Botulinum toxin A in cerebral palsy: Functional outcomes

Abstract

See related article, p. 331. In developed countries, cerebral palsy is the most common cause of childhood physical disability with an incidence of about 2.0 to 2.5 per 1000 live births.1Miller G. Cerebral palsies: an overview.in: The cerebral palsies, causes, consequences and management. Butterworth-Heineman, Boston, Oxford1988Google Scholar, 2Stanley F Blair E Alberman E. Clinics in developmental medicine No. 151. Cerebral palsies: epidemiology and causal pathways. MacKeith Press, London2000Google Scholar The spastic motor type is the most common, comprising about 80% of reported cases.1Miller G. Cerebral palsies: an overview.in: The cerebral palsies, causes, consequences and management. Butterworth-Heineman, Boston, Oxford1988Google Scholar, 2Stanley F Blair E Alberman E. Clinics in developmental medicine No. 151. Cerebral palsies: epidemiology and causal pathways. MacKeith Press, London2000Google Scholar Spasticity is an important feature of CP because it contributes to impairment of function and reduced longitudinal muscle growth. Reduced muscle growth in turn leads to fixed contractures and progressive musculoskeletal deformity. Spasticity is one of the positive features of the “upper motor neuron” syndrome and is associated with co-contraction, clonus, and hyperreflexia. The negative features of the upper motor neuron syndrome (weakness, loss of selective motor control, and sensory impairment) are also important and may have a greater impact on function and prognosis than the positive features.3Lance JW. Symposium synopsis.in: Spasticity: disordered motor control. Symposia Specialists, Miami1980: 485-494Google Scholar Although some studies suggest that spastic diplegia is the most common topographical type of juvenile CP, hemiplegia may have lower ascertainment than diplegia or quadriplegia in CP registers.2Stanley F Blair E Alberman E. Clinics in developmental medicine No. 151. Cerebral palsies: epidemiology and causal pathways. MacKeith Press, London2000Google Scholar Hemiplegia is very common, and management of the associated motor problems is time-consuming and costly. There are very few clinical trials examining the efficacy of intervention in this important group of children.4Corry I Cosgrove A Walsh E McClean D Graham H. Botulinum toxin A in the hemiplegic upper limb: a double-blind trial.Dev Med Child Neurol. 1997; 39: 185-193Crossref PubMed Scopus (226) Google Scholar In the last 20 years, several management tools for spasticity have been introduced, including pharmacologic agents and surgical procedures.5Pirpiris M, Graham HK. In: Barnes M, Johnston G, editors. Clinical management of spasticity in children. Cambridge: Cambridge University Press. In press.Google Scholar The inter-relationships of these tools, their indications, and the expected outcomes are not yet established. When spasticity is severe and generalized and refractory to oral medication, physical therapy, and splinting, invasive options may be considered. Selective dorsal rhizotomy is a neurosurgical procedure in which a percentage of the dorsal rootlets of the lumbar spinal nerves are sectioned, resulting in a dramatic and permanent reduction in lower limb spasticity.6Peacock WJ Staudt LA. Spasticity in cerebral palsy and the selective posterior rhizotomy procedure.J Child Neurol. 1990; 5: 179-185Crossref PubMed Scopus (63) Google Scholar SDR is most often used for spasticity management in children who have moderately severe spastic diplegia with the aim of improving walking. Randomized, controlled clinical trials, comparing the functional outcomes of SDR combined with physical therapy and physical therapy alone have been inconclusive.7Steinbok P Reiner AM Beauchamp R Armstrong RW Cochrane DD Kestle J. A randomized clinical trial to compare selective posterior rhizotomy plus physiotherapy with physiotherapy alone in children with spastic diplegic cerebral palsy.Dev Med Child Neurol. 1997; 39: 178-184Crossref PubMed Scopus (172) Google Scholar, 8Wright V Sheil E Drake J Wedges J Naumann S. Evaluation of selective dorsal rhizotomy for the reduction of spasticity in cerebral palsy: a randomized controlled trial.Dev Med Child Neurol. 1998; 40: 239-247Crossref PubMed Scopus (159) Google Scholar, 9McLaughlin JF Bjomson KF Astley SJ Graubert C Hays RM Roberts TS et al.Selective dorsal rhizotomy: efficacy and safety in an investigator-masked randomized clinical trial.Dev Med Child Neurol. 1998; 40: 220-232Crossref PubMed Scopus (161) Google Scholar The largest study showed no additional functional benefit from the addition of SDR to a physical therapy program.9McLaughlin JF Bjomson KF Astley SJ Graubert C Hays RM Roberts TS et al.Selective dorsal rhizotomy: efficacy and safety in an investigator-masked randomized clinical trial.Dev Med Child Neurol. 1998; 40: 220-232Crossref PubMed Scopus (161) Google Scholar SDR is not used in children with hemiplegia, but there may be an incidental improvement in upper limb function after SDR in children who have spastic diplegia.10Loewen P Steinbok P Holsti L MacKay M. Upper extremity performance and self care skill changes in children with spastic cerebral palsy following selective posterior rhizotomy.Pediatr Neurosurg. 1998; 29: 191-198Crossref PubMed Scopus (39) Google Scholar Baclofen, a γ-aminobutyric acid agonist, is of limited benefit in spasticity management when administered orally, mainly because of the low concentration reaching the spinal cord.11Albright AL. Baclofen in the treatment of cerebral palsy.J Child Neurol. 1996; 11: 77-83Crossref PubMed Scopus (125) Google Scholar Delivery of an appropriate dose to the cord can be achieved by continuous intrathecal administration of baclofen by an indwelling, implanted pump, controlled by a microprocessor.12Albright AL. Intrathecal Baclofen in cerebral palsy movement disorders.J Child Neurol. 1996; 11: 529-535Google Scholar Intrathecal baclofen has useful but incidental effects on upper limb spasticity.13Albright AL Barry MJ Fasick MP Janosky J. Effects of continuous intrathecal Baclofen infusion and selective posterior rhizotomy on upper extremity spasticity.Pediatr Neurosurg. 1995; 23: 82-85Crossref PubMed Scopus (59) Google Scholar ITB results in a reversible, controlled reduction in spasticity, improved muscle extensibility, improved joint range of motion, and a reduced requirement for corrective orthopedic surgery.14Gerszten PC Albright AL Johnstone GF. Intrathecal Baclofen infusion and subsequent orthopaedic surgery in patients with spastic cerebral palsy.J Neurosurg. 1998; 88: 1009-1013Crossref PubMed Scopus (110) Google Scholar The effects of ITB on gait and function have not been established by controlled trials. In summary, SDR and ITB are very effective in reducing spasticity, but the evidence for improved function is equivocal. Botulinum toxin A was first used for the management of strabismus and focal dystonia including blepharospasm, hemifacial spasm, and spasmodic torticollis.15Jankovic J Brin MF. Therapeutic uses of botulinum toxin.N Engl J Med. 1991; 324: 1186-1194Crossref PubMed Scopus (729) Google Scholar It is much more suited to the management of focal spasticity than SDR or ITB, although the debate as to what constitutes focal spasticity and what constitutes generalized spasticity is not yet resolved.16Boyd RN Graham HK. Botulinum toxin A in the management of children with cerebral palsy: indications and outcome.Eur J Neurol. 1997; 4: 15-22PubMed Google Scholar In general, BTA is used when there are between 1 and 4 large muscle groups to be treated, as in the hemiplegic upper limb.17Graham HK Aoki KR Autti-Ramo I Boyd RN Delgado MR Gaebler-Spira DJ et al.Recommendations for the use of botulinum toxin type A in the management of cerebral palsy.Gait Posture. 2000; 11: 67-99Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar Intramuscular injection of BTA results in a dose-dependent, fully reversible, chemodenervation of muscle. The release of acetylcholine is blocked at the motor end plate until a process of end plate repair takes place.18De Paiva A Meunier FA Molgo J Aoki KR Dolly JO. Functional repair of motor endplates after botulinum neurotoxin type A poisoning. Biphasic switch to synaptic activity between nerve sprouts and their parent terminals.Proc Natl Acad Sci USA. 1999; 96: 3200-3205Crossref PubMed Scopus (541) Google Scholar The period of muscle relaxation typically lasts for about 3 months, although functional benefits may last for much longer.4Corry I Cosgrove A Walsh E McClean D Graham H. Botulinum toxin A in the hemiplegic upper limb: a double-blind trial.Dev Med Child Neurol. 1997; 39: 185-193Crossref PubMed Scopus (226) Google Scholar In a randomized controlled trial in the hereditary spastic mouse model, Cosgrove and Graham19Cosgrove AP Graham HK. Botulinum toxin A prevents the development of contractures in the hereditary spastic mouse.Dev Med Child Neurol. 1994; 36: 379-385Crossref PubMed Scopus (141) Google Scholar confirmed the link between spasticity and impaired muscle growth and demonstrated a beneficial effect from injecting the gastrocnemius muscle early in the growth period. Subsequent open label and randomized clinical trials established dose ranges and injection sites for the lower limb muscle groups including the gastrocnemius muscle (equinus gait), the hamstrings (crouch gait), and the hip adductors (scissoring).20Cosgrove AP Corry IS Graham HK. Botulinum toxin in the management of the lower limb in cerebral palsy.Dev Med Child Neurol. 1994; 36: 386-396Crossref PubMed Scopus (325) Google Scholar, 21Koman LA Mooney III, JF Smith BP Goodman A Mulvaney T. Management of spasticity in cerebral palsy with botulinum-A toxin: report of a preliminary, randomized, double-blind trial.J Pediatr Orthop. 1994; 14: 299-303Crossref PubMed Scopus (293) Google Scholar, 22Corry IS Cosgrove AP Duffy CM Taylor TC Graham HK. Botulinum toxin A in hamstring spasticity.Gait Posture. 1999; 10: 206-210Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 23Heinen F Linder M Mall V Kirschner J Korinthenberg R. Adductor spasticity in children with cerebral palsy and treatment with Botulinum toxin type A—the parents’ view of functional outcome.Eur J Neurol. 1999; 6: 547-550Google Scholar The first clinical trial of intramuscular BTA in the hemiplegic upper limb was reported by Corry et al4Corry I Cosgrove A Walsh E McClean D Graham H. Botulinum toxin A in the hemiplegic upper limb: a double-blind trial.Dev Med Child Neurol. 1997; 39: 185-193Crossref PubMed Scopus (226) Google Scholar in 1997. They established that parents and physical therapists could detect the beneficial effects of intramuscular BTA in the context of a double-blind trial. They also demonstrated reduced muscle tone, improved joint range of motion, and reduced muscle stiffness using a validated objective tool, resonant frequency. Functional results were equivocal, and small sample size and the lack of a validated functional outcome tool hampered conclusions in this key domain. The study by Fehlings et al24Fehlings D Rang M Glazier J Steele C. An evaluation of botulinum-A toxin injections to improve upper extremity function in children with hemiplegic cerebral palsy.J Pediatr. 2000; 137: 331-337Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar in this issue of The Journal addresses many of the unanswered questions and is a model study in this difficult area. These investigators studied 30 children with spastic hemiplegia selected from a cohort of 50 children. Children with either very mild spasticity or a dense global upper limb paresis, with no retained voluntary motor function and dense contractures, are unlikely to benefit from spasticity management and were correctly excluded from the study. After fulfilling appropriate entry criteria, children were randomly assigned to receive BTA injections to 3 different muscle groups combined with occupational therapy or occupational therapy alone. It should be noted that the selection of target muscles and the choice of the dose of toxin were made on subjective clinical grounds. This approach, while appropriate, introduces a covariable that makes analysis of outcome more difficult. Intramuscular BTA reduces muscle tone and may help reestablish a functional balance between spastic flexors of the elbow, wrist, and fingers and the relevant weakened extensors.4Corry I Cosgrove A Walsh E McClean D Graham H. Botulinum toxin A in the hemiplegic upper limb: a double-blind trial.Dev Med Child Neurol. 1997; 39: 185-193Crossref PubMed Scopus (226) Google Scholar The study period was 6 months, with evaluations at baseline and 1, 3, and 6 months. A number of traditional outcome measures were used, including the modified Ashworth scale for spasticity, grip strength by sphygmomanometer, and goniometry for passive joint range of motion. The validity and repeatability of these measures were established in earlier studies.25Glazier JN Fehlings DL Steele C. Test-retest reliability of upper extremity goniometric measurements of passive range of motion and of sphygmomanometer measurement of grip strength in children with cerebral palsy and upper extremity spasticity.Dev Med Child Neurol Suppl. 1997; 75: 33-34Google Scholar It is usually easy to achieve and to demonstrate reduced muscle tone and improved joint range of motion after injection of BTA in both the upper and lower limbs.4Corry I Cosgrove A Walsh E McClean D Graham H. Botulinum toxin A in the hemiplegic upper limb: a double-blind trial.Dev Med Child Neurol. 1997; 39: 185-193Crossref PubMed Scopus (226) Google Scholar, 20Cosgrove AP Corry IS Graham HK. Botulinum toxin in the management of the lower limb in cerebral palsy.Dev Med Child Neurol. 1994; 36: 386-396Crossref PubMed Scopus (325) Google Scholar Surprisingly, improvements in these measures were not seen in this study but were seen in the study by Corry et al.4Corry I Cosgrove A Walsh E McClean D Graham H. Botulinum toxin A in the hemiplegic upper limb: a double-blind trial.Dev Med Child Neurol. 1997; 39: 185-193Crossref PubMed Scopus (226) Google Scholar In the study by Corry et al,4Corry I Cosgrove A Walsh E McClean D Graham H. Botulinum toxin A in the hemiplegic upper limb: a double-blind trial.Dev Med Child Neurol. 1997; 39: 185-193Crossref PubMed Scopus (226) Google Scholar 2 different preparations of BTA were used; those patients who received the same preparation used in this study were treated with higher doses. This suggests that the dose of BTA in this study may have been too low. On the other hand, too high a dose may result in decreased tone and increased passive joint range of motion, accompanied by weakness that may impair, rather than improve, function. After interventions to reduce spasticity, functional gains are more difficult to achieve and are more difficult to measure than reductions in muscle tone and increased joint range of motion. Sensitive, valid tools are required and in this study the Quality of Upper Extremity Skills Test and the Pediatric Evaluation of Disability Inventory were used.26De Matteo C Law M Russell D Pollock N Rosenbaum P Walter S. Quality of upper extremity test. Neurodevelopmental Clinical Research Unit, Hamilton, Ontario, Canada1992Google Scholar, 27De Matteo C Law M Russell D Pollock N Rosenbaum P Walter S. The reliability and validity of the quality of upper extremity skills test.Phys Occup Ther Pediatr. 1993; 13: 1-18Crossref Scopus (169) Google Scholar, 28Haley SM Coster SJ Ludlow LH Haltiwanger JT Andrellos PJ. Pediatric evaluation of disability inventory (PEDI): development, standardization and administration manual. New England Medical Center and PEDI Research Group, Boston1992Google Scholar, 29Haley SM Ludlow LH Coster WJ. Pediatric evaluation of disability inventory: clinical interpretation of summary scores using Rasch rating scale methodology.Phys Med Rehabil Clin North Am. 1993; 4: 529-540Google Scholar The mean QUEST scores increased in both the control and intervention groups at all 3 study intervals, but the increases were greater in the intervention group. The QUEST score increase in the group that received BTA was statistically significantly greater at the 1-month interval than in the group that received occupational therapy alone. The differences between the intervention and treatment groups were maintained at 6 months after injection but not at a statistically significant level. This would appear to be the result of further improvements in function as the result of occupational therapy in the control group, rather than a relapse in the intervention group. However, changes in the individual QUEST score were variable, with some children doing particularly well. This suggests that responses vary depending on as yet unidentified factors, perhaps the agonist-antagonist balance. Better selection of candidates for upper limb BTA is required, as suggested by Corry et al.4Corry I Cosgrove A Walsh E McClean D Graham H. Botulinum toxin A in the hemiplegic upper limb: a double-blind trial.Dev Med Child Neurol. 1997; 39: 185-193Crossref PubMed Scopus (226) Google Scholar Functional goals should be realistic. Ranked in order of importance, the most significant prognostic factors in relation to function in the hemiplegic upper limb are sensory impairment, loss of selective motor control, and weakness, followed by spasticity. When function cannot be improved or the gains are marginal, the cosmetic problems of the hemiplegic upper limb must not be forgotten. These children are in mainstream schooling and the majority will enter employment. In the upper limb trial, the single most reported benefit was the reduction in elbow flexion posturing when walking rapidly.4Corry I Cosgrove A Walsh E McClean D Graham H. Botulinum toxin A in the hemiplegic upper limb: a double-blind trial.Dev Med Child Neurol. 1997; 39: 185-193Crossref PubMed Scopus (226) Google Scholar This had little to do with function but everything to do with cosmesis. Spasticity trials in the hemiplegic upper limb should incorporate a measure of satisfaction with the appearance of the upper limb. Many questions remain to be answered and more studies are required. Technical issues include the need for better understanding of the toxin’s behavior in large muscle groups. How far does the toxin diffuse across fascial barriers in relation to the dose and dilution used? What are the appropriate doses for each muscle group? Can the correct dose be identified by pre-injection testing or only after a preliminary test dose? How should target muscles be identified? Is manual palpation sufficient, as described by Corry et al4Corry I Cosgrove A Walsh E McClean D Graham H. Botulinum toxin A in the hemiplegic upper limb: a double-blind trial.Dev Med Child Neurol. 1997; 39: 185-193Crossref PubMed Scopus (226) Google Scholar and Fehlings et al,24Fehlings D Rang M Glazier J Steele C. An evaluation of botulinum-A toxin injections to improve upper extremity function in children with hemiplegic cerebral palsy.J Pediatr. 2000; 137: 331-337Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar or should electromyography or muscle stimulation be used? If electromyography or muscle stimulation is to be used, what are the best means of providing analgesia or sedation? What additional therapy or splinting would augment or prolong the effects of BTA injections? Given that different muscles follow a different biological clock in the transition from reversible/dynamic posturing to fixed/musculotendinous contracture, what combinations of soft tissue surgery and BTA injections are appropriate? There may also be a diagnostic role for BTA before upper limb surgery; the effects of surgery can be partially simulated by BTA injection. Many surgeons use BTA during operations to reduce painful postoperative spasms and to protect the soft tissues from involuntary movement and spasms until healing occurs.30Barwood S Baillieu C Boyd R Brereton K Low J Nattrass G et al.Analgesic effects of botulinum toxin A: a randomized, placebo-controlled clinical trial.Dev Med Child Neurol. 2000; 42: 116-121Crossref PubMed Scopus (128) Google Scholar These are practical and important issues. The use of BTA injections in the hemiplegic upper limb, combined with intelligent use of occupational therapy and splinting, should reduce deformity and improve function for many children. The importance of this study lies in the valuable information provided regarding changes in upper limb function in children who have spastic hemiplegia as a result of maturation and occupational therapy. It confirms the functional benefits of adding injections of BTA and identifies areas for further research. An evaluation of botulinum-A toxin injections to improve upper extremity function in children with hemiplegic cerebral palsyThe Journal of PediatricsVol. 137Issue 3PreviewObjective: In a randomized, controlled, single-blind trial, to test the hypothesis that botulinum-A toxin (BTA) injections into the upper extremity of children with spastic hemiplegia improve upper extremity function. Study design: Thirty children with hemiplegia, aged 2.5 to 10 years, were randomly assigned to receive: (1) a BTA injection into 1 or more of 3 muscle groups (biceps, volar forearm muscles, adductor pollicis) plus occupational therapy or (2) occupational therapy alone. Blinded outcomes obtained at baseline and at 1, 3, and 6 months included the Quality of Upper Extremity Skills Test (QUEST), goniometry measurements, grip strength, and Ashworth scores. Full-Text PDF