Ebook Neurological rehabilitation - Spasticity and contractures in clinical practice and research: Part 2

(BQ) Part 2 book “Neurological rehabilitation - Spasticity and contractures in clinical practice and research” has contents: Clinical management of spasticity and contractures in multiple sclerosis, hereditary spastic paraparesis and other hereditary myelopathies, clinical assessment and management of spasticity and contractures in traumatic brain injury,… and other contents.

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

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 func-tional 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 excit-ability of spinal motoneurons below the level of lesion as derived from ani-mal 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 clini-cal practice Although there is some experimental work in the human that supports the notion of changing excitability of infra-lesional spinal moto-neurons 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

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

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, ticity is rated as the most disabling complication, followed by pain, sexual, bowel, and bladder dysfunction and pressure ulcers There is an interrelation

spas-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 tet-raplegia [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, characteris-tics of SCI will influence the manifestation and the distribution of spasticity Neural mechanisms are discussed to be the primary contributors to spas-ticity following SCI by some authors [9], whereas others emphasise the rel-evance 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 sug-gested 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 delin-eating indication for treatment as it does not explain the syndrome of spastic motor disorder Clinical signs of spasticity are not related to spastic move-ment disorder The functional impairment that follows a central motor lesion will be influenced and modified by spasticity However, it is not a direct con-sequence 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

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 excitability 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

hyper-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 ture of spasticity Other than exaggerated reflexes, it has both diagnostic and therapeutic significance [16] This heterogeneity in clinical presentation can-not be explained by exaggeration of the stretch reflex alone There is abun-dance 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

fea-in motor units from 5 out of 15 SCI patients [4] It was explafea-ined as a sequence of altered intrinsic voltage-dependent persistent inward currents (PICs; e.g., persistent inward calcium currents) [1] The hypothesis was pri-marily 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 fir-ing 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

con-be in contradiction with observations of reduced motor unit action tials [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

poten-on the poten-one, and enhanced short latency reflex excitability and sppoten-ontaneous 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

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

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 affer-ents [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 regulation, and later during the recovery phase would be associated primar-ily with pre-synaptic mechanisms [1,9,29] However, these changes are not observed immediately after spinal trauma They evolve with time, suggest-ing gradual changes of neural adaptation following SCI

up-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 tinguished between pathologies with acute onset and those that result in slow alteration of the cord, e.g., due to tumor or other etiology with increas-ing compression Following an acute onset there will be a phenomenon of

dis-a sudden loss of reflexes dis-and muscle tone, commonly referred to dis-as ‘spindis-al shock’ The term was introduced by Hall in 1841, who, in describing the sud-den 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 reap-pear 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 cardiovascu-lar 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 dura-tion 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 polysegmen-tal 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 out-come and clinical presentation of recovery of voluntary motor control and spastic motor disorder [35]

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 don 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 flaccid-ity as an indicator of complete SCI Within this spectrum of motor responses and gradually increasing motor activity following spinal shock it is difficult

ten-to distinguish spasticity as a single and clearly defined moten-tor 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 excitabil-ity In contrast to tetraplegic patients, paraplegia resulted in M-wave and flexor reflex amplitudes that were found to decrease, indicating that spas-tic motor disorder eventually is not associated with increased excitability of motoneurons and premotoneuronal network [12,24]

Neurophysiological methods have deepened our understanding of lying 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 spi-nal motor neurons, as tested by neurographic methods (F-waves) and with

under-a loss of flexor reflexes, whereunder-as only H-reflexes cunder-an be elicited becunder-ause 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 cowork-ers (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 occur-rence of spasms and is associated with the recovery of excitability of spi-nal 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

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

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 sition from spinal shock to spasticity, it must be emphasised that spasticity in SCI develops without a net increase in spinal excitability

tran-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 preser-vation’ 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 dis-tribution 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 sensa-tion 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, account-ing 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 lat-eral 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 plete 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

incom-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 func-tional level of all SCI clinical syndromes, which is a cofactor in determining relatively poor recovery of hand function in this group, despite its favor-able 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 consid-eration 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 character-istic 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 prototypi-cal 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 pro-prioceptive 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

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

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 func-tion 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 exten-sive 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 favor-able 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 col-laterals 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 drome to less than 1% in the analysis of McKinley and coworkers [43] Data

syn-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 activity’ in limb muscles mediated by exaggerated reflexes leading to muscle overactivity Also, most articles in this volume are focused on these phenom-ena The consequence of this thinking is that spasticity should be treated

‘extra-by attenuating reflex and muscle activity ‘extra-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])

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 spas-tic 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 move-ment 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 clini-cal 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 nor-mal 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 modu-late limb muscle activity [64] and thereby adapt the movement pattern to the environmental requirements

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

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 activ-ity required during movement performance (e.g., to support the body dur-ing 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 sub-jects Instead, muscle hypertonus develops with the stretching of the toni-cally activated muscle This represents a more simple mode of muscle tone generation, which is also based on structural alterations of a muscle second-ary 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 express-ing 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, ultrastruc-tural changes of the extracellular matrix such as expanded connective tis-sue, 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 adapta-tions outside and inside the muscle cells, which alter their passive mechani-cal 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 move-ments 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 exam-ination, 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 qualita-tive 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

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 conse-quently 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 weak-ness [71–73] In conclusion, therapeutic interventions in patients with spastic paresis due to an incomplete SCI should be focused on the training, relearn-ing, 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 reduc-ing muscle stiffness and relieving muscle spasms [77], which might in turn improve nursing care for these patients In cases where function is ham-pered 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 ing 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

facilitat-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 mus-cle activation In contrast, according to this study, a lack of training of natural movements leads to a chaotic sprouting associated with a neuronal dysfunc-tion, 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 train-ing 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 cation can impede recovery of natural movements, as the performance of natural movements requires some spastic muscle stiffness for compensation

medi-of the paresis, i.e., lack medi-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

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

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 indepen-dence 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 lying mechanisms associated with alteration of stiffness and reflex function, the management of spasticity in SCI is to a large extent empirical An indi-cation for treatment of spasticity in SCI exists when it may cause harm and interference with function, nursing, or subjective well-being [78] This may

under-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, improve-ment of reaching, grasping, grooming and dressing, relief from pain, and painful muscle spasms, improvement of tolerance to wear splints and ortho-sis, which in turn will be needed to improve mobilisation of limbs and secure therapy effects aimed at prevention of contractures, prevention of contrac-tures, promotion of hygiene, improve positioning, and facilitate mobilisation and other therapies [78]

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 spastic-ity 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 pro-tective 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 func-tional benefits from spasticity and its adverse effects in allowing and facili-tating 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 tion 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 cath-eterisation difficult Personal accounts of the patient as well as information from those who know the patient should be obtained This is particularly rel-evant when planning treatment of focal spasticity with chemo-denervation,

descrip-as it must be determined after first injection of botulinum b toxin whether the dosage and pattern of application is optimal When evaluating and dis-cussing treatment options, a clear goal should be determined for what is

to be achieved by the treatment In the clinical examination, it is tant to assess the range of active and passive movements as well as painful limitations of movement or abnormal limb positions While not function-ally 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 his-tory, 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

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

Measure [91–93] SCIM and other scores cover the main ADL domains evant 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 func-tion (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

rel-a trerel-atment rel-aim [93,99] In rel-any crel-ase, it is recommendrel-able to include prel-atient-reported 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

patient-6.3.3 Clinical Presentation and Anatomical Distribution of Spasticity

Patho-anatomical distribution and severity of spinal lesion, among other tors, determine localisation of spasticity Spastic symptoms may be more or less focal or regional, e.g., most prominent in the upper extremity in a cen-tral 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 extrem-ity after SCI typically presents with shoulder adduction and inward rota-tion, elbow, wrist, and finger and thumb flexion, and pronation Typically, patients’ hands tend to be fixed with closed fists, resulting in an impairment

fac-of reaching, grasping, and releasing Spastic hypertonus fac-of the pelvic striate muscles can impede micturition and defecation Distribution and localisa-tion of symptoms will guide the choice and form of application of anti-spastic treatment A sudden increase in spasticity should prompt the attending phy-sician to screen for underlying pathology that can be completely indepen-dent 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 pur-sue 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

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 simultane-ously affecting volitional control and spasticity [106] Endurance and pre-cision 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 com-ponents 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 strength-ened by the intervention, hence increase of motor control will parallel a decreased susceptibility for involuntary muscle spasms [106,107] Thus, vari-ous 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 cise If this is not sufficiently effective, the patient should have physiotherapy with guidelines for exercises that counteract the spasticity Physical ther-apy 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

exer-is able to move with help, regular transfers and mobilexer-isation 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

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

him in order not to lose his remaining capacities We have often seen tic 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]

spas-If no treatable causes triggering spasticity can be found, the team should decide whether focal or general signs of spasticity prevail and require treat-ment In focusing on functional deficits, the first level of treatment and the basis for any further escalation should be physical therapy This recommen-dation 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 pat-terned 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 spi-nal cord to improve its function [109] Increasing the excitation of the spinal cord with spared descending and/or peripheral inputs by facilitating move-ment, instead of suppressing it pharmacologically is therefore the primarily suggested approach to improve residual motor function and manage spastic-ity after SCI Any treatment of spasticity will then be a combination of phys-iotherapy 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 mention-ing 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 cle function for ambulation and stance balance control in SCI [110–112] The observation that LT can ameliorate spasticity is based on observations made

mus-in cats with complete spmus-inal lesions [113] LT on a treadmill is combmus-ined with bodyweight support, reducing gravitational forces by 20–50% by means

of mechanical support by an overhead harness As subjects walk on the

treadmill with a reduced load on their lower extremities, coordinated ping 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 ambu-latory 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.

step-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 can-nabinoids are not officially approved for the treatment of spasticity in SCI They are well-established drugs with known risk profiles and some low-level 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

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 quantita-tive 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 dif-ferential 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 qual-ity 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 pathophysi-ologic evidence has suggested that exaggerated reflexes contribute little to spastic muscle hypertonia [61] In the majority of mobile patients, impair-ment of functional movements is clinically more relevant than impairment

of muscle tone Functional movements were only assessed in half of the als 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 com-monly 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

tri-by oral route’ [85]

Based on empirical recommendations, a combination of logical agents at low dosage is assumed to help reduce side effects while

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

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 interac-tion 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 vari-ous 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 placebo-controlled 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 gen-eralised spasticity cannot be adequately controlled with oral medication, i.e., due to insufficient effects on muscle hypertonus despite maximum dos-age or due to intolerable side effects at sufficient dosage with a combina-tion 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 appli-cable Despite the considerable cost of the device and the effort required to test efficacy for each patient prior to implantation, this route of application

has clear advantages over oral administration Efficacy is empirically rior 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 admin-istration 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

supe-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 regulating 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,

rhythm-it can be placed between T6 and T10 [100]

It is recommended to evaluate the patients and their caretakers to mine 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

deter-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 inter-fere 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 familia-rise 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

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

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 respi-ratory 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 dedi-cated centers with experienced teams There should be an emergency ser-vice 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 able complication rate of 0.011 per month, or 12–13% per year Of these com-plications, the majority (78%) were related to catheter malfunction [115,127] Another more recent and prospective study presented an even higher fre-quency 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 dur-ing 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 hyper-thermia, hyperreflexia, potential autonomic instability, seizures, and hallu-cinations Patients should be taken under surveillance and treated by oral administration of the drug

consider-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 tions, side effects, and special considerations the reader is referred to the recent publication by Khurana [100]

complica-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,

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 spastic-ity 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 spastic-ity in etiologies other than SCI [130,131] In a RCT comparing BoNT to phe-nol 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 manage-ment 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 manage-ment 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 sis is usually mainly caused by weakness and the other ‘negative’ features of upper motoneuron syndrome, and not by muscle overactivity [19]

pare-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 eral 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

collat-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, addition-ally, dysesthesia or denervation pain in treatment with ethanol/phenol

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

Specific indications and aims for anti-spastic treatment with focal modenervation 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 feed-ing, etc.), enhanced service responses (prevention of need for unnecessary medication and other treatments, facilitation of therapy, delay or preven-tion of surgery) [78] It must be remembered that the treatment of spasticity

che-is physical primarily in order to influence and control consecutive chanical 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,

biome-as in other arebiome-as 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 injec-tions 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 num-ber 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 organisa-tion of services [78]

Contractures cannot be treated with BoNT as they indicate an inactive muscle However, in our experience contract muscle fibres in a spastic mus-cle 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 lengthen-ing 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 plantarflex-ion, flexion of the knee, or flexion-adduction of the hip, where it will lead

to impairment of positioning, gait, and transfers If not sufficiently able 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 func-tioning of antagonists when overpowering agonists are released, thereby reestablishing a better balance and synergy [150–152] Furthermore, surgi-cal 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

treat-of contractures may be part treat-of a concept treat-of reconstruction treat-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

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

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 ment is insufficient or causes intolerable side effects Another reason for focal surgery may be proof of antibodies against BoNT, rendering this drug inef-fective as a treatment alternative in dynamic focal spasticity Hypertonus should be stable over time and must have a limiting effect on daily activi-ties The patient should be well-informed and motivated to sustain and sup-port 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 func-tion and patient reported benefit can be substantial and may be expected during a time period up to one year [155]

treat-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 con-troversial 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 ben-efit 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 luxa-tion 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 per-formed 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 myeli-tis and myelomeningocele, were reported In a subgroup of traumatic SCI,

spasticity and pain could be improved in the majority of cases and tory performance was unchanged or also improved after the surgery in a case of spasticity following transverse myelitis [170] Another early report

ambula-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 pensate 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 spastic-ity following other surgical interventions involving SDR in SCI, e.g., with anterior sacral root stimulation for treatment of neurogenic bladder dysfunc-tion following SCI [172]

com-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 rigor-ous 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 neuroab-lative 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

Clinical Management of Spasticity and Contractures in Spinal Cord Injury

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 recov-ered walking ability using 2 canes within 5 months of rehabilitation and was released, returning to work as a part-time teacher Within the follow-ing 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 dur-ing 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 olar fracture treated surgically after 3.5 years, a right metatarsale III/IV frac-ture after 4.5 years, and a right tri-malleolar fracture with dislocation after

malle-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 exacerba-tion 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

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 tion could subsequently be tapered and alertness and participation in reha-bilitation training improved substantially Rehabilitation over a period  of

medica-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 exten-sion, 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 neuro-logical 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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