The three groups showed similar distributions in terms of baseline characteristics (Table I), including the topographic classification and the ability to walk at the time of the first clinical evaluation. Botulinum toxin type A injections, which were only applied as a result of an insufficient response to a conservative approach, were administered to 115 (87%) of the 132 patients in Group 3 before the age of seven years. Except for the use of daytime orthoses, the distribution of physical therapy and orthotic conditions did not differ among the three groups. Intensive use of daytime orthoses during follow-up was most often seen in Group 3 (p < 0.002) (Table I).
All children in Groups 1 and 2 were followed until the age of nine years. In Group 3, sixteen of the 132 children had not reached the age of eight years and forty of the 132 children had not reached the age of nine years at the time of data collection. By the age of seven years, sixty-four (52%) of the 122 patients in Group 1 had undergone at least one surgical procedure, compared with forty-six (27%) of the 170 patients in Group 2 and thirteen (10%) of the 132 patients in Group 3. By the age of eight years, seventy-three (60%) of the 122 patients in Group 1 had undergone at least one surgical procedure, compared with fifty-two (31%) of the 170 patients in Group 2 and fourteen (12%) of 116 patients in Group 3. By the age of nine years, seventy-nine (65%) of the 122 patients in Group 1 had undergone at least one surgical procedure, compared with sixty-five (38%) of the 170 patients in Group 2 and fourteen (15%) of ninety-two patients in Group 3. The difference between the prevalence of surgery in Groups 1 and 2 was significant at seven, eight, and nine years of age (p < 0.00001, chi-square test). There was a significant decrease in the frequency of surgery in Group 3 as compared with Group 1 (p <0.005 for the age of three years, p < 0.0001 for the ages of four to eight years, and p < 0.001 for the age of nine years) and Group 2 (p < 0.0025 for the ages of four to eight years, and p < 0.01 for the age of nine years). The rate of survival, with the occurrence of the first surgical procedure as the end point, was significantly different among the three groups for the ages of three to nine years (p < 0.0001, log-rank test) (Fig. 2). The median for survival was found to be 6.8 years for Group 1, 9.8 years for Group 2, and was never reached for Group 3 (Table II).
Survival analysis revealed differences among the four walking-status categories with regard to the risk of surgery (Table I). Although the baseline distribution with regard to walking status was similar among the three treatment groups, evaluation of the impact of covariates on the risk of surgery revealed a significant influence of walking ability at the time of the initial clinical evaluation. The survival estimates at the age of nine years are given in Table III. By the age of nine years, the proportion of patients who had not had surgery was always higher in Group 2 as compared with Group 1. These differences between Groups 1 and 2 were most pronounced for the children who walked with limited assistance (59% [101 of 170] for Group 2, compared with 21% [twenty-six of 122] for Group 1) and for the children who walked only with substantial assistance or who could not walk independently (47% [eighty of 170] for Group 2, compared with 21% [twenty-six of 122] for Group 1) at the time of the initial clinical evaluation (at a mean age of 4.4 years for Group 1 and of 5.4 years for Group 2). In Group 3, progression to surgery was never seen among the children who were able to walk at the time of the initial clinical evaluation (mean age, 3.3 years). The survival rate for Group 3 was 80% (106 of 132), with surgery being performed only for children who walked with limited assistance, and children who walked with substantial assistance, or children who could not walk independently at the time of the initial evaluation.
Analysis of the frequency distributions for the second surgical intervention by the age of seven years revealed that eleven (21%) of fifty-two children in Group 1 needed two surgery sessions, six (14%) of forty-three children in Group 2 needed two surgery sessions, and none of the children in Group 3 needed more than one surgery session. Before the age of thirteen years, fifty-five (45%) of the 122 children in Group 1 and twenty-four (41%) of fifty-nine children in Group 2 needed a second surgical procedure. No conclusions could be made about the children in Group 3 because they had not reached the age of thirteen years by the time of data collection. By the age of nine years, none of the twelve children in Group 3 who had had one session of surgery needed a second session of surgery, compared with nineteen (26%) of the seventy-four children in Group 1 and fourteen (21%) of the sixty-eight children in Group 2.
The frequency of single surgical interventions (Achilles tendon lengthening) as well as multiple-level interventions (other soft-tissue surgery with or without correction of osseous deformities) during the first session of surgery is presented in Figure 3. By the age of seven years, forty-seven (39%) of the 122 patients in Group 1, thirty-four (20%) of the 170 patients in Group 2, and three (3%) of 116 patients in Group 3 underwent Achilles tendon lengthening, whereas multiple-level surgery was performed for seventeen (14%) of the 122 patients in Group 1, nineteen (11%) of the 170 patients in Group 2, and eight (7%) of 116 patients in Group 3.
The differences in the risk of surgery between Group 1 and Group 2 became clear at the age of approximately six years (Fig. 1). The survival rate at the age of twelve years, with the first surgical procedure as the end point, was 27% for Group 1 and 42% for Group 2. For these children, the use of three-dimensional gait analysis for Group 2 was the only difference in follow-up data. Gait analysis was planned each time there was a need for more information about motor problems to define the optimal treatment plan as well as before and after each nonoperative or operative intervention. The children in Group 3 will reach the mean age of twelve years in 2006. The survival rate at the age of seven years, with the first surgical procedure as the end point, improved from 48% for Group 1 to 69% for Group 2 and to 90% for Group 3 (Fig. 2). Before the age of thirteen years, 45% (fifty-five) of the 122 children in Group 1 and 41% (twenty-four) of fifty-nine children in Group 2 needed a second session of surgery. Although no conclusions could be made about the follow-up of children in Group 3 until the age of thirteen years, none of the ninety-two children in Group 3 who reached the age of nine years needed a second session of surgery. The improved motor function after the initial surgical procedure could not be maintained. Therefore, the risk-benefit ratio of surgery38 also should be considered, as should the physical, social, and psychological impact of repeated surgery73.
Although the aim of the multiple-level treatment approach was to lengthen and/or transfer all major muscles that were involved and to correct all osseous deformities and leverarm dysfunction during the course of a single surgical procedure, multiple-level involvement was not always properly recognized at the time of the initial surgery session for the children in Group 1 because of a lack of objective three-dimensional gait analysis. Therefore, Achilles tendon lengthening at a young age was a common procedure for these children.
As previously discussed, there are clear advantages of delaying surgery until the age of eight years or older, by which time the gait is well established3,9,10,44. Koman et al.43 evaluated the effect of single-level botulinum toxin type A treatment on the need for Achilles tendon lengthening surgery after a mean duration of follow-up of 3.4 years (range, 0.4 to 6.5 years). The study demonstrated a 3.8-year delay in surgical treatment and an older age at which Achilles tendon lengthening was performed in comparison with the timing of surgery as cited in other studies7,9. We are not aware of any long-term studies on the outcome of multiple-level treatment with botulinum toxin type A. Bakheit et al.74, in a study of 1594 botulinum toxin type A injections in children with muscle spasticity, concluded that multiple-level injections resulted in a better overall response than single-level injections did. Galli et al.75 and Mall et al.76 also emphasized the need for multiple-level injections. However, it was surprising that, in the majority of the reported studies, application of botulinum toxin type A was limited to isolated treatment of spasticity of the gastrocnemius muscle. However, as discussed previously, most previous investigators have agreed with the principle of multiple-level treatment during one session3,7,45,77. We developed appropriate techniques to apply the multiple-level botulinum toxin type A approach safely29; however, the inter-relationship of botulinum toxin type A treatment with the general motor development of the child with cerebral palsy has not been examined in large cohorts.
The present study revealed the first intermediate to long-term effects of serial multiple-level botulinum toxin type A injections, combined with nonoperative treatment, on longitudinal muscle growth. It is important to note that no important adverse effects of the combined botulinum toxin type A and casting treatments were noted at the doses used and that only minor complications were seen. Unintended effects or side effects (incontinence and constipation) were noted in <5% of the patients (in association with four of ninety-one treatments)29,36.
The three groups had similar distributions of known factors (except for the use of daytime orthoses) that could influence motor development and progression to surgery. The same orthotic management was applied in all three groups, which was always the maximum of tolerated daytime and nighttime use. However, daytime orthoses were more intensively used in Group 3 as compared with Groups 1 and 2, suggesting that botulinum toxin type A may facilitate the use of orthoses, as evidenced by the results of previous studies29,36,39. For Group 3, there were no follow-up data for forty of 132 patients from the ages of seven to nine years because these children had not reached the age of nine years at the time of data collection. Although the survival analysis took the censored observations into account, care should be given to conclusions based on the results for the children in Group 3 after the age of seven years.
The retrospective nature of the present study limits the interpretation of the results, and the possibility of bias in favor of a delay of surgery should be considered. However, all of the children in the present study were evaluated and managed by the same multidisciplinary team according to the best practice guidelines of orthopaedic treatment. The treatment plan for each child was defined in the multidisciplinary outpatient clinic. The advantages of the multidisciplinary approach and single-event, multiple-level surgery were generally accepted at the onset of this retrospective study and had been applied by the senior member of this research team (G.F.) since 1972. The treatment philosophy per se did not change over the course of this retrospective study. Rather, the improved understanding and treatment of cerebral palsy-related primary problems in children helped to optimize the use of available treatment options. Although this treatment strategy might not be generally accepted by all clinicians, the presented strategy was stable throughout the course of the study.
In the present study, there also were small differences among the three groups with regard to the age of first contact. Children in Group 3, in particular, were younger at the time of the first clinical evaluation, which may have predisposed them to a better locomotor prognosis. However, these children also demonstrated a more severely restricted walking ability at the time of the initial evaluation (Table I). It is well known that walking ability is linked to the severity of pathology in patients with cerebral palsy1,4,78-82, and our survival analysis confirmed that more severely restricted walking ability at a young age significantly delayed the time to surgery. Therefore, it cannot be stated with certainty that a young age at the time of the first clinical evaluation was an advantage for the children in Group 3 as they also had more severely restricted walking ability at a younger age as compared with the children in Groups 1 and 2. This finding suggested that the severity of pathology in Group 3 might have been the same as, but was certainly not better than, that in Groups 1 and 2.
The results of the present intermediate-term study revealed that the children with the least walking ability (those who could walk only with substantial support or who could not walk independently) at the time of the initial evaluation progressed to surgery more frequently than did the children who were able to walk at a young age. However, the proportion of these children in Group 3 who had not had surgery by the age of nine years was lower than the proportion of the more functional children who were able to walk in Groups 1 and 2. Taken together, these data suggest that the locomotor prognosis of the children in Group 3 who were not able to walk was no better than that of children in Groups 1 and 2, despite the younger age of these children at the time of the first clinical evaluation. Additional study will be needed to establish the influence of young age as compared with that of walking status on locomotor prognosis.
Future data analysis in this retrospective study will focus on the general functional condition of the children who received botulinum toxin type A treatment at the age of six to ten years as compared with a control group. The functional outcome, evaluated with use of gait analysis, is beyond the scope of this study but will be analyzed in the near future. ▪
In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from Allergan, Inc., Irvine, California. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
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