Jean-Michel Gracies

Pathophysiology of spastic paresis. I: Paresis and soft tissue changes

Spastic paresis follows chronic disruption of the central execution of volitional command. Motor function in patients with spastic paresis is subjected over time to three fundamental insults, of which the last two are avoidable: (1) the neural insult itself, which causes paresis, i.e., reduced voluntary motor unit recruitment; (2) the relative immobilization of the paretic body part, commonly imposed by the current care environment, which causes adaptive shortening of the muscles left in a shortened position and joint contracture; and (3) the chronic disuse of the paretic body part, which is typically self‐imposed in most patients. Chronic disuse causes plastic rearrangements in the higher centers that further reduce the ability to voluntarily recruit motor units, i.e., that aggravate baseline paresis. Part I of this review focuses on the pathophysiology of the first two factors causing motor impairment in spastic paresis: the vicious cycle of paresis–disuse–paresis and the contracture in soft tissues. Muscle Nerve, 2005

Pathophysiology of spastic paresis. II: Emergence of muscle overactivity

In the subacute and chronic stages of spastic paresis, stretch‐sensitive (spastic) muscle overactivity emerges as a third fundamental mechanism of motor impairment, along with paresis and soft tissue contracture. Part II of this review primarily addresses the pathophysiology of the various forms of spastic overactivity. It is argued that muscle contracture is one of the factors that cause excessive responsiveness to stretch, which in turn aggravates contracture. Excessive responsiveness to stretch also impedes voluntary motor neuron recruitment, a concept termed stretch‐sensitive paresis. None of the three mechanisms of impairment (paresis, contracture, and spastic overactivity) is symmetrically distributed between agonists and antagonists, which generates torque imbalance around joints and limb deformities. Thus, each may be best treated focally on an individual muscle‐by‐muscle basis. Intensive motor training of the less overactive muscles should disrupt the cycle of paresis–disuse–paresis, and concomitant use of aggressive stretch and focal weakening agents in their more overactive and shortened antagonists should break the cycle of overactivity–contracture–overactivity. Muscle Nerve, 2005

Traditional pharmacological treatments for spasticity. Part II: General and regional treatments.

Systemic pharmacologic treatments may be indicated in conditions in which the distribution of muscle overactivity is diffuse. Antispastic drugs act in the CNS either by suppression of excitation (glutamate), enhancement of inhibition (GABA, glycine), or a combination of the two. Only four drugs are currently approved by the US FDA as antispactic agents: baclofen, diazepam, dantrolene soduim, and tizanidine. However, there are a number of other drugs available with proven antispastic action. This chapter reviews the pharmacology, physiology of action, dosage, and results from controlled clinical trails on side effects, efficacy, and indications for 21 drugs in several categories. Categories reviewed include agents acting through the GABAergic system (baclofen, benzodiazepines, piracetam, progabide); drugs affecting ion flux (dantrolene sodium, lamotrigine, riluzole); drugs acting on monoamines (tizanidine, clonidine, thymozamine, beta blockers, and cyproheptadine); drugs acting on excitatory amino acids (orphenadrine citrate); cannabinoids; inhibitory neuromediators; and other miscellaneous agents. The technique, advantages, and limitations of intrathecal administration of baclofen, morphine, and midazolam are reviewed. Two consistent limitations appear throughout the controlled studies reviewed: the lock of quantitive and sensitive functional assessment and the lack of comparative trials between different agents. In the majority of trials in which meaningful functional assessment was included, the study drug failed to improve function, even though the antispastic action was significant. Placebo‐controled trails of virtually all major centrally acting antispastic agents have shown that sedation, reduction of global performance, and muscle weakness are frequent side effects. It appears preferable to use centrally acting drugs such as baclofen, tizanidine, and diazepam in spasticity of spinal origin (spinal cord injury and multiple sclerosis), whereas dantrolene sodium, due to its primary perpherial mechanism of action, may be preferable in spasticity of cerebral origin (stroke and traumatic brain in jury) where sensitivity to sedating effects is generally higher. Intrathecal adminstration of antispastic drugs has been used mainly in cases of muscle overactivity occurring primarily in the lower limbs in nonambulatory, severely disbled patients, but new indications may emerge in spasticity of cerebral orgin. Intrathecal therapy is an invasive procedure involving long‐term implantation of a foreign device, and the potential disadvantages must be weighted against the level of disability in each patient and the resistance to other forms of antispastic therapy.In all forms of treatment of muscle overactivity, one must distinguish disability in each patient and the resistance to other forms of antispastic therapy. In all forms of treatment of muscle overactivity, one must distinguish between two different goals of therapy: improvement of active function and improvement of hygiene and comfort. The risk of global performance reduction associated with general or regional administration of antispastic drugs may be more acceptable when the primary goal of therapy is hygiene and comfort than when active function is a priority.

Traditional pharmacological treatments for spasticity part I: Local treatments

Spasticity is a velocity‐dependent increase in stretch reflex activity. It is one of the forms of muscle overactivity that may affect patients with damage to the central nervous system. Spasticity monitoring is relevant to function because the degree of spasticity may relect the intensity of other disabling types of muscle overactivity, such as unwanted antagonistic co‐contractions, permanent muscle activity in the absence of any stretch or volitional command (spastic dystonia), or inappropriate responses to cutaneous or vegetative inputs. In addition, spasticity, like other muscle overactivity, can cause muscle shortening, which is another significant source of disability. Finally, spasticity is the only form of muscle overactivity easily quantifiable at the bedside. Under the name pharmacological treatments of spasiticity, we understand the use of agents designed to reduce all types of muscle overactivity, by reducing excitability of motor pathways, at the level of the central nervous system, the neuromuscular junctions, or the muscle. Pharmacologic treatment should be an adjunct to muscle lengthening and training of antagonists. Localized muscle overactivity of specific muscle groups is often seen in a number of common pathologies, including stroke and traumatic brain injury. In these cases, we favor the use of local treatments in those muscles where overactivity is most disabling, by injection into muscle (neuromuscular block) or close to the nerve supplying the muscle (perineural block). Two types of local agents have been used in addition to the newly emerged botulinum toxin: local anesthetics (lidocaine and congeners), with a fully reversible action of short duration, and alcohols (ethanol and phenol), with a longer duration of action. Local anesthetics block both afferent and efferent messages. The onset of action is within minutes and duration of action varies between one and several hours according to the agent used. Their use requires resuscitation equipment available close by. When a long‐lasting blocking agent is being considered, we favor the use of transient blocks with local anesthetics for therapeutic tests or diagnostic procedures to answer the following questions: Can function be improved by the block? What are the roles played by overactivity and contracture in the impairment of function? Which muscle is contributing to pathologic posturing? What is the true level of performance of antagonistic muscles? A short‐acting anesthetic can also serve as preparation to casting or as an analgesic for intramuscular injections of other antispastic treatment. Alcohol and phenol provide long‐term chemical neurolysis through destruction of peripheral nerve. Experience with ethanol is more developed in children using intramuscular injection, while experience with phenol is greater in adults with perineural injection. In both cases, there are anecdotal reports of efficacy but studies have rarely been controlled. Side effects are numerous and include pain during injection, chronic dysesthesia and chronic pain, and episodes of local or regional vascular complications by vessel toxicity. In the absence of controlled studies, a theoretical comparison of neurolytic agents with botulinum toxin is proposed. Neurolytic agents may by preferred to botulinum toxin on a number of grounds, including earlier onset, potentially longer duration of effect, lower cost, and easier storage.

Botulinum Toxin Dilution and Endplate Targeting in Spasticity: A Double-Blind Controlled Study

OBJECTIVE To determine the effects of botulinum neurotoxin type A (BTX-A) dilution and endplate-targeting in spastic elbow flexors. DESIGN Double blind randomized controlled trial; 4-month follow-up after a 160-unit injection of BTX-A into spastic biceps brachii (4 sites). Randomization into: group 1: 100 mouse units (MU)/mL dilution, 0.4cc/site, 4-quadrant injection; group 2: 100MU/mL dilution, 0.4cc/site, 4 sites along endplate band; group 3: 20MU/mL dilution, 2cc/site, 4-quadrant injection (n=7 per group). SETTING Institutional tertiary care ambulatory clinic. PARTICIPANTS Referred sample of 21 adults with spastic hemiparesis. No participant withdrew due to adverse effects. INTERVENTION A 160-unit injection of BTX-A of different dilutions and locations into biceps brachii. MAIN OUTCOME MEASURES Primary: agonist and antagonist (cocontraction) mean rectified voltage (MRV) of elbow flexors/extensors during maximal isometric flexion/extension; secondary: maximal voluntary power of elbow flexion/extension; spasticity angle and grade in elbow flexors/extensors (Tardieu Scale); active range of elbow extension/flexion. RESULTS BTX-A injection overall reduced agonist flexor MRV (-47.5%, P<0.0001), antagonist flexor MRV (-12%, P=.037), antagonist extensor MRV (-19%, P<.01), flexion maximal voluntary power (-33%, P<.001), elbow flexor spasticity angle (-30%, P<.001) and grade (-17%, P=.03), and increased extension maximal voluntary power (24%, P=.037) and active range of elbow extension (5.5%, 8 degrees , P=.002). Agonist and antagonist flexor MRV reductions in group 3 (-81% and -31%) were greater than in groups 1 and 2, whereas increase in active range of elbow extension was greater in group 2 (10%) than in groups 1 and 3 (P<.05, analysis of covariance [ANCOVA]). Elbow flexor spasticity was significantly reduced in groups 2 and 3 only (P<.05, ANCOVA). CONCLUSIONS In spastic biceps, high-volume or endplate-targeted BTX-A injections achieve greater neuromuscular blockade, cocontraction and spasticity reduction, and active range of elbow extension improvement, than low volume, nontargeted injections.

Clinical pattern and risk factors for dyskinesias following fetal nigral transplantation in Parkinson's disease: A double blind video-based analysis†

The objective of this study is to assess dyskinesias in 34 Parkinsons disease patients randomized to receive bilateral fetal nigral transplantation with 4 donors per side (12), 1 donor per side (11), or placebo (11). Videotape recordings were performed at the baseline, 3, 6, 12, 18, and 24 month visits during the “practically defined off” (12 hours after last evening dopaminergic therapy) and “best on” (best response following morning dopaminergic therapy) states. Videotapes were analyzed in random order by a blinded investigator. Dyskinesias during “best on” (on‐medication dyskinesia) were observed in all, but 1 patient at baseline, and in all patients at each subsequent visit. There were no differences between groups. No patient had dyskinesia at baseline in “practically‐defined off” (“off‐medication” dyskinesia). Following transplantation, off‐medication dyskinesia was observed in 13 of 23 patients, but not in any patient in the placebo group (P = 0.019). There was no difference in dyskinesia score between patients in the 1 and 4 donor groups. On‐medication dyskinesias were typically generalized and choreiform, whereas off‐medication dyskinesias were usually repetitive, stereotypic movements in the lower extremities with residual Parkinsonism in other body regions. Off‐medication dyskinesias are common following transplantation and may represent a prolonged form of diphasic dyskinesias.

Physiological effects of botulinum toxin in spasticity

There is considerable evidence that injection of botulinum toxin (BTX) into muscles with spastic overactivity reduces resistance to passive movement in joints supplied by the injected muscles. The demonstration of improvement in active performance of the paretic limbs has been only anecdotal to date, and represents the most difficult challenge in research on BTX therapy in spastic paralysis. Data are reviewed that indicate several neurophysiological actions of BTX, other than the blocking of acetylcholine release at the neuromuscular ending: effects on the central nervous system, including retrograde axonal transport, reduced motoneuronal excitability, action on central synapses such as decreased Renshaw inhibition and increased presynaptic inhibition; action on gamma motoneuronal endings; action on most active terminals; spread of BTX to neighboring muscles; spread of BTX effects to remote muscles. Several of these neurophysiological actions are likely to contribute to improvement in active movements, as they may antagonize the primary mechanisms of functional impairment in patients with spastic paralysis: weakness, spastic cocontraction, spastic dystonia, and muscle shortening. We review the evidence for reduction of spastic cocontraction in both the injected muscle and its antagonist, and for improvement of antagonist weakness after BTX injection. The capacity of intramuscular BTX to reduce spastic dystonia and lengthen shortened muscles is also discussed based on prior literature. When injected into the more overactive of a pair of spastic antagonists around a joint, BTX should affect all the main mechanisms impairing active function around the joint.

Lower Limb Coordination in Hemiparetic Subjects: Impact of Botulinum Toxin Injections Into Rectus Femoris

Background. Botulinum toxin (BTX) injection into rectus femoris (RF) is a therapeutic modality used to improve knee flexion during the swing phase of gait in hemiparesis. The impact of this treatment on lower limb coordination is unknown. The authors evaluated whether BTX injection into RF is associated with modifications of intersegmental coordination in hemiparesis. Methods. The authors evaluated gait in 10 control and 14 hemiparetic subjects with low peak knee flexion associated with inappropriate RF activity in mid-swing, using 3-dimensional analysis before and 1 month after BTX injection into RF (Botox, 200 units). Thigh—shank coordination was measured in the sagittal plane by averaging the continuous relative phase (CRPThigh— Shank) during each phase of the gait cycle in both lower limbs. The CRP is a validated metric that integrates angle positions and velocities of 2 limb segments to quantify their temporal—spatial coordination. Results. Before treatment, the low peak knee flexion in hemiparetic subjects (paretic limb 29 ± 9°) was associated with a decreased CRP Thigh—Shank in the paretic limb in swing (paretic limb 26.0 ± 16.6° vs controls 73.5 ± 7.4°, P < .001) and with a trend of an increased CRPThigh —Shank in the nonparetic limb over the full gait cycle (nonparetic limb 77.9 ± 14.1° vs controls 66.2 ± 19.8°, P = .083). After treatment, the CRPThigh— Shank increased by 11.9° in the swing phase of the paretic limb (P = .002) and decreased by 8.0° over the full gait cycle ( P = .002) in the nonparetic limb. Conclusions. BTX injection into RF was associated with improved thigh—shank coordination in parts of the gait cycle, in both injected paretic and noninjected nonparetic limbs.

Walking velocity and lower limb coordination in hemiparesis

BACKGROUND/OBJECTIVE Gait training at fast speed has been suggested as an efficient rehabilitation method in hemiparesis. We investigated whether maximal speed walking might positively impact inter-segmental coordination in hemiparetic subjects. METHODS We measured thigh-shank and shank-foot coordination in the sagittal plane during gait at preferred (P) and maximal (M) speed using the continuous relative phase (CRP), in 20 healthy and 27 hemiparetic subjects. We calculated the root-mean square (CRP(RMS)) and its variability (CRP(SD)) over each phase of the gait cycle. A small CRP(RMS) indicates in-phasing, i.e. high level of synchronization between two segments along the gait cycle. A small CRP(SD) indicates high stability of the inter-segmental coordination across gait cycles. RESULTS Increase from preferred to maximal speed was 57% in healthy and 49% in hemiparetic subjects (difference NS). In healthy subjects, the main change was shank-foot in-phasing at stance (CRP(Shank-Foot/RMS), P, 98±10; M, 67±12, p<0.001). In hemiparetic subjects, we also found shank-foot in-phasing at late stance bilaterally (non-paretic CRP(Shank-Foot/RMS), P, 37±9; M, 29±8, p<0.001; paretic CRP(Shank-Foot/RMS), P, 38±13; M, 32±12, p<0.001), and thigh-shank in-phasing at mid-stance in the non-paretic limb (CRP(Thigh-Shank/RMS), P, 57±9; M, 49±9, p<0.001). CRP(Thigh-Shank) variability diminished in the paretic limb (CRP(Thigh-Shank/SD), P, 18.3±6.3; M, 16.1±5.2, p<0.001). CONCLUSION During gait velocity increase in hemiparesis, there is improvement of thigh-shank coordination stability in the paretic limb and of shank-foot synchronization at late stance bilaterally, which optimizes the propulsive phase similarly to healthy subjects. These findings may add incentive for rehabilitation clinicians to explore maximal velocity gait training in hemiparesis.

Botulinum toxin type B in the spastic arm: a randomized, double-blind, placebo-controlled, preliminary study.

OBJECTIVE To determine the efficacy and safety of 2 doses of botulinum toxin type B (rimabotulinumtoxinB, BoNT/B) in spastic upper limb muscles. DESIGN Randomized, double-blind, placebo-controlled trial with a 3-month follow-up. SETTING Tertiary care center. PARTICIPANTS Referred sample of adult hemiparetic patients (N=24) with disabling elbow flexor overactivity after stroke or traumatic brain injury. INTERVENTIONS Injection of 10,000U of rimabotulinumtoxinB (fixed 2500U dose into elbow flexors; n=8), 15,000U (5000U into elbow flexors; n=8), or placebo (n=8) into overactive upper limb muscles selected as per investigators discretion. MAIN OUTCOME MEASURES At 1 month postinjection, active range of elbow extension (goniometry; primary outcome); active upper limb function (Modified Frenchay Scale [MFS]); subjective global self-assessment (GSA) of arm pain, stiffness, and function; rapid alternating elbow flexion-extension movement frequency over the maximal range; elbow flexor spasticity grade and angle (Tardieu), and tone (Ashworth). RESULTS No adverse effects were associated with either BoNT/B dose. Both doses improved active elbow extension versus placebo (+8.3°; 95% confidence interval, 1.1°-15.5°; analysis of covariance, P=.028). The high dose of BoNT/B also improved subject-perceived stiffness (P=.005) and the composite pain, stiffness, and function GSA (P=.017), effects that persisted 3 months from injection. No MFS change was demonstrated, although subjects with a baseline MFS <70/100 seemed more likely to benefit from BoNT/B. CONCLUSIONS In this short-term study, BoNT/B up to 15,000U into spastic upper limb muscles, including the elbow flexors, was well tolerated and improved active elbow extension and subject-perceived stiffness.