparison study. Clin Rehabil, 2005. 19(7): pp. 751–9. 89. Penn, R.D. et al., Intrathecal baclofen for severe spinal spasticity. N Engl J Med, 1989. 320(23): pp. 1517–21. 90. Tardieu, G., S. Shentoub, and R. Delarue, Research on a technic for measurement of spasticity. Rev Neurol (Paris), 1954. 91(2): pp. 143–4. 91. Anderson, K.D. et al., United States (US) multi-center study to assess the validity and reliability of the Spinal Cord Independence Measure (SCIM III). Spinal Cord, 2011. 49(8): pp. 880–5. 92. Catz, A. et al., A multicenter international study on the Spinal Cord Independence Measure, version III: Rasch psychometric validation. Spinal Cord, 2007. 45(4): pp. 275–91. 93. Itzkovich, M. et al., The Spinal Cord Independence Measure (SCIM) version III: Reliability and validity in a multi-center international study. Disabil Rehabil, 2007. 29(24): pp. 1926–33. 94. van Hedel, H.J., V. Dietz, and G. European Multicenter Study on Human Spinal Cord Injury Study, Walking during daily life can be validly and responsively assessed in subjects with a spinal cord injury. Neurorehabil Neural Repair, 2009. 23(2): pp. 117–24. 95. van Hedel, H.J., M. Wirz, and A. Curt, Improving walking assessment in subjects with an incomplete spinal cord injury: Responsiveness. Spinal Cord, 2006. 44(6): pp. 352–6. 96. Kalsi-Ryan, S. et al., Defining the role of sensation, strength, and prehension for upper limb function in cervical spinal cord injury. Neurorehabil Neural Repair, 2014. 28(1): pp. 66–74. 97. Kalsi-Ryan, S. et al., Development of the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP): Reviewing measurement specific to the upper limb in tetraplegia. J Neurosurg Spine, 2012. 17(1 Suppl): pp. 65–76. 98. Catz, A. et al., The Catz-Itzkovich SCIM: A revised version of the Spinal Cord Independence Measure. Disabil Rehabil, 2001. 23(6): pp. 263–8. 99. Velstra, I.M. et al., Changes in Strength, Sensation, and Prehension in Acute Cervical Spinal Cord Injury: European Multicenter Responsiveness Study of the GRASSP. Neurorehabil Neural Repair, 2015. 29(8): pp. 755–66. 100. Khurana, S.R. and D.S. Garg, Spasticity and the use of intrathecal baclofen in patients with spinal cord injury. Phys Med Rehabil Clin N Am, 2014. 25(3): pp. 655–69, ix. 101. Wirth, B., H. van Hedel, and A. Curt, Foot control in incomplete SCI: Distinction between paresis and dexterity. Neurol Res, 2008. 30(1): pp. 52–60. 102. Krawetz, P. and P. Nance, Gait analysis of spinal cord injured subjects: Effects of injury level and spasticity. Arch Phys Med Rehabil, 1996. 77(7): pp. 635–8. 103. Gorassini, M.A. et al., Changes in locomotor muscle activity after treadmill training in subjects with incomplete spinal cord injury. J Neurophysiol, 2009. 101(2): pp. 969–79. 104. Knikou, M. and C.K. Mummidisetty, Locomotor training improves premotoneuronal control after chronic spinal cord injury. J Neurophysiol, 2014. 111(11): pp. 2264–75.

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105. Manella, K.J. and E.C. Field-Fote, Modulatory effects of locomotor training on extensor spasticity in individuals with motor-incomplete spinal cord injury. Restor Neurol Neurosci, 2013. 31(5): pp. 633–46. 106. Zewdie, E.T. et al., Facilitation of descending excitatory and spinal inhibitory networks from training of endurance and precision walking in participants with incomplete spinal cord injury. Prog Brain Res, 2015. 218: pp. 127–55. 107. Yang, J.F. et al., Repetitive mass practice or focused precise practice for retraining walking after incomplete spinal cord injury? A pilot randomized clinical trial. Neurorehabil Neural Repair, 2014. 28(4): pp. 314–24. 108. Sun, J. et al., Gradually increased training intensity benefits rehabilitation outcome after stroke by BDNF upregulation and stress suppression. Biomed Res Int, 2014. 2014: p. 925762. 109. D’Amico, J.M. et al., Reduction of spinal sensory transmission by facilitation of 5-HT1B/D receptors in noninjured and spinal cord-injured humans. J Neurophysiol, 2013. 109(6): pp. 1485–93. 110. Dietz, V., M. Wirz, and L. Jensen, Locomotion in patients with spinal cord injuries. Phys Ther, 1997. 77(5): pp. 508–16. 111. Dietz, V., G. Colombo, and L. Jensen, Locomotor activity in spinal man. Lancet, 1994. 344(8932): pp. 1260–3. 112. Wernig, A. et al., Laufband therapy based on ‘rules of spinal locomotion’ is effective in spinal cord injured persons. Eur J Neurosci, 1995. 7(4): pp. 823–9. 113. Barbeau, H. and J. Fung, New Experimental Approaches in the Treatment of Spastic Gait Disorders. Movement Disorders in Children, 1992. 36: pp. 234–46. 114. Morawietz, C. and F. Moffat, Effects of locomotor training after incomplete spinal cord injury: A systematic review. Arch Phys Med Rehabil, 2013. 94(11): pp. 2297–308. 115. Coffey, J.R. et al., Intrathecal baclofen for intractable spasticity of spinal origin: Results of a long-term multicenter study. J Neurosurg, 1993. 78(2): pp. 226–32. 116. Taricco, M. et al., Pharmacological interventions for spasticity following spinal cord injury. Cochrane Database Syst Rev, 2000(2): p. CD001131. 117. Nance, P.W. et al., Efficacy and safety of tizanidine in the treatment of spasticity in patients with spinal cord injury. North American Tizanidine Study Group. Neurology, 1994. 44(11 Suppl 9): p. S44–51; discussion S51–2. 118. Taricco, M. et al., Pharmacological interventions for spasticity following spinal cord injury: Results of a Cochrane systematic review. Eura Medicophys, 2006. 42(1): pp. 5–15. 119. Chu, V.W., T.G. Hornby, and B.D. Schmit, Effect of antispastic drugs on motor reflexes and voluntary muscle contraction in incomplete spinal cord injury. Arch Phys Med Rehabil, 2014. 95(4): pp. 622–32. 120. Halpern, R. et al., Adherence associated with oral medications in the treatment of spasticity. PM R, 2013. 5(9): pp. 747–56. 121. Hagenbach, U. et al., The treatment of spasticity with Delta9tetrahydrocannabinol in persons with spinal cord injury. Spinal Cord, 2007. 45(8): pp. 551–62. 122. Novotna, A. et al., A randomized, double-blind, placebo-controlled, parallelgroup, enriched-design study of nabiximols* (Sativex((R))), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol, 2011. 18(9): pp. 1122–31.

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123. Wade, D.T. et al., Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis. Mult Scler, 2010. 16(6): pp. 707–14. 124. Dario, A. and G. Tomei, A benefit-risk assessment of baclofen in severe spinal spasticity. Drug Safety, 2004. 27(11): pp. 799–818. 125. Middel, B. et al., Effect of intrathecal baclofen delivered by an implanted programmable pump on health related quality of life in patients with severe spasticity. Journal of Neurology Neurosurgery and Psychiatry, 1997. 63(2): pp. 204–9. 126. Miracle, A.C. et al., Imaging evaluation of intrathecal baclofen pump-catheter systems. AJNR Am J Neuroradiol, 2011. 32(7): pp. 1158–64. 127. Draulans, N. et al., Intrathecal baclofen in multiple sclerosis and spinal cord injury: Complications and long-term dosage evolution. Clin Rehabil, 2013. 27(12): pp. 1137–43. 128. Borrini, L. et al., Occurrence of adverse events in long-term intrathecal baclofen infusion: A 1-year follow-up study of 158 adults. Arch Phys Med Rehabil, 2014. 95(6): pp. 1032–8. 129. Soni, B.M. et al., Treatment of spasticity in a spinal cord-injured patient with intrathecal morphine due to intrathecal baclofen tolerance – a case report and review of literature. Spinal Cord, 2003. 41(10): pp. 586–9. 130. Burbaud, P. et al., A randomised, double blind, placebo controlled trial of botulinum toxin in the treatment of spastic foot in hemiparetic patients. J Neurol Neurosurg Psychiatry, 1996. 61(3): pp. 265–9. 131. Simpson, D.M. et al., Botulinum toxin type A in the treatment of upper extremity spasticity: A randomized, double-blind, placebo-controlled trial. Neurology, 1996. 46(5): pp. 1306–10. 132. Kirazli, Y. et al., Comparison of phenol block and botulinus toxin type A in the treatment of spastic foot after stroke: A randomized, double-blind trial. Am J Phys Med Rehabil, 1998. 77(6): pp. 510–15. 133. Lui, J., M. Sarai, and P.B. Mills, Chemodenervation for treatment of limb spasticity following spinal cord injury: A systematic review. Spinal Cord, 2015. 53(4): pp. 252–64. 134. Sheean, G.L., Botulinum treatment of spasticity: Why is it so difficult to show a functional benefit? Curr Opin Neurol, 2001. 14(6): pp. 771–6. 135. Dolly, J.O. and K.R. Aoki, The structure and mode of action of different botulinum toxins. Eur J Neurol, 2006. 13 Suppl 4: pp. 1–9. 136. Reiter, F. et al., Low-dose botulinum toxin with ankle taping for the treatment of spastic equinovarus foot after stroke. Arch Phys Med Rehabil, 1998. 79(5): pp. 532–5. 137. Gaebler-Spira, D. and G. Revivo, The use of botulinum toxin in pediatric disorders. Phys Med Rehabil Clin N Am, 2003. 14(4): pp. 703–25. 138. Koman, L.A., B. Paterson Smith, and R. Balkrishnan, Spasticity associated with cerebral palsy in children: Guidelines for the use of botulinum A toxin. Paediatr Drugs, 2003. 5(1): pp. 11–23. 139. Autti-Ramo, I. et al., Management of the upper limb with botulinum toxin type A in children with spastic type cerebral palsy and acquired brain injury: clinical implications. Eur J Neurol, 2001. 8 Suppl 5: pp. 136–44. 140. Gracies, J.M. et al., Botulinum toxin dilution and endplate targeting in spasticity: A double-blind controlled study. Arch Phys Med Rehabil, 2009. 90(1): pp. 9–16 e2.

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141. Van Campenhout, A. et al., Motor endplate-targeted botulinum toxin injections of the gracilis muscle in children with cerebral palsy. Dev Med Child Neurol, 2015. 57(5): pp. 476–83. 142. Childers, M.K. et al., Evaluating motor end-plate-targeted injections of botulinum toxin type A in a canine model. Muscle Nerve, 1998. 21(5): pp. 653–5. 143. Shaari, C.M. and I. Sanders, Quantifying how location and dose of botulinum toxin injections affect muscle paralysis. Muscle Nerve, 1993. 16(9): pp. 964–9. 144. Mayer, N.H. et al., Comparative impact of 2 botulinum toxin injection techniques for elbow flexor hypertonia. Arch Phys Med Rehabil, 2008. 89(5): pp. 982–7. 145. Turner-Stokes, L. and A. Ward, Botulinum toxin in the management of spasticity in adults. Clin Med, 2002. 2(2): pp. 128–30. 146. Ward, A.B. et al., Use of botulinum toxin type A in management of adult spasticity – a European consensus statement. J Rehabil Med, 2003. 35(2): pp. 98–9. 147. Eltorai, I. and R. Montroy, Muscle release in the management of spasticity in spinal cord injury. Paraplegia, 1990. 28(7): pp. 433–40. 148. Keenan, M.A. et al., Hamstring release for knee flexion contracture in spastic adults. Clin Orthop Relat Res, 1988(236): pp. 221–6. 149. McCarthy, J.J. and R.R. Betz, Hip disorders in children who have spinal cord injury. Orthop Clin North Am, 2006. 37(2): pp. 197–202, vi–vii. 150. Wangdell, J. and J. Friden, Rehabilitation After Spasticity-Correcting Upper Limb Surgery in Tetraplegia. Arch Phys Med Rehabil, 2016. 97(6 Suppl): p. S136–43. 151. Reinholdt, C. and J. Friden, Selective release of the digital extensor hood to reduce intrinsic tightness in tetraplegia. J Plast Surg Hand Surg, 2011. 45(2): pp. 83–9. 152. Treanor, W.J., E. Moberg, and H.J. Buncke, The hyperflexed seemingly useless tetraplegic hand: a method of surgical amelioration. Paraplegia, 1992. 30(7): pp. 457–66. 153. Friden, J., New concepts in reconstruction of arm and hand function in tetraplegia – basic research and clinical application. Handchir Mikrochir Plast Chir, 2005. 37(4): pp. 223–9. 154. Friden, J. and A. Gohritz, Tetraplegia Management Update. J Hand Surg Am, 2015. 40(12): pp. 2489–500. 155. Wangdell, J., G. Carlsson, and J. Friden, From regained function to daily use: Experiences of surgical reconstruction of grip in people with tetraplegia. Disabil Rehabil, 2014. 36(8): pp. 678–84. 156. Ross, S.A. et al., Quadriceps and hamstring strength changes as a function of selective dorsal rhizotomy surgery and rehabilitation. Pediatr Phys Ther, 2001. 13(1): pp. 2–9. 157. Wright, F.V. et al., Evaluation of selective dorsal rhizotomy for the reduction of spasticity in cerebral palsy: A randomized controlled trial. Dev Med Child Neurol, 1998. 40(4): pp. 239–47. 158. Steinbok, P. et al., A randomized clinical trial to compare selective posterior rhizotomy plus physiotherapy with physiotherapy alone in children with spastic diplegic cerebral palsy. Dev Med Child Neurol, 1997. 39(3): pp. 178–84. 159. Steinbok, P. et al., Relationship of intraoperative electrophysiological criteria to outcome after selective functional posterior rhizotomy. J Neurosurg, 1995. 83(1): pp. 18–26.

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160. McLaughlin, J.F. et al., Selective dorsal rhizotomy: Efficacy and safety in an investigator-masked randomized clinical trial. Dev Med Child Neurol, 1998. 40(4): pp. 220–32. 161. McLaughlin, J. et al., Selective dorsal rhizotomy: Meta-analysis of three randomized controlled trials. Dev Med Child Neurol, 2002. 44(1): pp. 17–25. 162. Josenby, A.L. et al., Functional performance in self-care and mobility after selective dorsal rhizotomy: A 10-year practice-based follow-up study. Dev Med Child Neurol, 2015. 57(3): pp. 286–93. 163. Josenby, A.L. et al., Motor function after selective dorsal rhizotomy: A 10-year practice-based follow-up study. Dev Med Child Neurol, 2012. 54(5): pp. 429–35. 164. Nordmark, E. et al., Long-term outcomes five years after selective dorsal rhizotomy. BMC Pediatr, 2008. 8: pp. 54. 165. Tedroff, K., K. Lowing, and E. Astrom, A prospective cohort study investigating gross motor function, pain, and health-related quality of life 17 years after selective dorsal rhizotomy in cerebral palsy. Dev Med Child Neurol, 2015. 57(5): pp. 484–90. 166. Tedroff, K. et al., Does loss of spasticity matter? A 10-year follow-up after selective dorsal rhizotomy in cerebral palsy. Dev Med Child Neurol, 2011. 53(8): pp. 724–9. 167. Bolster, E.A. et al., Long-term effect of selective dorsal rhizotomy on gross motor function in ambulant children with spastic bilateral cerebral palsy, compared with reference centiles. Dev Med Child Neurol, 2013. 55(7): pp. 610–6. 168. Hicdonmez, T. et al., Hip joint subluxation after selective dorsal rhizotomy for spastic cerebral palsy. J Neurosurg, 2005. 103(1 Suppl): pp. 10–16. 169. Gump, W.C., I.S. Mutchnick, and T.M. Moriarty, Selective dorsal rhizotomy for spasticity not associated with cerebral palsy: Reconsideration of surgical inclusion criteria. Neurosurg Focus, 2013. 35(5): p. E6. 170. Mazarakis, N.K., I. Ughratdar, and M.H. Vloeberghs, Excellent functional outcome following selective dorsal rhizotomy in a child with spasticity secondary to transverse myelitis. Childs Nerv Syst, 2015. 31(11): pp. 2189–91. 171. Laitinen, L.V., S. Nilsson, and A.R. Fugl-Meyer, Selective posterior rhizotomy for treatment of spasticity. J Neurosurg, 1983. 58(6): pp. 895–9. 172. Brindley, G.S. et al., Sacral anterior root stimulators for bladder control in paraplegia: The first 50 cases. J Neurol Neurosurg Psychiatry, 1986. 49(10): pp. 1104–14. 173. Reynolds, R.M. et al., Role of dorsal rhizotomy in spinal cord injury-induced spasticity. J Neurosurg Pediatr, 2014. 14(3): pp. 266–70.

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7 Clinical Management of Spasticity and Contractures in Multiple Sclerosis Lorna Paul and Paul Mattison CONTENTS 7.1 Multiple Sclerosis; Incidence, Epidemiology, and Disease Course..... 176 7.2 Pathophysiology of MS and Spasticity.................................................... 178 7.3 Disease-Modifying Therapy in MS.......................................................... 179 7.4 Spasticity in MS........................................................................................... 179 7.5 Management of Spasticity in MS.............................................................. 181 7.5.1 Pharmacological Treatments......................................................... 181 7.5.1.1 Treatments for Generalised Spasticity: Oral Medications....................................................................... 181 7.5.1.2 Baclofen............................................................................. 182 7.5.1.3 Tizanidine......................................................................... 182 7.5.1.4 Dantrolene......................................................................... 183 7.5.1.5 Gabapentin........................................................................ 183 7.5.1.6 Cannabinoids.................................................................... 184 7.5.1.7 Benzodiazepines.............................................................. 186 7.5.1.8 Evidence-Based Guidelines for Oral Antispasticity Medications: Spanish and German Consensus Document...................................................... 186 7.5.1.9 Treatments for Focal Spasticity...................................... 187 7.5.1.10 Phenol Chemodenervation............................................. 187 7.5.1.11 Botulinum Toxin.............................................................. 188 7.5.1.12 Intrathecal (IT) Baclofen.................................................. 189 7.5.2 Non-Pharmacological Treatments................................................ 190 7.5.2.1 Physical Activity/Exercise for the Management of Spasticity in MS........................................................... 191 7.5.2.2 Transcutaneous Electrical Nerve Stimulation (TENS) for the Management of Spasticity in MS......... 191 7.5.2.3 Transcranial Magnetic Stimulation for the Treatment of Spasticity in MS........................................ 193

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7.5.3 Other Non-Pharmacological Interventions for the Management of Spasticity in MS..................................... 194 7.5.3.1 Surgery.............................................................................. 195 7.5.4 Strategy for the Management of Spasticity in MS...................... 195 References.............................................................................................................. 197

7.1 Multiple Sclerosis; Incidence, Epidemiology, and Disease Course Multiple sclerosis (MS) is a common neurological disorder causing disability in young people in the developed world, with approximately 2 million people affected by the condition worldwide and 100,000 people affected in the UK (McAlpine and Compston 2005). MS is a progressive illness with neuro­ inflammatory and neurodegenerative components generally accepted to have an underlying auto-immune aetiology. While an epidemiological gradient of prevalence has long been recognised, with cases more commonly seen the farther away from the equator, there are exceptions to this trend, with rates in Sardinian people approaching those of Northern Europeans and prevalence being low in the Inuit people of Canada (Koch-Henriksen and Sorensen 2010). Present thinking suggests that MS occurs as a result of genetic predisposition allied to environmental factors. Circumstantial evidence implicating a lack of vitamin D as a significant environmental factor in the aetiology comes from studies which have demonstrated that season of birth may be important, with those born in the summer months in the Northern Hemisphere being more likely to develop the illness than those born during the winter (Torkildsen et al. 2012). This hypothesis was strengthened by the discovery of an association between the genetic locus HLA DRw1*15 on chromosome 6 and risk of MS, this particular gene being important in the regulation of immune responses and also critically being dependent on vitamin D for proper function (Ramagopalan et al. 2009). There have however been more than 50 genes linked to increased risk of MS, suggesting that the genetic predisposition is complex. Viral triggers have also been implicated with the strongest evidence linking Epstein Barr Virus (EBV) infection in childhood or early teenage years as a potential significant factor in producing the “abnormal” immune response (Ascherio and Munger 2010). Since the condition can affect any part of the central nervous system (brain and spinal cord) people with MS can experience a wide variety of sensory, motor, visual, brainstem, and autonomic dysfunction, d ­ epending upon which areas of the brain and spinal cord are involved. Different clinical courses and phases of the illness are recognised based primarily on symptom presentation and clinical findings. These have been

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used to categorise the illness and, since the introduction of disease-­modifying treatments in the mid-1990s, to inform treatment decisions (Figure 7.1). Relapsing-remitting MS (RRMS) describes a clinical course characterised by acute onset of new, or significant worsening of existing, symptoms lasting for more than 24 hours and not associated with infection. Recovery from such episodes may occur spontaneously or following treatment with corticosteroids. This pattern of disease is seen in approximately 80% of patients early in the course of the condition. The majority of these acute exacerbations either resolve completely or substantially at this stage. Progressive-relapsing disease describes a course where acute exacerbations are experienced similar to RRMS but with incomplete recovery from Progressive-relapsing multiple sclerosis Steady decline since onset with superimposed attacks.

Secondary progressive multiple sclerosis Initial relapsing-remitting multiple sclerosis that suddenly begins to have decline without periods of remission.

Primary progressive multiple sclerosis

Increasing disability

Steady increase in disability without attacks.

Relapsing-remitting multiple sclerosis Unpredictable attacks which may or may not leave permanent deficits followed by periods of remission.

Time FIGURE 7.1 Four clinical patterns of MS.

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each episode so that early disability accumulation becomes a marked feature of this presentation. The majority of patients who initially present with RRMS will eventually develop a more progressive phase of disability accumulation with an absence of the typical relapses that were a feature of the earlier presentation. This clinical situation is called secondary progressive MS and develops typically between 15 and 20 years after diagnosis. Primary progressive MS is a clinical entity in which relapses are not a feature but the patient experiences increasing levels of disability from diagnosis. It occurs in approximately 10% of those diagnosed with MS and the course of this type of clinical presentation is very variable, ranging from rapidly deteriorating levels of function to very little discernible change over a 20-year period.

7.2 Pathophysiology of MS and Spasticity Unlike the majority of neurological conditions causing spasticity, MS is not a monophasic illness. In conditions such as stroke, spinal cord injury, cerebral palsy, and traumatic brain injury there is a single insult to the central nervous system (CNS) resulting in an imbalance of efferent or afferent control of the normal spinal and cortical mechanisms of homeostasis that maintain normal muscle tone (this term and the anomalies associated with its use are d ­ iscussed in Chapter 1). Multiple sclerosis, however, is a dynamic condition with repeated injury to the CNS at different sites and affecting different pathways within the brain and spinal cord at different times over a long time interval. Acute exacerbations (relapses) occur in the majority of patients, particularly in the first 10–­ 15 years following diagnosis and these may sometimes manifest as changes in tone either because of inflammatory change within myelin causing interruption of normal nerve conduction or because of sensory symptoms brought on by the relapse causing adverse nociceptive afferent input. Such changes in tone may resolve spontaneously or with treatment of the relapse with steroids. MS is characterised by neuroinflammatory components which principally affect the myelin sheath and often give rise to acute neurological disturbances, which the patient may recognise as a relapse, although it is clear from the use of enhanced MRI imaging that many such inflammatory episodes are sub-clinical, i.e., do not give rise to symptoms. Such episodes may completely resolve or over time lead to scarring (sclerosis) and loss of metabolic support for the underlying nerve axon, which may degenerate as a consequence. However, it is also apparent, particularly in the primary progressive variant of MS, that axonal degeneration may occur independently of inflammation as a separate immunologically mediated process. There is also some evidence to suggest that axonal degeneration can occur as a separate process in the early stages of relapsing/remitting MS (Su et al. 2009).

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In either case, the overall effect is a progressive loss of nerve axons within the brain and spinal cord. Given the widespread distribution of lesions within the brain and spinal cord, clearly interruption to normal excitatory and inhibitory pathways may occur at any level, although loss of supraspinal inhibitory control of reflex activity is the dominant mechanism leading to progressive spasticity in MS. Axonal degeneration and spinal cord atrophy are cardinal features found in patients with MS affected by significant spasticity.

7.3 Disease-Modifying Therapy in MS Disease-modifying treatments for MS have so far been disappointing in relation to prevention of accumulation of disability, with clinical trial outcomes having been centred around relapse reduction. This has meant that regulatory bodies such as the National Institute for Care and Clinical Excellence (NICE) in the United Kingdom have defined the indications for use of disease-​ modifying treatments around this parameter. More recently introduced treatments, such as natalizumab, fingolimod, dimethyl fumarate, and alemtuzumab have a greater effect upon short-term accumulation of disability (as measured by EDSS) but are reserved at least in the case of nalaizumab and fingolimod for second-line treatment where firstline agents have been unsuccessful (Kappos et al. 2010, Polman et al. 2006). A range of newer disease-modifying drugs is imminent. Ocrelizumab, a monoclonal antibody treatment targeting B cells, has recently been reported to reduce disability progression in patients with primary progressive MS, by approximately 20% over a 24-week period compared to placebo, as well as having favourable effects upon both the number of T2 weighted lesions on MRI and total brain volume (Montalban et al. 2017). Further long-term studies are required to confirm this effect. Such developments and others in current clinical trials may well alter treatment strategies in the future, but for many people affected by MS the main therapeutic goal is to effectively manage symptoms rather than disease modification, although clearly the two aims are not mutually exclusive.

7.4 Spasticity in MS Spasticity is one of the commonest symptoms experienced by people affected by MS, occurring in up to 80% of patients at some stage of the disease, with approximately 50% of those affected having troublesome symptoms of pain and discomfort or impaired mobility as a consequence (Rizzo et al. 2004). Overall figures of between 40 and 80% are reported (Flachenecker et al. 2014).

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The different prevalence rates are explained in part to the various definitions of spasticity or the method used to assess spasticity, e.g., Rizzio et al. used self-report methods where spasticity was described as “unusual tightening of muscles,” whereas a number of other studies have used the Modified Ashworth Scale (Flachenecker et al. 2014). The classic clinical features of spasticity are increased muscle tone, stiffness, pain, and reduced mobility. This is also true in MS; however, other “symptoms” of spasticity in MS include muscle weakness, fatigue, bladder dysfunction, sleep disturbances, anxiety, and depression (Flachenecker et al. 2014, Rizzo  et  al. 2004). Specifically in MS, spasticity more commonly affects the lower limbs compared to the upper limbs or trunk (Flachenecker et al. 2014). Spasticity is not, however, an isolated symptom and there is a complex interrelationship with other symptoms, which may be factors in contributing to the burden of symptomatology. Pain and bladder dysfunction, symptoms experienced by more than 50% of people with MS, are important contributors producing or ­exacerbating spasticity. There are a number of factors that are known to be associated with increased levels of spasticity. In particular, there is a linear relationship between increasing severity of spasticity and both increasing disease duration and disability level (Flachenecker et al. 2014, Rizzo et al. 2004). There is also a clear relationship between spasticity and reduced walking ability, urinary dysfunction and sleep disturbance (Zettl et al. 2014). Other factors reported to be associated with the presence of spasticity in MS are increasing age, male gender, and progressive forms of the disease (Flachenecker et al. 2014, Rizzo et al. 2004). Furthermore, requiring a walking aid/wheelchair, being unemployed, and increased use of health care resources have also been stated as associated with spasticity in people with MS (Flachenecker et al. 2014, Rizzo et al. 2004). The few studies in this area have been cross-sectional, thus can only derive associations between spasticity in MS and demographic and clinical characteristics. In addition, the factors associated with spasticity are not independent, e.g., increasing age is associated with increasing levels of disability and both are associated with the presence of spasticity. Some relationships are direct and some and indirect; e.g., the association between unemployment and spasticity is unlikely to be a direct relationship, other associated factors such as fatigue may play a significant and more direct role. The situation is therefore complex, with many possible mediating factors involved. Ultimately, spasticity, as currently understood, has a negative impact on function, activities of daily living (ADL), and quality of life for people with MS (Flachenecker et al. 2014, Rizzo et al. 2004). This, in turn, has other consequences, with increased carer burden and reduced employability of the person affected. In addition, there are higher socio-economic costs for individuals and their families, as well as increased statutory social care and health service-related costs. A recent study of resource use related to spasticity in MS undertaken in Sweden estimated the costs per patient per year to exceed €114,000, with costs increasing proportionately to increasing levels of spasticity as indicated on a NRS (Svensson et al. 2014). Similarly quality of

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life scores on the EQ-5D were also related to increasing levels of spasticity in a study carried out on 419 patients with MS in Germany (Flachenecker et al. 2014). Interestingly, the health care costs only account for around 7% of all costs associated with spasticity; the main costs are attributable to nonmedical and indirect costs such as personal assistance, informal care, and patient and caregiver loss in productivity.

7.5 Management of Spasticity in MS The management of spasticity in MS requires a good understanding of the nature and natural history of the disease within an experienced multidisciplinary team setting. An understanding of the evidence base underpinning therapeutic interventions and an awareness of tolerability of the adverse effect/benefit relationship to treatment is essential. Spasticity itself can in some circumstances be of benefit with the bracing effect of a degree of increased lower limb spasticity compensating for muscle weakness and facilitating walking and transfer abilities. A review of the available management options follows, with examination of the evidence for efficacy of these interventions, followed by a suggested practical clinical approach to integrating the different treatment strategies into typical clinical scenarios. 7.5.1 Pharmacological Treatments Pharmacological management can be divided into systemic treatments, in situations where the patient has more generalised spasticity symptoms, or focal treatments that aim to target specific localised affected muscle groups. The evidence base for the most commonly used medications in treating spasticity related to MS is generally poor, reflected in both the Cochrane review (Shakespeare et al. 2000) and the NICE guidelines for MS; however, there have been more recent attempts to produce evidence-based guidelines by Spanish and German authorities using the Scottish Intercollegiate Guidelines Network (SIGN) guidance framework of weighting of evidence and strength of recommendations. 7.5.1.1 Treatments for Generalised Spasticity: Oral Medications Oral medication taken for spasticity is often poorly tolerated because of significant side effects, with adherence rates of less than 50% reported in a largescale retrospective study in the USA (Halpern et al. 2013). This is reflected in German data showing that 41% of physicians and 36% of patients were dissatisfied with their current management of spasticity (Flachenecker 2013).

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7.5.1.2 Baclofen Baclofen has been in use since the mid-1970s and is the most commonly prescribed oral anti-spasticity agent. It is structurally similar to GABA and acts agonistically on GABAB receptors, restricting the influx of calcium at presynaptic terminals, suppressing the release of excitatory neurotransmitters. It acts on both monosynaptic and polysynaptic reflex pathways leading to inhibition of γ efferent motor responses (Bormann 1988, Feldman et al. 1980), but more possibly on the presynaptic inhibitory pathways in the spinal cord. While its principal site of action is at spinal cord level, baclofen also has central actions at brainstem and cortical levels, which result in its major side effects of fatigue, somnolence, and nausea (Addolorato et al. 2006). Muscle weakness and liver function abnormalities also occur but are less frequent. Halpern et al. (2013) recently reported that adherence to baclofen therapy was only 20.4% in a large retrospective study of a population of patients commenced on antispasticity medication over a 5-year period in the USA (Halpern et al. 2013). A relatively small number of randomised controlled trials (RCTs) have compared baclofen with placebo in MS-related spasticity and have reported reducing spasticity and frequency and severity of spasms. However, none would be considered to be of sufficient quality to allow firm recommendations for treatment; suffering from a lack of consistency in outcome measurement, selection bias, or insufficient power (Shakespeare et al. 2000). A limited number of small-scale head-to-head studies comparing baclofen with tizanidine and baclofen with diazepam have not demonstrated the superiority of either drug in terms of clinical efficacy or patient tolerability (Bass et al. 1988). Pragmatically however, baclofen is commonly used and is recommended as first-line treatment for spasticity associated with MS in the most recent NICE guidelines for MS in the UK. Dosage ranges from 5 mg to 100 mg daily, with dose titration commencing with 5 mg at night increasing progressively until the desired clinical response is obtained or the patient experiences unacceptable side effects. In practice doses, above 60 mg daily in divided doses tend to produce only modest clinical benefits but significantly increase unwanted side effects. 7.5.1.3 Tizanidine Introduced in the early 1980s as a novel treatment for spasticity, tizanidine acts as an α-2 agonist modulating the release of excitatory neurotransmitters at pre-synaptic level. Animal studies have demonstrated effective suppression of polysynaptic reflexes in the spinal-transected cat. Its mode of action produces a reduction in facilitation of spinal motor neurones (Newman et al. 1982). The UK tizanidine study group reported a 20% mean reduction in overall muscle tone assessed by a composite Ashworth score at multiple sites compared with placebo in an RCT involving 182 subjects with MS (Group 1994),

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although a similar study from the USA published simultaneously involving similar numbers and primary outcome measure was unable to confirm this (Smith et al. 1994). Both studies, however, suffered from high drop-out rates; in the UK study, only 70 of the original 182 complied fully with the study protocol (29 tizanidine, 41 placebo). No functional gains were found in relation to improved ambulation or activities of daily living (ADL) capabilities. Dosage scheduling typically starts at 2 mg daily, increasing every third day in 2-mg increments. Effective adult daily dosages are usually within the range of 16–28 mg, with a maximum recommended daily dose of 36 mg in divided dosages. Side effects commonly include dry mouth, drowsiness and light-headedness; rarer adverse effects are hallucinations, asthenia, and liver function test abnormalities the latter being reversible on withdrawal of the drug. Tizanidine has similar rates of compliance to baclofen (Halpern et al. 2013) but is significantly more expensive than baclofen and for this reason is often listed as a second-line agent in hospital formularies. 7.5.1.4 Dantrolene Dantrolene differs from the centrally acting drugs baclofen and tizanidine in that its principal site of action is within skeletal muscle itself. It blocks calcium release from the sarcoplasmic reticulum in skeletal muscle, interfering with the excitation-contraction coupling necessary to produce muscle contraction (Pinder et al. 1977). Although several RCTs in people with MS have reported favourable reductions in muscle tone with dantrolene compared to placebo (Gelenberg and Poskanzer 1973) and one double-blind crossover comparative study showing equivalence of effect with diazepam (Schmidt et al. 1975), these studies were undertaken over 30 years ago, with no validated outcome measures (physician-assessed spasticity being the primary outcome measure). The principal limiting factor in the use of dantrolene is its propensity to produce significant muscle weakness very often within a narrow therapeutic range. Initial dosing is 25 mg daily, increasing in 25-mg increments every 3–4 days to a maximum of 200 mg daily if tolerated. Because of its muscle weakness-inducing properties, dantrolene may be more suitable for patients who are not mobile. Other commonly reported side effects include drowsiness and gastrointestinal upset, nausea, and diarrhoea. Severe and irreversible liver damage can occur with dantrolene therapy and routine monitoring of liver function tests is mandatory (Durham et al. 1984). 7.5.1.5 Gabapentin Gabapentin was originally developed as a novel anti-convulsant for the treatment of partial seizures in the early 1990s, and was subsequently demonstrated to have significant beneficial effects on neuropathic pain.

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Structurally, it is similar to the γ-aminobutyric acid (GABA) neurotransmitter, and it was postulated that it exerted its actions by GABA-mimetic properties acting on GABA receptors. However, this is not the case since it does not bind to GABAa, GABAb, or glutamate receptors (Shimizu et al. 2004). Experimental animal work has indicated a possible antagonistic effect on NMDA receptors producing calcium channel blockade and this may explain both the effects on pain modulation via dorsal root ganglia and ascending spinal cord afferent pathways as well as spinal motor output. It may also be that the amelioration of neuropathic pain as an external trigger is significant in reducing noxious afferent input and may explain its effects on reducing spasm and spasticity (Kukkar et al. 2013). Mueller et al. undertook a small study (n = 15) with a randomised crossover design of the short-term effects of gabapentin on spasticity in MS patients, and reported favorable outcomes in terms of Ashworth scores and spasm frequency compared to placebo (Mueller et al. 1997). A subsequent well-controlled crossover design RCT in 21 patients with MS confirmed the findings of the Mueller study (Mueller et al. 1997), with gabapentin producing significant benefits in relation to reduced Ashworth scores and spasm frequency with patient-reported improvement in functional ability (Cutter et al. 2000). Optimal dosage is within the range of 1200–1600 mg daily, but doses up to a maximum of 3600 mg daily are well tolerated. Current NICE guidelines for MS suggest that gabapentin should be considered as a first-line therapy for spasticity in patients with MS (National Clinical Guideline 2014). 7.5.1.6 Cannabinoids Cannabis has been used medicinally for over 4000 years, being mentioned in a pharmacopeia written by the Chinese Emperor Shen Nung in 2700 BC as a treatment for gout, rheumatism, malaria, and dysmenorrhoea. Historically, cannabis has been used by large numbers of patients affected by MS; Chong et al. reported a survey of UK MS patients in which over 80% of those surveyed had tried cannabis, with more than 70% claiming beneficial effects in terms of symptomatic relief (Chong et al. 2006). Two types of endogenous cannabinoid receptors have been identified in humans. The CB1 receptor is widely distributed throughout the central nervous system, most densely expressed within the substantia nigra and globus pallidus (Herkenham et al. 1990). Stimulation of the CB1 receptor produces suppression of neurotransmitter release presynaptically, in turn leading to suppression of excessive motor output, which provides a putative explanation for its potential to influence both muscle spasm and stiffness (Pan et al. 2008). CB2 receptors are expressed within the immune system, being found on lymphocytes and raising the possibility of an immune-modulatory effect on autoimmune disorders including MS; however, the recently completed

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CUPID study found no beneficial effects of cannador (2.5 mg δ9THC plus 1.25 mg of cannabidiol) on slowing progression of the disease compared to placebo (Zajicek et al. 2013). Two large RCTs have reported on the effects of oral cannador on spasticity in MS. The CAMS study involving 657 subjects demonstrated no difference in effect between the interventional and placebo treated groups over a 15-week period (Zajicek et al. 2003). However, the 1-year extension phase of the study showed that the active intervention group did have a significant reduction in Ashworth scores, suggesting that longer-term treatment may be required to produce an effect (Zajicek et al. 2005). The MUSEC study used a patient self-reported category rating scale (CRS) encompassing subjective muscle stiffness, body pain, muscle spasms, and quality of sleep as the primary outcome measures. Over a 10-week treatment phase, 279 patients were randomised to either cannador or placebo following dose titration. Although most participants reported improvement on the parameters of the CRS, the improvements reported were significantly greater for the cannador-treated group (Zajicek et al. 2012). Sativex is an oromucosal spray containing 27 mg of δ 9THC and 25 mg of cannabidiol (per ml, with each metred dose giving 2.7 mg and 2.5 mg, respectively, of each constituent per spray). The oromucosal route leads to quicker absorption and higher peak plasma concentrations than the oral route, while avoiding the much higher and unpredictable plasma concentrations that are a feature of inhaled (smoking) cannabis. This may to some extent explain the relatively low incidence of psychoactive side effects reported with sativex and oral cannador. Two RCTs (Collin et al. 2007, Wade et al. 2004) used an 11-point neurological rating scale to assess subjects symptomatic response to sativex on muscle stiffness. One study reported a 0.5 mean reduction in NRS compared with placebo for a 6-week treatment phase (Collin et al. 2007); the second showed no difference in NRS over a 14-week treatment phase (Wade et al. 2004). Post hoc analysis of subgroups, however, indicated that for some patients the magnitude of effect was much greater, which introduced the concept of responders versus non-responders. It is postulated that genetic variation in CB1 receptors affects ability for long-term potentiation of synaptic transmission (Mori et al. 2014), which may explain this finding. Two further studies have since been conducted with a 4-week sativex treatment phase to identify treatment responders before randomisation to a 12-week RCT for treatment responders only. These studies showed that for treatment responders sativex was effective compared with placebo with a least a 30% improvement in NRS. A meta-analysis published by Wade et al. calculated that the odds ratio for improvement in spasticity by sativex in treatment responders is 1.67 (CI) 1.05–2.65, p = 0.030 (Wade et al. 2010). Clinical trial experience showed that sativex was well tolerated; the most common adverse effects reported were drowsiness, dizziness, and ataxia.

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Sativex is now licensed in the UK for use in patients with moderate to severe spasticity due to MS who have not responded adequately to other anti-­ spasticity medication. However, it is not currently recommended by NICE for use within the National Health Service in the UK. 7.5.1.7 Benzodiazepines Benzodiazepines have GABAa-agonistic properties, resulting in pre-synaptic inhibition of post synaptic poly- and monosynaptic reflexes (Pedersen 1974). Evidence of efficacy of benzodiazepines is limited to small, poorly controlled clinical trials, the majority of which were comparative studies of diazepam with baclofen and dantrolene and showed comparable effects of diazepam in terms of reducing spasticity and muscle spasm (From and Heltberg 1975, Schmidt et al. 1975). Diazepam was, however, less well tolerated and its side effect profile means that it has limited usefulness in practice, as the dosage required for any effective spasticity reduction produces unacceptable levels of sedation for the majority of patients. Problems of dependency and concerns about safety exist, since overdosage can lead to significant respiratory depression, coma, and death, while abrupt withdrawal can produce severe anxiety and epileptic seizures. In practice, the most useful role of benzodiazepines is the control of painful nocturnal muscle spasm with clonazepam 1–3 mg at night being an effective regime, which, because of its shorter half-life, is less likely to produce unwelcome sedation the following day. 7.5.1.8 Evidence-Based Guidelines for Oral Antispasticity Medications: Spanish and German Consensus Document Grading the evidence base for the most commonly used anti-spasticity drugs utilising SIGN guidelines methodology was first reported by Gold and OrejaCuevara following a consensus meeting involving 250 Spanish neurologists and published in 2013 (Table 7.1) (Gold and Oreja-Guevara 2013). A similar process was undertaken in Germany using a PubMed literature review to derive evidence levels and to grade recommendations. The Spanish and TABLE 7.1 German/Spanish Guidelines for Anti-Spasticity Drugs in MS Medication Baclofen Tizanidine Gabapentin Sativex Dantrolene/benzodiazepines

Evidence Class

Recommendation Grade

Ib-II 1b 1b 1a Insufficient

A A A A None

Source: Adapted from Gold, R. and Oreja-Guevara, C., Expert Rev Neurother, 13(12 Suppl), 55–9, 2013.

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German guidelines are very similar and contrast with the conclusions of the draft NICE guidelines for spasticity management, which comment upon the paucity of good quality evidence to support recommendations in this area. 7.5.1.9 Treatments for Focal Spasticity Focal spasticity refers to a situation in which increased tone is particularly problematic and confined to isolated muscle groups where systemic treatment would be inappropriate because of unwanted side effects or a negative effect of producing muscle weakness in unaffected muscles. Treatment options are regional nerve blockade with neuroablative agents such as phenol or direct injection into the affected muscles with botulinum toxin. Clinical applications in MS would typically include alleviation of hip adductor tone “with scissoring” interfering with comfortable seating positioning or making toileting and perineal hygiene difficult, increased calf muscle tone producing equino varus-type deformation at the ankle joint, impairing gait and compromising the fitting of suitable orthoses. Less commonly in MS finger or wrist flexion tone, compromising function, will respond to local treatment. Phenol is significantly cheaper than botulinum and has the advantage that onset of action is instantaneous. 7.5.1.10 Phenol Chemodenervation Phenol in a concentration of between 5–7% mixed with glycerine has a neurolytic effect, causing chemolysis of myelin and nerve axons but preserving the endoneurial tubes, which form a framework for subsequent nerve regeneration (Felsenthal 1974). The onset of the anaesthetic effect is instantaneous, with reduction in spasticity of muscle groups supplied by the chemolyzed peripheral nerve being observed within 24 hours. The technique requires an experienced operator and is time-consuming. Closed-nerve blockade involves identification of individual nerve motor branches using a needle nerve stimulator in order to avoid injection into sensory nerve fibres, with consequent painful dysaesthesiae for the patient. Published evidence of the effectiveness of phenol chemodenervation in MS is sparse, with no RCTs being undertaken and most evidence coming from case reports or individual physicians’ experiences. Such reports, however, suggest gains in relation to relief from painful spasm, improved seating positioning, improved hygiene and personal care, and a reduction in skin breakdown. In MS, the technique is most usually reserved for severe lower limb spasticity and involves unilateral or bilateral lysis of the obturator nerve. The beneficial effects last for between 6–9 months on average and the technique can be repeated as often as required.

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In situations where it is difficult clinically to decide whether severe spasticity or fixed contractures are producing flexion deformities, a similar motor nerve injection of short-acting local anesthetic can be used to predict response to chemolysis prior to phenol ablation (Elovic et al. 2009). 7.5.1.11 Botulinum Toxin Botulinum toxin is derived from the bacterium clostridium botulinum, the organism responsible for botulism, a severe form of food poisoning characterised by widespread muscular paralysis. However, when injected directly into individual muscle groups, systemic absorption does not occur and effects are confined to local limited spread within 30–40 mm of the region injected. Botulinum blocks the neuromuscular junction, preventing presynaptic release of acetylcholine. Seven distinct toxins have been identified but botulinum toxin types A and B are the only types manufactured commercially. Type A is the most effective and most widely used (Hambleton 1992). There is limited adequately controlled clinical trial evidence of the use of botulinum toxin in MS related spasticity. Three RCTs have, however, reported positive effects on hip adductor tone, resulting in reduced spasticity scores, reduction in painful spasm, and improved hygiene (Snow et al. 1990). A dose-ranging study reported similar positive outcomes with response rates being better to higher doses (1500 units total dosage of Dysport) (Hyman et al. 2000). The positive effects on hip adductor spasticity were confirmed by a more recent study (Ochudlo 2012). There is evidence that intensive physiotherapy following botulinum injection improves the response, and one study reported improved outcomes with vibration therapy combined with botulinum (Paoloni et al. 2013). Specific muscles to be injected are identified using electromyography, neurostimulation, or ultrasound guidance. Dosing schedules are dependent upon the size of the muscle to be injected. Of particular note, the two most commonly used brands of botulinum, dysport (manufactured by Ipsen) and botox (manufactured by Allergan), are not interchangeable in terms of equivalent dosage scheduling and it is important to ensure that the correct dose  for  each of these products is used. The onset of action is within 3–5 days post-injection and beneficial effects last for between 3 and 6 months on average. Lessening effect with repeat injections may indicate the development of neutralising antibodies, the incidence of such development has been reported from as low as 2% of patients treated, up to 44% in different series. Development of antibodies is proportional to the frequency and number of total treatment sessions and to the dosage used (Jankovic and Brin 1991). Treatment is usually well tolerated, the most commonly reported side effects being transient discomfort at the injection site.

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7.5.1.12 Intrathecal (IT) Baclofen Patients with severe lower limb spasticity not responding to adequate doses of oral or local anti-spasticity treatment or who are intolerant of side effects of such treatments may be considered for intrathecal baclofen. This involves the surgical implantation of a subcutaneous battery-powered pump with a reservoir containing baclofen in liquid form into the tissues of the abdominal wall, from which a catheter is fed into the subarachnoid space allowing microdoses of baclofen to be delivered directly and continuously into the cerebrospinal fluid (CSF) bathing the lumbar and sacral spine. The net effect is to deliver concentrations of the drug at the site of action approximately four times higher than those achieved by oral dosing but with only 1% of the equivalent oral dose (Penn et al. 1989). The most troublesome systemic adverse effects of the drug are thus avoided, with reduced fatigue and improved cognition being reported by patients. Prior to surgical implantation patients are usually admitted for a test dose given via lumbar puncture. The initial dosage of 25 mcg is administered and the response monitored over a 6-hour period, where a 2-point drop in the composite Ashworth score summed at hip, knee, and ankle joints is considered a positive response. If no response is obtained to the starting dose, increasing dosages of 50 mcg, 75 mcg, and 100 mcg are given on successive days. If no response is obtained to a dose of 100 mcg then the definitive procedure to implant the system should not go ahead (Parke et al. 1989). However, most patients will respond and the dose at which a response is obtained determines the initial daily starting dose for the implanted system. Although few clinical trials have been undertaken specifically in MS patients there is consistency of reported outcomes in studies with mixed populations, including those with MS. Penn et al. reported reduced spasticity as measured with the Modified Ashworth scores, improved spasm scores, improvement in ADL skills, and also improved bladder function in a doubleblind placebo-controlled study with 20 subjects (10 MS and 10 spinal cordinjury subjects) (Penn et al. 1989). Although the majority of patients treated with IT baclofen are not ambulatory, the use of newer programmable pumps has extended treatment to patients who retain mobility with successful symptom improvement without mobility impairment (Lee et al. 2017). Long-term efficacy of intrathecal baclofen in MS patients was reported by Yardley et al., who undertook a retrospective review of patients treated with IT baclofen pump at the National Hospital for Neurology and Neurosurgery in London between 1997 and 2013 (Yardley et al. 2013). Data was obtained for 71 subjects, with a mean follow-up period of 3.54 years. Objective improvements in spasticity, as measured by the Ashworth scale, and patient-reported outcomes of reduced spasm, stiffness, pain, and discomfort were recorded and 56 of the subjects had been able to completely discontinue previous oral

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anti-spasticity medication. Adverse events were low but 10 subjects experienced intrathecal catheter dysfunction requiring replacement. Generally, adverse events including drowsiness, headache, and hypotension occur in less than 5% of patients undergoing the procedure once the dose titration phase is completed. Baclofen pump implantation is expensive, both in terms of neurosurgical expertise and time and the cost of the pump, and is therefore generally reserved for people who have had a full exposure to alternatives, oral, and/ or local treatments for spasticity. 7.5.2 Non-Pharmacological Treatments Almost one-third of those with MS take no medications for their spasticity (Flachenecker 2013) and rely on non-pharmacological methods of management. Between 50% (Rizzo et al. 2004) and 78% (Flachenecker 2013) of people with MS are referred to physiotherapy for spasticity management. A Cochrane review in 2013 evaluated the evidence for non-­pharmacological interventions for spasticity in MS (Amatya et al. 2013). The review identified only 9 randomised controlled trials, of which 3 studied treatments in combination, e.g., botulinum toxin injection with or without physiotherapy. The studies focussed on a range of interventions; physical activity (exercise, yoga, sports climbing), whole-body vibration (WBV), transcutaneous electrical nerve stimulation (TENS), transcranial magnetic stimulation (TMS), and electromagnetic therapy. The review reported that the studies were generally of low methodological quality and used a range of therapies, outcome measures, and heterogeneous patient populations such that a meta-analysis of the results of studies on non-pharmacological management of spasticity in MS was not possible. The overall conclusion of the Cochrane review was that there was “low-level” evidence that physiotherapy provides some added benefit to injection with botulinum, up to 12 weeks after injection; 2 weeks of intermittent theta burst stimulation (iTBS) reduces spasticity (either in isolation or combined with physiotherapy); transcranial magnetic stimulation (TMS), and pulsing magnetic field reduce spasticity in the short term. There was no evidence that TENS, WBV, or sports climbing reduced spasticity. Due to the small number of studies and the relatively poor overall quality of the studies, the review concluded that the effectiveness of most non-pharmacological interventions for spasticity in MS is unproven and that larger, more methodologically robust studies are required. It is clear, then, that, like many pharmacological treatments, further robust research is required before non-pharmacological interventions can with confidence be recommended for the management of spasticity in people with MS. In determining the future direction and the research priorities within this field it is important to look in more detail at studies that have previously

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been undertaken, and that may or may not have been included within the Cochrane review or that have been published more recently. 7.5.2.1 Physical Activity/Exercise for the Management of Spasticity in MS Tarakci et al. (2013), in a paper published since the Cochrane review, demonstrated that a 12-week, thrice-weekly group exercise programme consisting of balance, strengthening, stretching, and functional activities led to statistically significant reduction in lower limb spasticity as assessed by the Modified Ashworth Scale (MAS) (Tarakci et al. 2013). As well as improving the spasticity of the lower limb muscle groups (hip flexors, hamstrings, and soleus) there was also an improvement in walking speed and stair climbing, which may or may not have been related to the reduction in lower limb spasticity. Velikonja et al. (2010) evaluated the effectiveness of sports climbing and yoga, once a week for 10 weeks, on a range of outcome measures in 20 people with MS. Neither intervention reduced spasticity as measured by the MAS, but the pyramidal function component of the EDSS reduced in the climbing group (Velikonja et al. 2010). The authors proposed that when climbing downwards the lower limbs would be weightbearing and stretched, thus potentially reducing spasticity. They also suggested that sports climbing generally improves strength, balance, and co-ordination and may facilitate neuroplasticity. In terms of combined interventions, Giovanelli et al. (2007) demonstrated that botulinum toxin injections were effective in reducing spasticity, as measured by the Modified Ashworth Scale and a visual analogue scale; however, the addition of physiotherapy for 15 days after the injection augmented the effect. Physiotherapy was described as active and passive exercise, stretching, and strengthening (Giovannelli et al. 2007). One of the challenges in interpreting the results of physical interventions to reduce spasticity in people with MS, and indeed in other neurological conditions, is that interventions that are described as single interventions, for example, exercise or physiotherapy, are actually interventions that have a number of components, such as stretching, active muscle contraction, balance activity, etc. Future studies are required to examine the effects of physical interventions for the management of spasticity by systematically manipulating the frequency, intensity type, and time (FITT) of activity and evaluating the resultant effect of spasticity in people with MS. 7.5.2.2 Transcutaneous Electrical Nerve Stimulation (TENS) for the Management of Spasticity in MS Transcutaneous electrical nerve stimulation (TENS) is a non-invasive therapy where electrical stimulation is applied to pads on the skin that stimulate

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low-threshold mechanoreceptors. Although the focus of its clinical use is in the management of pain, there is some evidence to suggest that TENS is effective in reducing spasticity in neurological conditions such as stroke (Karakoyun et al. 2015, Laddha et al. 2016) and cerebral palsy (Alabdulwahab and Al-Gabbani 2010). There are few studies investigating the effects of TENS on spasticity in MS. The first study of the effects of TENS in MS that considered spasticity as an outcome measure, in this case the primary outcome measure, was a small pilot study of 10 people with MS (Armutlu et al. 2003). This study used muscle electromyography to assess spasticity along with the MAS. The study reported that 20 minutes of TENS per day for 4 weeks significantly reduced lower limb spasticity in people with MS, although there was no control group in this study. Miller et al. compared a 1-hour and 8-hour daily application of TENS for 2 weeks in terms of spasticity, pain, and spasm (Miller et al. 2007). The Global Spasticity Score was used, which encompasses the MAS, the clonus score, and the patellar tendon reflex. Spasm was assessed with the Penn Spasm Scale and pain using a simple visual analogue scale. Neither TENS application time resulted in a statistically significant reduction in lower limb spasticity, although there was more improvement with the 8-hour application as compared to the 1-hour application. However, pain and spasm reduced significantly when using TENS for 8 hours per day. The small but non-­ significant effect on spasticity, as measured by the Global Spasticity Scale, was encouraging, but longer-term studies are required. No adverse events were reported. In a more recent study, Shaygennejad et al. (2013) compared 4 weeks of oral baclofen (10 mg twice daily for 1 week, then 25 mg twice daily for 3 weeks) with 4 weeks of TENS in people with MS and lower limb spasticity (Shaygannejad et al. 2013). The results demonstrated that spasticity, as measured by the MAS, reduced in both groups but more so in the TENS group. Of note, four of the participants in the baclofen group had to withdraw to adverse side effects. In all three studies the TENS settings were similar (a pulse frequency of 100 Hz and a pulse width of 0.25–0.3 ms). Taken together, there is some evidence of the benefits of TENS for the management of spasticity in MS. One of the advantages of TENS, like many other non-pharmacological interventions, is that it is non-invasive and therefore there are few side effects beyond skin irritation from the application of electrodes. Against that, TENS requires some set-up by the person with MS (or assistance of someone else) and it is more useful for focal, as opposed to general, spasticity. So perhaps the limited evidence would support that clinicians consider TENS for patients with good upper limb function and focal spasticity, whereas for those with more generalised spasticity, pharmacological management may be more efficacious and appropriate. The optimum management strategy may be a

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combination of pharmacological and non-pharmacological interventions, but this requires further investigation. 7.5.2.3 Transcranial Magnetic Stimulation for the Treatment of Spasticity in MS Transcranial magnetic stimulation (TMS) is a commonly used non-invasive investigative method of activating the brain. Traditionally used as a tool in human neurophysiological studies, recent developments in stimulator design have created interest in its therapeutic use through an ability to produce localised repetitive or high-frequency burst stimulation of cortical areas. In MS, the number of studies investigating the effects of TMS on spasticity is currently limited, but there is evidence emerging that repetitive TMS (rTMS) or intermittent theta burst TMS (iTBS) protocols can evoke sustained reductions in markers of spasticity and that these effects can be potentiated and impact on function when combined with exercise therapy (Centonze et al. 2007, Mori et al. 2010, Mori et al. 2011). Centonze et al. (2007) initially demonstrated that repeated daily sessions of 5-Hz rTMS over a 2-week period when directed to cortical areas projecting to the spastic leg of MS patients resulted in a reduction of the H-reflex/ M-wave ratio and a reduction in spasticity as measured using the Modified Ashworth scale (MAS). These changes persisted for at least 7 days following the termination of rTMS treatment. Single or sham rTMS sessions had no effect. This work was further expanded to investigate the action of iTBS on spasticity in MS patients (Mori et al. 2010) and later used in combination with exercise therapy in a double-blind, sham controlled trial (Mori et al. 2011). When studied alone, iTBS (Mori et al. 2010), like rTMS (Centonze et al. 2007), reduced spasticity as measured by MAS and also decreased H-reflex excitability. The effects observed with iTBS were achieved at lower stimulation intensities when compared with rTMS, making this a more practical therapeutic approach. In these studies, the authors suggest that the observed effects on spasticity from rTMS and iTBS could result from induced neuroplasticity changes brought about by repetitive corticospinal conditioning of spinal circuits mediating presynaptic inhibition. While the mechanism of action of rTMS and iTBS require further research, the iTBS protocol, when used in combination with exercise therapy, showed significant reduction in spasticity when measured with the MSSS-88 (Mori et al. 2011). In addition, fatigue, ADL, and quality of life improved for people with MS treated with exercise and iTBS in combination. The results of this initial trial suggest that exercise therapy and iTBS, when combined, significantly improve spasticity and the functional consequences associated with spasticity. The mechanism by which this combined effect is seen is not fully understood, it may be that iTBS “primes” the motor cortex to anticipate the neuroplastic adaptations that may occur with repetitive exercise therapy.

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The changes in endogenous neurotransmitters and genetic expression may also explain these results. 7.5.3 Other Non-Pharmacological Interventions for the Management of Spasticity in MS Hippotherapy is an alternative or complementary therapy where the movement of the horse affects the movement of the patient’s trunk and pelvis in such a way as to elicit righting and balance reactions. A few studies, involving relatively small numbers of participants, have shown hippotherapy to have a positive effect on balance in people with MS (Bronson et al. 2010, SilkwoodSherer and Warmbier 2007). The mechanism by which this occurs has not been investigated. Although a reduction in spasticity may partly explain the results observed, no studies have included an evaluation of spasticity within their outcome measures, thus the effect of hippotherapy on spasticity in MS has yet to be elucidated. Although there is anecdotal evidence that Lycra garments may be effective in reducing spasticity in people with neurological conditions, equivocal results have emerged from the few studies undertaken (Elliott et al. 2011, Watson et al. 2007) and no studies have specifically investigated the effectiveness of Lycra garments in MS. Neuromuscular electrical stimulation cycling (NMES) has mainly been investigated following spinal cord injury. In NMES, the patient is seated on a recumbent exercise bicycle and electrical stimulation is applied to the affected, large muscle groups of the leg in a manner that allows the individual to cycle. One study has examined the effectiveness of NMES in MS where increases in the volume of the thigh were reported and anecdotally 2 of the 8 participants recounted a reduction in spasticity, although this was not formally determined (Fornusek and Hoang 2014). Whole-body vibration (WBV), where users stand on a vibrating platform, has been shown to have some positive effects on increasing muscle strength in MS (Schyns et al. 2009) and in improving mobility in those less severely disabled (Kantele et al. 2015). In terms of its effect on spasticity in MS, one study demonstrated that 4 weeks of thrice-weekly exercise with WBV reduced the spasm score of the MSSS-88 compared to 4 weeks of exercise alone (Schyns et al. 2009). There was no effect on the MAS or other functional outcome measures such as the timed up and go (TUG). As with other studies this was a small pilot study with only 16 participants, 4 of whom failed to complete the crossover study due to the WBV exacerbating an existing knee problem (n = 1) and being unable to commit to attending the therapy centre 3 times per week (n = 3). A recent systematic review suggested there was insufficient evidence to support the use of WBV in MS (Huang et al. 2017). In summary, and in agreement with the results of the Cochrane review, there is limited and early evidence that some non-pharmacological interventions (e.g., iTBS, exercise, TENS) might have a positive effect on spasticity for

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people with MS. There is an urgent need to move beyond small-scale pilot studies to undertake larger-scale multi-centre trials of these interventions to improve the evidence base to support or refute the use of these interventions in clinical practice. 7.5.3.1 Surgery Orthopaedic surgical procedures are generally undertaken for the consequences of spasticity, i.e., fixed contractures causing pain or interfering with function; either ambulation or positioning for sitting. Tenotomy or tendon-lengthening procedures are undertaken to allow positioning of joints into more natural angles, for example, achilles tenotomy will allow an inverted and flexed ankle joint to be placed into a more neutral and functional position to improve the gait pattern and ambulation or to facilitate fitting of an appropriate orthosis (Waters et al. 1982). Similar procedures can be undertaken on the hamstrings to allow a greater range of knee flexion or on the hip adductors to facilitate positioning for improved toileting and hygiene. Selective dorsal rhizotomy, first described over 100 years ago by Foerster as a potential treatment for spastic diplegia associated with cerebral palsy, involves selectively sectioning afferent nerve roots in the dorsal horn of the spinal cord, eliminating over-excitatory sensory stimulation of the reflex arc. The technique has been refined to limit the invasiveness of the surgical laminectomy required to expose the nerve roots and to allow much more selectivity of the individual nerve roots to be electrically ablated. Modern approaches now ensure preservation of proprioceptive afferent input using intra-operative electrophysiological identification of individual nerve fibres to be sectioned. Dorsal rhizotomy is now widely used with generally good functional outcomes in children and adults affected by cerebral palsy; however, experience is limited in adults with other neurological disorders. A recent review of the use of the procedure in adults with conditions other than cerebral palsy identified 74 MS patients who had undergone the procedure in North America (Gump et al. 2013). One study had specifically focused on MS with 15 subjects included where pre-operatively 11 subjects were completely bedridden and 4 were wheelchair-dependent. Post-operatively, 8 were ambulant with crutches, 4 used wheelchairs, and only 2 remained bedridden. Further prospective studies, specifically in MS patients, are required before the technique can be considered as an established treatment. 7.5.4 Strategy for the Management of Spasticity in MS Management of spasticity in MS is a multidisciplinary process and a recent consensus framework confirms treatment should be firmly based upon assessment, negotiation, and goal-setting (Turner-Stokes et al. 2017). Assessment consists of identifying functional difficulties or troublesome symptoms from the perspective of the patient and their carers, as appropriate.

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The presence of increased tone is of itself not a reason to intervene. Indeed, increased tone may have some benefits for the patient compensating for muscle weakness and allowing improved mobility or transferring ability. Once functional impairment/troublesome symptoms (e.g., pain, spasm) have been identified a full clinical assessment should be undertaken to identify affected muscle groups and the extent to which problems are focal, i.e., localised to a particular muscle group or region, or more generalised affecting muscles in different anatomical regions. The severity of the spasticity should be recorded, with the Modified Ashworth Scale being the most frequently used assessment in MS. Any exacerbating factors should be clearly identified and recorded. Differentiating between severe spasticity and fixed contractures may sometimes be difficult and regional anaesthetic blocks can be helpful in differential diagnosis and may prevent inappropriate treatment. Goal-setting follows on from assessment and involves a partnership approach with the patient identifying outcomes that are important to them, and may include relief of pain, improved mobility, functional capability, and improved seating position. Outcomes have to be realistic and achievable, taking into account the degree of spasticity, muscle groups affected, and natural history of the condition. Knowledge of disease-modifying treatments is essential. With the introduction of more effective drugs to control disability progression assumptions that disability levels (and degree of spasticity) will inevitably continue to increase may no longer be valid. There is some evidence that such an effect can be seen in terms of treatment with glatiramer acetate, a current first-line drug for treatment of RRMS. The ESCALA study showing improvement in terms of spasm frequency, muscle tone, and pain in patients who switched DMT from β-interferon to glatiramer (Meca-Lallana et al. 2012). Initial phases of management involve elimination, where possible, of noxious stimuli that affect afferent input, pain (neuropathic or nociceptive), pressure ulcers, bladder symptoms including recurrent infections, bladder instability/dysynergy, acute relapse/inflammatory activity of the underlying illness. This may involve obtaining up-to-date MRI imaging of brain and spinal cord with gadolinium enhancement. Optimising management of these factors should always be the first step in management of spasticity and spasm. With both generalised and focal spasticity where the degree of spasticity is moderate (MAS < 2) the patient should first be referred for physiotherapy (see above). Where spasticity is more extensive or not adequately responding to physical therapy the next level of intervention will depend upon whether the spasticity is generalised or focal. For generalised spasticity, initial treatment should be with one of the first-line agents baclofen, tizanidine, or gabapentin. Dosage should start at a low total daily dose titrating upwards at 3-day intervals until the desired effect is obtained or the patient experiences intolerable adverse effects.

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If sufficient control of spasticity is not obtained, combining first-line therapies, e.g., baclofen plus gabapentin, should be the next step. Second-line treatments, such as dantrolene or sativex, should be introduced where combinations of first-line drugs are ineffective or not tolerated. Treatment failure should trigger assessment for intrathecal baclofen therapy or surgery especially where lower limb spasticity is causing difficulties in seating position or toileting. With focal spasticity not responding to physical therapy, botulinum toxin is the first-line approach to management; such treatment needs to be combined with vigorous physiotherapy stretching to produce an optimal response (Giovanelli et al. 2007). Longer-term control of focal spasticity may be obtained by regional nerve ablation with phenol. Multidisciplinary reassessment of the effectiveness of treatment to ensure continued response and to determine whether additional measures are required is essential, particularly in an often-progressive condition such as MS.

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Wade, D. T., Collin, C., Stott, C. and Duncombe, P. (2010) Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis, Mult Scler, 16(6), 707–14. Wade, D. T., Makela, P., Robson, P., House, H. and Bateman, C. (2004) Do cannabisbased medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients, Mult Scler, 10(4), 434–41. Waters, R. L., Frazier, J., Garland, D. E., Jordan, C. and Perry, J. (1982) Electromyographic gait analysis before and after operative treatment for hemiplegic equinus and equinovarus deformity, J Bone Joint Surg Am, 64(2), 284–8. Watson, M. J., Crosby, P. and Matthews, M. (2007) An evaluation of the effects of a dynamic lycra orthosis on arm function in a late stage patient with acquired brain injury, Brain Inj, 21(7), 753–61. Yardley, M., Keenan, L., Flisher, L., Broome, K., Buchanan, K., Stevenson, V. and Farrell, R. (2013) Long-term efficacy of intrathecal baclofen to manage severe spasticity in people with multiple sclerosis, translated by Sage Publications. London: Sage, 523. Zajicek, J., Ball, S., Wright, D., Vickery, J., Nunn, A., Miller, D., Gomez Cano, M., McManus, D., Mallik, S. and Hobart, J. (2013) Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-­ controlled trial, Lancet Neurol, 12(9), 857–65. Zajicek, J., Fox, P., Sanders, H., Wright, D., Vickery, J., Nunn, A. and Thompson, A. (2003) Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial, Lancet, 362(9395), 1517–26. Zajicek, J. P., Hobart, J. C., Slade, A., Barnes, D. and Mattison, P. G. (2012) Multiple sclerosis and extract of cannabis: results of the MUSEC trial, J Neurol Neurosurg Psychiatry, 83(11), 1125–32. Zajicek, J. P., Sanders, H. P., Wright, D. E., Vickery, P. J., Ingram, W. M., Reilly, S. M., Nunn, A. J., Teare, L. J., Fox, P. J. and Thompson, A. J. (2005) Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up, J Neurol Neurosurg Psychiatry, 76(12), 1664–9. Zettl, U. K., Henze, T., Essner, U. and Flachenecker, P. (2014) Burden of disease in multiple sclerosis patients with spasticity in Germany: mobility improvement study (Move I), Eur J Health Econ, 15(9), 953–66.

8 Clinical Assessment and Management of Spasticity and Contractures in Traumatic Brain Injury Gerard E. Francisco and Sheng Li CONTENTS 8.1 Introduction................................................................................................. 204 8.2 Impact of Contractures and Spasticity on Recovery............................. 206 8.3 Clinical Presentations................................................................................ 207 8.4 Brain Injury Complications That May Worsen Spasticity.................... 209 8.5 Treatment Goals.......................................................................................... 209 8.5.1 Case 1................................................................................................ 210 8.6 Assessment.................................................................................................. 212 8.6.1 Clinical Assessment....................................................................... 212 8.6.2 Biomechanical Assessment........................................................... 214 8.7 Management................................................................................................ 216 8.7.1 Physical Modalities......................................................................... 216 8.7.2 Stretching and Casting for Contracture vs. Spasticity Management.................................................................................... 217 8.7.3 Electrical Stimulation..................................................................... 218 8.7.4 Oral Medications............................................................................. 219 8.7.5 Focal Therapies................................................................................ 220 8.7.5.1 Botulinum Toxins............................................................ 220 8.7.5.2 Case 2.................................................................................222 8.7.5.3 Phenol and Alcohol Neurolysis.....................................223 8.7.6 Intrathecal Therapies......................................................................223 8.7.7 Surgical Interventions.................................................................... 226 8.7.8 Controversial and Promising Treatments................................... 227 References.............................................................................................................. 227

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8.1 Introduction Disruption of upper motor neuron (UMN) pathways following a traumatic brain injury (TBI) results in a multitude of clinically meaningful sensorimotor limitations, among which is spasticity. Almost always, spasticity, along with muscle-shortening due to paralysis and immobilisation, leads to soft tissue and joint contractures, which further aggravate the loss of range of motion and limb movement. Muscle contracture, or shortening of muscle length, often develops when paralyzed muscles are immobilised as early as 2 weeks (Verplancke et al. 2005). In addition, immobilisation in a shortened position often facilitates muscle fibre loss and atrophy, accumulation of intramuscular connective tissue, increased fat infiltration, degenerative changes at myotendinous junctions, and may further result in an increase in mechanical spindle response by stretch (Gracies 2005). Therefore, muscle shortening is also often accompanied by a similar phenomenon in other soft tissues, including fascia, nerve, blood vessels, ligament, and skin. Contracture and spasticity often co-exist and, taken together, they constitute significant components of a vicious, mutually augmenting cycle (Botte et al. 1988; O’Dwyer et al. 1996; Gracies 2005) (Figure 8.1). As a result, a patient with TBI and spasticity not only has limited functional abilities but also has challenges in participating in a rehabilitation programme to promote recovery. Unlike in stroke, very little has been published regarding the incidence of spasticity following TBI. Potential reasons for this include the fact that majority of TBI are mild and without sensorimotor complications; the lack of universal criteria for diagnosing spasticity and distinguishing it from related conditions, such as dystonia; and that most studies report spasticity incidence in those with acquired brain injuries, which include non-traumatic aetiologies. Another major reason is that the distinction between spasticity and contractures is often unclear. Estimates of the incidence of contracture in TBI are limited by the potential co-existence of spasticity. In an investigation of 75 persons with ‘craniocerebral trauma’ consecutively admitted to inpatient rehabilitation, contractures were found in as many as 84% within a 12-month period, but it is unclear how many of these had co-morbid spasticity (Yarkony and Sahgal 1987). In a more recent study (Singer et al. 2004) of 105 persons with moderate-to-severe non-traumatic and traumatic brain injuries admitted to a rehabilitation unit, contracture was observed less frequently. Only 17 (16.2%) had ankle contracture, which was found to correlate closely with spastic hypertonia. Using the Ashworth Scale, spasticity was detected in only 13.3%. An additional 21.9% were classified as having dystonic muscle overactivity at rest and during volitional movement or change in body position. At our facility, spastic hypertonia as measured by the Modified Ashworth Scale was detected among 25.8% of 120 consecutive persons with TBI admitted to inpatient rehabilitation directly from acute trauma or neurosurgical care (Le et al. 2000).

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Interruption/damage of corticospinal pathways

Loss of supraspinal inhibition

Negative UMN findings

Positive UMN findings

Weakness incoordination

Muscle overactivity, spasticity

Immobilization due to paralysis

Immobilization due to tightness

Contracture

Hypertonia

FIGURE 8.1 Development of contracture due to spasticity and immobilisation.

Contracture can occur as early as 14 days in the ankle joint after a severe TBI (Verplancke et al. 2005). However, the incidence of contracture after TBI varies across major joints. In a prospective study of 105 patients with a new diagnosis of moderate-to-severe brain injury over a 12-month period, there was a 16.2% contracture rate (Singer et al. 2004). Pohl and Mehrholz (2005) reported that 56% of 50 patients with severe cerebral damage had a contracture in at least one shoulder. Yarkony and Sahgal (1987) documented contractures in the hip (81%), shoulder (76%), ankle (76%), and elbow (44%) joints within a 1-year period among 75 patients with TBI. Risk factors for development of contracture include spasticity (Singer et al. 2004), severity of injury (Singer et al. 2004; Pohl and Mehrholz 2005), and duration of coma (Yarkony and Sahgal 1987; Pohl and Mehrholz 2005). Pohl et al. (2007) also suggested

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that contractures may be associated with reduced non-spastic positive features of the upper motor neuron syndrome, such as reduced involuntary muscle activity in a stretched position in patients with severe brain damage.

8.2 Impact of Contractures and Spasticity on Recovery Spasticity and contracture usually co-exist in muscles that are shortened in patients with TBI, such as the shoulder adductors and internal rotators, elbow flexors, forearm pronators, and wrist and finger flexors in the upper extremity. Often, the presence of contracture influences assessment of spasticity in patients with severe brain injury, particularly in the shoulder and hand (Mehrholz et al. 2005). Contractures are more likely to develop in patients who do not recover motor function. Malhotra et al. (2011) examined the time course of development of spasticity and contractures at the wrist after stroke in a longitudinal observational study. Spasticity was measured by quantifying muscle activity during passively imposed stretches at two velocities. Contractures were measured by quantifying passive range of movement and stiffness. Upper limb functional movement was assessed using the action research time test. Thirty patients who had no arm function within the first 6 weeks of stroke were followed for 36 weeks. Twenty-eight (92%) patients developed spasticity throughout the study period. Patients who recovered arm function (n = 5) showed signs of spasticity at all assessment points but did not develop contractures. Patients who did not recover useful arm function (n = 25) had signs of spasticity and abnormalities associated with contracture formation at all time points tested. The findings from this study highlight the importance of early interventions to prevent development of contracture. Physical modalities such as stretching, casting, and splinting are beneficial for this purpose. Electrical stimulation has shown some evidence in reducing the rate of contracture formation (Malhotra et al. 2013). Presence of lower extremity spasticity may be used as a clinical marker to predict recovery of ambulation after TBI. Lower extremity spasticity is a sensitive (71.4%) and specific (81.5%) predictor of the inability to ambulate at discharge. The absence of lower extremity spasticity, however, was a better predictor of ambulation recovery than the presence of spasticity was a predictor of non-ambulatory status at hospital discharge (Dumas et al. 2003). In some situations, however, spastic hypertonia that results in extension of lower limb muscles may be beneficial in situations where weakness precludes the ability to maintain the upright posture during standing activities and walking. Although spasticity does not consistently hinder functional recovery, early management has shown to be beneficial for recovery (see Section 8.7).

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8.3 Clinical Presentations While the underlying aetiologies and anatomic lesions vary, the clinical presentations of spasticity, along with contractures, are not dissimilar from other conditions involving any insult to the brain. While the primary lesion in stroke is typically unifocal, in TBI multiple areas in both cerebral hemispheres may be involved in the development of spasticity and hence a mixed pattern of clinical presentation may be observed. Thus, the ‘classic hemiplegic’ posture often seen in stroke, characterised by shoulder internal rotation and adduction, forearm pronation, elbow, wrist, and finger flexion, knee extension, ankle plantarflexion, and toe flexion, may not be observed in persons with TBI. Instead, both sides of the body may be involved with varying degrees of spasticity of muscles within a limb. In some persons with TBI, spasticity is limited to only one or two muscle groups and is not significant enough to warrant treatment. Table 8.1 lists muscles that may be involved in commonly observed postural abnormalities due to spasticity. In evaluating spasticity in persons with TBI, a clinician should astutely assess not only the severity of spasticity and extent of muscle involvement, but also discern how much of the presenting problem is due to weakness versus spasticity. For instance, when a person with TBI walks with hip circumduction, knee hyperextension, and a foot drop, two possible underlying problems include weakness of the hip flexors, knee flexors, and ankle dorsiflexors, or spasticity of the hip extensors, knee extensors, and ankle plantarflexors. Different permutations of these possibilities may account for the presenting abnormality in gait and influence a clinician’s choice of interventions (e.g., oral medication, botulinum toxin injection, or intrathecal baclofen, with or without a concurrent strengthening programme). An interesting and clinically challenging sequela of traumatic brain injury that is often observed in those in vegetative or minimally conscious states is paroxysmal sympathetic hyperactivity, a prominent feature of which is posturing either in the decorticate or decerebrate pattern. An international, multidisciplinary consensus group (Baguley et al. 2014) described this syndrome as: recognised in a subgroup of survivors of severe acquired brain injury, of simultaneous, paroxysmal transient increases in sympathetic [elevated heart rate, blood pressure, respiratory rate, temperature, sweating] and motor [posturing] activity.

In the past, different terms have been used to describe this syndrome, including ‘autonomic storming’, ‘dysautonomia’, and ‘paroxysmal autonomic instability with dystonia’. The motor posturing part is often viewed as a severe form of spasm or spasticity and is frequently managed as such, in addition to treatment efforts to control the underlying sympathetic hyperactivity. Francois et al. (2001)

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TABLE 8.1 Muscles Potentially Involved in Common Postural Abnormalities Due to Spasticity Postural Abnormality Shoulder adduction

Shoulder internal rotation

Elbow flexion

Elbow extension Forearm pronation Wrist flexion Wrist extension Metacarpophalangeal (knuckle) flexion Finger flexion Thumb flexion Trunk flexion Hip flexion

Hip extension Hip adduction Knee extension Knee flexion Ankle plantarflexion

Ankle inversion

Great toe hyperextension Small toe flexion

Muscles Potentially Involved Pectoralis major Latissimus dorsi Coracobrachialis (especially when shoulder is flexed forward) Subscapularis Teres major Pectoralis major Brachialis Biceps Brachioradialis Pronator teres Triceps Pronator teres Pronator quadratus Flexor carpi radialis Flexor carpi ulnaris Extensor carpi radialis Extensor carpi ulnaris Lumbricals Flexor digitorum superficialis (proximal phalanx) Flexor digitorum profundus (distal phalanx) Flexor pollicis brevis (proximal) Flexor pollicis longus (distal phalanx) Quadratus lumborum Lattisimus dorsi Psoas Iliacus Rectus femoris Gluteus maximus Adductor complex Quadriceps complex Hamstrings Gastrocnemius Gastrocnemius Soleus Tibialis posterior Flexor digitorum longus Flexor hallucis longus Tibialis posterior Tibialis anterior Extensor hallucis longus Extensor hallucis longus Flexor digitorum brevis (proximal) Flexor digitorum longus (distal)

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reported successful treatment of this condition recalcitrant to conventional treatment with intrathecal baclofen. The successful outcome may have not been solely due to the well-known spasmolytic effect of baclofen, but to a sympatholytic effect of this GABA (gamma amino butyric acid) agonist.

8.4 Brain Injury Complications That May Worsen Spasticity Traumatic brain injury results in a wide spectrum of medical complications. In a retrospective study that reviewed medical complications of 116 patients in 2000–2006, the authors reported urinary incontinence in 32.7%, heterotopic ossification (HO) in 18.1%, and post-traumatic seizure in 13.8% on admission to rehabilitation (Safaz et al. 2008). These medical complications and their treatment may interact with spasticity. For example, HO is reported to be significantly associated with spasticity after a TBI. In a total of 107 TBI patients with spasticity, HO was present in 40 patients (Dizdar et al. 2013). In the experience of many clinicians, a sudden change in spasticity may result from progression intracranial complications, such as hydrocephalus, or co-morbidities, among which urinary tract infections are commonly observed. Medications used to treat TBI-related complications, such as psychostimulants used to treat inattention, benzodiazepines to manage agitation, and anti-epileptics, have also been observed to affect spasticity. Zafonte et al. (2004) suggest assessment of spasticity several times per day, since muscle tone may be affected by medications, procedures, and other medical conditions, such as pain.

8.5 Treatment Goals When planning interventions for spasticity, setting goals is of prime importance to help focus the type and course of therapies, and manage outcome expectations. It is not uncommon for a patient to desire recovery to ‘normal’, or close to normal, anatomy and function following treatment, but often this is not possible. Other typical goals include reduction in pain, easy use of orthosis, and decrease in caregiver burden. Many clinicians, on the other hand, focus on technical outcomes, such as reduction in spasticity as measured by the Ashworth or Tardieu scales, and improvement in range of motion, despite these scales having limited validity. Thus, a common challenge encountered in the clinical setting is how to accommodate the seemingly diametric goals identified by the patients, their caregivers, and clinicians. Esquenazi et al. (2013) categorised goals, identified by the patient, as either ‘active’ or ‘passive’. The former refers to tasks that are performed by the

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TABLE 8.2 Examples of Passive and Active Spasticity Treatment Goals Passive Prevention of contractures and deformities Spasm and pain relief Improved splint wear Facilitated hygiene

Active Increased active movement Improved ability to transfer from one surface to another Improved ankle dorsiflexion (‘heel strike’) during gait Increased ability to pick up and release objects with the hand

patient, while the latter, for the patient. Examples are illustrated in Table 8.2. This is a systematic way to define treatment objectives, in that it helps define further higher-order goals and therapy needs. Achievement of socalled active goals should not be seen as an end, but rather signals the need for re-assessment of other interventions, as illustrated by the following case (Figure 8.2). 8.5.1 Case 1 Mr AS is a 49-year-old male who suffered a non-penetrating brain injury from a motorcycle crash 2 years ago. He was discharged from therapies due to ‘lack of progress’ in recovering left arm function. He identified ‘difficulty extending elbow to reach’. He is able to grasp small objects, but is unable to open his hand volitionally to release objects. He is also unable to wear a hand splint and is concerned that he is unable to clean his hand well. He has been taking baclofen 10 mg twice daily, until a few weeks before review. On examination while seated, the left elbow was held in 75 degrees of flexion. The forearm was fully pronated, the wrist was flexed about 30 degrees and the fist clenched (thumb fully flexed underneath the fingers, which are

FIGURE 8.2 Case 1: 49-year-old male with TBI and spastic left upper limb.

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also fully flexed at both proximal and distal interphalangeal joints). He was able to actively extend the elbow through about 30 degrees from the resting position. He was able to actively extend the fingers, but not enough to open the fist. In the supine position, the following were the Ashworth and Tardieu findings (Tables 8.3 and 8.4). Mutual treatment goals were as follows: passive (1) relax finger and thumb flexors to allow hand hygiene; and passive (2) wear hand splint to prevent worsening of finger contractures; active (1) decrease elbow flexor tightness to increase reaching ability; and active (2) release objects from hand grasp. He received botulinum toxin injection to the biceps, brachialis, brachioradialis, flexor carpi ulnaris and radialis, pronator teres and quadratus, flexor digitorum superficialis and profundus, lumbricals, and flexor pollicis longus. Four weeks post-injection, there was dramatic improvement in Ashworth and Tardieu scores, and he recovered more active elbow extension, forearm supination, and hand opening. Based on these changes, new therapy goals were identified:

1. Serial casting to provide sustained stretch to the finger flexors, followed by re-fitting for a static hand splint; 2. Functional electrical stimulation of wrist and finger extensors to facilitate hand opening during functional activities; 3. Functional re-training for object reaching, grasping, and release. The above scenario is desirable to many, as the patient was able to recover more active movement, which has made it possible for further functional re-training, even after 2 years post-TBI. The appropriate intensity and task-specificity of the exercise programme, in turn, can facilitate cortical re-organisation and plasticity that translates to functional improvement. The evidence of efficacy of constraint-induced movement therapy in TBI is limited, but should not be discounted in light of the robust literature in the stroke population (Hakkennes and Keating 2005). Given the complexity of spasticity’s impact on function and wellness, both passive and active goals usually co-exist in one individual. Teasing out the individual goals may help identify specific treatments to address each goal TABLE 8.3 Case 1: Ashworth Scale Scores Muscle Group Elbow flexors Elbow extensors Wrist flexors Wrist extensors Finger flexors Finger extensors Thumb flexors

Ashworth Score 3 1 1 1 3 Unable to test 4

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TABLE 8.4 Case 1: Tardieu Scores Joint Elbow flexion Elbow extension Wrist flexion Wrist extension Finger flexion Finger extension (PIP) Thumb flexion Thumb extension (distal)

Tardieu Spasticity Angle

Tardieu Spasticity Grade

15 degrees 25 degrees 0 degrees 5 degrees Unable to test Approx. 10 degrees Unable to test Approx. 10 degrees

2 1 2 0 2 0 1 0

and prioritise the timing of interventions. While achievement of passive goals is largely meant to correct anatomic deformities and posture or as a means to prevent further complications, successful control of spasticity of the finger flexors may allow subsequent splinting efforts that will help prevent recurrence, or worsening of the clenched fist deformity. It is also important to remember that as a person recovers form a brain injury, the characteristic and impact of spasticity changes over time, perhaps as a reflection of recovery of upper limb movement (Katz et al. 1998). Thus, a regular re-assessment of functional status and re-identification of goals, and thus further treatment plan, should be carried out, as illustrated in the case above. Most goal-setting is done ‘informally’, in that the patient and clinician verbally agree on goals of treatment and assess outcome globally. There exist more formal goal-setting measures, among which the most popular is Goal Attainment Scaling (GAS). This tool was initially developed in the mental health field, but was later adapted to rehabilitation, specifically spasticity management (Turner-Stokes et al. 2010). GAS allows the patient (or caregiver) to identify meaningful goals, rather than relying upon a standardised list. Goals are identified and mutually agreed upon by the patient and clinician, and are weighted based on importance. The likelihood of achieving goals is identified a priori, and against which the degree to which goals are actually achieved during the course of treatment are compared.

8.6 Assessment 8.6.1 Clinical Assessment As with any other condition, a comprehensive assessment begins with a thorough history. Peculiar to spasticity assessment is obtaining information regarding the impact of spasticity on a person’s well-being and functional

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activities. Some important historical points included in Table 8.5 are examples of how to obtain information about spasticity and its functional impacts. These questions may influence further evaluation and treatment decisions. In certain situations, it is helpful to seek input from the patient’s caregivers if TBI-related cognitive and language problems preclude a person’s ability to provide accurate information. With regard to examination, a systematic approach to assessing impairments and functional capabilities is recommended (Figure 8.3). After obtaining a history with emphasis on the functional impact of spasticity, the examiner should observe the person move the limb in question. It is preferable to start with having the person perform active movements, as passive stretching of the limbs may affect active performance. This will also give the examiner an estimation of a person’s ability to overcome spasticity and the limitation in range of motion either due to strength deficit, co-contraction, or discomfort. TABLE 8.5 Some Important Historical Points in Spasticity Assessment Is the limb tight all the time or only at certain times? Does a particular position or movement trigger tightness? Is the tightness related to spasms? Does the tightness cause pain? Have there been episodes of skin compromise due to tightness or spasm? Does the tightness result in difficulty with cleaning? Does the tightness result in difficulty donning splints? Does the tightness limit ability to move limbs, reach for objects, and use the hands? Does the tightness of the lower limbs result in problems with transferring form one surface to another or with walking? What treatments for muscle tightness have been tried previously and their outcome? What are the current medications? Was there a recent increase in tightness (that may warrant further diagnostic testing to rule out a new neurologic problem)? Any recent medical problems?

History • See Table 8.5

Active assessment

Passive assessment

• Ask the patient to actively move limbs

FIGURE 8.3 Proposed sequence of clinical assessment of spasticity.

• Goniometric assessment of range of motion • Asworth scale (or modification) • Tardieu method

Functional assessment • Functional scales (e.g., Frenchay test; Timed up-and-go) • Assess gait • Patientspecific functional task assessment

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Following this, passive examination should be carried out. While it is known that the Ashworth Scale (and its modified version) (Ashworth 1964) is replete with limitations, chiefly because it measures hypertonia and contracture, rather than the velocity-dependent nature of spasticity, it remains the most widely used clinical measure of spasticity. This could be due to its historical popularity and simplicity, especially when compared the Tardieu method (Gracies 2009), which involves more detailed goniometric measurement. Various clinical assessment measures have been described, none of which are specific to TBI. These include the Penn Spasm Frequency Scale (Penn et al. 1989), Tone Assessment Scale (Gregson et al. 1999), and King’s Hypertonicity Scale (King 1987). As previously mentioned, most goals identified by patients are functional in nature, and their assessment requires active engagement of the patient in the upright position. Yet, it is not uncommon for clinicians to judge treatment outcomes based on changes in the Ashworth scores, which are assessed passively, while the patient is either supine or upright. Functional assessment can be performed systematically using a pre-designed scale, such as the Frenchay Scale (or its modification), which is not TBI-specific. Using this scale requires that an individual perform specific, pre-determined functional activities, such as putting toothpaste on a toothbrush and brushing teeth. Functional assessment can also be carried out using patient-specific, or individualised, tasks that the patient has identified as personal and meaningful treatment goals. Outcome of therapy in the latter method is usually a global impression both by the patient (or caregiver) and clinician. 8.6.2 Biomechanical Assessment Resistance to passive stretch is composed of three components: passive muscle stiffness, active muscle stiffness, and neurally mediated reflex stiffness. Experimentally, total joint stiffness is first measured in response to a controlled angular perturbation. The measured total stiffness is then decomposed into reflex and non-reflex components. Changes in non-reflex muscle stiffness could presumably be due to changes in peripheral muscle tissue, such as fibrosis, fat infiltration, and muscle atrophy. Change in reflex stiffness could be due to a change in the descending influences on the monosynaptic reflex between the muscle spindle afferents and the α-motor neurons. Therefore, the mechanical changes may provide insights into the underlying neural pathway or muscle tissue changes or both. Biomechanical quantification of joint stiffness is usually performed in the research laboratory. For example, for ankle joint stiffness quantification (Sinkjaer and Magnussen 1994), a patient is placed in a customised instrumented dynamometer in which joint movement is accurately measured during joint angular perturbation. Muscle EMG activity and limb dynamics are measured. The patient is instructed to voluntarily activate his muscle to generate a plantarflexion moment of ~5 Nm as background torque. Then

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the ankle is rapidly dorsiflexed (perturbation), resulting in abrupt torque increase. The initial portion of this torque increase is resulted from the nonreflex components of the system – passive and active muscle properties – as well as the inertial properties of the device. However, after significant reflex activity was present as indicated by the EMG activity, total torque increases further, reflecting the intrinsic muscle plus the reflex-mediated stiffness. In a separate experiment, the same patient receives electrical stimulation of the tibial nerve to cause the plantarflexors to generate the same amount of background torque (5 Nm). The ankle is plantarflexed and torque measured. This provides an estimate of the non-reflex stiffness component, which includes active muscle stiffness as well. Finally, subtraction of muscle stiffness from total stiffness yields both reflex and non-reflex components of the joint stiffness. There are numerous variations on this approach (Mirbagheri et al. 2000; Mirbagheri et al. 2001; Zhang et al. 2002; Li et al. 2006; Chung et al. 2008). When applied to spastic muscles, the common findings are velocitydependent increase in reflex component during controlled passive stretch (Kamper and Rymer 2000; Zhang et al. 2000; Zhang et al. 2002; Kamper et al. 2003; Li et al. 2006; Chung et al. 2008). The findings are consistent with the commonly used definition of ‘velocity-dependent increase in tonic stretch reflex’ (Lance 1980). It has also been reported that there is increased non-reflex intrinsic muscle stiffness (Sinkjaer and Magnussen 1994). This finding suggests that there was a change in the muscle itself rather than just a change in the nervous system that accounted for the clinical presentation of the spastic limb. These laboratory-based biomechanical quantifications can provide insights into changes in mechanical properties of spastic muscles and neutrally mediated reflex properties as well. These quantification devices are cumbersome or analysis is time-consuming, making it difficult to be directly utilised in the clinical settings. Findings from these biomechanical approaches, however, could help better assess spasticity clinically. For example, findings from the following laboratory research study could be translated into clinical practice. From animal studies, we have learned that primary muscle spindles (Ia) are velocity-sensitive and secondary spindle afferents are length-dependent and there are interactions between the two in animal models (Lennerstrand and Thoden 1968; Houk et al. 1981). In patients with spastic finger flexors after stroke, Li et al. (2006) reported that reflex responses (EMG and torque) of finger flexors were significantly greater at high stretching speeds than at lower speeds when the wrist joint was held in the same position. However, the reflex responses to a fixed stretching speed were significantly greater at longer muscle length (when the wrist was held in the neutral position) than a shorter muscle length (when the wrist was in 45 degrees of flexion). These results confirmed that velocity dependence was greater at longer lengths and length dependence was greater with faster stretches. Overall, stretch responses are both velocity- and length-dependent. Essentially, this study provides evidence that spasticity is also position-dependent, in addition to being velocity-dependent. Therefore, it is very important to pay attention to

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joint position (equivalent to muscle length) when examining spastic muscles at bedside. For instance, the severity of finger flexor spasticity varies when the wrist position changes. A few other instrumented methods have been developed to objectively quantify spasticity. But no measurement of passive stiffness is involved. Based on the tonic stretch reflex threshold measured from EMGs in response to manually stretching spastic muscles, Calota et al. (2008) developed a portable device and demonstrated velocity-dependent dynamic stretch reflex threshold for spasticity measurement. This method provides electrophysiological measures of spasticity. It is not able to measure mechanical properties of spastic muscles that is associated with contracture. Another device, such as the myotonometer, measures muscle stiffness at rest and/or during voluntary contraction by recording displacement of the probe perpendicular on the target muscle and the amount of force applied to the probe by the examiner. The myotonometer measurement is found to have good intra- and inter-rater reliability, and is correlated well with clinical measurement of spasticity by MAS (Leonard et al. 2001; Leonard et al. 2003). This measurement, however, does not differentiate active vs. passive stiffness, nor provide reflex component of the stretch response.

8.7 Management Management options include physical modalities and physiotherapy, oral medications, botulinum toxin injections, nerve blocks with alcohol and phenol, intrathecal baclofen pump, and surgery. When to initiate treatment of spasticity after a TBI is unclear but an astute clinical approach is to consider any of these options once spasticity becomes problematic, and especially if it appears to adversely affect recovery and progress in rehabilitation. In the acute care setting early intervention promotes prevention and management of the secondary effects of spasticity before they become severe. While, in the chronic setting, an additional treatment goal is to facilitate recovery of movement and function. 8.7.1 Physical Modalities Physical modalities are a mainstay in the first line of treatment, since they are widely available and not associated with systemic side effects such as those associated with drugs. Passive stretching with flexion and extension of the knee has been shown to be effective in reducing spasticity and increasing ROM in patients with brain injury (Starring et al. 1988). Splinting and serial casting can also be used in the acute setting for sustained stretching (Booth et al. 1983; Preissner 2002; Mortenson and Eng 2003; Pohl et al. 2003; Bovend’Eerdt et al. 2008).

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Casting has been extensively used in the clinical settings as an effective tool to reduce contracture and spasticity and to increase ROM in patients with neurological impairments, including TBI. A systematic review on the use of upper extremity casting to achieve reductions in spasticity, contracture, or pain in the elbow, wrist, or hand has revealed lack of high-quality evidence to support or abandon such practice (Lannin et al. 2007). The authors founded high variability in casting protocols, which indicates no consensus for casting. Casting alone seems sufficient to prevent contracture and reduce spasticity if the intervention is initiated early after severe brain injury. In a doubleblind placebo-controlled study (Verplancke et al. 2005), of the 235 subjects with severe brain injury who were screened, only 35 patients were enrolled and randomised into three groups within 10 days of initial brain injury: standard physical therapy treatment without casting (group I), lower leg casting plus injections with either saline (group II), or with Onabotulinum toxin A (group III, 200 units) into gastrocnemius and soleus muscles. All subjects received 12 weeks of treatment. The mean range of improvement in the angle of passive ankle dorsiflexion was 4.59 degrees in group I, 11.69  degrees in group II and 13.59 degrees in group III. Concomitantly, spasticity of plantarflexors was significantly reduced only in groups II and III, but not in group I. Group III patients also demonstrated a significant improvement in the Glasgow Outcome Scale. In other words, this study demonstrates that casting alone is sufficient in preventing ankle deformity and spasticity reduction in patients after severe brain injury. The role of additional botulinum toxin for this purpose needs further investigation. Casting may enhance the effect of botulinum toxins (Farina et al. 2008). In this study, 13 patients with stroke and equinovarus foot were randomised to receive either onabotulinumtoxin toxin injection or ankle-foot casting treatment (n = 6) or onabotulinumtoxin alone (n = 7). The time since onset of stroke ranged from 6 months to 2 years at enrollment. The tibialis posterior and calf muscles were injected in each patient. Castings were worn at night for 4 months. At 2  months, therapeutic effects were observed in both groups according to static and dynamic baropodometric tests, MAS and the 10-meter walking test. At four months, the injection and casting group showed further clinical improvement, while the injection alone control group returned to baseline performance. Therefore, prolonged stretching of spastic muscles after the injection affords long-lasting therapeutic benefit, enhancing the effects of the toxin alone. Although this study was in persons with stroke, the results may be applicable in persons with TBI who present with similar lower limb deformities. 8.7.2 Stretching and Casting for Contracture vs. Spasticity Management A recent study reported promising clinical outcomes using individualised stretching to reduce wrist and finger muscle stiffness and passive ROM (Copley et al. 2013). In this study, 10 patients with moderate (MAS 1+ or 2) wrist and finger flexor muscle stiffness after acquired brain injury, including

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traumatic brain injury, were randomised to the individualised splint and non-splint groups. The splint group received an individualised, thermoplastic resting mitt splint. The goal was to place each participant’s muscles on low-load, prolonged stretch. If the standard resting position (20-degree wrist extension) resulted in observable excessive stretch on the wrist, finger, or thumb flexor muscles (e.g., wrist flexing out of splint, fingers clawing into splint, fingernails blanching, or hyperextension of metacarpophalangeal or interphalangeal joints), the degree of wrist extension was decreased. The splint group patients received 2–4 hours of splinting each day for 3 months. A follow-up measure was taken 1 month later. As compared to baseline, splint-wear resulted in significantly increased wrist and finger passive ROM, and decreased finger spasticity and stiffness, while non-splint-wear had negative clinical effects on these parameters, ranging from zero effect to a large negative treatment effect. This study suggests that, in the selected group of patients, individualised stretching should be considered for reduction in muscle stiffness and spasticity and maintenance of passive ROM. Casting and physical therapy interventions could reduce the burden of care in patients with a vegetative or minimally conscious state. In a recent retrospective study, the authors examined the dependency levels and physiotherapy interventions in 10 patients in a vegetative or minimally conscious state (Wheatley-Smith et al. 2013). All patients presented with hypertonicity including contractures and all initially received a manual stretching/ passive movement programme. Casting/splinting was employed in 8 cases and 7 received botulinum toxin injections. Standing regimes were initiated for 8 patients. All patients were able to sustain a seating regimen, and care burden was reduced, although no patient emerged out of either vegetative or minimally conscious state, and remained fully dependent for care needs. 8.7.3 Electrical Stimulation Electrical stimulation may be utilised to temporarily reduce spasticity (Seib et al. 1994). In 5 patients with TBI and 5 with spinal cord injury (SCI) resulting in spasticity, surface electrical stimulation was applied over the tibialis anterior muscle. The authors found that ipsilateral ankle viscoelastic stiffness immediately decreased in 9 of 10 subjects and remained significantly depressed for up to 24 hours after electrical stimulation. Contralateral ankle spasticity did not significantly change, however. Using the same subjects under sham conditions, no significant decrease in spasticity occurred. In another report, a long-lasting effect on spasticity reduction was reported if electrical stimulation was triggered by voluntary breathing, i.e., BreEStim (Li and Rymer 2011). A group of chronic stroke and TBI patients with moderate to severe finger flexors spasticity received one session of 30 minutes of BreEStim to finger extensors; finger flexor spasticity was immediately significantly reduced, and the reduction lasted for 4 weeks in the follow-up period.

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The efficacy of electrical stimulation on spasticity reduction was not observed in another study (Leung et al. 2012). In this multi-centre, randomised, examinerblinded trial, 36 patients with first stroke or TBI and mild-to-moderate wrist flexion contractures were randomised into 2 groups. The experimental group received electrical stimulation to the wrist and finger extensor muscles  for 1 hour a day over 4 weeks while the control group received no electrical stimulation. Both groups wore a splint for 12 hours a day during this 4-week period. Outcomes were measured at baseline, at the end of the intervention period (4 weeks), and after a 2-week follow-up period (6 weeks). There was no statistically significant difference between 2 groups in passive wrist extension, wrist and finger extensor strength, wrist flexor spasticity, and motor control of the hand at 4 and 6 weeks. This study shows that splinting alone is as effective as the electrical stimulation and splinting treatment for the management of wrist contracture after acquired brain injury. A recent study confirmed that electrical stimulation treatment help reduce contractures in stroke patients with a nonfunctional arm, but had no effect on spasticity or stiffness (Malhotra et al. 2013). Overall, passive stretch via different methods including splinting, casting, sustained stretching, and positioning has been the mainstream of physical and occupational therapy management for contracture and spasticity prevention and treatment. There are various reports of effectiveness of this modality as described above. A Cochrance systematic review on the effects of passive stretch on contractures concludes that if stretch is performed over fewer than 7 months, it does not have clinically important effects on joint mobility for those with or at risk of contractures (Katalinic et al. 2010). When combined with other interventions, passive stretch may augment the effect of botulinum toxin treatment, and electrical stimulation effect. 8.7.4 Oral Medications Pharmacological agents are commonly used to reduce spasticity but their common adverse effects limit their use in this population. Commonly prescribed medications include baclofen, tizanidine, dantrolene, and benzodiazepine. Applications of these medications for spasticity management after TBI have recently undergone thorough reviewed by Zafonte et al. (2011) and in the other chapters of this book. While effective in decreasing spasticity, these medications’ side effects, such as sedation and drowsiness, can magnify arousal or cognitive dysfunction often experienced by persons with TBI. Perhaps this explains why adherence to oral anti-spasticity medications is poor. In a recent study (Halpern et al. 2013), retrospective administrative claims of 2840 persons in a large national US health system were analysed. These persons were treated with oral baclofen, tizanidine, and dantrolene for spasticity resulting from various aetiologies, including TBI, over a period of 5.5 years. Adherence was measured as continuous medication possession ration (MPR). MPR > 0.80 indicates a good adherent. MPR was 20.4% for baclofen and 9.1% for tizanidine. TBI patients had 77.5% lower odds of adherence than stroke patients.

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8.7.5 Focal Therapies 8.7.5.1 Botulinum Toxins Intramuscular botulinum toxin injection is an attractive therapeutic option for the management of spasticity in TBI patients because of its focal action without significant side effects (Esquenazi et al. 2013). The primary mechanism of action in spasticity is the pre-synaptic inhibition of acetylcholine release, at the neuromuscular junction, that leads to reduction in muscle contraction and consequently decreased spasticity (Jahn 2006). Due to functional repair of the neuromuscular junctions affected by the toxin (de Paiva et al. 1996), clinical effects last only about 3 months. In the USA, there are four commercially available toxins: abobotulinumtoxinA (Dysport™), incobotulinumtoxinA (Xeomin™), onabotulinumtoxinA (Botox™), and rimabotulinumtoxinB (Myobloc™). They are distinctly different in formulation, purification, and dosing. In the USA, doses of up to 600 units of onabotulinumtoxinA are commonly used. Although not supported by systematic dose-ranging studies, the safety of higher doses (800–1200 units) has been reported in the treatment of spasticity in adults (Goldstein 2006). Accumulated evidence from clinical research has supported a Level A recommendation (the AAN classification) for treatment of upper and lower limb spasticity (Esquenazi et al. 2013). One of the challenges, as mentioned earlier, is deciding how early botulinum toxin can be administered in persons with TBI. Findings from a recent randomised double-blind placebo-controlled study demonstrated effectiveness of early intervention on spasticity reduction (Fietzek et al. 2014). In this study, 52 patients within 3 months after stroke, traumatic brain injury, or hypoxic encephalopathy were randomised to receive either botulinum toxin or placebo treatment for unilateral or bilateral spastic pes equinovarus with MAS of at least 1+. Patients received unilateral or bilateral injections with 230 or 460 units of onabotulinumtoxinA, respectively, in the treatment group in the first cycle. A second, open injection was optional at week 12. Both groups of patients had a similar baseline. Patients who had received injection initially had lower MAS compared with placebo at week 12. During the open-label phase, patients from the placebo group showed further deterioration of muscle tone despite starting from a similar baseline and receiving injection. Spastic feet that had received injection in the first cycle had comparatively lower MAS scores over all follow-up data and at week 24. Overall, this study demonstrates benefits of botulinum toxin injection in the subacute phase for spasticity management. Early management of severe spasticity is unfortunately often neglected in the acute phase. Severe contractures may develop within a few weeks, particularly in patients with severe brain injury. This prolongs the recovery process and increases risks of developing contracture (Pohl et al. 2007). Early intervention with botulinum toxin with intensive therapies, e.g., injected on the sixteenth day after brain injury in a case report (Lippert-Gruner and Svestkova 2011), reported to increase the chance of a more favourable

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functional outcome. Similar to effectiveness of focal spasticity management with botulinum toxin injection, continuous administration of intrathecal baclofen is indicated to reduce generalised spasticity and autonomic disorders as well in the early phase of severe brain injury (Cuny et al. 2001; Francois et al. 2001). However, early treatment with focal injection needs to be judged carefully. Injection to calf muscles will reduce spasticity to allow casting and prevent predictable plantarflexion contracture, and thus better outcome. On the other end of the temporal spectrum, the use of botulinum toxin years after acquired brain injuries has been shown to be beneficial. Clemenzi et al. (2012) examined the efficacy of repeated botulinum toxin A injection in 21 patients with spasticity due to severe acquired brain injury and no further improving with rehabilitation treatment and oral anti-spastic medications with a 1-year follow-up. Half of the patients enrolled were treated for the first time with injection after a median length of 5 years since severe ABI. All patients received 2 to 4 repeated injections in the 12-month period. The authors found that a shorter interval between the onset of severe acquired brain injury and the first botulinum toxin injection correlated to a better spasticity reduction and Barthel index improvement. This study also demonstrated effective spasticity reduction and functional improvement even botulinum toxin injection was given later. However, this study did not find correlation between the number of injections and clinical outcome. The authors suggested secondary plastic changes in the motor cortex, in addition to peripheral mechanisms of botulinum toxin at the neuromuscular junction. The effect of dilution of botulinum toxin, i.e., the same dose of botulinum toxin mixed with a high volume of saline, has been studied (Francisco et al. 2002; Francisco 2004; Lee et al. 2004; Gracies et al. 2009; Lee et al. 2009). Gracies et al. (2009) reported enhanced neuromuscular block and spasticity reduction with dilutions. In a double-blinded randomised controlled trial, 21 patients were randomised into 3 groups: group 1: 100 mouse units (MU)/mL dilution, 0.4 cc/site, 4-quadrant injection; group 2: 100 MU/mL dilution, 0.4 cc/site, 4 sites along endplate band; group 3: 20 MU/mL dilution, 2 cc/site, 4-quadrant injection (n = 7 per group). Each patient received a total of 160 units of different dilutions and locations into biceps brachii. The injection reduced elbow flexor spasticity angle on the Tardieu scale, decreased co-contraction between biceps and triceps during voluntary elbow flexion, but increased maximal voluntary extension power and active range of elbow extension. Agonist and antagonist flexor EMG activity reduction in group 3 was greater than in groups 1 and 2, whereas increase in active range of elbow extension was greater in group 2 (10%) than in groups 1 and 3. Elbow flexor spasticity was significantly reduced in groups 2 and 3 only. These findings suggested that high-volume or endplate-targeted injections achieve better clinical outcomes, including greater neuromuscular blockade and spasticity reduction, and active range of elbow extension improvement, than lowvolume, non-targeted injection in spastic elbow flexors. High volumes of the

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same dose of botulinum toxin did not result in better clinical outcomes in two other studies (Francisco et al. 2002; Lee et al. 2009). Francisco et al. (2002) found no difference in Ashworth score reduction between high- and lowvolume injections of a 60-unit dose of botulinum toxin into spastic wrist and finger flexors of adult patients caused by acquired brain injury. As stated specifically in the commonly quoted definition by Lance (1980), spasticity is only 1 component of the UMNS. Thus, the management of spasticity should take into account the other UMNS components. Management should be interdisciplinary and centred on meaningful and practical goals, rather than the severity of spasticity in individual muscles. Since the severity and significance of spasticity vary amongst individuals, their impact on well-being and function are not the same. Severity is usually gauged by clinical measures, such as the Ashworth Scale or Tardieu method, whereas significance is characterised by the impact of spasticity on a particular task. Hence, a spastic elbow flexor with Ashworth score of 3 that does not cause discomfort or problem with hygiene may be left untreated, whereas finger flexors with an Ashworth score of 1 but limiting the ability to functionally use the hand may warrant treatment. That said, spasticity requires treatment only when muscle overactivity is disfiguring, disabling, predisposing to more complications, or intervening with functional activities. 8.7.5.2 Case 2 Mr AO is a 50-year-old male who suffered a TBI from a motor vehicle crash 12 years earlier. He complained of persistent tightness of the left index finger (digit II) that precludes the ability to bimanually type on the computer keyboard (Figure 8.4). He had previously received oral tizanidine, but had to discontinue due to drowsiness. He has been receiving botulinum toxin injections to his finger flexors over the last several years (dose range 50–100 units of onabotulinumtoxinA). While spasticity of digits III–V has improved to the point that he is able to once again type on a keyboard, tightness of the digit II flexor

FIGURE 8.4 Case 2: 50-year-old male with TBI and spastic left index finger.

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has made it impossible to use all fingers for this particular activity. He subsequently received 100 units of onabotulinumtoxinA chiefly to the part of the flexor digitorum superficialis muscle that appeared to represent fibres to digit II (as visualised on ultrasound). This resulted in relaxation of this digit, allowing him to re-train bimanual keyboard use. His Ashworth score improved from 2 to 1. When the spasticity recurred about 3 months later, i.e., the Ashworth score increased to 2 and he became unable to actively extend digit II, he received 125 units of onabotulinumtoxinA. The injection was once again limited to the part of the flexor digitorum superficialis muscle to digit II, confirmed by ultrasound. About 3 weeks later, the Ashworth score improved to 0, and although the patient felt some weakness in finger flexion, he was able to resume training on bimanual keyboard use. This case illustrates the importance of recognising the significance, rather than severity, of spasticity on the functional abilities of a person with TBI. It also illustrated individualisation of treatment, as the dose of onabotulinumtoxinA used was higher than what most clinicians would consider using. 8.7.5.3 Phenol and Alcohol Neurolysis A focal treatment that antedates botulinum toxin therapy is neurolysis using either phenol or alcohol (Gracies et al. 1997). Unlike botulinum toxins, the efficacy and safety of this technique in various patient populations with spasticity is not well-studied. Phenol (5–6%) and alcohol (35–60%) initially exert their spasmolytic effect through protein denaturation of the nerve membrane, and in some cases the axons, leading to chemical neurolysis. Further, phenol decreases muscle hypertonia probably as a result of denervation and degeneration of muscle spindles (Bodine-Fowler et al. 1996; Wolf and English 2000). Immediately after injection of phenol, muscle hypertonia decreases likely due to the agent’s anaesthetic properties. True neurolytic effect does not set in until a few hours after injection and depending on the dose and concentration used, may last for a few months. Muscle reinnervation is the likely mechanism for recurrence of hypertonia. Unlike botulinum toxins, phenol and alcohol appear to be associated with more side effects. Most commonly observed are injection site pain, swelling, weakness, and post-injection dysesthesia (Gracies 1997). The risk of pain and dysesthesia is high, particularly when mixed nerves are injected (Stevenson, Jarrett 2006). Accidental spread into the vascular system may result in systemic effects, such as such as tremors, convulsions, and CNS depression. 8.7.6 Intrathecal Therapies Various medications have been used for intrathecal delivery, but the most commonly used for spasticity is baclofen. Unlike the oral form, intrathecal baclofen involves infusion of small doses of the drug. Since intrathecal baclofen (ITB) is delivered close to its site of action in lamina III of the spinal

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cord, the need for a higher concentration (and thus, dose) to bypass the bloodbrain barrier is obviated. Consequently, the smaller dose that is therapeutically effective does not result in adverse events observed with the relatively higher effective doses of oral baclofen. To wit, many patients with TBI experience sedation or drowsiness with 80 mg/day of oral baclofen, but tolerate intrathecal doses of as much as 1000 mg/day, which is roughly one-eighth of the oral dose. Although baclofen introduced intraspinally primarily affects GABA receptors in the spinal cord, a certain amount of the medication is carried by the cerebrospinal fluid as it bathes the brain, where GABAB-ergic interneurons are also affected (Siebner et al. 1998). An implanted programmable pump that contains a refillable drug reservoir and a computer chip that regulates a battery delivers baclofen into the intrathecal space through a silicone catheter. Following clinical assessment for suitability for ITB therapy (see Table 8.5), a screening trial that involves a single intrathecal bolus of 50–150 mg of baclofen through a spinal needle is typically performed. An alternative technique, which involves continuous intrathecal infusion through an external catheter, is performed more commonly in children with dystonia or in those with dysautonomia (or paroxysmal sympathetic hyperactivity) due to anoxia or severe TBI. The literature supporting the efficacy of ITB in managing TBI-related spasticity is limited, largely because most studies enrolled persons with ‘acquired brain injuries’, which are typically dominated by stroke survivors. Meythaler et al. (1999) reported significant improvement in 17 patients with TBI after 1 year of continuous ITB treatment. The average lower extremity Ashworth score decreased from 3.5 ± 1.3 (SD) to 1.7 ± 0.9 (p < 0.0001), spasm score from 1.8 ± 1.3 to 0.2 ± 0.5 (p < 0.0001), and reflex score from 2.5 ± 1.1 to 0.1 ± 0.3 (p < 0.0001). The average upper extremity Ashworth score decreased from 2.9 ± 1.5 to 1.6 ± 1.0 (p < 0.0001), spasm score from 1.2 ± 1.5 to 0.2 ± 0.6 (p < 0.0001), and reflex score from 2.2 ± 0.5 to 1.0 ± 0.8 (p < 0.0001). Mean ITB dose was 302 mcg/day. In addition to improvement in these metrics, some patients obtained significant functional benefits: one who was wheelchairdependent became independent in ambulation, and another who was able to walk with assistive devices prior to ITB implantation became an independent ambulatory up to 2 miles per day with ITB therapy. ITB is usually indicated 1 year after onset of TBI, but it has also been used earlier. Concerns regarding early ITB use are largely extrapolated from animal studies, which suggested that baclofen, a GABA-ergic compound, slowed neurologic recovery (Brailowsky et al. 1986). However, it is widely acknowledged that delayed or inadequate treatment of spastic hypertonia may result in costly complications such as contractures, persistent pain, and failure to benefit from rehabilitation efforts. Francois et al. (2001) described four patients with severe TBI (Glasgow Coma Scale score 3 or 4) and ‘autonomic disorders and spasticity who failed to respond to conventional treatment’, who received ITB at a mean of 25 days (range 21–31) post-TBI. Through a subcutaneously tunneled intrathecal catheter, 25 mcg of baclofen was continuously infused.

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At a mean dose of 385 +/−185 mcg/day, Ashworth scores were significantly reduced on the upper and lower limbs. Concurrently, there was a significant improvement in the frequency and intensity of autonomic symptoms (tachycardia, episodic systolic hypertension, and profuse sweating). In a retrospective study (Francisco et al. 2005), 14 individuals with spastic hypertonia due to trauma (5), anoxia (6), and stroke (3) received ITB therapy within the first year of disease onset. On follow-up 14 months post-ITB implant (mean daily dose 591.5 mg/day) modified Ashworth scores significantly improved from baseline. Disability Rating Scale scores did not change significantly, suggesting that there was no deterioration in functional status. Other noted gains were decreased pain and improved gait speed and motor skills. The only complication reported was spinal leak in one subject. This appears to be supported by animal studies. Using a rat model of closed TBI, Bose et al. (Bose et al. 2013), demonstrated that 1 month of ITB treatment initiated 1 week postexperimentally induced TBI prevented early onset of spasticity (measured by using velocity-dependent ankle torque and ankle extensor muscle electromyography recordings) and significantly reduced occurrence of late-onset spasticity with no significant adverse effects on cognitive and balance performance. The positive spasticity outcome was observed to be accompanied by a remarkable up-regulation of gamma-aminobutyric acid (GABA)/ GABAB, norepinephrine, and brain-derived neurotrophic factor expression in spinal cord tissue. On the other end of the spectrum are patients benefitting from ITB many years after TBI onset. Three adult males who sustained a TBI 14, 17.1, and 19.9 years prior to receiving ITB pump experienced significant improvement in lower limb spasticity as measured by the Modified Ashworth Scale (Francisco et al. 2007). Although FIM-mobility scores did not change from baseline, some functional domains such as gait, transfers, and sitting, assistance for activities of daily living (ADL) and nursing care, community mobility, and participation in recreational activities improved. In another case series (Sara et al. 2009), sporadic cases of recovery from persistent vegetative state (PVS) after administration of ITB have been reported. Five patients with PVS treated with ITB showed signs of recovery of consciousness as early as 2 weeks after pump implantation, measured by the Coma Recovery Scale (Revised) (CRS-R). Although the exact mechanism is unknown, the authors hypothesised that the improvement in consciousness could have been due to modulation of spinal cord segmental activities and neuronal centripetal outputs reaching the cortex, or modulation of sleep-wake cycles. In general, ITB therapy is safe, although challenges, usually due to catheter malfunction, can occur. Abrupt reduction in infusion of ITB due to catheter or pump malfunction may result in a withdrawal syndrome that may appear similar to but pathophysiologically distinct from autonomic dysreflexia, malignant hyperthermia, and neuroleptic-malignant syndrome. It is best managed by early re-institution of baclofen administration. Delay in

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TABLE 8.6 Some Possible Causes of ITB System Malfunction Catheter Fracture Kink Disconnection of catheter from pump Occlusion (e.g., catheter tip granuloma) Pump Mechanical failure Battery failure Human error Refill error Programming error

addressing withdrawal symptoms may lead to a life-threatening syndrome characterised by high fever, altered mental status, severe rigidity, and, in more advanced cases, seizures and withdrawal. Coffey et al. (2002) and Francisco et al. (2009) reviewed the topic more extensively. In addition to immediate restoration of ITB infusion, other drugs, including dantrolene sodium and cyproheptadine (Meythaler et al. 2003), have been described as helpful in mitigating some of the symptoms of ITB withdrawal syndrome. After re-instituting baclofen infusion, the underlying cause of the withdrawal syndrome must be sought and addressed definitively. Table 8.6 lists some potential causes of ITB system malfunction. Special attention must be paid to persons with TBI, who have a ventricular shunt. Malfunction of the shunt may alter the relative concentration of baclofen in the cerebrospinal fluid and thus may cause symptoms of either over- or under-infusion. 8.7.7 Surgical Interventions The surgical management of spasticity is a well-accepted treatment option for children with cerebral palsy, as also indicated in patients with severe spasticity and/or contracture by other neurological impairments, including TBI. Surgical interventions include neuroablative procedures, such as peripheral neurotomies and dorsal rhizotomies, and orthopaedic reconstructive procedures, such as tendon lengthening and tendon transfer (Sindu et al. 2014). When excessive spasticity and/or contracture are not sufficiently controlled by therapy and pharmacological treatment, tendon lengthening is often considered in persons after TBI. By lengthening the tendon, correcting abnormal joint posture, and relieving the associated pain, surgical treatment allows therapy to resume, and sometimes results in meaningful functional gain. Surgical intervention is a permanent treatment, however. Optimal management of spasticity by non-surgical means should be reached before surgical treatment is recommended. As in Case 1, patients regain

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functional movement in the hand and fingers after aggressive botulinum injections for spasticity management. The functional gain in Case 1 may not have been achieved if the patient had had tendon lengthening of finger and thumb flexors. On the other hand, it is prudent to differentiate contributions of spasticity and contracture to abnormal joint postures before considering surgical treatment. A diagnostic nerve block can help characterise how much of the loss of range of motion and resistance to passive movement is due to contracture or spasticity, since an anaesthetic agent is likely to affect only the latter. Results of a diagnostic nerve block can help guide the plan of care. For example, in a patient with flexed knee deformity, if a temporary diagnostic sciatic nerve motor branch block results in increased knee extension, spasticity is likely the primary cause of the deformity. Botulinum toxin injection or motor branch block with phenol should be considered. Stretching of the knee flexors and strengthening of the knee extensors should be employed. If there is no significant change in the knee range of motion after a sciatic nerve block, a static deformity, i.e., knee contracture, is determined. In the early period of recovery, orthotic management to control knee flexion is considered, while surgery in the form of distal hamstring lengthening is considered for a static deformity in late recovery. 8.7.8 Controversial and Promising Treatments Various treatment modalities have been described in the literature as potential treatments for spasticity. Most of these are single case reports or case series and are not specific to TBI. These include acupuncture (Fink et al. 2004), aromatherapy (Ashworth et al. 2012), peripheral nerve (Bakhtiary and Fatemy 2008), spinal (Pinter et al. 2000), and non-invasive brain stimulation (Gunduz et al. 2014).

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Dizdar D, Tiftik T, Kara M, Tunc H, Ersoz M, Akkus S (2013) Risk factors for developing heterotopic ossification in patients with traumatic brain injury. Brain Inj 27:807–11 Dumas HM, Haley SM, Carey TM, Ludlow LH, Rabin JP (2003) Lower extremity spasticity as an early marker of ambulatory recovery following traumatic brain injury. Child’s Nerv System 19(2):114–18 Esquenazi A, Albanese A, Chancellor MB, Elovic MB, Elovic E, Segal KR, Simpson DM, Smith CP, Ward AB (2013) Evidence-based review and assessment of botulinum neurotoxin for the treatment of adult spasticity in the upper motor neuron syndrome. Toxicon 67:115–28 Farina S, Migliorini C, Gandolfi M, Bertolasi L, Casarotto M, Manganotti P, Fiaschi A, Smania N (2008) Combined effects of botulinum toxin and casting treatments on lower limb spasticity after stroke. Funct Neurol 23:87–91 Fergusson D, Hutton B, Drodge A (2007) The epidemiology of major joint contractures: A systematic review of the literature. Clin Orthop Related Res 456:22–9 Fietzek UM, Kossmehl P, Schelosky L, Ebersbach G, Wissel J (2014) Early botulinum toxin treatment for spastic pes equinovarus – A randomized double-blind placebo-controlled study. Eur J Neurol. 21:1089–95 Filippi GM, Errico P, Santarelli R, Bagolini B, Manni E (1993) Botulinum A toxin effects on rat jaw muscle spindles. Acta Otolaryngol 113:400–404 Fink M, Rollnik JD, Bijak M, Borstädt C, Däuper J, Guergueltcheva V, Dengler R, Karst M (2004). Needle acupuncture in chronic poststroke leg spasticity. Arch Phys Med Rehabil 85:667–72 Francisco GE (2004) Botulinum toxin: Dosing and dilution. Am J Phys Med Rehabil 83:S30–7 Francisco GE, Boake C, Vaughn A Botulinum toxin in upper limb spasticity after acquired brain injury: A randomized trial comparing dilution techniques. Am J Phys Med Rehabil 81:355–63 Francisco GE, Hu MM, Boake, C, Ivanhoe CB (2005) Efficacy of early use of intrathecal baclofen therapy for treating spastic hypertonia due to acquired brain injury. Brain Inj 19(5):359–64 Francisco GE, Latorre JM, Ivanhoe CB (2007) Intrathecal baclofen therapy for spastic hypertonia in chronic traumatic brain injury. Brain Inj (3):335–8 Francisco GE, Saulino MF, Yablon SA, Turner M (2009) Intrathecal Baclofen Therapy: An Update. PM&R 1:852–8 Francois B, Vacher P, Roustan J, Salle JY, Vidal J, Moreau JJ, Vignon P (2001) Intrathecal baclofen after traumatic brain injury: Early treatment using a new technique to prevent spasticity. J Trauma 50:158–61 Friden J, Lieber RL (2003) Spastic muscle cells are shorter and stiffer than normal cells. Muscle Nerve 27:157–64 Goldstein EM (2006) Safety of high-dose botulinum toxin type A therapy for the treatment of pediatric spasticity. J Child Neurol 21:189–92 Gracies JM, Elovic E, McGuire J, Simpson DM (1997) Traditional pharmacological treatments for spasticity. Part I: Local treatments. Muscle Nerve Suppl 6:S61–91 Gracies JM, Marosszeky JE, Renton R, Sandanam J, Gandevia SC, Burke D (2000) Short-term effects of dynamic lycra splints on upper limb in hemiplegic patients. Arch Phys Med Rehabil 81:1547–55

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Gracies JM (2005) Pathophysiology of spastic paresis. I: Paresis and soft tissue changes. Muscle Nerve 31:535–51 Gracies JM, Burke K, Clegg NJ, Browne R, Rushing C, Fehlings D, Matthews D, Tilton A, Delgado MR (2010) Reliability of the Tardieu Scale for assessing spasticity in children with cerebral palsy. Arch Phys Med Rehabil 91(3):421–8 Gracies JM, Lugassy M, Weisz DJ, Vecchio M, Flanagan S, Simpson DM (2009) Botulinum toxin dilution and endplate targeting in spasticity: A double-blind controlled study. Arch Phys Med Rehabil 90:9–16, e12 Gregson JM, Leathley M, Moore AP, Sharma AK, Smith TL, Watkins CL (1999) Reliability of the Tone Assessment Scale and the modified Ashworth scale as clinical tools for assessing poststroke spasticity. Arch Phys Med Rehabil 80(9):1013–16 Gunduz A, Kumru H, Pascual-Leone A (2014) Outcomes in spasticity after repetitive transcranial magnetic and transcranial direct current stimulations. Neur Regener Res 9(7):712. Hakkennes S, Keating JL (2005) Constraint-induced movement therapy following stroke: A systematic review of randomised controlled trials. Aust J Physiother 51(4): 221–31. Halpern R, Gillard P, Graham GD, Varon SF, Zorowitz RD (2013) Adherence associated with oral medications in the treatment of spasticity. PM R 5:747–56 Houk JC, Rymer WZ, Crago PE (1981) Dependence of dynamic response of spindle receptors on muscle length and velocity. J Neurophysiol 46:143–66 Jahn R (2006) Neuroscience. A neuronal receptor for botulinum toxin. Science 312:540–1 Kamper DG, Harvey RL, Suresh S, Rymer WZ (2003) Relative contributions of neural mechanisms versus muscle mechanics in promoting finger extension deficits following stroke. Muscle Nerve 28:309–18 Kamper DG, Rymer WZ (2000) Quantitative features of the stretch response of extrinsic finger muscles in hemiparetic stroke. Muscle Nerve 23:954–61 Katalinic OM, Harvey LA, Herbert RD, Moseley AM, Lannin NA, Schurr K (2010) Stretch for the treatment and prevention of contractures. Cochrane Database Syst Rev 9:CD007455 Katz DI, Alexander MP, Klein RB (1998) Recovery of arm function in patients with paresis after traumatic brain injury. Arch Phys Med Rehabil 79(5):488–93 Khorasani A, Peruzzi WT (1995) Dantrolene treatment for abrupt intrathecal baclofen withdrawal. Anesth Analg 80:1054–6 King T (1987) A scale for more definitive measurement of hypertonicity. Paper presented at the Occupational Therapy Forum, Stockholm, May 8–12, 1987 Lance J (1980) Spasticity: Disorders motor control. In: Feldman RG, Young RP, Koella WP, eds. Symposium synopsis. Miami, FL: Year Book Medical Publishers Lance JW (1980) The control of muscle tone, reflexes, and movement: Robert Wartenberg Lecture. Neurology 30:1303–13 Lannin NA, Novak I, Cusick A (2007) A systematic review of upper extremity casting for children and adults with central nervous system motor disorders. Clin Rehabil 21:963–76 Le T, Motaparthi M, Nguyen B, Francisco GE (2000) The incidence of abnormally increased tone during acute brain injury rehabilitation (abstract). Arch Phys Med Rehabil 81:1267

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Lee JH, Sung IY, Yoo JY, Park EH, Park SR (2009) Effects of different dilutions of botulinum toxin type A treatment for children with cerebral palsy with spastic ankle plantarflexor: A randomized controlled trial. J Rehabil Med 41:740–5 Lee LR, Chuang YC, Yang BJ, Hsu MJ, Liu YH (2004) Botulinum toxin for lower limb spasticity in children with cerebral palsy: A single-blinded trial comparing dilution techniques. Am J Phys Med Rehabil 83:766–73 Lennerstrand G, Thoden U (1968) Position and velocity sensitivity of muscle spindles in the cat. III. static fusimotor single-fibre activation of primary and secondary endings. Acta Physiol Scand 74:30–49 Leonard CT, Deshner WP, Romo JW, Suoja ES, Fehrer SC, Mikhailenok EL (2003) Myotonometer intra- and interrater reliabilities. Arch Phys Med Rehabil 84:928–32 Leonard CT, Stephens JU, Stroppel SL (2001) Assessing the spastic condition of individuals with upper motoneuron involvement: Validity of the myotonometer. Arch Phys Med Rehabil 82:1416–20 Leung J, Harvey LA, Moseley AM, Tse C, Bryant J, Wyndham S, Barry S (2012) Electrical stimulation and splinting were not clearly more effective than splinting alone for contracture management after acquired brain injury: A randomised trial. J Physiother 58:231–40 Li S, Kamper DG, Rymer WZ (2006) Effects of changing wrist positions on finger flexor hypertonia in stroke survivors. Muscle Nerve 33:183–90 Li S, Rymer WZ (2011) Voluntary breathing influences corticospinal excitability of nonrespiratory finger muscles. J Neurophysiology 105:512–21 Lippert-Gruner M, Svestkova O (2011) Early use of Xeomin neurotoxin for local antispasticity therapy for pes equines after acquired brain injury (ABI). Brain Inj 25:1266–9 Malhotra S, Pandyan AD, Rosewilliam S, Roffe C, Hermens H (2011) Spasticity and contractures at the wrist after stroke: Time course of development and their association with functional recovery of the upper limb. Clin Rehabil 25:184–91 Malhotra S, Rosewilliam S, Hermens H, Roffe C, Jones P, Pandyan AD (2013) A randomized controlled trial of surface neuromuscular electrical stimulation applied early after acute stroke: Effects on wrist pain, spasticity and contractures. Clin Rehabil 27:579–90 Mayer NH, Esquenazi A (2013) Managing upper motoneuron muscle overactivity. In: Zasler N, Katz DI, Zafonte R (eds). Brain Injury Medicine, 2nd edn. New York: Demos Medical, 821–49 Mehrholz J, Major Y, Meissner D, Sandi-Gahun S, Koch R, Pohl M (2005) The influence of contractures and variation in measurement stretching velocity on the reliability of the Modified Ashworth Scale in patients with severe brain injury. Clin Rehabil 19:63–72 Meythaler JM, Guin-Renfroe S, Grabb P, Hadley MN (1999) Long-term continuously infused intrathecal baclofen for spastic-dystonic hypertonia in traumatic brain injury: 1-year experience. Arch Phys Med Rehabil 80(1):13–19 Meythaler JM, Roper JF, Brunner RC (2003) Cyproheptadine for intrathecal baclofen withdrawal. Arch Phys Med Rehabil 84(5):638–42 Mirbagheri MM, Barbeau H, Kearney RE (2000) Intrinsic and reflex contributions to human ankle stiffness: Variation with activation level and position. Exp Brain Res 135:423–36

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Mirbagheri MM, Barbeau H, Ladouceur M, Kearney RE (2001) Intrinsic and reflex stiffness in normal and spastic, spinal cord injured subjects. Exp Brain Res 141:446–59 Mortenson PA, Eng JJ (2003) The use of casts in the management of joint mobility and hypertonia following brain injury in adults: A systematic review. Phys Ther 83:648–58 O’Dwyer N, Ada L, Neilson P (1996) Spasticity and muscle contracture following stroke. Brain 119:1737–49 Penn RD, Savoy SM, Corcos D, Latash M, Gottlieb G, Parke B, Kroin JS (1989) Intrathecal baclofen for severe spinal spasticity. N Engl J Med 320:1517–21 Pinter MM, Gerstenbrand F, Dimitrijevic MR (2000) Epidural electrical stimulation of posterior structures of the human lumbosacral cord: 3. Control Of spasticity. Spinal cord 38(9):524–31 Pohl M, Mehrholz J (2005) A new shoulder range of motion screening measurement: Its reliability and application in the assessment of the prevalence of shoulder contractures in patients with impaired consciousness caused by severe brain damage. Arch Phys Med Rehabil 86:98–104 Pohl M, Mehrholz J, Rockstroh G, Ruckriem S, Koch R (2007) Contractures and involuntary muscle overactivity in severe brain injury. Brain Inj 21:421–32 Pohl M, Mehrholz J, Ruckriem S (2003) The influence of illness duration and level of consciousness on the treatment effect and complication rate of serial casting in patients with severe cerebral spasticity. Clin Rehabil 17:373–9 Preissner KS (2002) The effects of serial casting on spasticity: A literature review. Occup Ther Health Care 14:99–106 Safaz I, Alaca R, Yasar E, Tok F, Yilmaz B (2008) Medical complications, physical function and communication skills in patients with traumatic brain injury: A single centre 5-year experience. Brain Inj 22:733–9 Sarà M, Pistoia F, Mura E, Onorati P, Govoni S (2009) Intrathecal baclofen in patients with persistent vegetative state: 2 hypotheses. Arch Phys Med Rehabil 90:1245–9 Seib TP, Price R, Reyes MR, Lehmann JF (1994) The quantitative measurement of spasticity: Effect of cutaneous electrical stimulation. Arch Phys Med Rehabil 75:746–50 Shaw LC, Price CI, van Wijck FM, Shackley P, Steen N, Barnes MP, Ford GA, Graham LA, Rodgers H; BoTULS Investigators (2011) Botulinum Toxin for the Upper Limb after Stroke (BoTULS) Trial: Effect on impairment, activity limitation, and pain. Stroke 42:1371–9 Siebner HR, Dressnandt J, Auer C, Conrad B (1998) Continuous intrathecal baclofen infusions induced a marked increase of the transcranially evoked silent period in a patient with generalized dystonia. Muscle Nerve 21(9):1209–12 Sindu M, Georgoulis G, Mertens P (2014) Neurosurgery for spasticity – A practical guide for treating children and adults. Springer-Verlag Wien Singer BJ, Jegasothy GM, Singer KP, Allison GT, Dunne JW (2004) Incidence of ankle contracture after moderate to severe acquired brain injury. Arch Phys Med Rehabil 85:1465–9 Sinkjaer T, Magnussen I (1994) Passive, intrinsic and reflex-mediated stiffness in the ankle extensors of hemiparetic patients. Brain 117:355–63 Starring DT, Gossman MR, Nicholson GG, Jr., Lemons J (1988) Comparison of cyclic and sustained passive stretching using a mechanical device to increase resting length of hamstring muscles. Phys Ther 68:314–20

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Stevenson VL, Jarrett L (2006) Spasticity Management: A practical multidisciplinary guide. London: Informa Healthcare Turner-Stokes L, Baguley IJ, De Graaff S, Katrak P, Davies L, McCrory P, Hughes A (2010). Goal attainment scaling in the evaluation of treatment of upper limb spasticity with botulinum toxin: A secondary analysis from a double-blind placebo-controlled randomized clinical trial. J Rehabil Med 42:81–9 Verplancke D, Snape S, Salisbury CF, Jones PW, Ward AB (2005) A randomized controlled trial of botulinum toxin on lower limb spasticity following acute acquired severe brain injury. Clin Rehabil 19:117–25 Wheatley-Smith L, McGuinness S, Colin Wilson F, Scott G, McCann J, Caldwell S (2013) Intensive physiotherapy for vegetative and minimally conscious state patients: A retrospective audit and analysis of therapy intervention. Disabil Rehabil 35:1006–14 Wolf JH, English AW (2000) Muscle spindle reinnervation following phenol block. Cells Tissues Organs 166(4):325–9 Yarkony GM, Sahgal V (1987) Contractures. A major complication of craniocerebral trauma. Clin Orthop Relat Res:93–6 Young RR (1994) Spasticity: A review. Neurology 44(S9):S12–20 Zafonte R, Co S, Srikrishana A (2011) Spasticity in traumatic brain injury. In: Brashear A, Elovic E, eds. Spasticity: Diagnosis and management. Demos Medical Publishing, LLC, New York, 371–86 Zafonte R, Elovic EP, Lombard L (2004) Acute care management of post-TBI spasticity. J Head Trauma Rehabil 19:89–100 Zhang L-Q, Wang G, Nishida T, Xu D, Sliwa JA, Rymer WZ (2000) Hyperactive tendon reflexes in spastic multiple sclerosis: Measures and mechanisms of action. Arch Phys Med Rehab 81:901–909 Zhang LQ, Chung SG, Bai Z, Xu D, van Rey EM, Rogers MW, Johnson ME, Roth EJ (2002) Intelligent stretching of ankle joints with contracture/spasticity. IEEE Trans Neural Syst Rehabil Eng 10:149–57

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9 Hereditary Spastic Paraparesis and Other Hereditary Myelopathies Jon Marsden, Lisa Bunn, Amanda Denton and Krishnan Padmakumari Sivaraman Nair CONTENTS 9.1 Introduction................................................................................................. 236 9.2 Distal Axonopathies: Hereditary Spastic Paraparesis........................... 237 9.2.1 Prevalence and Genetics................................................................ 237 9.2.2 Clinical Presentation...................................................................... 237 9.2.3 Pathology......................................................................................... 238 9.2.3.1 Cellular Changes.............................................................. 238 9.2.3.2 Changes in Descending and Ascending Tract Function............................................................................. 240 9.2.3.3 Changes in Cortical Activation with Movement......... 241 9.2.4 Symptoms Associated with HSP.................................................. 243 9.2.4.1 Limb Stiffness................................................................... 243 9.2.4.2 Paresis................................................................................ 246 9.2.4.3 Sensory Loss..................................................................... 247 9.2.4.4 Bladder............................................................................... 247 9.2.4.5 Bony Changes................................................................... 247 9.2.4.6 Fatigue............................................................................... 248 9.2.4.7 Mood and Quality of Life............................................... 248 9.2.5 Impact of Spasticity and Associated Symptoms on Functional Ability................................................................248 9.2.6 Balance.............................................................................................. 248 9.2.7 Walking............................................................................................ 249 9.2.8 Outcome Measurement.................................................................. 252 9.2.9 Interventions.................................................................................... 253 9.2.9.1 Pharmacological and Surgical Treatment of Spasticity....................................................................... 253 9.2.9.2 Physical Interventions..................................................... 257 9.2.9.3 Service Delivery............................................................... 258 9.3 Spinocerebellar Degenerations................................................................. 258 9.3.1 Autosomal Dominant..................................................................... 258

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9.3.2 SCA3 or Machado-Joseph Disease............................................... 259 9.3.2.1 Symptomatic Management............................................. 262 9.3.3 Autosomal Recessive...................................................................... 266 9.3.4 Friedreich’s Ataxia and Late-Onset Friedreich’s Ataxia........... 266 9.3.4.1 Management of FDRA..................................................... 267 9.4 Motor Neuron Disorders and Familial Amyotrophic Lateral Sclerosis........................................................................................................ 268 9.4.1 Amyotrophic Lateral Sclerosis...................................................... 268 9.4.1.1 Prevalence and Genetics................................................. 268 9.4.1.2 Pathology........................................................................... 269 9.4.1.3 Clinical Presentation....................................................... 269 9.4.2 Interventions.................................................................................... 271 9.4.2.1 Disease-Modifying Therapy........................................... 271 9.4.2.2 Symptomatic Management............................................. 271 9.5 Leukodystrophies....................................................................................... 273 9.5.1 Demyelinating and Dysmyelinating Disorders......................... 273 9.5.2 Hypomyelinating Disorders......................................................... 273 9.5.3 Spongiform Disorders.................................................................... 273 9.5.4 Cystic Disorders.............................................................................. 274 9.6 Adrenoleukodystrophy.............................................................................. 274 9.6.1 Prevalence and Genetics................................................................ 274 9.6.2 Clinical Presentation...................................................................... 274 9.6.3 Interventions.................................................................................... 275 9.7 Summary...................................................................................................... 275 References.............................................................................................................. 276

9.1 Introduction This chapter will explore the impact of spasticity and associated symptoms in hereditary myelopathies with a particular focus on hereditary spastic paraparesis (HSP). Hereditary myelopathies include syndromes with a genetic cause that involves spinal cord structures. To a variable extent they will have upper motor neuron (UMN) symptoms of spastic paraparesis. Importantly, in the majority of cases, structures outside the spinal cord are affected, resulting in a diversity of symptom presentation. Four main clinical groups can be distinguished.1 1. Distal axonopathies of the spinal cord, e.g., HSP. 2. Spinocerebellar degenerations, e.g., spinocerebellar ataxia3 (SCA3), late-onset Freidreich’s ataxia. 3. Motor neuron disorders, e.g., familial amyotrophic lateral sclerosis.

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4. Inborn errors of metabolism, e.g., adrenomyeloneuropathy, biotinidase deficiency, cerbrotendinous xanthomatosis, glycogenosis type IV, Krabbe’s disease metachromatic leucodystrophy, and phenyl ketoneuria. Based on clinical presentation alone it can be often quite difficult to distinguish between conditions. People with the complex forms of HSP, for example, can have cerebellar signs and mimic the presentation seen in spinocerebellar ataxias. Similarly, spinocerebellar ataxias such as SCA3 (Machado-Joseph disease) can present with significant spasticity and mimic HSP.2 Adrenomyeloneuropathy can sometimes mimic HSP.3–6 An example of the clinical presentation and management from each clinical group of hereditary myelopathies will be described. The level of understanding of the underlying genetics can vary between the different hereditary myelopathies and this will be briefly described. Further, the hereditary myelopathies can have quite diverse additional symptoms and pharmacological and rehabilitation management. This will be described with particular emphasis placed on the management of spasticity and the upper motor neuron syndrome and its impact on functional ability.

9.2 Distal Axonopathies: Hereditary Spastic Paraparesis 9.2.1 Prevalence and Genetics Hereditary spastic paraparesis (Strumpell-Lorrain syndrome) has a prevalence of 4–6 per 100,000, although this can rise up to ~20 per 100,000 in isolated populations.7 It is a heterogeneous genetic condition. More than 50 gene loci have been identified that can cause HSP.8 All types of inheritance have been described: autosomal dominant (70% of cases), autosomal recessive, X-linked, and maternal mitochrondrial. The age of onset can vary from childhood to late adult life (70 years of age).8 There is also a high incidence of spontaneous mutations and asymptomatic carriers.9 In SPAST(SPG4), the most common type of autosomal dominant HSP (40–45% of cases), spontaneous mutations to the spastin gene, can occur in 13% of cases where symptoms are restricted to the legs.10 Epidemiological studies suggest that 45–67% of autosomal dominant and 71–82% of autosomal recessive cases diagnosed with spastic paraparesis have no genetic diagnosis after systematic testing.11 9.2.2 Clinical Presentation Anita Harding originally described two broad classifications for HSP.12 The type 1, uncomplicated presentation is characterised by the symptoms

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of lower limb spasticity, hyperreflexia, paresis, and a positive (up-going) Babinski response. Additional symptoms of urinary urgency and impaired vibration thresholds may also be present. Most cases of autosomal dominant HSP are the type 1, pure presentation. In the type 2 presentation people have the same spastic paraparesis presentation as seen in type I but with other additional symptoms. Autosomal recessive presentations tend to have a complicated presentation and additional symptoms include: • Cerebellar ataxia and signs. • Dementia and cognitive deficits. These are associated with thinning of the corpus callosum. • Amyotrophy. • Peripheral neuropathy. • Cataracts or pigmentary retinopathy. • Dry, itchy skin (ichthyosis). • Epilepsy. The most common types of HSP for each mode of inheritance and pertinent clinical features are presented in Table 9.1, with more rare presentations described in detail elsewhere.8,13 9.2.3 Pathology 9.2.3.1 Cellular Changes In the last decade, there has been an increase in the understanding of the changes in neuronal cell function that lead to HSP. This section will briefly review these changes and more detail can be gained from recent reviews of this area.8,13 Neurons within ascending and descending tracts that connect the brain and the lower segments of the spinal cord are over 1 m long. Protein and lipid synthesis and detoxification of harmful substances mainly occur within the cell body and the endoplasmic reticulum (ER)-golgi apparatus system. A system of axonal transport is therefore required that actively transports newly synthesised materials from the cell body to the axon and neurotrophic factors and damaged organelles from the axon terminal to the cell body.14 Axonal transport relies on a cytoskeletal network within the axon made of microtubules and actin filaments. Specialised motor proteins bind to and move substances in an anterograde or retrograde direction through this network, a process that is ATP-dependent, i.e., requires energy. Genes causing HSP encode proteins that are involved in the ER-golgi system (e.g., ATL-1 (SPG3A); REEP(SPG31); RTN2 (SPG12)); or axonal transport. SPAST (SPG4), for example, plays a role in microtubule turnover, whilst KIF5A (SPG10) is a member of the kinesin family of motor proteins.8

Protein

ATP synthase 6

Mitochondrial localisation, ATP synthesis

1 family

<100 cases

Over 100 cases

~30 families

50% of AR–HSP

10% of cases

40–45% of AD cases

Estimated Prevalence Pertinent Features

Late onset disorder

Cognitive impairment hypoplasia of the corpus callosum, adducted thumbs and hydrocephalus Quadriplegia, nystagmus, cognitive impairment, seizures

Thin corpus callosum, cognitive impairment, and severe axonal neuropathy Variable onset, cerebellar signs, optic atrophy, neuropathy

Early onset Pure HSP

Childhood–late adult Mainly pure HSP

Source: Adapted from Salinas, S. et al., Lancet Neurol 7, 1127–1138, 2008; and Noreau, A. et al., Exp Cell Res, 18–26, 2014

Mitochondrial No SPG designation

PLP1

L1CAM

X-linked SPG1 Xq28

SPG2

Mitochondrial m-AAA ATPase

Paraplegin

SPG7 16q

Cell adhesion and signalling, neurite outgrowth, neuronal cell migration and survival Major myelin protein in oligodendroglia

Endosomal trafficking

Atlastin

Microtubule severing, ER morphogenesis, Endosomal trafficking, inhibition of bone morphogenic protein signalling Intracellular trafficking, ER morphogenesis, and BMP signalling

Cellular Function

Autosomal Recessive (AR-HAP) SPG11 15q Spatascin

SPG3A 14q12-q21

Autosomal Dominant (AD-HSP) SPAST (SPG4) 2p22 Spastin protein

Gene Name & Locus

Genetic Location; Protein and Broad Cellular Function; Prevalence and Key Clinical Features

TABLE 9.1

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Molecules can be internalised (endocytosis) or externalised (exocystosis) into the cells or degraded by lysosomes. Endosomes are central to the movement of vesicles that contain these molecules. The endosomes are linked with the plasma membrane, golgi apparatus, and lysosomes. There are several genes linked with HSP that encode proteins that are involved in endosomal trafficking (e.g., in SPG47 & SPG50-52 components of protein complexes that play a role in secretory/endocytic pathway are affected). All cells require the mitochondria to produce ATP via oxidative phosphorylation. Longer axons with their large volume and reliance on axonal transport seem particularly susceptible to disorders of mitochondrial function and several genes have been identified that impair mitochondrial regulation and cause HSP (e.g., SPG7 encodes paraplegin and SPG13 encodes chaperonin 6). More recently, genes involved in lipid metabolism have been associated with HSP. Lipids are involved in energy storage, signaling, and in the formation of the plasma and intracellular membranes, which cover a large area in longer neurons. Proteins have been described, for example, that are involved in lipid metabolism, hydrolyzing phospholipids into fatty acids (DDHD2, SPG54), or in the processing of gangliosides that are signal transducers within the plasma membrane (e.g., B4GALNT-1, SPG26). The production of the myelin sheath by oligodendrocytes can also be affected and genes causing HSP can be expressed in oligodendroglia, but not in motor neurons (e.g., SPG2).8,13 Overall, the pattern suggests that abnormal cellular trafficking/axonal transport results in degeneration of the nerves. The distal-most parts of the long axons are first affected as molecules need to be transported across a long distance and this requires more energy to function (i.e., those axons projecting to/from the spinal cord segments supplying the lower limb). The recent finding of genes being involved in lipid metabolism and in oligodendrocyte function, however, highlights that a common mechanism for all causes of HSP may not be present. Given the heterogeneous presentation of HSP, more work is required to understand the genotype-phenotype relationship in terms of symptom presentation, longitudinal progression, and prognosis with intervention. 9.2.3.2 Changes in Descending and Ascending Tract Function The pathology in HSP is one of a dying back axonal degeneration predominately affecting the corticospinal tracts. The longer tracts that supply the lower limbs are affected first, with shorter tracts supplying the trunk and arms being affected later with disease progression.15 In keeping with this, the lower limb motor-evoked potentials (MEPs) following stimulation of the motor cortex using transcranial magnetic stimulation (TMS) are either absent or have a higher threshold. Further, when a response is present the

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central conduction time is prolonged. In contrast, hand muscle responses to motor cortex stimulation are usually normal.16–20 The most common MRI change is thinning of the cervical and thoracic spinal cord. Although MRI and volume-based morphometry of the brain may be normal, in SPAST (SPG4), changes are seen with diffusor tensor imaging (DTI).21 The DTI reveals white matter changes in the posterior limb of the internal capsule and peritrigonal white matter. Frontal lobe white matter changes are more marked, with longer disease duration.21 In complicated presentations, such as SPG11, white matter changes are more marked and also involve the striatum and brainstem.22–24 Degeneration of the ascending tracts lying in the fasiculus gracilis of the dorsal columns carrying somatosensory information from the lower limbs have also been described.17 Lower limb somatosensory-evoked potentials can be reduced in size. A reduction in vibration threshold is seen in ~40–60% of patients, although, interestingly, other sensory signs are not commonly seen on clinical testing.25 Similarly, although people with HSP do not usually present with brainstem signs, white matter loss in the brainstem and abnormal brain stem auditory-evoked responses may be seen.26 Degeneration of the spinocerebellar tracts and an associated with loss of volume in the posterior fossa have also been described in SPG427 and in complicated forms overt cerebellar signs can be seen. Cerebellar signs are particularly prominent in SPG7 and 15. 9.2.3.3 Changes in Cortical Activation with Movement On fMRI, comparisons have been made between activation patterns associated with movement of the relatively unaffected hand and ankle movements. Ankle movements in autosomal dominant (AD)-HSP and SPG4 show variable changes with reduced contralateral sensorimotor cortical activation28 and increased activation of bilateral motor cortex and supplementary and premotor cortex29 and the ipsilateral cerebellum.28 In two studies normal activation was seen with hand movements,28,29 whilst Koritnik et al. (2009) found increased contralateral sensorimotor cortex and bilateral posterior parietal cortex activation with hand movements.30 The finding that changes in activation may be seen when moving an unaffected body part (the hand) is suggestive of functional reorganisation. Therefore, changes in cortical activation when moving an affected body part (the ankle) may not be solely related to performance differences between people with HSP and healthy controls.30 As described after stroke, the different patterns of cortical activation may reflect differences in the degree of pathology affecting the sensorimotor system with more widespread, bilateral changes reflecting more severe pathology.31 Patterns of functional re-organisation will also reflect additional factors such as the impact of environmental factors and task-related activity.

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BOX 9.1  PATIENTS’ EXPERIENCE OF HSP: POTENTIAL BENEFITS OF ACTIVITIES AND EXERCISE CLASSES Bob was a keen runner; he had experienced symptoms of pain around the pelvis for 7–8 years before he was diagnosed with HSP-type SPG4 in 1999. With hindsight, his pain may have been related to strategies he adopted while running to compensate for his increasing stiffness in the legs. Following diagnosis, Bob trialled baclofen at a low dose. He described ‘minor, if any’ improvement in his walking, and unfortunately he experienced significant and intolerable side effects of fatigue, drowsiness, and ‘brain fog’. Bob stopped taking the baclofen and has not tried any other type of anti-spasticity medication. In part, this is because he feels that his spasticity still has a low-to-medium impact on his walking but also because he has taken up flying on a regular basis and, under civil aviation authority rules, cannot take baclofen. Bob’s walking difficulties have progressed over time; he currently has difficulty walking in the house and tends to cling onto furniture and walls. Outside, he uses two crutches; he finds that ball-point ferrules provide the most effective grip when he places his crutches at more acute angles. He drives an automatic car with hand controls. In Bob’s description: ‘my legs—they refuse to do what my Brain is telling them to do. When walking my knees hyperextend, and I get this swelling, pain, and tenderness at the back of my knees. I often drag my toes and then my foot turns in [inverts] and can roll over’. Bob describes his legs as stiff when he walks; he does get ankle clonus but very rarely gets spasms. To compensate for the stiffness in his legs Bob moves his trunk a lot while walking; unsurprisingly, he has gradually, over the years, developed lower back pain and reduced standing balance. He falls occasionally and this tends to be immediately after getting up from sitting for a prolonged period (>1 hr). Bob can experience significant fatigue, particularly toward the end of the day. At these times he may choose to use a wheelchair or rollator. Bob is clear that his fatigue is not only related to how much he physically does but also the degree of concentration required to safely move and function plus the emotional stress and impact this can have. For the first 10–15 years, Bob found functional electrical stimulation (FES) useful. He worked with the clinicians at the National FES centre in the UK, where he developed a stimulation pattern of the trunk and hip abductors that helped to minimise the excessive trunk sway he experienced while walking (described in 2). Bilateral stimulation for foot drop was also useful for a time. Recently, Bob decided to stop using FES as it was no longer significantly helping his walking. He feels

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that FES may be more beneficial in the early stages of the condition. Instead he uses rigid ankle-foot orthoses; these keep his toes up and stop the inversion of his foot. Throughout the years of managing his symptoms Bob has remained active and incorporates daily stretches for up to 5–10 minutes targeting his plantarflexors, hamstrings, and quadriceps. Once a week he attends a 30-minute exercise class that is run by a trainer who is an ex-Olympic athlete with multiple sclerosis. In addition, Bob has recently discovered Riding 4 the Disabled’; he describes this as ‘fantastic’; as well as being enjoyable it helps his balance and core trunk strength.

9.2.4 Symptoms Associated with HSP 9.2.4.1  Limb Stiffness Increased limb stiffness is a defining feature of HSP. The stiffness is due to a combination of increased passive stiffness and enhanced excitability of the stretch reflexes.32 People with HSP do not seem to have continuous muscle activity whilst trying to rest, i.e., ‘spastic dystonia’. Cramps, particularly of the ankle plantarflexors, and lower limb flexor/extensor spasms, elicited by stimulation of the plantar aspect of the foot, have been reported. Increases in passive stiffness can be seen when the joints of relaxed participants (as confirmed using surface EMG) are slowly stretched at speeds that do not elicit a stretch reflex (e.g., at 5o/s). Faster stretches elicit a short-latency stretch reflex that is higher in amplitude compared to healthy controls and results in a further increase in stiffness. The difference between the stiffness measured at fast and slow speeds is an estimate of the stretch-reflex mediated stiffness and is proportional to the evoked EMG response.32 Measuring stiffness in this way, however, does not take into account the impact of passive changes and stretch reflex activity on the viscous response.33 We have recorded stretch reflex thresholds as low as 10o/s in people with HSP. This has implications for clinical assessments using scales such as the Tardieu scale, where the slow stretch that measures the passive component should be purposefully below the stretch reflex threshold (e.g., a 90° movement should take >9 s to perform). The mechanisms underlying hypertonia in HSP have not been as fully explored as they have been in other conditions. Whether increased passive stiffness is associated with an increase or change in the amount or quality of the connective tissue as seen in cerebral palsy and spinal cord injury or is associated with shortened muscle fascicles as measured using ultrasound has, to date, not been reported.34,35 A limited exploration of the role of altered spinal cord inhibitory circuits in the genesis of spasticity has been performed. Mazzocchio and Rossi (1989) found in people with progressive spastic paraparesis and HSP that the

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Renshaw-mediated recurrent inhibition was less than in healthy controls. Further, there was a smaller reduction in recurrent inhibition with volitional movement compared to controls.36 This may in part explain why stretch reflex-mediated stiffness is not significantly different from healthy controls when a muscle is preactivated to ~10% of the maximum voluntary contraction and then stretched.32 A theoretical explanation based on current evidence from people with HSP and other conditions is as follows: at rest, reductions in spinal cord inhibitory circuits (e.g., recurrent and reciprocal inhibition) in people with spasticity contribute to a heightened stretch reflex size.37 In contrast, with preactivation of the muscle, inhibitory activity reduces in healthy participants but does not reduce as much in people with HSP.38 This could result in similar values of spinal cord inhibition when the muscle is preactivated and thus a similar response to muscle stretch. Further, the overall stiffness is, in part, mediated by active cross bridge formation resulting in similar stiffness values between the two groups. From a practical basis, as other groups have highlighted, this has implications for the role of spasticity in causing difficulties with functional movements.39,40 The high resistance to movement when a resting muscle is passively stretched during a clinical examination on a treatment couch may therefore not correspond to the resistance occurring when the same muscle is stretched during a functional task when it is pre-activated (see also impact on functional ability, below). Changes in other spinal cord inhibitory circuits, such as reciprocal and presynaptic inhibition, the development of motor neuronal plateau potentials and changes in 1a afferent neurotransmitter release that occurs with repetitive stimulation (reduction in post-activation depression) reported in other UMN syndromes have not been assessed in people with HSP. Recent work has found that there are differences in the patterns of inhibitory spinal cord circuit alterations in adults where spasticity developed over the developmental period (people with cerebral palsy) compared to adults with acquired spasticity (people with adult-onset stroke).41 In adult cerebral palsy a reduction in presynaptic inhibition is observed but there are no reductions in reciprocal inhibition in contrast to the person with adult-acquired spasticity.41 Given that many types of HSP have an onset in early childhood (1 year and above42), it would be interesting to compare spinal cord inhibitory circuitry in early- and late-onset HSP and whether this leads to any quantifiable impact on the response to muscle stretch and function. Cortical modulation of stretch reflexes is also abnormal in HSP. Usually in healthy control participants the soleus H-reflex is facilitated by prior stimulation of the motor cortex leg area at interstimulus intervals of 10 and 20 ms and 70–90 ms. This early facilitation is lost in people with HSP and a new form of facilitation at an interstimulus interval of 40 ms is seen. This was felt to reflect the longer desynchronised central conduction times in HSP 43 (Figure 9.1). These changes were not related to motor function. Whether soleus H-reflex modulation during the stance and swing phases of walking is disrupted in HSP as described in other conditions with spasticity is currently unknown. However,

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FIGURE 9.1 Cortical modulation of the H-reflex was assessed by stimulating the cortex using TMS at different inter-stimulus intervals (ISI) in the range 0–100 ms prior to stimulating the H-reflex. The H-reflex responses for a healthy participant (a) and person with HSP (b) are shown with ISI 0–90 ms superimposed. A comparison of the control (n = 10) and HSP (n = 10) groups show that early facilitation of the H-reflex at ISI = 10 and 20 ms is less in HSP, possibly reflecting longer desynchronised central conduction times. Panel (c) shows the mean amplitude of the soleus muscle H reflex for each interstimulus interval. This is expressed as a percentage of the baseline H reflex which was about 10% of the supramaximal M response. (Adapted from Serranova, T. et al., Neurosci Lett, 437, 15–19, 2008.)

phase-dependent modulation of cutaneous reflexes elicited in tibialis anterior and biceps femoris by stimulation of the sural nerve are smaller in HSP.44 As with other conditions, the central changes resulting in spasticity in HSP are unclear. The degree of spasticity (as measured by the Modified Ashworth Scale) is negatively correlated to activity in Brodman’s area 4 and 1-2-3, measured using fMRI during ankle movements.28 However, here spasticity may simply be a marker of disease severity and not reflect a causative relationship. The cortical silent period is an interruption of a voluntary muscle contraction following stimulation of the contralateral motor cortex using TMS. Earlier inhibition is in part spinally mediated, whilst later suppression reflects the activation of GABAB (gamma-aminobutyric acid) receptor-mediated cortical inhibitory circuits.45 In HSP (SPG4), the cortical silent period is shortened, indicating reduced activity of motor cortical inhibitory interneurons. The reduction in the cortical silent period in turn was associated with the degree of spasticity as measured by the Ashworth Scale.17 This has correlates in stroke and amyotrophic lateral

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sclerosis (see below), where a shortened cortical silent period is associated with the development of spasticity.46–48 Using paired-pulse TMS, other groups have found an increase in intracortical facilitation in AD-HSP.49 The increase in intracortical facilitation may reflect a reduction in GABA-interneuronal activity (in keeping with the shortened cortical silent period) but may also reflect an increase in glutamateric transmission or a compensatory mechanism to increase corticospinal transmission. Interestingly, the changes in intracortical facilitation were found in areas controlling hand muscles. Thus, the association between changes in cortical silent period and spasticity may either be causative or reflect the co-occurrence of paresis and spasticity and compensatory mechanisms to maintain or increase corticospinal output.49 9.2.4.2 Paresis Lower limb weakness co-occurs with spasticity in HSP. Muscle strength is commonly described as being clinically less affected than that seen in other acquired UMN syndromes.13 Objectively isometric maximal voluntary contraction of lower limb muscles in HSP has been measured using dynamometry.32 The isometric contraction aimed to avoid reductions in applied torque by stretch reflex activation in antagonist muscle groups that may occur during isokinetic testing. Isometric muscle strength was lower in all lower muscle groups tested (Figure 9.2). When combined flexor and extensor muscle strength at the ankles, knees, and hips was compared to healthy controls there was a proximal to distal gradient of weakness. 2.5 HSP

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The two muscles most affected were the ankle dorsiflexors and the hip abductors, which were on average ~50% the strength of that seen in age and gender matched controls.32,50 Significant differences in the ratio between agonist-antagonist muscle strength are also seen. The ratio of hip abductor/hip adductor strength, for example, is significantly lower in people with HSP. This muscle imbalance with relative sparing of some muscle groups such as the hip adductors may account for ‘spastic gait patterns’ such as scissoring while walking rather than being attributable to spasticity per se. 9.2.4.3 Sensory Loss Vibration threshold is increased in ~40% of people with HSP and is greater distally at the hallux.25 This may reflect degeneration of the fasiculus gracilis but also spinocerebellar degeneration as conscious perception of vibratory signals may be mediated by both pathways.51,52 9.2.4.4 Bladder Bladder dysfunction is seen in ~75% of people with HSP,53,54 but is often not reported. A retrospective review revealed symptoms of urgency (51.0– 72.4%), frequency (55.1–65%), urinary incontinence (55.2–69.4%), hesitancy (51.7%), and incomplete bladder emptying (36.75%).53,54 Urodynamic analysis revealed detrusor overactivity in 82.7% of cases and detrusor sphincter dyssynergia in 65.5% of cases. Detrusor overactivity was associated with higher post-void residuals and symptoms of urinary frequency and nocturia.53 9.2.4.5 Bony Changes As HSP is a condition that can have an onset during development there is the potential for bony change similar to that seen in CP or Freidriech’s ataxia/ Charcot-Marie Tooth disease. These may contribute to motor dysfunction. In children with HSP, hip joint motion in the transverse plane while walking is similar to typically developing children, in contrast to children with cerebral palsy and spastic diplegia (CP-SD) who demonstrate high internal rotation. Although not confirmed by X-rays, this suggests that in early-onset HSP there is a physiological correction of femoral anteversion compared to children with CP-SD, in whom symptoms are present from birth. Pes cavus is commonly seen in HSP. The high arched foot and altered heel alignment could affect the line of pull of the plantarflexors, reducing the effective plantarflexor torque during the push-off phase of walking. People with HSP commonly have an increased lumbar lordosis and, as highlighted below, trunk motion is often increased while walking; this is associated with a high incidence (>75%) of lower back pain.

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9.2.4.6 Fatigue As with other long-term neurological conditions, fatigue is common and shows similar complexities. The degree of fatigue, for example, is not always related to the amount of physical activity performed and cognitive tasks, stress, and anxiety may also impact on fatigue and walking performance. 9.2.4.7 Mood and Quality of Life Reduced mobility is also associated with the presence of depression, as measured by the Beck depression inventory, with 28/48 (58%) of cases showing depression, which in 75% of these cases was mild.55 Quality of life is reduced in people with HSP and is lower in people with more severe disease (as measured by the Spastic Paraplegia Rating Scale56), reduced walking ability, and the presence of a type 2 complicated presentation.57,58 9.2.5 Impact of Spasticity and Associated Symptoms on Functional Ability People with HSP in particular have difficulties with walking, balance, and falls. Discussion and focus groups with people with HSP in the UK (n = 30; unpublished, observations59) have highlighted the difficulties with functional tasks. Understanding these perceptions are important when elucidating the relative impact of symptoms such as spasticity and limb stiffness. People with HSP find that walking backwards (such as stepping back to open a door), walking on uneven terrain, and walking on cambers or slopes can be particularly difficult. Falls can be precipitated by a loss of balance but also by tripping caused by foot drop as the foot either contacts external objects or catches the other foot or leg in swing phase. Walking is reported to require increased attention as people have to concentrate on their foot placement and performing concurrent tasks (i.e., walking and talking) can be difficult. Walking and lower limb stiffness was often (>50% of respondents) modulated by the environmental temperature, with stiffness higher and walking more difficult in cold weather compared to warm weather – although very hot, humid climates were reported to cause excessive fatigue and limit walking ability. 9.2.6 Balance Causes of poor balance in HSP could be due to multiple factors, such as impaired central afferent and/or efferent signal processing, poor central integration of multi-sensory afferent signals, spasticity, and secondary changes in muscle strength and musculo-tendinous stiffness. People with HSP show delayed lower limb muscle responses to forward and backward postural perturbations.60 This is presumably in part due to dorsal column-medial leminiscal and spinocerebellar degeneration leading

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to impaired processing of afferent signals that detect the onset, size, and direction of the perturbation. An important role in afferent as opposed to efferent pathway pathology in causing balance dysfunction is supported by the fact that the onset of the lower limb muscle response following a perturbation is normalised when the perturbation is paired with an acoustic signal eliciting a startle response.60,61 This suggests that the efferent pathways mediating the startle response (presumed to be the reticulospinal tract) are intact. An improvement in muscle onset times with a startle response is also seen in healthy controls but it is more marked in people with HSP.60,61 Enhanced startle responses have been reported following pontine stroke, where they are felt to arise due to a disruption of the cortical control of lower brain stem centres.62 As many cortical projections to the brainstem arise from collaterals of the corticospinal tract a similar cause of enhanced responses to a startle could occur in people with HSP. The relative importance of abnormal processing of afferent information is supported by other groups that have found that higher degrees of standing postural sway are associated with increased vibratory thresholds.50 Muscle weakness also contributes to poor balance. Greater postural sway in the mediolateral plane is associated with greater weakness in the hip abductors. Greater antero-posterior sway during quiet standing and following a forward perturbation is correlated with greater weakness in the ankle plantarflexors.50,63 The role of spasticity in mediating imbalance remains unclear. De Niet et al. (2012) found that greater stffness (as measured by the Modified Ashworth Scale) resulted in greater imbalance following a toe-up perturbation in HSP.63 This perturbation stretches the ankle plantarflexors and requires a stabilising response in the tibialis anterior. Interestingly, the strength of the tibilais anterior (as measured using manual testing) did not affect the response size. In contrast, Marsden and Stevenson (2012) measured ankle passive and stretch reflex mediated stiffness in people with HSP using motor-driven perturbations. They found that greater total ankle stiffness and stretchmediated stiffness were associated with less antero-poterior sway.50 They suggested that higher ankle stiffness may serve to aid stability. 9.2.7 Walking Walking difficulties is a characteristic feature in HSP. A study of 194 people with HSP in Norway highlighted that 31% were classified as having mild symptoms; 32% as walkers that were unable to run; 25% as walkers dependent on walking aids; and 11% as wheelchair-dependent.42 People with HSP walk with a slower velocity, have a smaller step length, an increased stride and step time, and a larger base of support.64–66 The walking pattern in HSP has been characterised in several studies. Using cluster analysis, Wolf et al. (2011)66 identified 5 clusters similar to that described previously for children with cerebral palsy67–69 (Figure 9.3).

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FIGURE 9.3 Walking patterns in people with HSP and CP, highlighting different types of gait presentation. Crouch gait: characterised by increased hip and knee flexion during stance phase. Recurvatum: characterised by increased knee hyperextension in mid-stance. Stiff knee: characterised by reduced knee motion in swing phase. Jump knee: characterised by increased knee flexion at loading response and almost-normal knee function later in the gait cycle. Normative: a gait cycle similar to normative data obtained from healthy control participants.

Comparisons have been made between people with HSP and spastic diplegia due to cerebral palsy (CP-SD). In part, this is driven by the desire to identify characteristics that may aid in the differential diagnosis of CP-SD. The proportion of people with prolonged knee and hip extension characteristic of a recurvatum pattern and prolonged ankle plantarflexion in stance phase was higher in people with HSP.64,66 Increased amplitude and speed of trunk movement in the sagittal plane was also greater in people with HSP compared to people with CP-SD who tend to show higher shoulder motion (flexion/extension and elevation) akin to the ‘guarding’ seen by infants in the early stages of walking.65 There are several impairments that correlate with the characteristic walking patterns seen in people with HSP. For example, greater stiffness in the hip flexors, as assessed using the Ashworth Scale, is associated with reduced active range of movement and slower walking speeds. Other studies have focused on specific aspects of the gait cycle, such as ankle equinus and stiff knee gait, as outlined below.

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Early studies modeling walking have highlighted that movement of the leg in swing phase from knee flexion through to knee extension in terminal swing is in part passive in nature, reflecting the motion of a multi-linked pendulum moving as a result of torques generated at the end of stance phase.70 More recent modeling studies have highlighted the importance of muscle activity during swing phase in regulating the motion of the leg.71,72 Eccentric lengthening of the rectus femoris muscle, for example, controls the initial rapid knee flexion at the start of the swing phase while hamstring muscle activity acts to control the subsequent extension of the knee at the end of the swing phase. Modeling studies have also highlighted the importance of the ankle plantarflexors and hip flexors in generating torques that initiate swing phase.73,74 Using dynamometry to produce motor-driven perturbations and test strength, Marsden et al. (2012) explored impairments that were associated with reduced knee flexion; the stiff knee gait. Of the variables prospectively assessed (knee extensor passive and stretch-mediated stiffness, ankle plantarflexion and hip flexion strength) they found that increased knee extensor passive stiffness and weakness in the ankle plantarflexors were associated with reduced ankle power and an increased knee extensor moment in preswing, and in turn reduced knee flexion velocity and amplitude.32 Lower knee flexion velocity at the start of swing phase was also associated with less knee extension at the end of stance phase, reflecting the impact on the pendular motion of the leg (unpublished observations). This study highlights the relative importance of passive stiffness and weakness in producing stiff knee gait. It also brings into question the relative role of knee extensor spasticity in limiting knee motion. Although knee extensor spasticity was significantly higher in people with HSP compared to controls, this was not correlated with a limitation in knee flexion.32 This could reflect the fact that with activation of the muscle at the end of stance phase the stretch-reflex mediated stiffness is normalised, as described above. However, the lack of correlation could also reflect the methods used. Knee extensor stiffness was measured with the participant in supine while they rested or preactivated the muscle. Although this reflects the assessment of limb stiffness in clinical practice, stretch reflex activation during walking was not assessed. In other UMN conditions it has been reported that the stretch reflex activity in the knee extensors normally modulates while walking, being higher in amplitude during stance as opposed to swing phase. This is felt to reflect changes in the degree of muscle activation (and so the excitability of the motor neuron pool) but also modulation in pre- and postsynaptic inhibitory circuits within the spinal cord.75 In other conditions with spasticity, this degree of modulation is reduced.76 Therefore, stretch reflex behavior at rest may not reflect that seen during functional movements. However, in support of the finding of a lack of relationship between knee extensor spasticity and stiff knee gait, Piccini et al. (2011) recorded less rectus femoris activity while walking in children with HSP in contrast to those

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with CP-SD where excessive activity was noted.65 Other studies measuring spasticity using motor-driven stretches have highlighted a potential role of spasticity in limiting joint motion while walking. Higher plantarflexor stiffness (due to a combination of passive and stretch-mediated stiffness) was associated with reduced ankle dorsiflexion during walking.77 This effectively lengthens the limb during swing phase and contributes to the trips and falls seen in people with HSP. Central motor conduction time to leg muscles as assessed using TMS does not correlate with gait parameters in HSP.78 This is in keeping with studies in stroke suggesting that corticospinal tract damage (as determined via DTI, MRI, and TMS) may not be a key determinant in limiting walking ability,79,80 unlike its fundamental role in fine fractionated finger motion and hand function. This may be because walking is more dependent on subcortical circuitry81 and/or because people are able to compensate for weakness by using other body segments to aid progression and by altering lower limb alignment relative to the ground reaction force to aid stability in stance. There are several compensatory strategies that people with HSP seem to adopt to aid walking. Increased hip flexion during swing phase is associated with greater toe clearance.65,77 The excessive trunk and pelvic motion seen in many people with HSP may also aid leg swing.65 Higher trunk and pelvic horizontal and coronal motion is seen in people with less flexion of the knee during swing phase (unpublished observations) and may aid leg swing. Knee recurvatum brings the ground reaction force in front of the knee and could be a compensatory strategy to compensate for weakness in antigravity muscles such as the knee extensors, which are more frequently MRC grade 1–2 and weaker compared to people with CP-SD.64,65 Alternatively, knee hyperextension may be related to an increase in the plantarflexion/knee extension couple associated with increased plantarflexion stiffness as is often reported in CP-SD.65 Determining the exact reasons for knee hyperextension in HSP is important in guiding treatments as reducing the ability to hyperextend the knee (e.g., with splinting) may result in instability in the presence of knee extensor weakness.65 These potential compensatory strategies may not be wholly beneficial. Increased trunk motion associated with an increased lumbar lordosis, anterior tilt of the pelvis,65,66 and tight hip flexors may contribute to the high incidence of lower back pain. Further, knee recurvatum can be associated with stretching of the soft tissue on the posterior aspect of the knee and subsequent knee pain. 9.2.8 Outcome measurement There is a relative paucity of disease-specific rating scales for HSP. The spastic paraplegia rating Ssale (SPRS) described by Schule et al. (2006) is a standardised, 13-item tool that combines measures of walking performance, stair climbing, rising from a chair, lower limb spasticity, muscle power, range of

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BOX 9.2  PEOPLE’S EXPERIENCES OF HSP: THE BENEFITS OF ITB AND KEEPING ACTIVE Pam describes symptoms of HSP occurring throughout all of her life; she was finally diagnosed 18 years ago, after 2 years of investigations, when she was 33. Within her family, her grandmother, mother, and brother all experience walking difficulties. She does not have a genetic diagnosis and does not feel that having one would make much difference. Pam walks with one stick and describes poor balance and the need to rest every 5 minutes as her legs become tired. She has difficulty climbing and descending stairs. Pam has lost confidence in her walking and falls about once a week. She tends to catch her toes as she lifts her feet: ‘I go straight down and am unable to use my arms to save myself’. Pam explains that her legs can feel both stiff and weak and is particularly marked after any activity. She used to do stretches but did not find them helpful; instead, she explains: ‘I find a couple of hours out in the afternoon wandering around the shops is more beneficial than being sat in the house doing exercises’. Pam has an intrathecal baclofen pump that was implanted 1.5 years ago. She found that oral baclofen made her very sleepy but this is no longer a problem with the ITB pump. Since having the pump, Pam feels she stoops less and has a more upright posture when walking. Before the operation, she had symptoms of urgency (‘wanting to go quickly’). In the last year Pam feels her bladder function has deteriorated. She now feels she wants to go but the urinary flow has stopped, leading to her having an accident afterwards (symptoms akin to bladder sphincter dyssynergia). She has her pump filled locally and finds this very convenient and sees a rehabilitation consultant once a year.

movement, pain, and bladder and bowel function. An inventory of complicating signs and symptoms differentiates between pure and complex forms of HSP. The SPRS takes 15 minutes to complete and higher scores indicate worsening disease severity. The SPRS has high levels of inter-rater agreement (intraclass correlation coefficient = 0.99), internal consistency (Cronbach, α = 0.91), criterion (r = 0.83, p < 0.001), and construct validity.56 9.2.9 Interventions 9.2.9.1 Pharmacological and Surgical Treatment of Spasticity The role of anti-spasticity medications in the management of spasticity and function have been explored in several studies. However, they show

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considerable bias with studies showing low sample sizes, a lack of control groups, and blinding. A retrospective review of botulinum toxin injections into the hamstrings, hip adductors, and gastrocnemius of 12 children (6.9 years +/− 4.9 years) with HSP reported a decrease in stiffness (as measured by the Ashworth Scale) and improvement in motor function (as measured by a 2.4 +/− 3.2 change in the gross motor function measure [GMFM]) over an average 13.2-month (11.0) period.82 The GMFM is an ordinal measure assessing movement ability in lying, sitting, standing, and walking. Given the lack of a control group, the results on function should be interpreted with caution. Comparing the results to children with CP of the same age and severity (as measured by the gross motor classification scale), the GMFM changes by ~5 points over a 1-year period83 as the child develops new skills. Therefore, these results could simply result from changes in motor function with development. Subjectively, 11 out of 12 parents felt that there was an improvement in motor function with 2 out of 12 reporting an improvement in activities of daily living.82 A series of 19 case reports in adolescents and adults with HSP described the use of botulinum toxin injections into multiple muscle groups (hip adductors, Iliopsoas, plantarflexors, rectus femoris, and posterior tibial). Reductions in stiffness were widely reported and this could be associated with changes in posture (e.g., the ability to cross the legs) and function (e.g., walking) although 7 out of 19 reported no or minimal global subjective effect. The functional effects were more marked in people with mild or moderate spasticity. Increased weakness was reported in 3 out of 19 people, which was felt to be an unmasking of underlying weakness following spasticity reduction.84 Similar effects have been reported in 15 people with HSP who had injections into the hip adductors, plantarflexors, or posterior tibial muscles. Reductions in adductor and plantarflexor spasticity were reported and 6 out of 15 showed an improvement in walking velocity. The functional ambulation category (FAC) and Rivermead motor assessment did not change.85 Oral anti-spasticity medications are frequently used in HSP, including baclofen and tizanidine. To date, there have been no trials of these medications in HSP. Clinical opinion suggests that they can be associated with widespread fatigue and improve function in only a limited number of people.84,85 Gabapentin is a GABA agonist originally used to treat epilepsy and neuropathic pain. Its effects were assessed in a cross-over trial of 10 people with HSP (SPG4).86 Blood samples confirmed that a therapeutic dose (4000 mg/ day) was present during the intervention periods. There were no differences between gabapentin and placebo in terms of subjective report of disability, clinical assessment of lower limb reflexes, strength or limb stiffness, walking scales or motor intracortical excitability as measured using TMS. In an openlabel trial of methylphenidate in people with sporadic and hereditary spastic paraparesis no effect was found on walking speed or walking parameters after a 6-month period of use.87 Intrathecal baclofen has the advantage of reducing side effects associated with oral baclofen such as weakness and fatigue. Double-blind

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administration of a bolus of baclofen into the intrathecal space is associated with a clear reduction in stiffness and deep tendon reflexes that is maintained with long-term administration.88 However, the impact on walking has only been assessed using case studies. Without the use of control groups or single case study designs with multiple baseline measures these studies clearly present with a risk of bias, although they do highlight some potential benefits and limitations. Improvements have been seen in walking speed, walking kinematics/kinetics, and angle-angle plots with either a single bolus or continuous infusion over time.89–91 Other movements such as squatting also show a normalisation with a change from co-contraction to a reciprocal pattern of lower limb activation with a bolus of baclofen.92 The timing of administration and the titration of the ITB dose is important. Satisfaction is higher in people in whom the implant occurs while they are still ambulant. Initially, people can report weakness.93 The reported therapeutic dose has varied from 60–264 mg/day and may vary depending on the underlying pattern of symptoms.89 As well as potentially impacting on walking ability, ITB may improve sleep time and efficiency and reduce periodic leg movements. These improvements were reported in a study of 20 people with spasticity, of whom 1 had HSP; they were not accompanied by any change in lung function tests or sleep-related respiratory patterns.94 Bladder function has also been reported to have improved with ITB.95 In 4 adults with pure (type 1) hereditary spastic paraparesis (genetic diagnosis not given) the effects of selective dorsal root rhizotomy from L2–S2 nerve roots have been described. Following the procedure, reductions in tone and spasm frequency accompanied a subjective improvement in standing posture, stability, and walking with a decrease in scissoring of gait.96

BOX 9.3  PATIENTS’ EXPERIENCES OF HSP: HSP ACROSS THE LIFESPAN BIll is 54 years old, he has experienced symptoms since birth. Up to the age of 27 his diagnosis was described as a ‘best estimate’ of cerebral palsy. There was no known family history in previous generations. When his elder brother became affected in his early thirties, this acted as a trigger for Bill to get ‘re-diagnosed’. At the time there was no specific gene testing but they were both given the diagnosis of HSP. Gene testing followed later with a positive diagnosis of SG4. Since that time, Bill’s mother (aged 80) has tested positive for SPG4. She had experienced difficulty with mobility since her mid-sixties but not to the same extent as her son’s; she has recently had a fairly severe stroke and now is unable to bear weight. Another brother has also recently tested positive for SPG4 but so far is not showing any symptoms.

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Bill walked without aids for several years. People would often comment: ‘we don’t know how he walks, but he does’. Bill describes: ‘typically I used to aim at where I needed to be, and grabbed hold of walls/ furniture/shoulders to get there’. He started to use a wheelchair at the age of 38. It had been suggested a number of years previously, but he had resisted. It turned out to be of great benefit, enabling outdoor mobility, which he had previously lost. Bill now uses a wheelchair for most of his community mobility; at home he uses elbow crutches, but is limited to very short distances and describes his walking as ‘both uncomfortable and very slow’. He tends to swing on his crutches, rather than take steps. Bill can just manage the stairs, so long as there are hand rails on both sides, but this too is very effortful and slow. A significant problem continues to be spasticity and painful spasms; these are problematic in the day, but also at night, causing sleep disturbance. This exacerbates his fatigue, which is an ongoing symptom requiring management. He also experiences a constant ‘ache’ and the feeling that ‘my muscles never properly relax’. Bill did experience bladder frequency and urgency – this is now managed with self-catheterisation. Bill had an intrathecal baclofen pump implanted in 2011. He describes this as very beneficial; he has noticed a big improvement in his spasticity, with the drug now delivered over 24 hours without any of the unwelcome side effects of the oral medications. He had tried most of the anti-spasticity medications and had found them problematic mostly for 2 main reasons. ‘The dose required to positively affect my legs caused too much weakness in my upper body – which was a key part in enabling me to get around. So overall the drugs tended to make me less mobile, and, second, they caused fatigue and I needed to sleep most afternoons’. Bill has tried various other treatments over the years. Plaster casts to stretch his calf muscles were a regular feature in his younger years. He remembers ‘hating those casts’. He would wear casts for 6–8 weeks a year, with them being changed weekly to increase the stretch. At other times in his childhood he had removable plaster casts for regular but intermittent use. Bill has tried functional electrical stimulation but did not find any benefit from it, unlike other HSP support group members. He has found physiotherapy, exercises, and stretching to be ‘very beneficial’, but finds physiotherapy difficult to get to. He regularly stretches and feels it is important for stretching at home to become ‘routine’. Bill has invested in a ‘Theratrainer’ bike and an ‘EasyStand’ hydraulic chair; he aims to use each of them for 30 mins, once a week.

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9.2.9.2 Physical Interventions Physical therapy is commonly prescribed for people with HSP. Techniques include progressive resisted exercises, stretches, task-related training of walking, and interventions targeting cardiovascular fitness.97,98 Although focus groups highlight that people feel they benefit from physical therapy, there have been no studies exploring their benefits. Given the paucity of evidence following systematic reviews for techniques such as stretching on spasticity and passive stiffness in other upper motor neuron syndromes, it is important that this is evaluated.99 Orthoses have been prescribed to aid foot drop caused by combined anterior tibial weakness. If plantarflexor spasticity or stiffness is marked, the orthosis often needs to be quite rigid; hinging the ankle joint in these cases can aid stair descent, which requires a degree of ankle dorsiflexion. The aim of an orthosis has to be clearly defined. Some people with HSP may hyperextend their knee to compensate for knee extensor weakness; in these cases reducing ankle plantarflexion may actually enhance instability by bringing the ground reaction force behind the knee joint requiring knee extensor activation.65 Marsden et al. investigated the immediate effects of functional electrical stimulation (FES) of the common peroneal nerves bilaterally to aid foot drop during swing phase.77 Participants were long-term (>1 year) users of FES with either sporadic or hereditary spastic paraparesis. Walking speed increased with FES by 10% compared to no stimulation; there was no effect on walking efficiency as measured using the physiological cost index. Some participants had novel patterns of stimulation including stimulating the contralateral hip abductors and ipsilateral trunk extensors at the start of swing phase that also aided the clearance of the toe during swing phase.77 Chronic electrical simulation to improve muscle strength has also been reported in one case with familial spastic paraparesis. Here the quadriceps and tibialis anterior muscles were stimulated bilaterally 2–3 times/week over 3 months. A 27% improvement in walking speed was observed with an improvement in the degree of crouch in stance phase.100 Further work is required to ascertain whether there are long-term carry-over effects of FES and whether isolated electrical stimulation produces objective changes in muscle strength and function. Hydrotherapy offers people with HSP the opportunity to use the buoyancy and drag of water to perform range of motion, strengthening, and endurance exercises and to take advantage of the effects of warming (see below). A 10-week hydrotherapy (5 weeks group, 5 weeks individual, with sessions twice/week) programme was assessed in 10 people with HSP. Following the programme, the participants showed reduced total range of movement at the ankle, knee, and hip in the transverse plane, enhanced hip internal rotation, and an increase in hip extension moment in initial stance phase while walking. This was interpreted as being due to an increased use of compensatory strategies (see above) to aid foot clearance rather than a change in underlying impairment.101

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The effects of localised changes in temperature of neuromuscular func­ tion, foot tap speed, and walking ability have been explored in HSP by Denton et al. (2016). On separate days, the temperature of 1 shank was raised (~10°C) or lowered (~13°C) using a temperature-controlled water bath. Increases in lower limb peripheral nerve conduction velocity, the rate and amplitude of ankle muscle force output, and a reduction in plantarflexor stretch-reflexmediated stiffness was observed with warming, with opposite effects being seen with cooling. Further, despite only one leg being targeted there was an increase in maximal walking speed with warming (~10%) and a similarly sized decrease with cooling. Many of the effects on temperature were similar in magnitude in people with HSP compared to matched controls. However, the decrease in walking speed with cooling was more marked in people with HSP. This was interpreted as resulting from the fact that due to bilateral lower limb involvement a slight reduction in neuromuscular function in one leg has a marked effect on functional ability. In contrast, healthy participants were able to compensate for this by using other body parts (e.g., trunk and opposite leg). These findings support the subjective view of people with HSP that their symptoms are worse in cold weather and suggests that strategies such as the use of insulating garments in colder weather, external warming (e.g., with heat packs, hydrotherapy) or exercise to increase internal temperature may aid stiffness and mobility. 9.2.9.3 Service Delivery Due to the rarity of HSP knowledge of the condition and service delivery for this condition can be variable. Poor local knowledge about the condition and its management by health care professionals, difficulty in accessing specialist services (in terms of availability and time), poor service co-ordination (e.g., between neurologists, genetic counsellors, and allied health professionals) and access to evidence-based treatments were issues raised in focus groups of people with HSP in a rural setting within the UK. Further, focus groups with carers highlighted the often large and continual burden placed upon them and the need to establish supportive networks.59 One particular source of network support is the national support groups present in many countries that provide educational and emotional support throughout the disease process.

9.3 Spinocerebellar Degenerations 9.3.1 Autosomal Dominant Anita Harding originally described three classifications of autosomal dominant cerebellar ataxias (ADCAs).12 Type 1 is characterised by a cerebellar

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syndrome with ophthalmoplegia, pyramidal or extra pyramidal signs, cognitive impairment, or peripheral neuropathy. This presentation is caused by variable degenerations of the cerebellum, basal ganglia, cerebral cortex, optic nerve, pontomedullary systems, spinal tracts, or peripheral nerves. Pigmentary retinopathy accompanies a variable presentation of cerebellar and extra-cerebellar signs in ADCA II, otherwise similar to ADCA I. A third group, ADCA type III, includes relatively pure cerebellar ataxias where the degenerative process is limited to the cerebellum. Clinically characterised ADCAs are now increasingly also referred to as the spinocerebellar ataxias (SCA) denoting the genetic classification system. There are numerous SCAs identified and some labels reserved, as outlined in Table 9.2.106 The SCAs are clinically heterogeneous but they often present with progressive cerebellar ataxia. This usually starts with symptoms of ataxia while walking and poor balance followed by symptoms of limb ataxia, dysarthria, and visual problems. Visual problems, although often not the first signs/ symptoms detected by the patient have been proposed as an early sign, since the advent of pre-symptomatic genetic testing.102 Visual problems can be caused by either oculomotor abnormalities secondary to cerebellar degeneration (e.g., saccadic dysmetria, impaired smooth pursuit and nystagmus) or non-cerebellar causes (e.g., maculopathy, gaze palsies, slowed saccades). Maculopathy can precede the appearance of the cerebellar ataxia in SCA7 by up to 20 years.103,104 Cerebellar degeneration often is accompanied by involvement of the brainstem and spinal cord, although relatively isolated cerebellar degeneration can occur (e.g., in SCA6).105 A description of the pathology, clinical presentation, and intervention of SCA3 the most common SCA presenting with additional UMN signs will be described. 9.3.2 SCA3 or Machado-Joseph Disease Depending on ethnicity, SCA3 accounts for between 21 and 56% of SCA cases.107 Prevalence varies according to founder effects. It is a polyglutamate (polyQ) disease caused by a CAG repeated expansion of the ATXN3 gene on chromosome 14q. The protein encoded by ATXN3, ataxin-3, is a deubiquitinating enzyme that cleaves ubiquitin off substrates. It is felt that this enzyme’s function, and thus biochemical pathways dependent upon ubiquitin, are affected in SCA3.108 The age of onset varies from childhood to late adult life and there is an inverse correlation between the number of CAG repeats and the age of onset and disease severity.109 The pathology includes atrophy of the middle cerebellar peduncles, dentate nucleus of the cerebellum, and pontine nucei, i.e., cerebello-thalamo-cortical motor loops. The pathology also affects the substantia nigra, subthalamic nuclei (basal ganglia thalamocortical loops), red nuclei, anterior horn cells, and motor cranial nerves. Additional pathology has been described in the somatosensory, auditory, and occulomotor systems. Brainstem involvement affecting the dopaminergic and cholinergic system is also present.

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TABLE 9.2 Spinocerebellar Types, Genetics, and Clinical Features Gene Name (Chromosome Location and Locus)

Protein and Mutation

ADCA I

SCA1 6p22.3 ATXN1

Ataxin 1 CAG repeat

SCA2 12q24.13 ATXN2 SCA3 14q32.12 ATXN3

Ataxin 2 CAG repeat Ataxin 3 CAG repeat

SCA4 16q24-qter SCA4 SCA8 13q21 KLHL1AS SCA9 Reserved SCA10 22q13.31 ATXN10 SCA12 5q32 PPP2R2B SCA13 19q13.33 KCNC3 SCA14 19q13.42 PRKCG SCA17 6q27 TBP

Unknown Kelch-like 1 CTG repeat Unknown Ataxin 10 ATTCT repeat PPP2R2B CAG repeat KCNC3 MM PRKCG MM TBP CAG repeat

SCA18 7q31-q32 SCA19* 1p21-q21

Unknown Unknown

SCA20 11 SCA21 7p21.3-p15.1 SCA22* 1p21-q23 SCA23 20p13-p12.2 SCA25 2p21-p15 SCA27 13q33.1 FGF14 SCA28 18p11.22-q11.2 DRPLA 12p13.31 ATN1

Unknown Unknown Unknown Unknown Unknown FGF14 MM Unknown Atrophin 1 CAG repeat

Undefined** 16q22.1

PLEKHG4 Puratrophin 1 5’ SNS

ADCA II

SCA7 3p14.1 ATXN7 ADCA III

Ataxin 7 CAG repeat

Pertinent Features Cerebellar syndrome plus ophthalmoplegia, pyramidal or extra pyramidal signs, cognitive impairment or peripheral neuropathy Ataxia, pyramidal signs, neuropathy, ophtalmoplegia Ataxia, slow saccades, neuropathy Ataxia, pyramidal signs, ophthalmoplegia, neuropathy, dystonia Ataxia, sensory neuropathy Ataxia, sensory neuropathy Ataxia and epilepsy Ataxia, tremor Ataxia, mental retardation Ataxia, myoclonus dystonia Ataxia, chorea, psychiatric manifestations, dementia, epilepsy Ataxia, sensory neuropathy Ataxia, myoclonus, cognitive impairment Ataxia, disphonia Ataxia, parkinsonism Ataxia Ataxia, sensory neuropathy Ataxia, sensory neuropathy Ataxia tremor mental retardation Ataxia, opthalmoplegia Ataxia, myoclonus, seizures, psychiatric manifestation, dementia Ataxia, sensory neuropathy Variable similar presentation to ADCA plus the presence of pigmentary retinopathy Cerebellar ataxia, pyramidal signs, pigmentary maculopathy Relatively pure cerebellar ataxias where the degenerative process is limited to the cerebellum (Continued)

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TABLE 9.2 (CONTINUED) Spinocerebellar Types, Genetics, and Clinical Features Gene Name (Chromosome Location and Locus)

Protein and Mutation

Pertinent Features

SCA6 19p13.13 CACNAIA

CACNAIA CAG repeat

SCA5 11q13.2 SPTBN2 SCA11 15q14-q21.3 SCA11 SCA15 3p24.2-pter ITRP1 SCA16 8q23-q24.1 SCA24 1p36 SCA26 19p13.3

Beta-III spectrin D, MM Unknown ITRP1 D Unknown Unknown Unknown

Almost pure cerebellar ataxia (occasional dystonia or Parkinsonism described) Almost pure cerebellar ataxia Almost pure cerebellar ataxia Almost pure cerebellar ataxia Almost pure cerebellar ataxia Almost pure cerebellar ataxia Almost pure cerebellar ataxia

Source: Adapted from Giunti, P. and Wood, N. Adv Clin Neurosci Rehabil 75, 18–21, 2007.

The corticospinal tract, however, is not severely affected and central motor conduction times have been found to be normal.107,110–112 Symptoms include progressive ataxic gait and balance and dysarthria. Associated with this are symptoms of spasticity, hyperreflexia, and nystagmus. In some cases, cerebellar-cognitive changes are also observed, namely deficits in memory, executive dysfunction, naming, and attention; visuospatial processing and calculation, however, appear spared.113 In later stages, there is opthalmoplegia and slowing of saccades, amyotrophy, and dystonic posturing. There can also be peripheral nerve involvement leading to a loss of distal sensation and areflexia that is more prominent in older people. Difficulty falling asleep and increased nocturnal wakening are more common in older people with brainstem involvement and can be associated with central apnoea and restless legs syndrome.107 The presenting symptoms vary with the age of onset, and different types of presentation have been described (Table 9.3), type 2 being the most common, TABLE 9.3 Clinical and Subtype Clinical Characteristics SCA3 Type

Mean Age of Onset (Range)

1

25 years

2

38 years (20–50)

3

48 years (40–75)

4 5

Variable age of onset 25 years (12–48)114

Symptoms Spasticity, rigidity, bradykinesia with minimal ataxia Progressive ataxia and upper motor neuron signs (spasticity, paresis) Ataxia and peripheral nerve involvement with amyotrophy and generalised areflexia Parkinsonian phenotype ‘Pure’ progressive spastic paraplegia

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seen in ~57–75% of cases. Earlier-onset cases and those with large CAG repeat expansions tend to have signs of spasticity.110 The presence of early UMN signs with minimal cerebellar signs can make SCA3 difficult to distinguish from HSP and this has been described as the type 5 presentation.2,110,114 9.3.2.1 Symptomatic Management SCAs are progressively degenerative in nature and ultimately lead to death over a typical period of 15 to 30 years. SCA6 is, however, an exception due to the late onset and slower progressive nature of the disease and is often not life-limiting. No therapeutic strategies are as yet available to target primary disease pathways in those with SCA and therefore current management approaches involve designing treatments to alleviate symptoms. Recommendations for the symptomatic treatments of spasticity, Parkinsonism, dystonia, and cramps have been outlined and include benzodiazepines, baclofen, and carbamazepine.115,116 A case study has described the use of botulinum toxin injections for lower limb spasticity and cramps that produced no side effects although the clinical benefits were not described.117 In contrast botulinum toxin injections for associated cervical dystonia have been associated with dysphagia.118 A double-bind randomised controlled trial119 of the antibiotics sulfamethoxazole and trimethoprim (co-trimoxazole) have not supported the improvements in spasticity and rigidity described by earlier smaller trials.120,121 Some people with SCA3 can show levadoparesponsive dystonia and therefore patients should undergo a levadopa trial if dystonia is present. SCAs involving Parkinsonian features, such as SCA2 and 3 (MJD), often respond to dopaminergic therapy, such as levodopa122–125 and dopaminergic drugs can also be helpful in ameliorating restless legs to aid uninterrupted sleep.125–127 Amantadine is sometimes used to treat BOX 9.4  SYMPTOM PRESENTATION AND BALANCE DYSFUNCTION IN SCA3 AND SCA6 Despite balance being an early and well-described symptom, the mechanistic underpinnings of balance impairment remain poorly understood. Tables 1–3 of Box 9.4 compare the differences between a relatively pure group of 16 people with cerebellar ataxia (SCA6) to 4 individual subjects with SCA3. These presentations outline the variability of SCA3 presentations and the multi-factorial potential for signs and symptoms to contribute to balance impairment, in contrast to SCA6, where the balance impairment involved is likely to solely be due to cerebellar disease. Table 1 highlights differences in clinical scores. As can be seen in Table 2, people with SCA3 more frequently have abnormalities in upper motor neuron signs, sensory loss, and spasticity/ spasms.

Age

40

53 49

54

62.3 (10.2)

SCA Type

SCA3a

SCA3b SCA3c

SCA3d

SCA6: mean (SD)

7m, 9f

f

f M

m

Sex

52.2 (16.4)

40

45 35

28

Age at Onset

12 (6.1)

27.5

2 14

17

SARA (/40, Most Severe Ataxia)

Gait

Gait

Gait Gait

Gait

HighestScoring Elements of SARA

35.0 (17.4)

5

56 20

31

Berg Score (/56, Best Balance Function) Y (n = 3, lost balance) N Y (n = 3, legs gave way/ lost balance) Y (n = 7, lost balance) 1.9 (2.1)

Falls in Last 6 Months

Y 122.3 (4.7)

Y (117)

N (126) Y (120)

Y (117)

Loss of Functional Independence (FIM Score /126, Best Independence)

Functional Overview of Individual SCA3C Cases Contrasted with Typical SCA6 Group

TABLE 1

None (n = 8) Stick (n = 5) Crutch (n = 3) Rollator (n = 2) WCH (n = 2, outdoor only)

Y (WCH)

N Y (sticks)

Y (rollator)

Mobility Aid Use

Abnormal MMSE (score)

Y (12)

N (30) N (24)

N (24)

Abnormal MMSE (Score)

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SCA3a SCA3b SCA3c SCA3d SCA6: mean (SD)

SCA type

N N Y (bilateral) Y (bilateral) No

Proprioceptive Loss (Hallux Longus Position in Space Test)

N Y (absent) N Y (absent) No

Abnormal Babinski N (av 10) Y (av 8.5) Y (av 1) Y (av 4) No (mean: 9.9 SD: 0.3)

Abnormal Monofilament (< 9/10) N (5/5 bilateral) N (5/5 bilateral) Y (4/5 bilateral) N (5/5 bilateral) Mean: 4.6 SD: 0.6

Muscle Weakness (Triceps Surae), (/5, Best Muscle Strength)

Individual SCA3 Sensorimotor Assessment Contrasted to Typical SCA6 Group

TABLE 2

N (1/5 bilateral) N (1/5 bilateral) Y (3/4 bilateral) N (1/5 bilateral) No

Increase in Tone (Ashworth Scale, Ankle PF)

N Y (-5 DF bilateral) Y (-5 DF bilateral) N No

N N Y (4) Y (2) None

Spams (Penn ROM Restrictions Spasm Scale)

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Gait

5 1 3 6 3 (1.7)

SCA Type

SCA3a SCA3b SCA3c SCA3d SCA6: mean (SD)

2 0 3 5 1.5 (1.0)

Stance

2 0 0 2 0.3 (0.7)

Sitting Balance 0 0 2 3 2.1 (1.1)

Speech 3 0.5 1 3 1.3 (1.0)

Finger Chase (Dysmetria)

Individual SCA3 SARA Scores Contrasted to Typical SCA6 Group

TABLE 3

1 0 1 3 0.5 (0.5)

Nose to Finger (Tremor) 2 0 1 2.5 1.6 (1.0)

Hand Movements (Dysdiadochokinesia) 2 0.5 3 3 1.7 (1.2)

Heel Shin (Co- ordination)

17 2 14 27.5 12.0 (6.1)

Total

9 1 6 13 4.8 (3.1)

BalSARA

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dystonia and bradykinesia.125,128 Those experiencing muscle cramps, most commonly encountered in SCA3, can trial magnesium, chinine, quinine, or mexiletine drug therapies.129 As with other SCAs and cerebellar disorders the pharmacological management of ataxia is limited.115,130 Tandospirone may improve symptoms of ataxia, depression, and insomnia.116 Rehabilitation is recommended, including physical therapy to address strength, balance, and gait and offer advice on falls management as well as speech therapy and dietetics to address issues of dysphagia and dysarthria, to prevent aspiration pneumonia, weight loss, and dehydration.131 Maintenance of mobility and fatigue management with appropriate use of walking aids and wheelchairs is also required as the disease progresses and it is recommended that these should be prescribed before falls cause fractures and long-lasting immobilisation.125 Splints and orthoses may prevent trauma from oversupination or pain from over-extension of the knee.125 No evidence exists, however, for the efficacy of these interventions leading to uncertainty and variability in approaches. Management recommendations for SCA3 are currently mainly based on the evidence base for treating people with Parkinson’s disease.108,132 9.3.3 Autosomal Recessive Most autosomal recessive ataxias have symptoms of limb ataxia and impaired balance and walking. Additional signs include vertigo, dysphagia, and diplopia.133 Unlike the autososomal dominant ataxia that present with associated extrapyramidal and pyramidal signs, the autosomal recessive ataxias often have additional signs of sensorimotor neuropathy, resulting in loss of proprioception and vibration sense.133 9.3.4 Friedreich’s Ataxia and Late-Onset Friedreich’s Ataxia Friedreich’s ataxia (FRDA) is the most common autosomal recessive ataxia, affecting 2 per 100,000. In ~98% of cases it is caused by a GAA repeat expansion on the Frataxin gene on chromosome 9q13. The age of onset is inversely related to the size of the repeat. Frataxin is localised to the mitochondrial matrix and associated with iron metabolism and homeostasis. It is deficient in FRDA and increased mitochondrial iron accumulation, increased oxidative stress, impaired ATP production, and cell death are seen.133,134 Degeneration of the dorsal columns, spinocerebellar tracts, and dentate nucleus occurs in FRDA. It is characterised by progressive ataxia (affecting balance, walking limbs, and speech) and sensory signs. Axonal sensory neuropathy results in areflexia and a loss of proprioception and vibration sense. Corticospinal tract involvement leads to paresis and extensor plantar responses.135 Non-neurological involvement includes cardiomyopathy in ~50% and diabetes mellitus in ~10%. With disease progression, symptoms of kyphoscoliosis and pes cavus/equinovarus become prominent and these can affect respiratory function and walking.136

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Variations of the typical Friedreich’s ataxia presentation exist in ~10% of cases having a positive molecular test for Friedreich’s ataxia. People can show Friedreich’s ataxia with retained reflexes (FARR) and also late-onset Friedreich’s ataxia (LOFA) or very late-onset Friedreich’s ataxia (VLOFA) where symptom onset occurs after 25 and 40 years, respectively.137 Unlike typical Friedreich’s ataxia, people with LOFA show signs of spasticity (40% of cases) and have retained reflexes (46% of cases).138,139 Non-neurological symptoms such as cardiomyopathy, sphincter disturbances, scoliosis, and pes cavus are less frequent in atypical FRDA.139 In VLOFA, a spastic tetraparesis without marked ataxia or neuropathy has been described.140 Oculomotor abnormalities may be absent in atypical FA. People with LOFA have a slower progression and smaller GAA expansions. Another atypical FRDA is found in Acadian families from New Brunswick, Canada. These individuals can have the same onset and symptoms as FRDA but without the involvement of cardiomyopathy and diabetes and may also show retained reflexes and spasticity. 9.3.4.1 Management of FDRA There is currently no specific information on the management of LOFA and VLOFA. Therefore, a brief overview of the management of FRDA will be provided. 9.3.4.1.1 Co-enzyme Q10 and Idebenone Co-enzyme Q10 is a mitochondrial molecule that is part of the electron transfer chain. It is a potent antioxidant and can maintain other antioxidants such as vitamin E. Idebenone is a structural analogue of co-enzyme Q10 but it is more water-soluble and has a lower molecular weight and may thus show greater bioavailability.134 There is some evidence from randomised controlled trials in the USA and Europe to suggest improved cardiac function and maintenance or improvements in fine motor skills following idebenone.134 However, as reviewed by Parkinson et al., this seems to be dependent on the prescribed dose and baseline disease severity (improvements may be more marked in ambulant, less severe children). The impact on neurological signs and in particular functional ability and quality of life is unclear.134 9.3.4.1.2 Symptomatic Management Rehabilitation for FRDA involves a multi-disciplinary team, including speech therapists and dieticians (to address communication issues, dysphagia, diabetesmanagement), occupational therapists, orthotists, and physiotherapists.141 A retrospective review of in-patient rehabilitation in people with FRDA found improvements in function (as measured by the functional independent measure) that continued to improve on discharge.142 Physiotherapy commonly consists of progressive resisted exercises and stretching.143 In addition, mobility can be improved by aids (e.g., walking aids/wheelchairs) and orthoses

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or shoes for pes cavus.144 Orthopaedic management of scoliosis may also be required and early management of the pes cavus foot has been suggested.145 Uptake of home rehabilitation programmes by people with FRDA can be sparse (~10%).143 This could be related to perceptions of a lack of expertise by prescribing therapists about the condition as well as a lack of access to appropriate therapists. Issues around a lack of time and energy and the association of treatment with the presence of disability are further barriers highlighted.143 The compliance with therapy may be increased by the use of interactive whole-body controlled video game technology. Intensive training over an 8-week period of balance and co-ordination skills resulted in improvements in ataxic symptoms, balance, and walking.146,147 Endurance training is feasible in people with FRDA and can lead to improvements in markers of cardiovascular fitness. A static exercise bike was used for training, which has the advantage of reducing balance requirements, and cardiac function was monitored during training.148 Intrathecal baclofen has been used to reduce painful spasms in a case with FRDA,149 whilst oral baclofen and botulinum toxin have been recommended for spasticity management.141 There are no clinical trials or reports on the management of spasticity in late onset FRDA.

9.4 Motor Neuron Disorders and Familial Amyotrophic Lateral Sclerosis Motor neuron disease: amyotrophic lateral sclerosis (ALS) accounts for 70–90% of cases of motor neuron disease and is characterised by predominant lower motor neuron (LMN) signs of weakness in combination with mild UMN signs of spasticity and brisk reflexes. A minority of people with ALS, termed UMN-Dominant, have pyramidal signs and severe spino-bulbar spasticity with slight LMN signs. In 2–5% of people with motor neuron disease there is exclusive involvement of UMNs, termed primary lateral sclerosis. In contrast, people without any clinical or electrophysiological UMN signs and only LMN signs are labeled as progressive muscular atrophy. The remaining subtypes of MND are characterised by LMN signs affecting the bulbar muscles (progressive bulbar palsy) or UMN involvement affecting the bulbar muscles (pseudobulbar palsy).150 9.4.1 Amyotrophic Lateral Sclerosis 9.4.1.1 Prevalence and Genetics ALS has a prevalence of 3.4–5.4 per 100,000. The age of onset is usually in late adult hood (65 years), and survival time is 2–3 year for bulbar onset and

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3–5 years for limb presentation onset. People with an UMN-dominant presentation have a longer survival time.150 Familial ALS (FALS) is diagnosed where there is a first- or second-degree relative of the index case. FALS accounts for 4.6% of cases of ALS.151 Familial ALS is usually inherited in an autosomal dominant manner but autosomal and recessive patterns of inheritance have been described. Mutations in the SOD1 gene, the first gene on chromosome 21 found to cause FALS, accounts for 20% of familial ALS cases. The gene C9ORF72 is linked to chromosome 9p21 and makes up ~43% of FALS and 7% of sporadic cases. This form of FALS is associated with frontotemporal dementia. The genes TARDBP, FUS, VCP, UBQLN2 and OPTN comprise the majority of the remaining genes causing FALS.152,153 9.4.1.2 Pathology ALS is associated with degeneration of the corticospinal tract and alpha and gamma motor neurons and interneurons in the spinal cord and Betz cells within the primary motor cortex. There is additional degeneration in the deep frontal and temporal white matter, corpus callosum, brainstem (including serotonergic neurons), and motor nuclei of the basal ganglia.154 People with ALS and an expansion in the gene C9ORF72 have additional pathology in the frontal cortex and hippocampus (CA4 area) in keeping with the association of frontotemporal dementia.153 Hyperexcitability in the motor cortex is seen early on in the disease course; there is a reduction in GABAA-mediated short-interval intracortcal inhibition (SICI), a reduced motor threshold, and a decrease in the cortical silent period, which is mediated in part by GABAB interneurons. Cortical hyperexcitability is felt to reflect degeneration of inhibitory interneurons in the motor cortex and may contribute to the presence of positive symptoms such as cramps, fasciculations, fibrillations, sharp waves, and spasticity. With disease progression there is a reduction in cortical excitability reflecting degeneration of corticomotorneuronal pathways.155 Signs of hyperexcitability in the motor system such as the UMN positive signs are poor prognostic indicators. In SOD1 carriers cortical hyperexcitability can be seen prior to symptom onset and is associated with early weakness.156,157 The reduction in SICI correlates with disease duration and motor deficit. It is hypothesised that cortical hyperexcitability can alter glutamate metabolism and lead to a dying forward of connected anterior motor neurons. An alternate hypothesis is that the hyperexcitability reflects a compensatory process that aims to increase central drive to the degenerating LMNs.155 9.4.1.3 Clinical Presentation In ALS, the onset of symptoms is usually focal weakness in the proximal or distal upper or lower limbs. Weakness develops in the other segments and

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limbs and this may be accompanied by bulbar and respiratory weakness. On examination, muscle fasciculations are visible. Upper limb symptoms are associated with bulbar signs (dysphagia and dysarthria).158 The degree of lower limb weakness predicts the level of walking ability (e.g., inability, independence in the community, home ambulation).159–161 Loss of ambulation occurs when the lower limb strength was on average 13.7% (±7.4) of the predicted normal level.159 In one cohort, loss of ambulation occurs on average after 46.7 months, about 11–15 months after provision of gastrostomy and non-invasive ventilation.162 In people with genetic linkage to chromosomes 9p21 and an expansion in the gene C9ORF72 there are associated signs of frontotemporal dementia in 35% of cases including personality change, irritability, obsessions, poor insight, and deficits in frontal executive tests.2,163 In many people, painful cramps and flexor spasms can occur in the latter stages. Bulbar symptoms may be UMN and LMN in nature. Tongue movements may be slow due to spasticity and fasciculations and wasting of the tongue may be present. The jaw jerk may be brisk, especially with bulbar onset disease. Respiratory muscle weakness can lead to dyspnoea on exertion, orthopnoea, disturbed sleep, morning headaches, daytime somnolence, weak cough, and paradoxical abdomen movements.153 Death is usually due to respiratory failure and pulmonary complications. Spasticity is present in ALS as determined using clinical and electrophysiological measures (i.e., the H-reflex).164,165 However, upper motor neuron signs can be difficult to elicit in ALS, with only 50% of cases showing an extensor plantar response.154 Spasticity is often hard to detect in weak muscles in ALS.154 This may reflect the co-occurrence of lower motor neuron signs that mask patterns of cortico-spinal tract-induced paresis and enhanced tendon reflexes. LMN signs are not seen in progressive lateral sclerosis and here spasticity is more marked.154 In addition, interneuronal degeneration within the spinal cord in ALS could also limit the emergence of hyperexcitable tendon reflexes.154 Direct pathology affecting the Renshaw cells within the spinal cord, for example, may explain why the Renshaw-mediated recurrent inhibition is reduced to a greater extent than seen after spinal cord injury.165 Rigidity, felt as an increased resistance of a limb to movement in both directions, can also be present in ALS. Extrapyramidal signs as indicated by rigidity and a shortening reaction were assessed in a selected cohort of people with ALS (n = 39) who had stiffness (> 2 Ashworth in both legs) but minimal weakness (at least 4/5 MRC manual testing). People who met this inclusion criterion made up 17% of the total sample assessed. In this subsample extrapyramidal signs in combination with spasticity were seen in 69%, with the remainder presenting with spasticity alone.166 People with mixed rigid-spasticity presentation had worse balance, more retropulsion, and more severe neck stiffness.166 The presence of extrapyramidal signs is reflected in the reduced dopaminergic activity assessed using PET and reduced D2-receptor binding as assessed using SPECT.167–169 As there are large corticostriatal connections, striatal involvement may be caused by glutamate excitotoxicity.

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In ALS degeneration of serotonergic (5-HT) neurons that project to the spinal cord is observed post-mortem and in the SOD1 animal model.170 In spinal cord injury loss of serotonergic projections from the brainstem dorsal raphe nuclei leads to secondary up-regulation of 5HT receptors on lower motor neurons that results in hyperexcitability, plateau potential generation, and spasticity.171,172 Therefore, the loss of serotonergic neurons in ALS may underlie the development of spasticity. The involvement of tracts other than corticospinal tract in the genesis of spasticity in ALS is underlined by the fact that corticospinal tract degeneration can be seen in 50% of people with a clinical diagnosis of progressive muscle atrophy who had no UMN signs when alive.173 Therefore, findings such as a correlation between precentral gyrus degeneration, as measured by DTI, and spasticity174 may simply reflect the co-occurrence of motor cortex pathology and spasticity in more severe cases of ALS and not reflect a causative link. 9.4.2 Interventions 9.4.2.1 Disease-Modifying Therapy Riluzole prolongs median survival by 2–3 months if taken for 18 months (100 mg) in people with clinically definite ALS and symptoms of less than 5 years who are under 75 years and have a forced vital capacity of >60%.175 Riluzole partly resolves the reduction in SICI and may act by inhibiting glutamate release and reducing cortical hyperexcitability.176 In addition, effects on peripheral nerve function (a reduction in superexcitability and refractoriness) have been reported.176 9.4.2.2 Symptomatic management Respiratory management: monitoring of respiratory function using force vital capacity (FVC), sniff nasal inspiratory pressures, and nocturnal oximetry is important as respiratory insufficiency is the major cause of death. Criteria for starting non-invasive ventilation (NIV) are outlined in Table 9.4. NIV increases survival and quality of life. NIV is usually initially used for nocturnal hypoventilation with support during the day provided with increasing symptoms.150 Nutritional management: dysphagia and upper limb weakness can lead to aspiration, malnutrition, weight loss, and dehydration.150 Early management of dysphagia includes dietary advice, alteration of food consistency, and teaching swallowing techniques. Due to a ~10% increase in the metabolic rate, people with ALS require higher calorie intake.177 Supplementary enteral feeding is recommended if the body weight falls below 10% of a person’s pre-diagnostic weight. A PEG (percutaneous endoscopic gastrostomy) is the usual option for enteric feeding. However, insertion does require sedation and so may compromise respiratory function and should be performed before the FVC is < 50%. Insertion of PEG under NIV assistance or percutaneous radiologic gastrostomy or radiologically inserted gastrotomy may be required under these conditions.150

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TABLE 9.4 Suggested Criteria for Non-invasive Ventilation (NIV) Symptoms related to respiratory muscle weakness. At least one of: • Dyspnoea • Orthopnoea • Disturbed sleep (not caused by pain) • Morning headache • Poor concentration • Anorexia • Excessive daytime sleepiness (Epsworth Sleep Score > 9) and evidence of respiratory muscle weakness (FVC ≤ 80% or SNP ≤ 40 cmH2O) and evidence of either: significant nocturnal desaturation on overnight oximetry or morning ear lobe blood gas pCO2 ≥ 6.5 kPa Note: Provisional European consensus criteria for NIV (European ALS/MND Con­ sortium and European Neuromuscular Centre workshop on non-invasive ventilation in MND, May 2002). Source: With permission from Leigh PN, Abrahams S, Al-Chalabi A, Ampong MA, Goldstein LH, Johnson J, Lyall R, Moxham J, Mustfa N, Rio A, Shaw C, Willey E. King’s MND Care and Research Team. The management of motor neurone disease. J Neurol Neurosurg Psychiatry. 2003 Dec;74[4]:iv32–iv47.

Spasticity and rigidity in ALS: oral medications such as baclofen and gabapentin are not always effective in relieving spasticity and pain associated with spasms.178,179 Side effects such as weakness, sleepiness, and fatigue have also been described with higher doses of oral baclofen.180 In these cases, the effects of intrathecal baclofen has been explored. In a retrospective assessment of 6 cases who had ALS for a mean of 47.4 months, ITB reduced pain in 75% of people with the degree of pain relief being predicted by the response to a preoperative bolus test dose.181 In two other cases ITB was also associated with reduction in painful spasms.180,182 Exercise in ALS: exercise trials in early-stage ALS have been systematically reviewed by Lui et al. (2009).183 Exercise regimes consisted of treadmill training and moderate progressive resisted exercises and stretches. Although small-tomoderate effect sizes were found favoring the intervention (e.g., for FVC, fatigue, strength, and function), the variability of the effect was very large and overall the results are inconclusive to date. Reductions in spasticity have been described following exercise but only after the first 3 months, with no effect being seen after 6 months between the no-exercise control group and the intervention group.164 More recently the feasibility of supported treadmill training has been investigated in ALS (n = 9). Patients undertook an 8-week programme consisting of training 3 times/week for 30 minutes where 5 minutes of exercise were interspersed with 5 minutes of rest. There was a 33% dropout but improvements were seen in walking over 6 minutes and fatigue rating with no deterioration in perceived function, FVC, or muscle strength, which showed non-significant improvements.185

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Cortical stimulation: cortical hyperexcitability is felt to cause a dying forward of connected anterior motor neurons in ALS and is thus a potential target for therapy.155 Repetitive cortical stimulation using TMS has been used to reduce cortical hyperexcitability. Other groups have used high-frequency transcranial excitatory stimulation, as there is evidence from animal studies that this may have a neuroprotective effect by increasing brain-derived neurotrophic factor (BDNF) expression. Synapse-specific activity has been shown to regulate BDNF transcription, transport, secretion, and trafficking of its receptor. BDNF in turn is felt to regulate synaptic efficacy and growth of dendrites and axons; processes that underpin synaptic plasticity.186 There is evidence that a single nucleotide polymorphism in the BDNF gene can affect the response to r TMS in healthy participants and post-stroke.187,188 These differences in people’s responsiveness to stimulation may underlie the variability in the results seen; a Cochrane review of randomised controlled trials of cortical stimulation studies in ALS up to 2010 found no evidence of effect in the trials thus far performed.189

9.5 Leukodystrophies The leukodystrophies are inherited myelin disorders affecting myelin development and maintenance in the central nervous system. A classification of the leukodystrophies is given below, with examples of the more common types.190 Up to half of people with leukodystrophies do not get a specific diagnosis. The age of onset varies with the type. The involvement of white matter tracts commonly leads to spasticity and UMN signs, although reduced limb stiffness (hypotonia) can be seen, e.g., in childhood onset. Extrapyramidal signs and ataxia may also be present. Impaired swallowing, respiration, and cognition, and epilepsy, may also be seen.190,191 9.5.1 Demyelinating and Dysmyelinating Disorders • X-linked adrenoleukodystrophy • Krabbe disease 9.5.2 Hypomyelinating Disorders • Pelizaeus-Merzbacher disease • Alexander disease 9.5.3 Spongiform Disorders • Canavan disease

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9.5.4 Cystic Disorders • Vanishing white matter disease

9.6 Adrenoleukodystrophy 9.6.1 Prevalence and Genetics Adrenoleukodystrophy (ADL) is an X-linked recessive disorder characterised by adrenal insufficiency and demyelination in the central and peripheral nervous system. They are caused by a defect in a peroximal membrane transporting protein, leading to the accumulation of very-long-chain fatty acids in tissues and plasma. De novo mutations occur in 19% of cases.192 Clinical severity is not related to the length of the very-long-chain fatty acids. It occurs in 0.5–3.3 per 100,000 males and there are several forms. 9.6.2 Clinical Presentation Cerebral inflammatory presentation can start during childhood (3–10 years), adolescence (11–21 years), or adult life (>21 years). It accounts for ~50% of cases and is characterised by perivascular lymphocyte infiltration in the parieto-occipital region (85% of cases) or frontal lobe region (15% of cases).193 Child ADL has symptoms of ataxia, spasticity, dysphagia, deafness, visual deficits, personality changes, and, in ~30%, seizures.194 Neurological deterioration occurs over 2–3 years until there is complete disability, a vegetative state, and death. Adrenomyeloneuropathy (AMN) is seen in ~45% of cases.193 Here, onset is 28 (+/−9) years. It is characterised by non-inflammatory distal axonal loss and secondary demyelination affecting the dorsal columns and corticospinal tracts and a peripheral neuropathy.195 It is characterised primarily by lower extremity spasticity, paresis, and loss of vibration sensibility that affects walking and balance.195 Bladder and bowel function can also be affected. Sensory loss can appear in isolation or with symptoms of paresis and spasticity.195 In ~20% of cases there is additional cerebral pathology. Somatosensory and brainstem EPs and MEPs, transcortical, long-latency stretch reflexes from the hand, are prolonged and/or reduced in amplitude, in keeping with the pathology affecting the dorsal columns and corticospinal tract.196–199 In AMN, postural sway is increased in amplitude and correlates with the degree of lower limb weakness and sensory loss.195,200 Walking is slower than normal but the pattern is relatively unimpaired in patients with isolated sensory loss. Strength loss and spasticity result in a crouch and stiff knee gait with reduced ankle motion. A cross-sectional study of 142 people with AMN found that lower limb strength is the main predictor of

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functional ability. Vibration thresholds also predicted functional ability, while ankle spasticity was correlated with walking velocity and a timed up-and-go test.200,201 AMN symptoms can mimic hereditary or familial SP 3,4,202 and symptoms of  ataxia mimicking a spinocerebellar degeneration have also been described.5,6 Differential diagnosis is important in cases of sporadic SP and where male-to-male transmission is absent as the more severe cerebral childhood form arises from the same gene mutation as AMN.3 Primary adrenal insufficiency (‘Addison-only presentation’) comprises the remaining 20% of cases. Here, people do not have neurological symptoms. Symptom-free males with the gene deficit have been described. Females are carriers and can exhibit symptoms of adrenal failure. In 55–63% of cases, neurological symptoms akin to AMN are seen with/without peripheral neuropathy (~57%) and a high incidence of fecal incontinence (28%).204 The age of symptom onset in females is a decade later than males (~38 years), the symptoms milder, and the progression slower. Cerebral involvement can be seen in female carriers. 9.6.3 Interventions Management of AMN consists of the following193,205: 1. Adrenal hormone replacement therapy for those with adrenal insufficiency. 2. Dietary therapy: Lorezo’s oil (a 4:1 mixture of glyceryl trioleate and glyceral trierucate) and moderate reduction of fat intake can lower VLCFA in the plasma.193 The therapy does not slow progression rate of those who are already symptomatic, especially if they have the cerebral inflammatory presentation. Open-label trials suggest that Lorezo’s oil can slow the progression of pure AMN and can be preventative in asymptomatic boys. 3. Hematopoietic stem cell transplantation has been reported to be effective in presymptomatic or early symptomatic childhood cerebral ADL. Treatments of symptoms such as spasticity have only been reported in case reports, for example, for the use of dantrolene effect in AMN206 and ITB in cerebral child ADL.194

9.7 Summary The hereditary myelopathies represent a relatively rare and diverse group of conditions. As such, research into the pathophysiology of a condition is

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often sparse and requires multi-centre and multi-national approaches. An understanding of the underlying genetics of each condition over time could lead to disease-modifying therapies and improvements in the information provided during genetic counselling. In many cases spasticity and paresis are seen in combination with a variety of other signs such as ataxia, extrapyramidal signs (rigidity, bradykinesia, tremor) and sensory loss. Symptom onset can occur at various times throughout life and this may result in differences in the presence and relative impact of secondary complications such as contracture, increased passive stiffness, and bony deformity. Spasticity is therefore just one of a multitude of impairments that may impact on functional ability. Although spasticity and hypertonia can limit mobility it may have a positive impact on stability and therefore should not be considered an obligate target for treatment. Future work will help to elucidate the relative importance of different impairments in limiting function and quality of life and the effectiveness of symptomatic interventions. With the hereditary myelopathies there is symptom progression over time. Differences in the rate of disease progression and the severity and extent of CNS damage will presumably affect the ability of the neuromusculoskeletal system to adapt to environmental demands (e.g., training and rehabilitation) and therefore the effectiveness of interventions that aim to restore functional ability. In cases where the adaptability and plasticity of the system is limited compensatory techniques that aim to maintain or improve functional ability through the use of altered strategies and aids and adaptations may be more appropriate. Which approach is adopted and the overall goals of treatment may vary over the disease trajectory in an individual and with the aims of the patient, their family, and carers. A greater understanding of these issues will lead to improved symptomatic management.

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http://taylorandfrancis.com

Index Page numbers followed by f, t, and n represent figures, tables, and notes, respectively. A AbobotulinumtoxinA, 220 Accelerometers, 18 Achilles tendon, 127 Action research arm test (ARAT) score, 15f, 107, 121 Activation of muscles, 69 Activities of daily life (ADL), 137, 148, 154, 180, 225 Activity and participation, 121 Addison-only presentation, 275 Adolescents, 83, 254 Adrenal hormone replacement therapy, 275 Adrenoleukodystrophy (ADL); see also Hereditary spastic paraparesis (HSP) clinical presentation, 274–275 interventions, 275 prevalence and genetics, 274 Adrenomyeloneuropathy (AMN) about, 237, 274–275 management of, 275 Adults acquired brain injury, 222 adult-onset stroke, 244 affected by cerebral palsy, 82 cerebral palsy in, 244 dorsal rhizotomy in, 195 femoral anteversion in, 84 with hereditary spastic paraparesis, 254, 255 hyperexcitable stretch reflexes in, 63 inhibitory spinal cord circuit alterations in, 244 motor branch to soleus in, 102 routine walking, 108 spasticity in, 220 with stroke, 65

tizanidine dosage scheduling in, 183 traumatic brain injury in, 225 Alcohol neurolysis, 223 Altered tone, 9–12; see also Spasticity Ambulatory stroke patients, 126 Amyotrophic lateral sclerosis (ALS), 268–269 Ankle dorsiflexion, 127 Ankle dorsiflexors, 68, 113 Ankle-foot orthosis, 83f, 94 Ankle kinetics, 96f Antagonist muscles, regulation of, 63 Anterior cord syndrome (ACS), 141 Anti-gravity distribution, 104 Antigravity strength, 93 Anti-spastic drug therapy, 146, 152 Areflexic flaccid paresis, 105 Arm and hand function, role of spasticity in about, 115–116 spasticity in patients with mildly affected upper limb (UAT 4-7), 118 with moderately affected upper limb (UAT 2-3), 117–118 with severely affected upper limb (UAT 0-1), 117 Ashworth scale, 94, 120, 148, 211t Ashworth score, 17 ASIA impairment scale C, 163, 164 Athetosis, 80n Autogenetic Ib inhibition, 43; see also Postsynaptic inhibition of motoneurons Autosomal dominant cerebellar ataxias (ADCA), 258–259, 260t–261t; see also Spinocerebellar degenerations Autosomal recessive ataxias, 266; see also Spinocerebellar degenerations

289

290

Axonal degeneration, 179 Axonal sensory neuropathy, 266 B Baclofen, 37, 123, 152, 163, 182 pump implantation, 190 Balance dysfunction, 262 Basal ganglia lesion, 46 Beck depression inventory, 248 Benzodiazepines, 85–86, 124, 152, 186 Biomechanical evaluation of spasticity, 27; see also Spasticity Biomechanical measurement methods, 120 Bladder dysfunction, 247 Body function/structure, 119–121, 119t, 120t Bone growth, 84 Bony changes, 247 Botulinum neurotoxin (BoNT), 158–160 treatment of toe-walking in children, 64 Botulinum toxin, 124–125 focal therapies for TBI, 220–222 management of spasticity in MS, 188 type A, 86–87 Brain-derived neurotrophic factor (BDNF), 273 Brain injury complications on spasticity, 209; see also Spasticity Brown-Séquard Syndrome (BSS), 142 Brunnstrom stages, 106f Bulbar symptoms, 270 C Calf spasticity, 83f, 84f; see also Spasticity Canadian Occupational Performance Measure, 121 Cannabinoids, 152, 184–186 Casting, 217 for contracture vs. spasticity management, 217–218 Central cord syndrome (CCS), 141, 142 Central pattern generators (CPG), 108 Cerebral inflammatory presentation, 274 Cerebral palsy, characteristics of, 80–82

Index

Cerebral palsy and spastic diplegia (CP-SD), 247, 250 Cerebral palsy/clinical management of spasticity cerebral palsy, characteristics of, 80–82 injection therapies botulinum toxin type A, 86–87 phenol, 87–88 oral medication benzodiazepines, 85–86 gabapentin and pregabalin, 86 oral baclofen, 86 overview, 70–80 surgical treatment intrathecal baclofen, 89–91 neurotomy, 89 selective dorsal rhizotomy, 91–96, 95t therapy strengthening spastic muscles, 88 stretching, 88 treatment objectives, 82–85 Chemodenervation, 148, 157–160 Children botulinum toxin injections, 87 with cerebral palsy, 64 contractures in, 94 dorsal rhizotomy for, 195 with dystonia, 224 with HSP, 247, 251 hyperexcitable stretch reflexes in, 63 neronal migration disorder in, 81 oral baclofen for, 86 selective dorsal rhizotomy (SDR) for, 161 SPARCLE study of in, 82 with spastic cerebral palsy, 88, 254 surgical management of spasticity, 226 upper extremity in, with cerebral palsy, 159 Clasp-knife response, 11f, 16 Clonidine, 152 Clonus, 8–9, 13, 44–45 Closed-nerve blockade, 187 Clostridium botulinum, 188 Co-contraction; see also Spasticity abnormal movement patterns and, 12–13 for joint stiffness, 69–70

Index

Cognitive dysfunctions, 107 Collateral sprouting, 35 Coma, 90, 186, 205, 224, 225 Coma Recovery Scale (Revised) (CRS-R), 225 Commissural interneurons, 68 Complex spastic SCI patient combination therapies intrathecal systemic/focal (case study), 164 oral systemic/focal (case study), 163 Composite Spasticity Index, 17 Compound muscle action potentials (CMAP), 141 Contractures biomechanical methods to measure, 18 in cerebral palsy, see Cerebral palsy/ clinical management of spasticity defined, 14 measurement of, 17–19 in patients with upper motoneuron syndrome, 14–16 by spasticity/immobilisation, 204, 205f surgical correction of, 160–161 surgical treatment of, 81 Contralateral ankle spasticity, 218; see also Spasticity Conus medullaris syndromes, 143 Coordination, 141, 142, 161, 205f, 265t interjoint, 67–68 interlimb, 68–69 Cortical activation with movement, 241 Cortical hyperexcitability, 269 Cortical stimulation, 273 Corticospinal tract, 266 Cramps, 243 Cystic disorders, 274; see also Leukodystrophies D Dantrolene, 152, 183 Dantrolene sodium, 124 Deep tendon reflexes (DTR), 139

291

Delayed plantar response (DPR), 139 Demyelinating/dysmyelinating disorders, 273; see also Leukodystrophies De novo mutations, 274 Depression, 40, 43, 62, 63, 65, 156, 266 CNS, 223 post-activation, 36, 37–39, 244 respiratory, 157, 186 Diazepam, 37, 85, 186 Dietary therapy, 275 Diffusor tensor imaging (DTI), 241 Disability-adjusted life years (DALY), 102 Disability Rating Scale, 225 Disease-modifying therapy, 271 Disordered motor control, 70 over-activity and, 70 Disordered sensori-motor control, 7 Distal axonopathies; see also Hereditary spastic paraparesis (HSP) balance in HSP, 248–249 cellular changes, 238–240, 239t clinical presentation, 237–238 cortical activation with movement, 241 descending/ascending tract function, changes in, 240–241 outcome measurement, 252 physical interventions, 257–258 prevalence and genetics, 237 service delivery, 258 spasticity, pharmacological/surgical treatment of, 253–255 spasticity/associated symptoms on functional ability, 248 walking difficulties, 249–252 Disynaptic reciprocal Ia inhibition, 40–41; see also Postsynaptic inhibition of motoneurons Dorsal rhizotomy, 195 Dorsiflexors, 40, 41 Dynamometry, 251 Dysdiadochokinesis, 118 Dysfunctional equinovarus posture, 113 Dystonia, 80n about, 46 clinical management, 81

292

E Education of patient, 123 Electrical stimulation, 206, 218–219 Electromyography (EMG), 10, 64, 148 Endocytosis, 240 Endosomes, 240 Endurance training, 268 EPSP, 34, 64–65 Epstein Barr Virus (EBV) infection, 176 Exaggerated reflexes, 8 Exaggerated stretch reflex activity; see also Spasticity, pathophysiology of about, 31–32 motoneuronal changes, pathophysiological role of, 32–35 postsynaptic inhibition of motoneurons, pathophysiological role of changes in, 40–44 presynaptic sites, regulation at, 35–39 sprouting, 35 transmission in group II pathways, 39–40 Exercise in ALS, 272 in MS, 191 Exocystosis, 240 Extensor hallucis longus, 114 Extrapyramidal signs, 270 F Familial ALS (FALS), 269; see also Motor neuron disorders/ familial ALS Fatigue, 248 Femoral anteversion, 84 Flexor reflex afferent (FRA) circuitries, 45 FMRI, 241, 245 Focal anti-spastic pharmacotherapy, 157–160 Focal anti-spastic surgical treatment, 161–162

Index

Focal chemodenervation, 159, 164 Focal spasticity, 125; see also Spasticity treatments for, 187 Focal therapies botulinum toxin injection, 220–222 case study, 222–223 phenol/alcohol neurolysis, 223 Force vital capacity (FVC), 271 Frataxin, 266 Frenchay Scale, 214 Frequency, intensity type, and time (FITT), 191 Friedreich’s ataxia (FRDA) about, 266–267; see also Spinocerebellar degenerations management of Co-enzyme Q10 and idebenone, 267 symptomatic management, 267–268 Frontal lobe white matter, 241 Functional ambulation category (FAC), 254 Functional electrical stimulation (FES), 257 Fusimotor drive, gamma-spasticity, 43–45; see also Postsynaptic inhibition of motoneurons F-wave measurements, 19 G GABAergic drugs, 37 Gabapentin, 86, 152, 183–184, 254 GABA receptor, 36, 86, 89, 184 Gait control, role of spasticity in, see Postural control/gait control, role of spasticity in Gamma-aminobutyric acid (GABA), 123, 152, 245 Gamma-spasticity, 43–45; see also Spasticity Glasgow Outcome Scale, 217 Global Spasticity Score, 192 Goal Attainment Scale, 121 Goal Attainment Scaling (GAS), 212 Golgi tendon organs, 39, 43

293

Index

Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP), 149 Gross motor function measure (GMFM), 254 H Handheld dynamometers, 27 Hand spasticity, 142, 160 Hematopoietic stem cell transplantation, 275 Hemiplegic gait, 109 Hereditary myelopathies, 236 Hereditary spastic paraparesis (HSP) adrenoleukodystrophy (ADL) clinical presentation, 274–275 interventions, 275 prevalence and genetics, 274 case study, 242, 253b, 255b–256b distal axonopathies balance in HSP, 248–249 cellular changes, 238–240, 239t clinical presentation, 237–238 cortical activation with movement, 241 descending/ascending tract function, changes in, 240–241 outcome measurement, 252 physical interventions, 257–258 prevalence and genetics, 237 service delivery, 258 spasticity, pharmacological/ surgical treatment of, 253–255 spasticity/associated symptoms on functional ability, 248 walking difficulties, 249–252 leukodystrophies cystic disorders, 274 demyelinating/dysmyelinating disorders, 273 hypomyelinating disorders, 273 spongiform disorders, 273 motor neuron disorders/familial amyotrophic lateral sclerosis amyotrophic lateral sclerosis (ALS), 268–269

clinical presentation, 269–271 disease-modifying therapy, 271 pathology, 269 symptomatic management, 271–273, 272t overview, 236–237 spinocerebellar degenerations autosomal dominant cerebellar ataxias (ADCA), 258–259, 260t–261t autosomal recessive ataxias, 266 Friedreich’s ataxia (FRDA)/ late-onset Friedreich’s ataxia (LOFA), 266–268 SCA3 or Machado-Joseph disease, 259–262, 261t, 266 symptoms associated with bladder dysfunction, 247 bony changes, 247 fatigue, 248 limb stiffness, 243–246 mood/quality of life, 248 paresis, 246–247 sensory loss, 247 Heterotopic ossification (HO), 209 High tone, 4 Hippotherapy, 194 Hoffmann reflex, 121 H-reflex about, 43, 140 measurements, 19 technique, 41 5-HT receptors, 34, 35, 45 Hydrotherapy, 257 Hyper-excitable reflexes, 8 Hyperexcitable stretch reflexes, 62–63 Hypertonia, 4 Hypertonicity in paralysis, 5 Hypomyelinating disorders, 273; see also Leukodystrophies Hypotonia, 4–6 I Idebenone, 267 Impairments, classification of, 17 IncobotulinumtoxinA, 220

294

Increased reflexes, 8 Injection therapies; see also Cerebral palsy/clinical management of spasticity botulinum toxin type A, 86–87 phenol, 87–88 Interjoint coordination, 67–68 Interlimb coordination, 68–69 Interlimb reflexes, 139 Intermittent theta burst stimulation (iTBS), 190 Intermittent theta burst TMS (iTBS), 193 Intramuscular botulinum toxin injection, 220 Intrathecal anti-spastic pharmacotherapy, 155–157 Intrathecal application of baclofen (ITB), 155, 255 Intrathecal baclofen (ITB), 89–91, 125–126, 146, 189–190, 254 Intrathecal therapies, for TBI, 223–226, 226t Intrinsic stiffness, 28 Invasive/permanent methods, for stroke patients, 126–128 Invasive/reversible methods, for stroke patients, 124–126 Isometric muscle strength, 246 J Joint posture, measurement of, 119 Joint stiffness, 214 K Kernicterus, 80 King’s Hypertonicity Scale, 214 L Late-onset Friedreich’s ataxia (LOFA), 266–268; see also Spinocerebellar degenerations Leukodystrophies; see also Hereditary spastic paraparesis (HSP) cystic disorders, 274 demyelinating/dysmyelinating disorders, 273

Index

hypomyelinating disorders, 273 spongiform disorders, 273 Limb stiffness, 243–246 Lipids, 240 Locomotor training (LT), 151, 152 Long-latency, defined, 29 Long-latency stretch reflexes/ coordination of movement, 66–67 Lower extremity spasticity, 206 Lower limb weakness, 246 Lower motor neuron (LMN), 268 M Machado-Joseph disease, 259–262, 261t, 266; see also Spinocerebellar degenerations Maculopathy, 259 Mechanical resistance, 29 Medication possession ration (MPR), 219 Microneurography, 43 Mildly affected upper limb (UAT 4-7), spasticity in patients with, 118 Moderately affected upper limb (UAT 2-3), spasticity in patients with, 117–118 Modified Ashworth Scale (MAS), 26, 102, 115, 148, 191, 193 Monoaminergic neurotransmitters, 39 Monosynaptic Ia afferent pathway, 65 Mood/quality of life, 248 Motoneuronal changes, pathophysiological role of, 32–35 Motoneurons, 32 postsynaptic inhibition of, see Postsynaptic inhibition of motoneurons Motor-evoked potentials (MEP), 240 Motor nerve, 89 Motor neuron disorders/familial ALS amyotrophic lateral sclerosis (ALS), 268–269 clinical presentation, 269–271 disease-modifying therapy, 271 pathology, 269 symptomatic management, 271–273, 272t

295

Index

Motor recovery/motor control after stroke, 105–108 Movement patterns, abnormal, 12–13; see also Spasticity MS, see Multiple sclerosis (MS) Multiple sclerosis (MS) disease-modifying treatments for, 179 incidence/epidemiology/disease course, 176–178 pathophysiology of/spasticity, 178–179 spasticity in, 179–181 spasticity management in MS hippotherapy, 194 neuromuscular electrical stimulation cycling (NMES), 194 non-pharmacological treatments, 190–194 pharmacological treatments, 181–190, 186t strategy for, 195–197 surgery, 195 whole-body vibration (WBV), 194 Muscle afferents, 35 Muscle fibre atrophy, 105 Muscle hypertonia, 138, 140 Muscle overactivity, 104 and increased co-contraction, 118 during stance phase, 111–113 during swing phase, 113–115 Muscle reinnervation, 223 Muscle resistance, 26 Muscle stiffness, 38 Muscle weakness, 249 Myotonometer, 216 N National Institute for Care and Clinical Excellence (NICE), 179, 181 Neuroleptic malignant syndrome, 89 Neurolysis, 124 Neuromuscular electrical stimulation cycling (NMES), 194 Neurons within ascending/descending tracts, 238 Neurotomy, 89 NIHSS score, 15

Nocturnal oximetry, 271 Noninvasive treatment, for stroke patients with spasticity, 123–124 Non-invasive ventilation (NIV), 271, 272t Non-pharmacological treatments, in MS about, 190–191 physical activity/exercise for spasticity management in MS, 191 transcranial magnetic stimulation (TMS) for, 193–194 transcutaneous electrical nerve stimulation (TENS) for, 191–193 Non-reflex stiffness, 214, 215 Nonsurgical management of spasticity, 126 Normal tone, 4 Nutritional management, 271 O Obturator nerve, 124 Ocrelizumab, 179 Onabotulinum toxin A, 217, 220 Oral anti-spasticity medications, 254 evidence-based guidelines for, 186–187, 186t Oral baclofen, 86 Oral medication; see also Cerebral palsy/clinical management of spasticity about, 181, 219 benzodiazepines, 85–86 gabapentin and pregabalin, 86 oral baclofen, 86 Oral spasmolytic drugs, 123 Oral systemic anti-spastic pharmacotherapy, 152–155, 153t Orthopaedic surgical procedures, 195 Orthoses, 257 Orthotic devices, 88, 123 Orthotic management, 82 Over activity phenomena, 35, 70 P Paralysis, hypertonic, 5 Paresis, 246–247 Participation, activity and, 121

296

Passive stretching, 216 Penn Spasm Frequency Scale, 17, 214 Perceived resistance to passive movement (PRPM) test, 120t Percutaneous endoscopic gastrostomy (PEG), 271 Persistent inward currents (PIC), 32, 34, 45, 138 Persistent vegetative state (PVS), 225 Phenol and alcohol neurolysis, 223 chemodenervation, 187–188 in injection therapies, 87–88, 158, 223 Physical activity for spasticity management in MS, 191 Physical modalities, 216–217 Physical therapy, 123, 150, 257 Physiotherapy, 151, 191 Pigmentary retinopathy, 259 Plantarflexor, 40, 41, 64 spasticity, 257 Plastic surgery, 126 Polyglutamate (polyQ) disease, 259 Polysegmental reflexes, 140 Polysynaptic reflexes, 144 Position-dependent spasticity, 10f–11f, 16 Post-activation depression, 36, 38 Postsynaptic inhibition of motoneurons autogenetic Ib inhibition, 43 disynaptic reciprocal Ia inhibition, 40–41 fusimotor drive, gamma-spasticity, 43–44 recurrent inhibition, 41 Postural control/gait control, role of spasticity in about, 108–111 muscle overactivity during stance phase, 111–113 muscle overactivity during swing phase, 113–115 Pregabalin, 86 Premature birth, 81 Presynaptic inhibition, 36–37 Presynaptic sites, regulation at; see also Spasticity, pathophysiology of about, 35–36 post-activation depression, 37–39 presynaptic inhibition, 36–37

Index

Primary adrenal insufficiency, 275 Primary afferent depolarisation (PAD), 36 Problematic spasticity, 110 Progressive-relapsing disease, 177 Proprioceptive feedback, 107 Proteins, 240 Pyramidal tract, lesion of, 29–30 Q Quality of life, 248 R Ramp and hold method, 10f Randomised controlled trials (RCT), 154, 182, 185 Range of Motion (ROM), measurement of, 119 Recurrent inhibition, 41; see also Postsynaptic inhibition of motoneurons Reduced range of motion (ROM), 160 Reflexes in antagonist, control of, 63 excitability, 61 increased, 8 integrated part of voluntary movement, 59–60 modulation in simple contraction of agonist muscle, 60–62 in swing phase, suppression of, 63–64 Reflex hyperexcitability, 31 Reflex-mediated stiffness, 28–29 Reflex response, 8 Rehabilitation about, 266 after stroke, 106 Rehabilitation Medicine spasticity, 102; see also Spasticity Relapsing-remitting MS (RRMS), 177 Relaxed muscle, response of, 9–12 Renshaw cells, 41 Renshaw-mediated recurrent inhibition, 270 Repetitive cortical stimulation, 273 Repetitive TMS (rTMS), 193

Index

Respiratory muscle weakness, 270 Rigidity, 3 Rimabotulinumtoxin B, 220 Routine walking, 108 S Sativex, 185 SCI, see Spinal cord injury (SCI) Scottish Intercollegiate Guidelines Network (SIGN) guidance, 181 Sedation, 123 Selective dorsal rhizotomy (SDR), 91–96, 95t, 161–162 Self-report instruments, 121 Sensitivity, 8n Sensory feedback contribution to movement, 64–66 Sensory loss, 247 Severely affected upper limb (UAT 0-1), spasticity in patients with, 117 Short-interval intracortcal inhibition (SICI), 269 Smooth rectified EMG (SRE), 111f Sniff nasal inspiratory pressures, 271 Soleus H-reflex, 37, 62, 244 SPARCLE study, 82 Spasm about, 8–9, 13 causes of, 45 defined, 8 SPASM Consortium defining spasticity, 7, 7t Spasm Frequency Score, 17 Spastic dystonia, 16, 45–46, 70 Spasticity and associated symptoms on functional ability, 248 biomechanical evaluation of, 27–28 biomechanical methods to measure, 18 clinical evaluation of, 26–27 clinical presentation/anatomical distribution of, 149–150 clinical signs of, 144 definition abnormal movement patterns/ co-contractions, 12–13 about, 2–3, 3t

297

contractures in patients with upper motoneuron syndrome, 14–16 framework development for, 6–12, 7t altered tone or response of relaxed muscle, 9–12 increased (hyper-excitable/ exaggerated) reflexes, 8 spasms and clonus, 8–9 hypertonia (or high tone), 4 hypotonia, 4–6 measurement of spasticity/ contracture, 17–19 by SPASM Consortium, 7, 7t in upper motoneuron syndrome, 13–14 in multiple sclerosis (MS), 179–181 neurophysiological methods to measure, 19 overview, 1–2 pathophysiology-based treatment of about, 143–144 clinical signs of spasticity, 144 spastic movement disorder, 144–145 therapeutic consequences, 145–147 pharmacological/surgical treatment of, 253–255 in SCI, clinical assessment of, 148–149 treatment in SCI, 150–152 Spasticity, pathophysiology of by adaptive changes in spinal networks, 30–31 clonus, relation to spasticity, 44–45 exaggerated stretch reflex activity about, 31–32 motoneuronal changes, 32–35 postsynaptic inhibition of motoneurons, 40–44 presynaptic sites, regulation at, 35–39 sprouting, 35 transmission in group II pathways, 39–40 by lesion of pyramidal tract, 29–30 muscle response to stretch, nature of, 28–29 spasms, causes of, 45

298

spastic dystonia, 45–46 spasticity measurement (from clinical evaluation to biomechanical techniques), 26–28 Spasticity management in MS; see also Multiple sclerosis (MS) hippotherapy, 194 neuromuscular electrical stimulation cycling (NMES), 194 non-pharmacological treatments about, 190–191 physical activity/exercise for, 191 transcranial magnetic stimulation (TMS) for, 193–194 transcutaneous electrical nerve stimulation (TENS) for, 191–193 pharmacological treatments baclofen, 182 benzodiazepines, 186 botulinum toxin, 188 cannabinoids, 184–186 dantrolene, 183 focal spasticity, treatments for, 187 gabapentin, 183–184 intrathecal (IT) baclofen, 189–190 oral antispasticity medications, evidence-based guidelines for, 186–187, 186t oral medications, 181 phenol chemodenervation, 187–188 tizanidine, 182–183 strategy for, 195–197 surgery, 195 whole-body vibration (WBV), 194 Spastic movement disorder development of, 139–141 on patho-anatomy, 141–143 pathophysiology-based treatment of, 144–145 Spastic paraplegia rating Scale (SPRS), 252 Spastic patients, functional problems in co-contraction for joint stiffness, 69–70 interjoint coordination, 67–68 interlimb coordination, 68–69 long-latency stretch reflexes/ coordination of movement, 66–67

Index

over-activity as general adaptation to central lesion, 70 reflexes, integrated part of voluntary movement, 59–60 sensory feedback contribution to movement, 64–66 stretch reflex modulation in spastic subjects control of reflexes in antagonist, 63 hyperexcitable stretch reflexes in stance phase of gait, 62–63 reflex modulation during simple contraction of agonist muscle, 60–62 suppression of reflexes in swing phase, 63–64 training for learning, 70–71 Specificity, 8n Spinal cord atrophy, 179 Spinal Cord Independence Measure (SCIM), 149 Spinal cord injury (SCI) complex spastic SCI patient combination therapies, intrathecal systemic/focal (case study), 164 combination therapies, oral systemic/focal (case study), 163 epidemiology/specific aspects of spasticity in, 137–139 overview, 136–137 patient selection/therapeutic approach clinical assessment of spasticity in, 148–149 clinical presentation/anatomical distribution of spasticity, 149–150 contractures, surgical correction of, 160–161 focal anti-spastic pharmacotherapy, chemodenervation, 157–160 focal anti-spastic surgical treatment, selective dorsal rhizotomy (SDR), 161–162 indication for treatment, spasticity in SCI, 147–148 intrathecal anti-spastic pharmacotherapy, 155–157 mainstay of spasticity treatment in SCI, physical therapy, 150–152

Index

oral systemic anti-spastic pharmacotherapy, 152–155, 153t physiological effects of training, 150 spasticity, pathophysiology-based treatment of about, 143–144 clinical signs of spasticity, 144 spastic movement disorder, 144–145 therapeutic consequences, 145–147 spastic movement disorder and patho-anatomy, 141–143 spinal shock/recovery of spinal excitability/development of spastic movement disorder, 139–141 Spinal excitability, recovery of, 139–141 Spinal networks, adaptive changes in, 30–31 Spinal shock, 31, 139–141 Spinocerebellar ataxias (SCA), 259–262, 261t, 266 Spinocerebellar degenerations autosomal dominant cerebellar ataxias (ADCA), 258–259, 260t–261t autosomal recessive ataxias, 266 Friedreich’s ataxia (FRDA)/late-onset Friedreich’s ataxia (LOFA), 266–268 spinocerebellar ataxia3 (SCA3)/ Machado-Joseph disease, 259–262, 261t, 266 Splinting, 218 Splints and orthoses, 266 Spongiform disorders, 273; see also Leukodystrophies Sprouting, 35 Standing posture, 109 Stiff knee gait, 113, 251 Stiffness at elbow, 5f measured at knee joint, 7f Strengthening spastic muscles, 88 Stretching, 88 for contracture vs. spasticity management, 217–218 Stretch reflex activation, 251 Stretch reflexes, 38, 43, 62

299

Stretch reflex-mediated resistance, 28 Stretch reflex modulation in spastic subjects control of reflexes in antagonist, 63 hyperexcitable stretch reflexes in stance phase of gait, 62–63 reflex modulation during simple contraction of agonist muscle, 60–62 suppression of reflexes in swing phase, 63–64 Striatal toe, 113, 114 Stroke about, 101–102 motor recovery/motor control after, 105–108 pathophysiology of spasticity after, 102–105 spasticity management after about, 122–123, 122t invasive, permanent methods, 126–128 invasive, reversible methods, 124–126 management strategy for, 128 noninvasive treatment, 123–124 Stroke, contractures in/clinical management of spasticity about stroke, 101–102 in arm and hand function about, 115–116 with mildly affected upper limb (UAT 4–7), 118 with moderately affected upper limb (UAT 2–3), 117–118 with severely affected upper limb (UAT 0–1), 117 motor recovery/motor control after stroke, 105–108 in postural control/gait control about, 108–111 muscle overactivity during stance phase, 111–113 muscle overactivity during swing phase, 113–115 stroke, pathophysiology of spasticity after, 102–105 stroke, spasticity management after about, 122–123, 122t

300

invasive, permanent methods, 126–128 invasive, reversible methods, 124–126 management strategy for stroke patients with spasticity, 128 noninvasive treatment, 123–124 stroke patients, spasticity assessment in about, 118–119 activity and participation, 121 body function and structure, 119–121, 119t, 120t Stroke patients, spasticity assessment in about, 118–119 activity and participation, 121 body function/structure, 119–121, 119t, 120t Stroke Upper Limb Capacity Scale, 121 Strumpell-Lorrain syndrome, 237 Supraspinal control of spinal networks, 69 Surface electromyography (sEMG), 121 Surface neuromuscular electrical stimulation, 123 Surgical treatment intrathecal baclofen, 89–91 in MS, 195 neurotomy, 89 selective dorsal rhizotomy, 91–96, 95t for TBI, 226–227 Symptomatic management, SCA, 262 T Tardieu scale, 27, 243 Tardieu Score, 17, 212t TBI, see Traumatic brain injury (TBI) Tendon-lengthening procedures, 195 Tendon transfers, 128 Tenotomy, 195 Tetrahydrocannabinol (THC), 155 Tetraplegia, 160 Tibial nerve, 124, 126 Timed Up and Go Test, 121 Tizanidine, 40, 124, 152, 163, 182–183 Tone about, 3, 4 altered, 9–12 Tone Assessment Scale, 102, 214 Tongue movements, 270

Index

Tonic supraspinal inhibition, 31 Tonus, 3, 4 Training for learning, 70–71 physiological effects of, 150 Transcranial magnetic stimulation (TMS), 193–194, 240 Transcutaneous electrical nerve stimulation (TENS), 191–193 Transmission in group II pathways, 39–40 Traumatic brain injury (TBI) biomechanical assessment, 214–216 brain injury complications on spasticity, 209 clinical assessment, 212–214, 213t clinical presentations, 207–209, 208t contractures/spasticity on recovery, 206 management options electrical stimulation, 218–219 focal therapies, 220–223 intrathecal therapies, 223–226, 226t oral medications, 219 physical modalities, 216–217 stretching/casting for contracture vs. spasticity management, 217–218 surgical interventions, 226–227 treatment modalities, 227 overview, 204–206 treatment goals, 209–212, 210t–212t Treadmill training, 69 Trunk control, 108 U Upper limb symptoms, 270 Upper motoneuron syndrome spasticity in, 13–14 Upper motor neuron (UMN), 204, 236, 268 Utrecht Arm/Hand Test (UAT), 116, 116f V Velocity-dependent response, 10f–11f Very late-onset Friedreich’s ataxia (VLOFA), 267

301

Index

Visual Analogue Scaling, 121 Visual problems, 259 W Walking difficulties, 249–252 Walking index in SCI (WISCI), 149 Walking Test, 121

Wallerian degeneration, 88, 142 Water therapy, 151 Whole-body vibration (WBV), 194 Wolff’s law, 85n Z Zone of partial preservation, 141