Journal of Pediatrics

Journal of Pediatrics
Volume 137 • Number 3 • September 2000
Copyright © 2000 Mosby, Inc.

Original Articles

An evaluation of botulinum-A toxin injections to improve upper extremity function in children with hemiplegic cerebral palsy

Darcy Fehlings MD, MSc

Mercer Rang MB, BS

Janet Glazier BSc(OT)

Catherine Steele PhD

From the Division of Neurology and General Pediatrics, Department of Pediatrics and the Division of Orthopedics, Department of Surgery, Bloorview MacMillan Centre and The Hospital for Sick Children, Toronto, Ontario, Canada.

Supported by the Easter Seal Research Institute (Kids Action Research).
Submitted for publication Oct 13, 1999.
Revision received Feb 23, 2000.
Accepted Apr 28, 2000.

Reprint requests: Darcy Fehlings, MD, MSc, Bloorview MacMillan Centre, 350 Rumsey Rd, Toronto, Ontario, M4G 1R8, Canada.

Copyright © 2000 by Mosby, Inc.

0022-3476/2000/$12.00 + 09/21/108393

Objective: 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. The caregiver completed the self-care domain of the Pediatric Evaluation of Disability Inventory.
Results: Twenty-nine subjects completed the study. The QUEST demonstrated a significant improvement favoring the treatment group on a 2-way analysis of variance (F = 4.69, df = 1,83; P = .039). BTA treatment was also associated with an improvement in score on the self-care domain of the Pediatric Evaluation of Disability Inventory (F = 4.68, df = 1,82; P = .04).
Conclusions: This study supports the effectiveness of BTA injections to improve upper extremity function of children with hemiplegia who have at least moderate spasticity. (J Pediatr 2000;137:331-7)

ANOVA

Analysis of variance

BTA

Botulinum-A toxin

CP

Cerebral palsy

PEDI

Pediatric Evaluation of Disability Inventory

QUEST

Quality of Upper Extremities Test

See editorial, p. 300.

Intramuscular injections of Clostridium botulinum-A toxin into spastic muscles cause a local temporary muscle paralysis associated with decreased spasticity. The biologic effects of BTA are well understood. [1] Botulinum toxin has been used therapeutically in adults over the last 25 years in neuromuscular conditions associated with focal dystonia (strabismus, torticollis).[2]

The use of BTA in cerebral palsy[3] has received much interest recently because of the high prevalence of CP (1-2 in 1000 in developed countries)[4] [5] and conservative nature of the treatment. It is postulated that by decreasing spasticity, there will be improved control of movement patterns, stretching and increased excursion of shortened muscles, improved posture, and secondary strengthening of antagonistic muscles. By implication, these changes should be associated with improved motor function. Most studies to date have focused on the use of BTA injections into the lower extremity gastrocnemius muscle and have demonstrated a temporary reduction in spasticity, temporary improvement in gait, and improved range of motion.[6] [9] Minimal information is available on the impact on function of upper extremity injections in children with CP. Wall et al[10] report positive gains in function and cosmetic appearance in a prospective case series of 5 children with a "thumb in palm" deformity associated with CP treated with BTA injected into the adductor pollicis muscle and rigid splinting of the thumb.[10] Denislic and Meh[11] injected BTA into the upper limbs of 10 children with CP and found an improvement in upper limb function in 9. A double-blind controlled study by Corry et al[12] reports mixed results on the impact on function in hemiplegic CP. Functional improvements were not found 2 weeks after injection. A small improvement was found at 12 weeks, favoring the BTA group in a grasp-and-release activity, but was not found in another grasp activity (the ability to pick up coins).

We report the results of a randomized, controlled, single-blind trial of BTA injections into the involved hand or arm of 30 children with hemiplegic CP using the Quality of Upper Extremity Skills Test, a standardized measure of quality of function of the upper extremity, as our principal outcome.

METHODS

Participants

Eligible children met the following criteria: 2.5 to 10 years of age; a diagnosis of hemiplegic CP; moderate spasticity at the elbow, wrist, or thumb with a modified Ashworth score 2[13] ; full passive range (defined in this study as elbow extension to neutral, wrist extension to 30 degrees past neutral with the fingers extended, forearm supination to 30 degrees past neutral, and thumb extension to neutral); and the ability to initiate voluntary movement of the digits. Children were excluded if they were using a rigid splint to maximize homogeneity and allow active movement in the hand.

Study Design

The study was approved by the Bloorview MacMillan Centre Research Ethics Review Board. The ethics board, guided by Canadian ethical standards, did not grant approval for a double-blind BTA study in which the control group would receive an intramuscular injection of saline solution because this was judged to be too painful and invasive for a placebo.[14] When the eligibility criteria were met and written informed consent was obtained, children were randomly assigned, by using a uniform random number generator, to a treatment or control group. The treatment group received an intramuscular injection of BTA (Botox, Allergan, USA), at a dosage of 2 to 6 U/kg body weight, into at least 1 of 3 muscle groups (biceps, volar forearm muscles, or adductor pollicis muscle). Two investigators (D.F. and M.R.) determined jointly which muscle groups to inject during reach-and-grasp activities of the involved hand or arm. If the child demonstrated persistent elbow flexion, the biceps was injected; for thumb adduction, the adductor pollicis muscle was injected. In the volar forearm muscles, for pronation, the pronator teres muscle was injected; wrist flexion was an indication for flexor carpi ulnaris muscle injections; and finger flexion was an indication for injection of the finger flexors. The location of the injection was determined by anatomic knowledge and muscle palpation.[15] [17] The biceps was injected in the top third of the muscle at 2 sites, the volar flexor muscle was injected at 2 sites, 2 to 3 cm below the medial epicondyle. The pronator teres was injected at one site in the upper third of the muscle, and the adductor pollicis was injected in one site in the belly of the muscle.

Children in both groups were asked to continue with community-based occupational therapy at a minimum frequency of one session every 2 weeks. Research funding was not available to provide occupational therapy by research personnel. An occupational therapy manual with guidelines was developed for the study and sent to each of the participating occupational therapists. The guidelines were based on standard practice for therapy management of spastic hemiplegia and incorporated activities for upper extremity strengthening and the development of skills for activities of daily living.[18] [19]

Children were seen at baseline and at 1, 3, and 6 months. A single investigator (J.G.), blinded to the subject group assignment, obtained all objective outcome measurements. The primary outcome measure was the QUEST.[20] [22] This is an objective standardized measure evaluating the quality of upper extremity function in 4 domains: dissociated movement (an isolated joint movement of the upper extremity that counters a pattern of spastic synergy), grasp, protective extension, and weight bearing. Scores for the QUEST are calculated as percentages with a maximum score of 100. The QUEST was designed with minimal developmental sequencing so that scoring reflects the severity of the disability rather than age.

A caregiver completed the self-care domain of the Pediatric Evaluation of Disability Inventory to assess the child's activities of daily living.[23] The self-care domain has 73 items in 15 skill areas, such as hand washing. Raw scores can be converted to a scaled score with a 0 to 100 distribution based on Rasch scale modeling. The PEDI has been designed to measure function in children with physical disabilities and has established reliability, validity, and responsiveness.[23] [26]

Secondary outcome measures included manual goniometric measurements of passive range of motion[27] ; modified sphygmomanometer measurements of grip strength[28] ; and the modified Ashworth score of spasticity at elbow extension, wrist extension, forearm supination, and thumb extension.[13] Test-retest reliability for passive goniometry measurements and grip strength was evaluated before the study in children with upper extremity spasticity and was found to be high, with correlation coefficients ranging from 0.58 to 0.97.[29]

Statistical Analyses

The analyses were conducted by using the SAS microcomputer-based package. [30] The following tests were used.

1. A preliminary analysis included a thorough check of the data (review of outliers and missing data), a descriptive summary, and plots of each variable.
2. Chi-square and unpaired t tests were used to check the comparability of the BTA treatment and control groups at baseline for age, sex, involved side, and baseline Ashworth, QUEST, and PEDI scores.
3. A 2-way analysis of variance was computed to detect differences between the BTA treatment and control groups during the study period in the QUEST, the PEDI, grip strength, Ashworth scores, and passive goniometry measurements. To account for baseline effects, the differences between baseline and 1 month, baseline and 3 months, and baseline and 6 months were used. Statistical significance was set a priori at P < .05 for the 2 functional outcomes, the QUEST and the PEDI, and set at P < .01 for the secondary outcomes to account for the multiple testing.
4. A post hoc Wilcoxon rank sums test was performed to examine the significance of group differences at 1, 3, and 6 months for variables that demonstrated statistical significance on the ANOVA.

RESULTS

Participant Characteristics

Fifty children were screened; 20 did not meet the eligibility criteria (13 had an Ashworth score <2, 6 had an inability to initiate voluntary movement in the involved hand, and 2 had fixed contractures). Thirty children were recruited into the study and randomly assigned to the treatment (n = 15) and control (n = 15) groups. Thus 29 children completed the study, with one child in the treatment group dropping out before the 1-month assessment. Table I outlines the comparability of the 2 groups at baseline.

Table I. Baseline comparability of the treatment and control groups* /
Characteristic / Treatment group
(n = 14) / Control group
(n = 15) / P value /
Age (mo) / 68 ± 31 / 64 ± 28 / .71
Gender (M/F) / 10/5 / 10/5 / 1.00
Involved side (right/left) / 10/4 / 7/8 / .17
Modified Ashworth score* / 2.3 ± 0.75 / 2.2 ± 0.59 / .89
QUEST baseline / 19.2 ± 15.1 / 27.6 ± 19.0 / .41
PEDI baseline / 50.2 ± 11.1 / 52.2 ± 15.4 / .25
Grip strength (mm Hg) / 56.40 ± 16.59 / 53.38 ± 21.33 / .46
Values are expressed as means ± SD.
*Represents the mean of Ashworth measurements for elbow and wrist extension, forearm supination, and thumb extension.

No significant differences were found.

Table II outlines the BTA treatment for each child with respect to dosage and location.

Table II. Dosage and location of injection for each participant in the BTA treatment group /
Subject No. / BTA (U/kg) / QUEST change (to 1 mo) / Biceps / Muscle injected (U/kg) /
Volar flexors / Pronator teres muscle / Adductor pollicis muscle /
1 / 4 / 36.67 / -- / 4.0 / -- / --
2 / 4 / 4.48 / -- / 4.0 / -- / --
3 / 2 / 19.36 / 2.0 / -- / -- / --
4 / 4 / 12.19 / -- / 4.0 / -- / --
5 / 4 / 8.53 / -- / 4.0 / -- / --
6 / 4 / 23.90 / -- / 1.3 / 1.3 / 1.3
7 / 5.2 / -1.97 / -- / 3.6 / 1.6 / --
8 / 3.8 / 21.37 / -- / 2.9 / -- / 1.0
9 / 4.3 / 2.21 / 3.2 / 1.1 / -- / --
10 / 2.7 / 0.78 / -- / 1.8 / -- / 0.9
11 / 3.3 / -9.71 / -- / 2.2 / -- / 1.1
12 / 3.6 / 30.18 / 1.8 / -- / -- / 1.8
13 / 6.6 / 14.29 / -- / 4.9 / -- / 1.6
14 / 3.4 / Dropout / -- / 1.1 / 1.1 / 1.1
15 / 6.3 / 12.79 / 1.6 / 3.2 / -- / 1.6

Both groups received occupational therapy in the community at a recommended frequency of once every 2 weeks. The treatment group received a mean of 11.93 (SD 6.89) treatment sessions, and the control group received a mean of 16.07 (SD 7.60) treatment sessions over the 6-month period of the study. This difference favored the control group but was not statistically significant (P = .74).

Main Results

The total score for the involved side on the QUEST, the primary outcome measure, demonstrated a statistically significant improvement favoring the BTA treatment group on the ANOVA (F = 4.69, df = 1,83; P = .039). The time-group interaction was not significant (P = .50). Post hoc testing with the Wilcoxon rank sum test showed significant differences between the treatment and control groups at 1 month (P = .01) but not at 3 (P = .13) or 6 months (P = .14). These results are outlined in the Figure.