SPASTICITY—Its Nature and Treatment

There are a number of physiological means of relaxing spasticity, including active resistive exercise, cold hydrotherapy, heat, electrical stimulation of antagonistic muscles, passive stretch in diagonal movement patterns, and the Von Bechterew reflex. Although none of them will cure spasticity, temporary relaxation may permit a patient to achieve better functioning of an affected joint. The choice of procedure will depend on the nature of the lesion and the muscular distribution of the spasticity.     

Identifying the brain regions associated with acute spasticity in patients diagnosed with an ischemic stroke

Spasticity is a common impairment found in patients that have been diagnosed with a stroke. Little is known about the pathophysiology of spasticity at the level of the brain. This retrospective study was performed to identify an association between the area of the brain affected by an ischemic stroke and the presence of acute spasticity. Physical and occupational therapy assessments from all patients (n?=?441) that had suffered a stroke and were admitted into a local hospital over a 4-year period were screened for inclusion in this study. Subjects that fit the inclusion criteria were grouped according to the presence (n?=?42) or absence (n?=?129) of acute spasticity by the Modified Ashworth Scale score given during the hospital admission assessment. Magnetic resonance images from 20 subjects in the spasticity group and 52 from the control group were then compared using lesion density plots and voxel-based lesion–symptom mapping. An association of acute spasticity with the gray matter regions of the insula, basal ganglia, and thalamus was found in this study. White matter tracts including the pontine crossing tract, corticospinal tract, internal capsule, corona radiata, external capsule, and the superior fronto-occipital fasciculus were also found to be significantly associated with acute spasticity. This is the first study to describe an association between a region of the brain affected by an infarct and the presence of acute spasticity. Understanding the regions associated with acute spasticity will aid in understanding the pathophysiology of this musculoskeletal impairment at the level of the brain.     

Combinational spinal GAD65 gene delivery and systemic GABA-mimetic treatment for modulation of spasticity

Background

Loss of GABA-mediated pre-synaptic inhibition after spinal injury plays a key role in the progressive increase in spinal reflexes and the appearance of spasticity. Clinical studies show that the use of baclofen (GABA_B receptor agonist), while effective in modulating spasticity is associated with major side effects such as general sedation and progressive tolerance development. The goal of the present study was to assess if a combined therapy composed of spinal segment-specific upregulation of GAD65 (glutamate decarboxylase) gene once combined with systemic treatment with tiagabine (GABA uptake inhibitor) will lead to an antispasticity effect and whether such an effect will only be present in GAD65 gene over-expressing spinal segments.

Methods/Principal Findings

Adult Sprague-Dawley (SD) rats were exposed to transient spinal ischemia (10 min) to induce muscle spasticity. Animals then received lumbar injection of HIV1-CMV-GAD65 lentivirus (LVs) targeting ventral α-motoneuronal pools. At 2–3 weeks after lentivirus delivery animals were treated systemically with tiagabine (4, 10, 20 or 40 mg/kg or vehicle) and the degree of spasticity response measured. In a separate experiment the expression of GAD65 gene after spinal parenchymal delivery of GAD65-lentivirus in naive minipigs was studied. Spastic SD rats receiving spinal injections of the GAD65 gene and treated with systemic tiagabine showed potent and tiagabine-dose-dependent alleviation of spasticity. Neither treatment alone (i.e., GAD65-LVs injection only or tiagabine treatment only) had any significant antispasticity effect nor had any detectable side effect. Measured antispasticity effect correlated with increase in spinal parenchymal GABA synthesis and was restricted to spinal segments overexpressing GAD65 gene.

Conclusions/Significance

These data show that treatment with orally bioavailable GABA-mimetic drugs if combined with spinal-segment-specific GAD65 gene overexpression can represent a novel and highly effective anti-spasticity treatment which is associated with minimal side effects and is restricted to GAD65-gene over-expressing spinal segments.     

The relationship between the soleus H-reflex amplitude and vibratory inhibition in controls and spastic subjects. II. Computer model

A computer model is presented that describes soleus H-reflex recruitment as a function of electric stimulus intensity. The model consists of two coupled non-linear transfer functions. The first transfer function describes the activation of muscle spindle (Ia) afferent terminals as a function of the electric stimulus intensity; whereas the second describes the activation of a number of motoneurons as a function of the number of active Ia afferent terminals. The effect of change in these transfer functions on the H-reflex recruitment curve is simulated. In spastic patients, a higher average maximal H-response amplitude is observed in combination with a decreased H-reflex threshold. Vibration of the Achilles tendon reduces the H-reflex amplitude, presumably by reducing the excitatory afferent input. Vibratory inhibition is diminished in spasticity. In the model, the afferent-motoneuron transfer function was modified to represent the possible alterations occurring in spasticity. The simulations show that vibratory suppression of the H-reflex is determined only in part by the inhibition level of the afferent input. With a constant level of presynaptic inhibition, the suppression of reflexes of different sizes may vary. A lowering of the motoneuron activation thresholds in spastic patients will directly contribute to a decrease of vibratory inhibition in spasticity.     

Espasticidad tras ictus: ¿la edad es un factor de riesgo? Estudio observacional de la espasticidad en pacientes neurovasculares en una serie retrospectiva de dos centros

ObjectiveApproximately one third of patients who have suffered a stroke develop spasticity. Since clinical observations that spasticity in the elderly population is lower after stroke, and disagreement about risk factors between different authors, an analysis is performed on the variables that influence the development of spasticity.The objective of the study is to determine the how many factors influence spasticity outcome, and the prevalence of spasticity in patients who have suffered a stroke and require intensive rehabilitation treatment.MethodA retrospective assessment was carried out on a total of 554 patients from two neurorehabilitation centres. A record was made of sociodemographic data, aetiology, type and location of stroke, motor and sensory deficits, language and swallowing impairment, incontinence, cognitive and mood state. Spasticity levels at admission and at the third month were studied in 462 patients using the Ashworth scale. Multivariate regression analyses were used to assess the risk factors for spasticity present at the third month after stroke.ResultsThe mean age of the patients was 67.3 years, of which 67.1% were men, and with ischemic aetiology in 76.5%. On admission 31.4% of patients had spasticity, and this increased to 54.8% at the 3^rd month. The absolute risk factor for spasticity was motor index (OR 1.04; 95% CI 1.03-1.05). When this factor was omitted, the variables with predictive ability were: age less than 75 years (OR 0.52; 95% CI 0.30-0.90), sensory impairment (OR 0.66; 95% CI 0.37-1.20), and lower Barthel index score (OR 1.02; 95% CI 1.01-1.03). There was no significant relationship for gender, physiopathological mechanism (ischaemic/haemorrhagic), stroke location, aphasia, or cognitive impairment.ConclusionThe prevalence of spasticity in stroke at third month of follow-up was 54.8%. Motor index is the independent predictor of spasticity. Patients younger than 75 years old, with sensory impairment and low Barthel index score are more likely to develop spasticity.     

Assessment of post-stroke elbow flexor spasticity in different forearm positions

Abstract

Purpose/Aim: There have been conflicting results regarding which muscle contribute most to the elbow spastic flexion deformity. This study aimed to investigate whether flexor spasticity of the elbow changed according to the position of the forearm, and to determine the muscle or muscles that contributed most to the elbow spastic flexion deformity by clinical examination.

Methods: This study is a single group, observational and cross-sectional study. Sixty patients were assessed for elbow flexor spasticity in different forearm positions (pronation, neutral and supination) with Modified Tardieu Scale. The primary outcome measure was a domain of the Modified Tardieu Scale, the dynamic component of spasticity (spasticity angle).

Results: In general, there was a significant difference between forearm positions regarding spasticity angle (p?<?.001). In pairwise comparisons, median spasticity angles in pronation (70 degrees) and neutral position (60 degrees) were significantly higher than those in supination (57.5 degrees) (adjusted p?<?.001 and adjusted p?=?.003, respectively). However, median spasticity angle in pronation did not differ significantly from those in neutral position in favour of pronation (adjusted p?=?.274).

Conclusions: The severity of spasticity changes according to the elbow position which suggests that the magnitude of contribution of each elbow flexor muscle to spastic elbow deformity is different. Reduction of spasticity from pronation to supination leads us to consider brachialis as the most spastic muscle. Since biceps was suggested to be the least spastic muscle in this study, and also to avoid spastic pronation deformity of the forearm, it should be rethought before performing chemodenervation into biceps muscle.     

Pendulum testing of spasticity

Simple and inexpensive instrumentation required for pendulum testing of spasticity is described. It is based on the use of an electrogoniometer and tachometer. Eight parameters are extracted from the goniogram and the tachogram to evaluate the degree of spasticity. The correlation coefficients are calculated to determine the parameters relevant for the estimation of spasticity. Spasticity was assessed in the knee extensors of ten spinal cord injury patients and in five hemiplegics. The described instrumentation and evaluation of the pendulum test provide an effective spasticity testing in the clinical environment.     

Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review

Background

Cannabis therapy has been considered an effective treatment for spasticity, although clinical reports of symptom reduction in multiple sclerosis (MS) describe mixed outcomes. Recently introduced therapies of combined Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) extracts have potential for symptom relief with the possibility of reducing intoxication and other side effects. Although several past reviews have suggested that cannabinoid therapy provides a therapeutic benefit for symptoms of MS, none have presented a methodical investigation of newer cannabinoid treatments in MS-related spasticity. The purpose of the present review was to systematically evaluate the effectiveness of combined THC and CBD extracts on MS-related spasticity in order to increase understanding of the treatment's potential effectiveness, safety and limitations.

Methods

We reviewed MEDLINE/PubMed, Ovid, and CENTRAL electronic databases for relevant studies using randomized controlled trials. Studies were included only if a combination of THC and CBD extracts was used, and if pre- and post-treatment assessments of spasticity were reported.

Results

Six studies were systematically reviewed for treatment dosage and duration, objective and subjective measures of spasticity, and reports of adverse events. Although there was variation in the outcome measures reported in these studies, a trend of reduced spasticity in treated patients was noted. Adverse events were reported in each study, however combined TCH and CBD extracts were generally considered to be well-tolerated.

Conclusion

We found evidence that combined THC and CBD extracts may provide therapeutic benefit for MS spasticity symptoms. Although some objective measures of spasticity noted improvement trends, there were no changes found to be significant in post-treatment assessments. However, subjective assessment of symptom relief did often show significant improvement post-treatment. Differences in assessment measures, reports of adverse events, and dosage levels are discussed.     

Stretch reflex inhibition using electrical stimulation in normal subjects and subjects with spasticity

The effect of electricallys timulating the tibialis anterior muscle on the stretch reflex of the soleus muscle in normal subjects and subjects with spasticity is investigated. Stimulation of the tibialis anterior just prior to the onset of a mechanical disturbance, which causes a stretch in the soleus, inhibits the stretch reflex of the soleus in normal subjects and may inhibit clonus in subjects with spasticity.     

Spasticity and spastic dystonia: the two faces of velocity-dependent hypertonia

BackgroundSpasticity and spastic dystonia are two separate phenomena of the upper motor neuron syndrome. Spasticity is clinically defined by velocity-dependent hypertonia and tendon jerk hyperreflexia due to the hyper-excitability of the stretch reflex. Spastic dystonia is the inability to relax a muscle leading to a spontaneous tonic contraction. Both spasticity and spastic dystonia are present in patients who are at rest; however, only patients with spasticity are actually able to kept their muscles relaxed prior to muscle stretch. The idea that has inspired the present work is that also in patients with spastic dystonia the stretch reflex is likely to be hyper-excitable. Therefore, velocity-dependent hypertonia could be mediated not only by spasticity, but also by spastic dystonia.MethodsTonic stretch reflexes in the rectus femoris muscle were evoked in 30 patients with multiple sclerosis showing velocity-dependent hypertonia of leg extensors and the habituation of the reflex was studied. Moreover, the capability of relax the muscle prior to muscle stretch (spastic dystonia) was also investigated.ResultsA tonic stretch reflex was evoked in all the enrolled patients. 73% of the patients were able to relax their rectus femoris muscle prior to stretch (spasticity). In the overwhelming majority of these patients, the tonic stretch reflex decreased during repeated stretches. In the remaining 27% of the subjects, the muscle was tonically activated prior to muscle stretch (spastic dystonia). In the patients in whom spastic dystonia progressively increased over the subsequent stretches (50% of the subjects with spastic dystonia), the habituation of the reflex was replaced by a progressive reflex facilitation.DiscussionThis study shows for the first time that velocity-dependent hypertonia can be caused by two distinct phenomena: spasticity and spastic dystonia. The habituation of the tonic stretch reflex, which is a typical feature of spasticity, is replaced by a reflex facilitation in the half of the subject with spastic dystonia. These preliminary findings suggest that differentiating the two types of velocity-dependent muscle hypertonia (spasticity and spastic dystonia) could be clinically relevant.     

Presynaptic inhibition in humans: a comparison between normal and spastic patients.

During the last 40 years, several studies in man have been devoted to the pathophysiological mechanisms underlying spasticity. Spasticity is characterised by a velocity dependent increase in muscle tone. Many spinal pathways control stretch reflex excitability and a malfunction in any one of them could theoretically produce the exaggeration of the stretch reflex. Delwaide showed that the vibration-induced inhibition of Ia fibres is reduced in spastic patients. However, the relation between a decrease in presynaptic Ia inhibition and the pathophysiology of spasticity has been recently questioned since it was argued that homosynaptic depression (or post-activation depression) also contributes to the vibratory-induced depression of monosynaptic reflexes. This paper is thus devoted to a review of the methods recently developed to study selectively presynaptic Ia inhibition in man and to a reevaluation of the relations between modifications in presynaptic Ia inhibition and spasticity in hemiplegic and spinal spastic patients.     

Excessive reflexes in spinal cord injury triggered by electrical stimulation

Interaction of electrocutaneous stimulation with an impaired human motor control system may result in unstable reflex loops causing excessive spastic reactions. These contractions are usually excluded from analysis since the presence of spasm is one of the criteria commonly applied for discarding a contraction. They may, however, provide interesting information on the nature of spasticity. The dorsiflexor muscles of four SCI subjects were activated by means of surface electrical stimulation and the isometric ankle moment was measured. Short bursts of constant stimulation frequency at seven different frequencies (8, 12, 16, 20, 25, 33, 50 Hz) triggered spastic reactions in all subjects. The onset times of spastic activity during an electrically elicited contraction shortened with increased stimulation frequency. A stimulation burst may also have a spasticity reduction effect on a subsequent burst, indicating potential short term therapeutic effects of stimulation on spasticity in isometric conditions.     

The relationship between the soleus H-reflex amplitude and vibratory inhibition in controls and spastic subjects. I. Experimental results

The effect of continuous Achilles tendon vibration on the soleus H-reflex amplitude was quantified over the entire H-reflex recruitment trajectory in 30 controls and 33 patients with spasticity in the lower limbs. The results show that with increasing stimulus intensities, vibratory inhibition of the Hreflex initially increases, then subsequently decreases. This is probably a direct consequence of how the activation thresholds of the motoneurons are distributed over the motoneuron pool. In patients, vibratory inhibition of the H-reflex was less over the entire recruitment trajectory than in controls. The decrease in vibratory inhibition in spasticity is commonly attributed to a decrease in presynaptic inhibition or post-activation depression. However, the average Hreflex threshold was lower in the patients, suggesting a decrease of the motoneuron activation thresholds. A lower reflex threshold in spasticity, therefore, may contribute to the observed reduction of vibratory inhibition.     

Thoracic 9 Spinal Transection-Induced Model of Muscle Spasticity in the Rat: A Systematic Electrophysiological and Histopathological Characterization

The development of spinal hyper-reflexia as part of the spasticity syndrome represents one of the major complications associated with chronic spinal traumatic injury (SCI). The primary mechanism leading to progressive appearance of muscle spasticity is multimodal and may include loss of descending inhibitory tone, alteration of segmental interneuron-mediated inhibition and/or increased reflex activity to sensory input. Here, we characterized a chronic thoracic (Th 9) complete transection model of muscle spasticity in Sprague-Dawley (SD) rats. Isoflurane-anesthetized rats received a Th9 laminectomy and the spinal cord was transected using a scalpel blade. After the transection the presence of muscle spasticity quantified as stretch and cutaneous hyper-reflexia was identified and quantified as time-dependent changes in: i) ankle-rotation-evoked peripheral muscle resistance (PMR) and corresponding electromyography (EMG) activity, ii) Hoffmann reflex, and iii) EMG responses in gastrocnemius muscle after paw tactile stimulation for up to 8 months after injury. To validate the clinical relevance of this model, the treatment potency after systemic treatment with the clinically established anti-spastic agents baclofen (GABA_B receptor agonist), tizanidine (α₂-adrenergic agonist) and NGX424 (AMPA receptor antagonist) was also tested. During the first 3 months post spinal transection, a progressive increase in ankle rotation-evoked muscle resistance, Hoffmann reflex amplitude and increased EMG responses to peripherally applied tactile stimuli were consistently measured. These changes, indicative of the spasticity syndrome, then remained relatively stable for up to 8 months post injury. Systemic treatment with baclofen, tizanidine and NGX424 led to a significant but transient suppression of spinal hyper-reflexia. These data demonstrate that a chronic Th9 spinal transection model in adult SD rat represents a reliable experimental platform to be used in studying the pathophysiology of chronic spinal injury-induced spasticity. In addition a consistent anti-spastic effect measured after treatment with clinically effective anti-spastic agents indicate that this model can effectively be used in screening new anti-spasticity compounds or procedures aimed at modulating chronic spinal trauma-associated muscle spasticity.     

Change of stretch reflex threshold in spasticity: effect of botulinum toxin injections

Spasticity is a disorder of hypertonus associated with neurological diseases, characterized by a decrease in stretch reflex threshold. Stretch reflex threshold of wrist flexors has been recorded in subjects affected by forearm spasticity due to acute neurological lesions, occurred from one to sixty-one months before. In all the subjects a decreased stretch reflex threshold was recorded and a negative correlation between stretch reflex threshold and time of the disease resulted. In five subjects affected by mild spasticity the velocity stretch reflex threshold was tested one-three months after stroke and then six months later. In three cases a further decrease in stretch reflex threshold was recorded. Sixteen subjects affected by heavy forearm spasticity (quantified by Ashworth scale), were treated with Botulinum toxin injections to reduce spasticity. Fourteen of 16 subjects were responsive to the antispastic therapy: a decrease of at least 1 point in the Ashworth scale was detected after the treatment. In all the responsive cases an increase of stretch reflex threshold was recorded. The results confirm that the stretch reflex threshold is decreased in spastic muscles; it decreases progressively in time after the acute lesion. In addition, these results demonstrate that the decreased stretch reflex threshold can be reversed with Botulinum toxin injections. It is known that Botulinum toxin reduce the presynaptic release of Acetylcholine of neuromuscular synapses, but there are experimental evidences that it acts even on spindle's fibres, decreasing the sensitivity of intrafusal muscle fibres. This effect explains how Botulinum toxin increases the stretch reflex threshold in spastic muscles.     

Endocannabinoids control spasticity in a multiple sclerosis model.

Spasticity is a complicating sign in multiple sclerosis that also develops in a model of chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice. In areas associated with nerve damage, increased levels of the endocannabinoids, anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG), and of the AEA congener, palmitoylethanolamide (PEA), were detected here, whereas comparable levels of these compounds were found in normal and non-spastic CREAE mice. While exogenously administered endocannabinoids and PEA ameliorate spasticity, selective inhibitors of endocannabinoid re-uptake and hydrolysis-probably through the enhancement of endogenous levels of AEA, and, possibly, 2-arachidonoyl glycerol-significantly ameliorated spasticity to an extent comparable with that observed previously with potent cannabinoid receptor agonists. These studies provide definitive evidence for the tonic control of spasticity by the endocannabinoid system and open new horizons to therapy of multiple sclerosis, and other neuromuscular diseases, based on agents modulating endocannabinoid levels and action, which exhibit little psychotropic activity.     

NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6)

The hereditary spastic paraplegias (HSPs) are genetically heterogeneous disorders characterized by progressive lower-extremity weakness and spasticity. The molecular pathogenesis is poorly understood. We report discovery of a dominant negative mutation in the NIPA1 gene in a kindred with autosomal dominant HSP (ADHSP), linked to chromosome 15q11-q13 (SPG6 locus); and precisely the same mutation in an unrelated kindred with ADHSP that was too small for meaningful linkage analysis. NIPA1 is highly expressed in neuronal tissues and encodes a putative membrane transporter or receptor. Identification of the NIPA1 function and ligand will aid an understanding of axonal neurodegeneration in HSP and may have important therapeutic implications.     

Modified constraint-induced movement therapy or bimanual occupational therapy following injection of Botulinum toxin-A to improve bimanual performance in young children with hemiplegic cerebral palsy: a randomised controlled trial methods paper

Background  

Use of Botulinum toxin-A (BoNT-A) for treatment of upper limb spasticity in children with cerebral palsy has become routine clinical practice in many paediatric treatment centres worldwide. There is now high-level evidence that upper limb BoNT-A injection, in combination with occupational therapy, improves outcomes in children with cerebral palsy at both the body function/structure and activity level domains of the International Classification of Functioning, Disability and Health. Investigation is now required to establish what amount and specific type of occupational therapy will further enhance functional outcomes and prolong the beneficial effects of BoNT-A.     

Intrathecal baclofen withdrawal syndrome- a life-threatening complication of baclofen pump: A case report

Background  

Intrathecal baclofen pump has been used effectively with increasing frequency in patients with severe spasticity, particularly for those patients who are unresponsive to conservative pharmacotherapy or develop intolerable side effects at therapeutic doses of oral baclofen. Drowsiness, nausea, headache, muscle weakness, light-headedness and return of pretreatment spasticity can be caused by intrathecal pump delivering an incorrect dose of baclofen. Intrathecal baclofen withdrawal syndrome is a very rare, potentially life-threatening complication of baclofen pump caused by an abrupt cessation of intrathecal baclofen.