Wallerian degeneration

ABSTRACT

The use of clinical chemodenervation, the combination of botulinum toxins and chemical neurolysis, for the treatment of spasticity has increased in recent years. The purpose of this paper is to review the literature describing neurological patients whose outcomes after chemodenervation are evaluated for utility and efficacy. In this paper, mechanisms of action, the side effects, an overview of injection techniques, the duration of benefit and its contraindications are reviewed. The selection of articles to review was based on whether chemodenervation was studied for the resolution of neurological impairments, most often spasticity. The articles reviewed ranged from single case studies to double blind placebo-controlled trials.

Applications of chemodenervation are discussed for neurological populations including diagnoses of spinal cord injury, traumatic brain injury, cerebral palsy, multiple sclerosis, Parkinson disease, and stroke. A discussion of the potential for enhancing treatment effectiveness combining physical therapy treatments with chemodenervation is presented.

INTRODUCTION

Pharmacological neuromuscular blockades such as botulinum toxins and phenol injections are collectively defined as chemodenervation. The primary goal of any pharmacological intervention is to provide the best relief of symptoms with the least side effects. Since 1989 botulinum toxin has been licensed for the use in the treatment of a small number of focal dystonias. Botulinum toxin and neurolytic blocks contribute significantly to the armamentarium of treatments available for spasticity. These interventions are used to produce focal effects rather than systemic effects that oral medications may have. Enthusiasm about their use has fluctuated over the years but these techniques remain the only nonsurgical, nonsystemic intervention for the treatment of disabling motor dysfunction such as spasticity. The mechanisms of chemodenervation are relevant to physical therapists that work with neurological patients in order to have the most successful impact on clinical care. Furthermore, physical therapists need to understand the mechanisms of these pharmacological interventions so that their patients may receive the best therapies that may augment the effects of chemodenervation. The purpose of this paper is to review the mechanisms of action, the side effects, provide an overview of injection techniques, the duration of benefit and its contraindications of chemodenervation. Addition-ally, this paper reviews the literature that evaluates the use and efficacy of chemodenervation for the treatment of neurologic patients.

MECHANISM OF ACTION OF NEUROMUSCULAR BLOCKADES

Botulinum Toxin

Botulinum toxin (BTX) is made by clostridium botulinum that produces seven serotypes:A, B, C, D, E, F, and G.1 Botulinum toxin type A (BTX-A) blocks peripheral nerve cholinergic synaptic transmission. Axonal conduction is unaffected. The toxin blocks the release of acetylcholine by binding to the presynaptic nerve ending followed by an internalization of the toxin by endocytosis thereby blocking exostosis or the release of neurotransmitter at the release sites. The mechanism for neurotransmitter blockade is not completely understood but BTX-A selectively cleaves a protein called SNAP-25 that is responsible for the fusion of neurotransmitter vesicles at the nerve terminal. The complexity of this mechanism may explain why there is a relatively slow onset of action of BTX-A. For example, spastic muscles are directly injected for the treatment of undesired movements, producing a graded musele weakness. The dosage is based on adjusted patient weight, muscle size, and desired effect. The onset of action is 24 to 72 hours although the clinical effect is seen more often in 2 to 3 days.2 The duration of effect averages around 3 to 4 months but is variable. The effect of BTX on individual nerve terminals is irreversible therefore recovery of neuromuscular control begins when nerve sprouting occurs to create new terminal formation. If symptoms recur, re-injection is necessitated.3

BTX-A is manufactured in the United States by Allergan, Inc. as Botox, and in Europe by Speywood Pharmaceuticals as Dysport,. BTX-A is packaged in vials of 100 Units, shipped on dry ice, and stored at -5°C. One unit (U) of Botox, is equivalent to enough toxin to kill 50% of 20g mice.1 One unit of Botox, is roughly equal to 3 to 5U of Dysport,. The maximal recommended dose of Botox, is 400U every 3 months to avoid developing resistance to the medication. Still about 5% to 10% of patients becomes resistant to BTX-A. In these cases, botulinum toxin type B (BTX-B) can be used.4 BTX-B is manufactured in the United States by Elan Pharmaceuticals as Myobloc,. The maximal recommended dose of Myobloc, is 25,000U every 3 months. Botulinum toxin B (BTX-B) is an antigenically distinct form of BTX, which has unique physical and clinical properties that distinguish it from BTX-A. BTX- B has been reported to have a more rapid onset, greater diffusion characteristics as well as diminished longevity compared to type A; however, studies to date are limited.5,6 Currently, BTX-B is most often used over type A when the body is resistant to type A and very high dosages are required to achieve the initial effect. It is important to note that the units used for different commercially available BTX products are not interchangeable with each other. The doses are unique to each commercial drug.

Chemical Neurolysis

Reports of the use of phenol to perform peripheral and intramuscular nerve blocks exist from the 1960s.7 Phenol and ethyl alcohol were the agents of choice prior to the introduction of the botulinum toxins. Glenn defined a nerve block as the application of a chemical to impair nerve function, either for the short term or permanently. Phenol has been used for chemical neurolysis for many years.8,9 Percutaneous block of a peripheral nerve trunk produces a chemical neurolysis and damage to the nerve by demyelinating it, thereby weakening the muscle. There is an increase risk of dysesthesias and phlebitis with more distal and deeper muscles injected with phenol.2 Alcohol can also be used for nerve blocks to produce neurolysis. Ethyl alcohol is a potent drug, causing extraction of lipids from the neuron and precipitation of proteins. One hundred percent alcohol is used which can cause edema of the Schwann cells and axons with separation of the myelin sheath. Eventually, wallerian degeneration begins without differential action on specific nerve roots.7

Phenol injections or nerve blocks are often used for their clinical effect on larger proximal muscle groups because the nerve injected often supplies multiple muscles and therefore can have a greater effect for a given dosage.10 When BTX is injected into proximal muscles, a much larger dosage is needed to have a clinical effect, based on muscle size, compared to that needed for smaller muscles. Since there is a limited safe dosage of the total BTX allowable every 3 months, the clinician can 'use up' the entire dosage on one or two larger proximal muscles. Because BTX does not destroy the nerve fibers, it is sometimes considered preferable when there is hope of recovery of the injected muscle function.11 However, if a person with spinal cord injury was not expected to have a return of function either due to the neurological completeness of the injury or the chronicity of the injury, neurolysis may be more preferred when several muscles could benefit from reduced activation. Alternatively, a combination of neurolysis and BTX may produce more desirable effects when there is significant spasticity in many muscles. However, this combination of therapies while practiced clinically, has not been studied systematically.

On et al3 conducted a preliminary study of the effect of BTX-A compared to phenol on electrophysiological tests such as the H reflex, M response, H:M ratio, and the Achilles tendon response.The H-reflex is used to determine the I-A afferent input to the [alpha]-motor neuron. The M-response is simply the signal in response to the direct stimulation of the motor nerve.3 The Achilles tendon response is the amplitude of the neuromuscular signal due to 5 consecutive taps to the Achilles tendon and evaluates the spindle mechanism that the H-reflex bypasses.

On and colleagues evaluated the afferent and efferent spinal motor pathways involved in spasticity of the ankle plantar flexors and invertors. Patients were either injected with 400U of BTX-A or 3 ml of 5% phenol. The authors demonstrated that the greatest change in the Achilles tendon response was due to BTX-A and a reduction in the M response was due to phenol, both of which correlated with clinical recovery as measured by the Ashworth12 scale of spasticity severity. The conclusion was that the BTX-A decreased spasticity by affecting the fusimotor system and muscle spindle whereas the phenol decreased spasticity by affecting the a-motor fibers within the fusimotor system. Therefore, the authors concluded that the two agents have the capability of correcting different pathological disturbances. Understanding the different effects that these agents have on the neurophysiological pathway may help direct with rehabilitation interventions.

Potential Side Effects of Chemodenervation Treatment

Side effects are pain with injection, hematoma, and transient fatigue or nausea.1 Intramuscular injections can be painful and a burning sensation can follow the injections for around 24 hours. Lidocaine can be used to reduce this effect. Other complications include phlebitis, permanent nerve damage, muscle necrosis, and systemic effects.13 Dysphagia has also been reported to be a side effect of BTX in the treatment of cervical dystonia presumed to be related to toxin diffusion from an injection into the sternocleido-mastoicl muscle.14 Some patients after numerous injections of BTX may develop antibodies, thereby rendering the injections ineffective. However, if only the minimum doses of 400U are used and injections are given at 3 month intervals, this can be minimized. Swelling can occur at or around the injection site, especially if given in the lower leg. This effect can be minimized if the injection is followed by the application of a cold compress and an elastic wrap.

If a nerve trunk is selected for neurolytic injection, to produce a more complete block of muscle activity, there is more risk of partially involving the sensory nerves causing dysesthesias. Where there is complete sensory loss such as in spinal cord injury (SCI) with American Spinal Injury Association (ASIA) A15 classification, complete neurolysis may be less risky in producing dysesthesias. Treatments of dysesthesias include oral steroids, tricyclic antidepressants, carbamazepine, gabapentin, transcutaneous electrical nerve stimulation (TENS), or a repeat block.11 A repeat block may be helpful because the dysesthesia may be secondary to an incomplete initial block of sensory fibers. If pain is severe and unremitting, a course of steroids may be indicated.16 Chemical neurolysis with alcohol or phenol is often unsuccessful when the procedure is repeated more than a few times theoretically because of fibrous tissue formation at the injection.17

Weakness is the most common adverse effect with the use of BTX. The toxin does spread to neighboring muscles and possibly into the central nervous system via retrograde transmission. This may be an important concern when larger muscles are injected that may be needed for functional tasks. Therefore, it is important when considering treatment with BTX, that loss of muscle function will not limit functional capacity. For example, in the quadriceps group, injection of the rectus femoris may decrease knee extension during the swing phase of gait while still preserving knee extension during stance through the action of the other rccti. Due to potential loss of hip flexion after injection of the rectus femoris, sufficient strength of the iliopsoas muscles must be available to compensate.

Hyman et al18reported the 2 most frequent adverse events of patients treated with Dysport were hypertonia (new or worsening spasticity after the drug wears off) of injected and/or noninjected muscles, and weakness of non-injected muscles, due to spread of the drug. The authors report however, that this could have been attributed to the normal variation of the disease-state in the study sample (multiple sclerosis).

Contraindications

Clinical experience indicates that caution should be used when performing injections on patients who are on anticoagulation therapy due to the potential bleeding at the injection site. Better safety in injecting BTX with patients on anticoagulation therapy may be in monitoring clotting rates within a 2-week period prior to injection. Another factor to consider is if patients already demonstrate significant weakness or flaccidity. Mild weakness may be overshadowed in spastic patients thereby making it difficult to assess. Chemodenervation could further weaken these muscles potentially reducing function. Therefore, other muscles must be capable of compensating for the functional control of the muscles weakened by BTX injections. Finally, if there are joint deformities or restrictions located where the muscle to be injected crosses, there will likely be few gains. Reducing muscle spasticity cannot increase limb mobility if the restriction is primarily orthopedic in nature. Additionally, it is in the author's experience, as this is yet unsubstantiated in the literature, that where there is significant muscle shortening that is chronic in nature, the mobility gains from chemodenervation will be more protracted compared to when there is limited muscle shortening or spasticity is more short term in duration.

INJECTION TECHNIQUES

Botulinum toxin

BTX should be diluted with preservative-free 0.9% saline solution and used within 4 hours. Dilution, needle size, and injection sites per muscles vary according to clinician preference. BTX injections can be guided by muscle palpation, with electromyographic (EMG) or by using electrical stimulation using a Teflon-coated needle.19 Some have suggested that injecting near the motor endplate produces greater denervation20 but these areas can be difficult to locate due to variability of location/ EMG obtained during gait analyses can guide future injection sites, especially during complex activities such as gait to identify where muscles are overactive. Deeper muscles or muscles not under volitional control can demonstrate improved clinical benefit when identified with electrical stimulation.21,22 Typically when the needle is inserted to locate the muscle using electrical stimulation, the same site is used for the insertion of the needle for BTX injections.

Neurolytic Blocks

Injection of phenol and alcohol chemoneurolysis requires much greater skill than the use of botulinum toxins and a more cooperative patient. The injection techniques for ncurolytic blocks also use small portable stimulators. The anode is attached behind the limb and the cathode is a hollow Teflon-coated needle attached to the stimulator. The bare needle tip serves to localize the stimulation site attached to which is the neurolytic agent, such as phenol or alcohol. The needle is directed toward the nerve trunk or at an electrically active site. In locations where the current can be reduced to approximately 0.5mA while still producing a palpable contraction, the phenol is then injected.7 Initially, after the limb is injected, it may be erythematic and warm due to the sympathetic block in the nerve distribution. The sites of neurolytic blocks could include mixed sensorimotor nerves such as the musculocutaneous nerve to decrease elbow flexion and the median nerve to decrease finger flexion. Other examples include injection of the obturator nerve to decrease hip adduction, the sciatic nerve to address the hamstrings and the tibial nerve to decrease clonus and equinus at the ankle.8 The clinical implications of these sites are either to improve hygiene or functional mobility.

Motor Points

Muscle motor point injections are more time consuming and less effective than nerve trunk blocks.7 The difficulty lies in the multiple end plate zones that most muscles have. It is unlikely that enough zones can be targeted to result in a significant decrease in tone.23 Motor point blocks are performed lower down on the nerve terminal trunk where only fibers that control activity will sustain an effect.8 Therefore, a more graded response can be obtained than with a nerve block. These injections are useful if total reduction in elevated tone is not desired. In addition there is little risk of side effects such as dysesthesias.

Motor point blocks can he combined with nerve trunk blocks for improved results. For example, the brachioradialis muscle can be affected by a phenol block in conjunction with the musculocutaneous nerve to maximize elbow extension. Motor points are identified by surface stimulation so higher stimulation levels are needed than are for phenol blocks where stimulation is rendered through a needle. Physical therapists may treat patients who have had motor point blocks alone or in combination with phenol blocks depending on the severity of spasticity. This may serve as an opportunity to introduce strengthening or motor control strategies, or the fitting of an orthosis prior to the return of spasticity some weeks to months after the initial injections.

Local anesthetics can allow for the evaluation of the effects of chemodenervation by providing a temporary block of muscle activity. Local anesthetics prevent the influx of sodium ions at the nerve axon, preventing depolarization. Short-acting agents such as lidocaine used for a peripheral nerve block have approximately a 60-minute duration of action and a 5-minute time of onset. The longer-acting agents such as bupivacaine may last 4 to 8 hours and a 10 to 20 minute time of onset.24 This approach can be useful in determining the effect of planned chemodenervation or tendon surgeries. Temporary blocks can be an important diagnostic tool because they allow for careful analysis of the contributors to functional gait that if permanently blocked might result in loss of function. Additionally, temporary blocks allow for better control of the limb during serial casting procedures. The decrease in hypertonus permits therapists to position the limb optimally for better cast tolerance and skin protection.7

Duration of Benefit

The benefits of BTX are reversible and slowly wear off. Therefore, treatment has to be repeated. The duration of action of BTX appears to be approximately 2 to 4 months. Snow et al25 concluded from their double-blind placebo-controlled cross-over study that the duration of response in their spastic patients to be 2.4 months and in their rigid patients was 3.4 months. As expected, the duration of benefit of neurolytic blocks depends on the agent, the skill of the practitioner, good localization of the anatomy, and the etiology of the muscle tone. The range of results for phenol is between a few months to over a year, depending on these factors. Halpern et al have reported that 'good' and 'fair' relief of hypertonus lasted 4 to 6 months.9

CLINICAL APPLICATIONS OF CHEMODENERVATON

Spasticity

Stroke, brain injury, SCI, neurodegenerative diseases, and multiple sclerosis (MS) may all cause upper motor neuron deficits that result in spasticity. Spasticity leads to functional impairments and can cause increases in energy requirements necessary for movement.26 The manifestations of spasticity may depend on the location, extent, and chronicity of the brain injury or SCI. Intramuscular injections of BTX-A have been found to produce reduced extremity muscle tone of neurologically injured patients, including those with multiple sclerosis (MS),25,27 cerebral palsy (CP),28,29 cerebral vascular accident (CVA),30-32 traumatic brain injury (TBI),33-35 Parkinson disease (PD),36 and other chronically spastic patients.25,28-44

Richardson et al45 conducted a randomized placebo-controlled trial of BTX-A in the upper and lower limbs for the treatment of focal hypertonia. The investigators evaluated 52 adults with focal hypertonia, including patients with stroke, head injury, incomplete SCI, tumors, and CK The authors identified improvements with the Ashworth scale of spasticity severity, passive range of motion (ROM), motor scores, and subjective ratings of severity. This underscores the notion that BTX can alleviate spasticity regardless of its etiology. Moore46 conducted a review of evidence from uncontrolled trials and randomized controlled trials in the use of BTX-A for spasticity in adults. Moore concluded that BTX appears to work whatever the cause but is especially effective in treating focal spasticity using specific injection sites. According to Moore, BTX-A may reduce the need for systemic drugs and may best be combined with other therapies.

In the cases where functional recovery cannot be reasonably be respected, BTX has been demonstrated to be efficacious in increasing mobility to improve personal care and hygiene. For example, 2 placebo-controlled randomized double blind studies have indicated that a reduction of adductor spasticity through the use of botulinum toxin allowed for improved hygiene in the genital region.18,25 Other authors have indicated that there has been an improvement in hand hygiene when positional flexor spasticity through open-label studies of botulinum toxin47 including its use for a nonfunctional arm affording ease of dressing.48,49

Spinal cord Injury (SCI)

Spasticity is one of the most disabling complications affecting individuals with SCI.11 Despite the prevalence of spasticity in SCI, there is a paucity of studies evaluating the effect of BTX. Spasticity after SCI can include extensor spasms, flexor withdrawal spasms, and clonus with the variability being due to degree of completeness of injury. Spasticity tends to be more severe the more motor incomplete the injury is.50 Keren et al51 found that injection of 200 to 300 units of BTX into the lower limbs for the improvement of gait was effective in reducing spasticity in SCI patients, with some subjective feelings of improved well-being. However he concluded that both a more objective measurement and larger drug dose might show greater functional improvements.

Al-Khodairy and colleagues52 conducted a single case study of a person with T12 SCI who received 8 treatments with BTX-A to reduce painful lower limb muscle spasms. BTX-A produced a significant reduction in spasticity measured by the Ashworth scale of spasticity severity and spasm frequency measured by the spasm frequency scale and had significantly less pain measured by a visual analogue scale (VAS). From a quality of life point of view, the patient was able to reduce any remaining oral medications and was finally able to sleep undisturbed by flexor spasms.

Several studies evaluated global spasticity in mixed neurological populations including patients with SCI. Grazko et al36 conducted a double blind placebo-control crossover study of 12 patients with spasticity and rigidity, 2 of which were patients with SCI. The patients demonstrated an improvement by 2 grades on the Ashworth scale of spasticity severity and one patient demonstrated significant reduction in painful spasms. Pierson et al54 evaluated multiple diagnostic groups using BTX-A for the treatment of spasticity. Only 3 of the 39 patients studied had a SCI, 2 of which had received BTX-A in the upper limb and 1 in the lower limb. Two of the 3 subjects demonstrated a 1.5 point improvement in spasticity as measured by the Ashworth scale of spasticity severity. Unfortunately, these studies are either case reports or studies of small sample sizes. Further research is needed in the area of randomized controlled clinical trials that demonstrate improvements beyond the impairment level of measurement to demonstrate the functional benefits of BTX in SCI.

Traumatic brain injury (TBI)

There is limited research conducted on the effects of chemodenervation of patients with TBI. Wilson et al53 performed a 3 Dimensional (3D) gait analysis on a single subject with spasticity who received BTX in the ankle plantarflexor. The subject demonstrated improved kinematic angles, such as knee extension and ankle dorsiflexion throughout the gait cycle. Additionally, increased stride time and gait velocity was exhibited. No changes in passive ROM were noted. The authors also reported a high reproducibility of the 3D kinematics between trials showing that the methodology may be useful in detecting clinically meaningful changes. However, no EMG profiles were captured to detect changes in kinematics due to predictable changes in muscle patterns. This study would indicate the potential for improvements in joint angles during gait that led to functional gains in walking speed.

Dengler et al34 did evaluate the use of BTX in spastic foot drop of individuals with brain injury. While passive ROM did improve in a non weight bearing condition, the only functional task assessed was standing to determine if the heel of the originally plantarflexed foot made contact with the floor after injections. Six of the 10 made contact with the floor or improved in the proper direction. Two already had good floor contact prior to injection and 2 did not improve. The authors reported that the physiotherapists indicated that therapy was 'easier' after injection and there was a subjective improvement in stance and gait. This study may indicate the possible benefits of chemodenervation in more severe TBI to ease mobility training by physical therapists during rehabilitation due to an improved plantigrade position.

Yablon and colleagues47 studied the effect of BTX on upper limb spasticity in 21 patients with TBI, categorized as either acute or chronic. Chemodenervation combined with physical therapy exercises such as passive ROM exercises and modalities. Range of motion significantly improved and spasticity was significantly reduced as measured by the Ashworth scale of spasticity severity. Unique to this study was the injection of the same muscles across all participants and the evaluation of BTX-A in combination with adjunctive therapy on improving spasticity related impairments. Unfortunately, there was no control group or blinded evaluators ensuring unbiased measurement however the study demonstrates significant potential in improving upper limb impairments of individuals with TBI after chemodenervation.

Pierson and colleagues54 evaluated 39 patients who had received BTX for improvements in functional activities using a retrospective analysis. The majority of the patients whose study outcomes were reviewed were brain injured, either traumatic or vascular. Both upper and lower limbs were injected with the treatment goals to improve hygiene, positioning, and brace tolerance. Objective improvements in ROM and Ashworth scale of spasticity severity scores were noted as well as improvements in brace tolerance. Due to the retrospective nature of this study, it is unclear whether clinical biases may have been introduced or whether subject selection criteria were consistent. Despite the range of severity of spasticity and duration since time of onset, objective improvements were noted. In may be concluded that chemodenervation can improve static positioning in TBI that may aid the physical therapists' ability to focus on training of mobility tasks and activities of daily living. In general, the paucity of evidence to support the use of chemodenervation indicates the potential benefit in improving gait, brace tolerance, positioning, and hygiene. Further research is needed to determine functional benefits with larger sample sizes and control group comparisons.

Cerebral palsy (CP)

BTX-A has been studied for its application in CP Wissel et al29 evaluated 2 doses, a high dose and a low dose, of BTX-A in a randomized double-blind study of children and teenagers with spastic gait. The authors examined muscle tone assessed by the Ashworth scale of spasticity severity of the quadriceps, knee and ankle ROM, gait parameters, and subjective measurements of improvement. Both dosage groups demonstrated significant improvement in muscle spasticity, and knee ROM but significantly only for the high dose for ankle ROM, gait velocity, and stride length after injection. However, 200U of BTX-A distributed to 4 to 5 muscles per leg was better than 100U without significant side effects. This study implies a functional benefit to chemodenervation in patients with CP, particularly in the area of gait and subjective perception of improvement. Corry and associates41 found modest improvement in gait patterns measured with a 3D gait analysis system, in children with CP after BTX injections to the hamstrings. Knee joint angles improved during gait, which was associated with increased patient satisfaction. However, the mean pelvic tilt increased indicating caution using isolated hamstring injections.

Metaxiotis et al55 found consistent improvements in gait parameters and equinovarus foot deformities after the injection of BTX to the calf muscles of 21 children with CR Koman et al28 conducted a randomized controlled, double-blind placebo-controlled clinical trial on BTX-A for lower limb spasticity in CE One hundred fourteen children with dynamic equinus foot deformity were evaluated using a Physician Global Rating Score of the dynamic gait pattern, ankle ROM, and nerve conduction. The physician rating scale is an ordinal scale of overall gait pattern, hind foot and knee position in stance, degree of crouch, and gait speed. The higher the score, the better the outcome chemodenervation for pediatric gait. Approximately 50% to 60% of the children in the BTX group demonstrated significantly higher physician rating scores (specifically the ankle component of gait), ROM (increased between 3-7 degrees), and a significant reduction in the M response. Spastic diplegic vs. hemiplegic patients responded similarly, despite the fact the children with hemiplegia received twice the dosage in the gastrocnemius as did the children with diplegia, in order to receive the same total dosage across study participants. The changes in the M-response indicated partial chemical denervation of the injected muscle as expected. The lack of evidence in the H-reflex, an electrically stimulated form of the muscle stretch reflex, indicates that the potential direct central or sensory mechanisms through the alteration of muscle spindle activity were not found. Similar to the On et al study,3 the H response was altered only with the phenol and not with BTX. These electrophysiological results indicate the denervation goal was achieved in the muscles injected locally. The results from this study imply that BTX for CP may be beneficial to improve gait based on observational changes in both hemiplegia and diplegia.

Multiple sclerosis (MS)

Snow et al25 conducted a randomized cross-over placebo-controlled double-blind clinical trial of the effect of BTX type A on leg adductors in chair or bed-bound patients with MS. There was a significant reduction in spasticity and improvement in nursing care, with no adverse events.

Hyman et al18 studied adductor spasticity in 74 patients with severe MS using different closes of Dysport, compared to placebo. After 4 weeks, the authors found that 1500 units of Dysport, resulted in a statistically significant improvement in maximal distance between the knees indicating reduced adductor muscle tone. Muscle tone and spasm frequency also improved in the Dysport groups, though not statistically different. Importantly, request for re-treatment with BTX was significantly longer than the placebo group. Hyman recommended that the clinical close of 500 to 1000 units divided between both legs was best since the group who received 1500 units sometimes demonstrated too much weakness. One of the challenges of conducting a randomized clinical trial (RCT) is determining the effect of the intervention on patients who are receiving concurrent treatments. In this study, participants were asked to maintain a constant dose of oral antispastic and analgesic medications and continue with physiotherapy throughout the study period. Despite these concurrent treatments a benefit in muscle tone was still evident.

Grazko et al36 studied 12 patients with spasticity and rigidity, 5 of whom had the diagnosis of MS. The study was a double-blind placebo-controlled crossover trial with BTX. Spasticity in the lower limb muscles decreased by at least 2 grades on the Ashworth scale of spasticity severity. BorgStein et al27 evaluated 2 patients with clinically definite MS who had a stable clinical course over the last several months. Improvements were noted in muscle tone of the injected (adductors of the hip) and noninjected muscles, leading to some disruption of function. The authors correctly point out the limitations of the lack of controls in this study but describe the potential for the use of BTX in MS, even if it is of the relapsing-remitting type. There appears to be substantial evidence that the use of chemodenervation does appear to improve adductor spasticity thereby improving positioning in MS. Further research is needed to determine the adequacy of chemodenervation for functional mobility in patients with MS.

Parkinson disease

Giladi and Honigman56 studied a single case of BTX injection into one leg of a patient with Parkinson disease (PD) to alleviate freezing of gait. The freezing of gait was determined to have been due to focal foot dystonia. After injections to the extensor hallicus longus and gastrocnemius, the patient reported almost complete reduction in gait hesitation. These preliminary results support the potential for the use of BTX for patients with PD especially when the primary complaint is the 'freezing' phenomenon or when medications have either lost their effectiveness or produce dyskinesias when dosages are increased. To the author's knowledge, this appears to be the only study investigating the use of chemodenervation in patients with PD but demonstrates the need and potential for future research in this area.

Stroke

Hesse and associates31 studied 12 chronic hemiparetic patients using electronic goniometry and EMG, and found that approximately 75% of these patients demonstrated a more normal temporal pattern of muscle activity with a prominent reduction of the premature activity of the plantar flexors. The authors indicated that stretch reflex excitability resulting in premature calf muscle activation, evidenced by observation of EMG patterns, was predictive of a positive outcome after the use of BTX. This effect was most notable during the midstance phase of gait with a lesser effect at heel contact. The authors attribute this difference to the position of the foot at heel contact (plantigrade vs forefoot) when stretch reflex excitability threshold is less sensitive. Therefore, the relative decrease in muscle firing is less improved because it is less evident in the first place due to improved foot positioning after injection. Several patients did not change or even worsened in their kinematic EMG patterns. The authors attributed these findings to structural changes in the muscle since these individuals exhibited chronic spasticity.

Hesse and colleagues57 also noted improvements in vertical ground reaction forces gait velocity, stride length, stance symmetry, and center of pressure profiles after BTX injections for extensor spasticity in chronic hemiplegic subjects. Gait velocity improvements were deemed clinically significant, as the increases were greater than 25%.58 Step length and stride length were reported to have improved due to reduced plantar flexor activation allowing for greater forward progression and improved weight acceptance.

Das and Park59 studied 6 patients with poststroke hemiplegia and found both subjective and objective improvements in the upper limb as a result of chemodenervation. There was significant improvement in the elbow and wrist ROM and there was an overall improvement in self care and mobility skills as measured by the Barthel index. Brashear et al60 performed a placebo-controlled clinical trial of 126 poststroke patients with upper-limb spasticity. The injections produced a significant decrease in wrist and finger muscle tone as measured by the Ashworth scale of spasticity severity, especially at week 4 of a 12-week protocol. Improvements in function also were noted, as measured by the disability assessment scale.

Simpson and colleagues61 conducted a multicentered, randomized, double-blind, placebo-controlled trial of 3 doses of BTX on spasticity in the upper limbs of 39 stroke patients. The Ashworth scale of spasticity severity ratings and global rating scores improved significantly in the high and low dose groups but not in the middle dose group 4 and 6 weeks after injection. There was no significant improvement in ROM and functional scales. This raises the possibility that BTX reduces spasticity but may not improve function, but the authors point out that the lack of change in the functional and ROM measures may have been due to the chronicity of the study sample. Additionally, the study design required injections into the same muscles across subjects, which may not have been optimal in all cases. While difficult to study systemically, injections based on patient-specific deficits are likely to produce more significant improvements.

Sampaio et al32 studied focal arm and hand spasticity of 19 stroke patients in a phase III open label clinical trail using BTX. There was a significant improvement in the Ashworth scale of spasticity severity and the Frenchay Arm Test but two-thirds of the patients rated their functional improvement as none or mild. Perhaps the upper limb is another location for physical therapists to evaluate the effectiveness of combined therapies with chemodenervation to evoke the greatest functional change. Overall, there appears to be evidence supporting the efficacy of chemodenervation for the upper and lower limbs for patients with a CVA. Primarily the factors that appear to improve the most are the temporal-spatial characteristics of gait, elbow and hand ROM, and self-care activities.

Focal dystonia

The use of BTX for focal dystonia originated because ophthalmologists used it for the treatment of blepharospasm, which was the first focal dystonia treated with the toxin.43 Cervical dystonia is a focal dystonia affecting the neck muscles. The BTX is considered a favorable treatment for dystonias because therapeutic weakness can be induced with the specific muscles involved in the dystonia. There have been a number of double-blind randomized trials that have demonstrated the value of BTX in the treatment of cervical dystonia.22,62,63 Several authors14,64,65 reported a significant improvement in pain associated with the motor improvements of patients with cervical dystonia. The authors suggest that the pain associated with muscle over-activity may be alleviated by BTX. Neurological physical therapists who treat patients with cervical dystonia with ROM and strengthening exercises but who have difficulty in relief of pain, may recommend BTX therapy.

Pain

Pain can be associated with disorders treated by neurological physical therapists. Lang66 conducted a focused review on the treatment of chronic pain disorders using BTX type A. The effects of pain reduction may be explained by inhibition of inflammatory pain through the prevention of local sensitization of nociceptors, although this mechanism has not formally been established. Barwood et al67 conducted a double-blind randomized placebo-controlled clinical trial of 16 patients who had spasticity due to CP and had undergone adductor surgery to release the muscle for the prevention of hip dislocation. The study intended to evaluate the use of BTX preoperatively in the reduction of pain due to muscle spasm after surgery. In the BTX group, there was a reduction in pain severity, compared to the placebo group and a reduction in the analgesic requirements and length of stay.

Dunne et al39 also evaluated the effects of BTX-A on 40 patients with severe spasticity of both upper and lower limbs. Ninety percent of the participants demonstrated a reduction of pain some of which were associated with improved function. This study was an open study where there was no placebo or control group with whom to compare the results; however, the outcome variables were evaluated based on blinded clinical videotapes. The authors also noted that the degree of improvement did not correlate with the duration of spasticity, presuming the limitations in mobility were not due to fixed contractures. Wissel et al29 also found a reduction in pain in 90% of 60 patients with acute and chronic spasticity in a multicenter open clinical trial.

Wheeler et al68 conducted an open-label retrospective study of changes in pain as a result of BTX-A injections in 44 patients with myofascial pain syndrome. The authors found that 80% of the patients reported reduced pain and nearly OO of the patients had required more than one injection. This supports their earlier randomized double-blind prospective pilot study69 where clinical improvement of pain responses increased dramatically when given a second injection. Lang66 reported an 'excellent' or 'good' physician global rating score for 65% of the treatments for myofascial pain syndrome using a unique injection technique.

Fishman et al70 conducted a double-blind placebo-controlled clinical trial of 67 patients with piriformis syndrome diagnosed with a positive FAIR (flexion, adduction, internal rotation) test.71 This test is a validated test positioning the leg in hip flexion, adduction, and internal rotation. The authors evaluated subjective pain responses before and after BTX injections vs. lidocaine with steroid, vs placebo. Using a visual analogue pain scale, 65% of the patients who received BTX improved at least 50% vs 32% improved from lidocaine and steroid vs 8% improvement in the placebo group.

Interestingly, Grazko et al36 studied 12 patients with spasticity and rigidity, one of whom suffered from pain due to paraspinal spasms. The study was a double-blind placebo-controlled crossover trial with BTX administered to the L1-L5 paraspinal muscles 4 times every 3 months. While the authors noted that it was difficult to assess paraspinal tone, the spasms decreased by 2 grades on the spasm frequency scale, responding positively in the same way at each 3-month injection period.

Other therapeutic applications

Botulinum toxin has been evaluated in a variety of other disorders such as detrusor hyperreflexia or dyssynergia. This problem is common in SCI where urinary retention can lead to other problems such as autonomie dysreflexia, urinary tract infection, and renal damage. Dykstra et al72 conducted a double blind placebo-controlled trial to evaluate reduction in outflow constriction as a result of BTX injections. The BTX was found to be effective in improving urodynamics in 5 patients. Wheeler et al69 evaluated 3 patients with SCI with voiding dysfunction. Two of the patients improved in voiding residuals and catheterization ease; however, one required a sphincterotomy. The authors concluded that due to the procedure being minimally invasive and without side effects, BTX is an excellent treatment method for managing voiding dysfunction especially for those who refuse or who are ineligible for surgery.

EFFECT OF COMBINED THERAPIES

Moore46 indicates that the toxin cannot treat widespread spasticity on its own and is best combined with other types of therapy. Clinical experts73 have reported that results of BTX are best when combined with physiotherapy and oral antispasticity medication. Electrical stimulation has been reported to improve the action of BTX in patients with leg spasticity74 and those with arm flexor spasticity after stroke.75 Physical therapists are key members of the neurological team to help determine goals and interventions to enhance functional outcomes. For example, if the spasticity is under greater control, it may allow for the use of stretching, strengthening and neurofacilitation techniques to be more successful. Serial casting or electrical stimulation may also be more successful when the spasticity is under control allowing for a better fit or elimination of an orthosis. Effective collaboration of physical therapists and occupational therapists can also enhance recovery, particularly when involving the upper limb.76 Phenol and BTX can be used together, although it is recommended to allow time between these two treatments to prevent phenol neutralization of BTX. Gormley et al26 reports experience with these combined treatments and indicates that the BTX dose may be lower with concurrent phenol denervation.

Boyd and Graham77 suggested that BTX administered in conjunction with physical therapy may improve patient outcomes. For example, Fehlings et al,78 reported that in patients with CP where BTX was combined with therapy, there was a significant functional improvement compared to therapy alone. According to Gracies and associates,10 shortening of a muscle increases spindle sensitivity and spasticity. Therefore BTX can relax the muscle to allow for muscle lengthening that could be further enhanced by physical therapy interventions. Lang66 recommended adjunctive physical therapy to improve outcomes of patients treated with BTX-A.

DISCUSSION AND RECOMMENDATIONS

The purpose of this paper was to review the pharmacology of chemodenervation, including botulinum toxins and chemical neurolysis. Further background on the side effects, injection techniques, duration of benefit and contraindications was provided. Finally, a summary of the scientific evidence of the applications of chemodenervation for neurological disorders was presented. There are limitations in the available literature supporting the use of chemodenervation for neurological disorders. The literature can be more seriously considered to be valuable when looking at randomized clinical trials compared to open studies but these too are fraught with differing indications, differing dosages, and injection techniques. Controlled trials are needed to test dosing, injection techniques and sites, and follow-up of outcome measures with detailed descriptions of subject characteristics. This avoids the over generalization of specific study samples to the general population of the disability group. Other difficulties arise when pooling data to form conclusions of effectiveness are the heterogeneity of the patients studied, different muscles being injected, and the interactions of other interventions.46 To date there are no long-term randomized clinical trails evaluating the effectiveness of BTX for spasticity.

Additional reasons for the possible lack of effects of BTX in nonresponders include inadequate dose, poor injection technique, muscle weakness or atrophy, errors in drug reconstitution, and the development of antibodies.52 Future studies need to address these factors as well as the research design and reporting of research findings. Furthermore, chemodenervation needs to be evaluated for its potential to delay the need for other interventions, improve the effectiveness of existing interventions, and to reduce the overall cost of clinical care.

Physical therapists treating patients with neurologic disorders may encounter patients who have received or are being considered for chemodenervation. Evidence is presented that indicates the benefits of chemodenervation to improve bed and wheelchair positioning, gait, and upper limb ROM and function. Physical therapists who are involved in the selection process of patients who may be considered for chemodenervation should consider whether positioning or function is the goal, whether injection-induced paresis will result in loss of important functional skills needed for activities of daily living. Physical therapists also should evaluate the adequacy of the remaining agonist muscles in maintaining function or the potential spasticity or weakness of the antagonist muscles that might be exaggerated after chemodenervation. Additionally, physical therapists should assist in the evaluation of the impact of systemic pharmacological agents on patient performance. If these agents are either no longer effective or are producing undesirable side effects, local injections may be considered for more desirable functional benefits.

There are no ideal measures available for quantifying spasticity but physical therapists may choose to use validated scales, such as the Ashworth scale of spasticity severity, to assess their patients before and after chemodenervation. It is also important to recognize that initial dosages may not produce ideal results and subsequent injections are often adjusted based on improvements in spasticity reduction from the initial injection. Finally, physical therapists should evaluate the effects of a combination of strengthening, electrical stimulation or stretching/casting, and chemodenervation on the reduction of impairments and improvement of function and community participation for neurologic patients.

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Sue Ann Sisto, PT, MA, PhD

Director, Human Performance and Movement Analysis Laboratory, Research Department, Kessler Medical Rehabilitation Research and Education Department, West Orange, New Jersey (ssisto@kmrrec.org)

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