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Article

Efficacy of Repeated Botulinum Toxin Type A Injections for Spastic Equinus in Children with Cerebral Palsy—A Secondary Analysis of the Randomized Clinical Trial

by
Bo Young Hong
1,†,
Hyun Jung Chang
2,†,
Sang-Jee Lee
3,
Soyoung Lee
4,
Joo Hyun Park
5 and
Jeong-Yi Kwon
6,*
1
Department of Rehabilitation Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, South Korea
2
Department of Physical Medicine & Rehabilitation, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, South Korea
3
Department of Rehabilitation Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Daejeon 34943, South Korea
4
Department of Physical Medicine & Rehabilitation, Keimyung University, Dongsan Medical Center, Daegu 41931, South Korea
5
Department of Rehabilitation Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
6
Department of Physical and Rehabilitation Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
*
Author to whom correspondence should be addressed.
†
These authors contributed to this work equally.
Toxins 2017, 9(8), 253; https://doi.org/10.3390/toxins9080253
Submission received: 12 July 2017 / Revised: 8 August 2017 / Accepted: 18 August 2017 / Published: 21 August 2017
(This article belongs to the Section Bacterial Toxins)
Versions Notes

Abstract

:
Botulinum toxin A is considered an important tool to control spasticity in children with cerebral palsy. Several factors are known to affect the efficacy of botulinum toxin, such as dosage, appropriate muscle selection and application, age, and accompanying therapy. A multicenter, double-blind, randomized, prospective phase III clinical trial of botulinum toxin A for the treatment of dynamic equinus in 144 children with cerebral palsy was performed to compare the efficacies of letibotulinumtoxin A and onabotulinumtoxin A. Secondary analyses were performed to evaluate factors that affected the outcome, focusing on the number of times injections were repeated. Effectiveness was defined as a change of 2 or more in the physician’s rating scale. Multivariate regression analyses were performed with multiple variables. The first injection of botulinum toxin A significantly improved D subscale of Gross Motor Function Measure-88 scores at 3 months compared to repeated injections (p < 0.05). After 6 months, patients who had one injection or none before the study showed significantly better outcomes than those who had more than one injection in terms of observational gait scores.

1. Introduction

Cerebral palsy (CP), a group of disorders in movement and posture resulting from non-progressive injury of the immature brain [1], is the most common cause of disability in the pediatric population [2,3]. Among various subtypes grouped according to neurologic dysfunction (spastic, hypotonic, dystonic, athetotic, or others), the spastic type is the most common. It can involve unilateral or bilateral sides [4,5,6] and accounts for 70–80% of CP [5,7,8]. Spasticity is defined as a velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex, as one component of the upper motor neuron syndrome [9]. In CP, spasticity is known to increase up to 4 years of age, after which it decreases up to 12 years of age [10]. Spasticity results in the shortening of myotendinous units, joint contracture, bony deformity, joint subluxation or dislocation, abnormal posture, and pathologic gait [3]. Identifying the severity and distribution of spasticity is important in decisions about the options for managing spasticity [11]. Physiotherapy and occupational therapy remain the mainstays of treatment in spastic CP [3]; botulinum toxin A (BoNT) is widely used for spasticity control, and many studies support its safety and efficacy [12,13,14].
BoNT has been commonly used to reduce muscle spasticity in children with CP since the first report of its use in 1993 [15]. BoNT selectively and reversibly blocks the release of acetylcholine in the neuromuscular junction, thus reducing muscle overactivity [3,14,16]. Although there are general side effects, injections of BoNT are known to be relatively safe [17,18]. Oral medications have more systemic adverse effects, such as drowsiness and sedation [19], which make it hard to maintain the medications, especially in children. One of the most common indications for BoNT in ambulatory children with spastic CP involves the need to improve gait patterns [12,19]. Furthermore, BoNT also has positive effects on upper limb function and the kinematics of gait [19,20,21].
The response to the treatment depends on the dosage of BoNT, appropriate administration, and adjunctive rehabilitation therapies [20,22,23,24,25,26]. However, there is sometimes no effect after injection of BoNT. Secondary unresponsiveness has been thought to be related to antibody formation [27], but antibodies were infrequently detected in recent studies, including this clinical trial [26,28]. More common causes of unsatisfactory outcomes might be the wrong choice of or missed target muscles, inappropriate indications, or a lack of complementary rehabilitation treatment [12]. Several studies have been performed to identify factors that affect the efficacy of BoNT in the management of spasticity of the lower extremities. Fazzi et al. showed that, compared with those older than 48 months, children aged 48 months or younger showed significantly increased gross motor function measure (GMFM) scores after 3 months of injections. Additionally, those who could walk with support showed a significantly greater increase in GMFM scores than non-walkers [29]. Repeated injections of BoNT have long-term effects on gross motor function in children with CP, but the short-term effect (4 weeks) on functional improvement and reduction of spasticity was significantly higher after the first injection than after the last injection [30]. Kristina et al. reported that repeated injections produced an immediate reduction in muscle tone; however, the improvement in range of motion was brief, and was noted only after the first injections [31]. In a systematic review, Kahraman et al. concluded that the first two injections (one repeat) are especially effective for relieving spasticity and improving fine and gross motor activities [13].
A multicenter, double-blinded, randomized, prospective phase III clinical trial (n = 144, 92 boys) of BoNT for the treatment of dynamic equinus in children with CP was undertaken recently with the primary intention of comparing the efficacy of letibotulinumtoxin A (Botulax; Hugel, Chuncheon, South Korea) and onabotulinumtoxin A (Botox; Allergan, Irvine, CA, USA). The study found injection of letibotulinum toxin A to be as effective and safe as that of onabotulinum toxin A for the treatment of dynamic equinus foot deformity in children with spastic CP (co-submitted) [32]. Secondary analyses of data from those patients who completed the trial were performed to evaluate the factors that affect the efficacy of BoNT for dynamic equinus in children with CP. This report provides a more detailed evaluation in the context of these factors, focusing on the number of times the injections were repeated, which might have influenced the observational gait analysis scores and gross motor outcomes of BoNT.

2. Results

2.1. Physician’s Rating Scale

A physician’s rating scale for gait (PRS), based on that used in a trial of BoNT calf injections, was employed [33]. A PRS score difference of 2 or more was considered a successful response. The numbers and percentages of successful responses in terms of PRS scores at 6, 12, and 24 weeks after BoNT injection in the calf muscles are described in Table 1. There was a significant difference in efficacy at 6 weeks; children who had had two or fewer injections of BoNT before the study showed a better effect compared to those who had had more than two prior BoNT injections. However, there were no significant differences in the success rate between children who were first injected versus those who had been injected before, or between children who had received one or no injection versus those who were injected more than once, at 6, 12, and 24 weeks after BoNT injections. Additionally, there was no significant differences according to the limb involvement pattern (i.e., unilateral or bilateral). However, the proportion of children for whom the treatment was effective (PRS ≥ 2) was marginally greater, as shown by increases in the Gross Motor Function Classification System (GMFCS) level, after 24 weeks of injection (p = 0.05).

2.2. Gross Motor Function Measurement

Gross Motor Function Measure-88 (GMFM-88) total and subgroup D and E scores were evaluated to assess gross motor function. GMFM-88 scores are known to be useful outcome measures for detecting changes in gross motor function in children with CP undergoing interventions [31]. The standing dimension D includes 13 items that deal with various aspects of standing. The walking, running, and jumping dimension E includes 24 items that evaluate a variety of activities that begin with standing [33]. Subgroup D scores were significantly more improved in botulinum toxin-naïve patients compared to patients who had had previous injections at 12 weeks (Table 2, p = 0.042). However, there were no significant differences in total, D, and E GMFM-88 scores at 24 weeks after injection according to the number of the previous injections (Table 2, p > 0.05). The mean age (SD) of the groups according to previous injection was significantly different: no previous injection (none) 3.86 (1.93), previous injection (yes) 5.66 (2.02); one or none 4.11 (1.98), more than one 5.99 (1.93); two or less 4.36 (1.98), more than two 6.39 (1.87) (p < 0.001).

2.3. Multivariate Regression Analyses

When patients were grouped according to the number of previous injections (none or one, two or more), the baseline PRS score was a significant predictor of outcome (PRS ≥ 2) at 12 weeks after injection (odds ratio = 0.825, 95% confidence interval: 0.686–0.992, p = 0.0410; Table 3). At 24 weeks after injection, patients with two or more previous injections had significantly poorer outcomes than those with none or one previous injection (odds ratio = 0.412, 95% confidence interval: 0.179–0.948, p = 0.0371; Table 4). When previous injection history was grouped as yes vs. none in the multivariate regression analyses, age, sex, baseline total PRS and GMFM-88 score, GMFCS level, type of CP (unilateral vs. bilateral), and previous injection history did not significantly impact BoNT efficacy (PRS ≥ 2) at 12 and 24 weeks after injection (Tables S1 and S2). When previous injection history was grouped as three or more vs. two or less, none of the factors significantly affected BoNT efficacy at 12 and 24 weeks after injection (data not shown).

3. Discussion

The effect of BoNT on neuromuscular junction continues for 12 to 16 weeks [34]. Because of the temporary effect, the injection needs to be repeated in some patients. As cerebral palsy is a lifelong disease, it is important to know the long-term effect and efficacy of repeated injections. Multivariate analyses showed that initial observational gait score (PRS) could affect the efficacy (PRS ≥ 2) at 12 weeks after injection, and efficacy was significantly better at 24 weeks in children who had injections once or not at all before the study than in those who had injections more than once. This result is similar to those in a recent systematic review including 13 original articles (893 children), which concluded that the first two injections were especially effective. However, this study focused on spasticity control and improvement of gross motor activities and not on gait quality [13]. The effect on range of motion and reduction of spasticity occurs immediately after injection and is greater with the first injection [30,31], but functional improvement or maintenance of the effect could occur later in the course of the continuum of care. The difference in the scores on the standing dimension of the GMFM-88 at 3 months after the injection was significantly greater in patients who had not previously been injected compared to those who had previous injections. The ability to maintain various standing positions and to perform specific tasks from the standing position might have improved because the stability of the base of support increased significantly more through management of spasticity with BoNT in the first-injected children compared to those who had injections before. However, the total GMFM-88 and the walking, running, and jumping dimension scores did not significantly differ between first-injection and repeated-injection groups. Papavasiliou et al. reported that an important improvement occurred in the GMFM (eight-point difference) at 3 months after the first injection, but the improvement decreased with later injections in GMFCS level I–V children [35]. Injected muscles varied according to clinical needs (e.g., calf muscles, hip adductors, hamstrings) [35], but only calf muscles including the gastrcocnemius and soleus were targeted in this study. Differences in the muscle selected and gross motor levels of participants might have contributed to different outcomes regarding gross motor function after BoNT injection. Also, the age should be considered in interpreting this result. The children who had no previous BoNT injection were significantly younger (3.86 vs. 5.66 years old) than those who had had injection before.
Weakness, disuse, and chronic spasticity results in muscle shortening and contracture, and these might contribute to the increase of contractures and deformities in children with CP with ageing [19]. Younger age is known to be related to greater improvement in gross motor function [29,36,37,38]. Previous studies have treated age as a continuous variable or categorized it as 4 or 5 years old, younger, or older. However, in our study, multiple regression analyses showed that age was not a significant determinant of efficacy as evaluated by the PRS at 12 and 24 weeks after BoNT injection. The participants were relatively young, and the range of age was not wide. The oldest child was 10 years old, and the mean and median ages were around 5 years old, which might be the reason for the differences between our results and those of previous reports. In a study on the prognosis for gross motor function, the age at which children were expected to achieve 90% of their potential GMFM-66 score was younger than 5 years old: that is, 4.8 and 3.7 years old for those in GMFCS levels I and III, respectively [39]. Also, an increase in the gross motor function score flattens after achievement of functions, which means that GMFCS level and age could affect the results. There may also have been a ceiling effect on the GMFM test itself [40,41], and this may have contributed to difficulty in detecting subtle changes of gross motor function.
At 24 weeks, the efficacy of BoNT measured by the PRS increased marginally as the GMFCS level increased. Although other factors were not calibrated, this means that BoNT could be more beneficial for the maintenance of the effect on the gait pattern at 6 months after the injection as the GMFCS level increases. The result differed from that of previous studies by Linder et al. and Papavasiliou et al., which found evident improvement in children at GMFCS level III [38], and reported that children at GMFCS level IV gained significant enough gross motor function to change their GMFCS level [35]. However, the muscles injected and the outcomes addressed were different from those in our study. Indeed, PRS scores, such as those on the GMFM-88, might not always be linked to improvements in gross motor function. Although the GMFM-88 is a useful outcome measure with which to detect changes in gross motor function in children with CP [42,43], it focuses on function and does not reflect the quality of movement.
As the previous studies showed different effective dose in diplegic and hemiplegic patients, hemiplegic patients required higher doses [37]. This study used different doses for patients with unilateral and bilateral involvement, 3 IU/kg and 4 IU/kg, respectively, for each triceps surae. Therefore, there was no difference in their response according to the involvements of limbs, unilateral or bilateral. This also suggests that a higher dosage is needed for the children with unilateral involvement compared to bilateral involvement for a similar effect.
There are several limitations in this study. First, additional or supplemental therapies are known to be a significant influence on the outcome of BoNT injection [20,26], and the number of therapies or activities and the time spent performing them were not considered in this study. Also, participants were strongly advised not to change their usual therapies or activities during the clinical trial, but changing the frequency or intensity of therapies was not a cause for dropout from the study and was not investigated. Second, there are several types of BoNT available in South Korea; however, our data did not include information about what kind of BoNT the patients received before the study. Therefore, we could not investigate the cross-reactivity of BoNT preparations made by different manufacturers. Additionally, because of the 6-month observation duration, some data were missing due to the level of patients’ compliance. However, data in this study were from a multicenter, double-blind, randomized, prospective clinical trial, and the observation period for 144 spastic CP children was 6 months [32]. The study provides evidence about the factors affecting outcomes, observational gait scores, and gross motor function after BoNT intervention. In conclusion, at 3 months, the first injection of BoNT for the control of dynamic tip-toeing was associated with more improvement than repeated injection with regard to the standing ability of children with CP. At 6 months after the injection, patients who had had injections once or never before the study showed significantly better outcomes in terms of observational gait scores (PRS). Age was not a significant factor affecting the efficacy (PRS) of BoNT at 12 and 24 weeks after injection.

4. Materials and Methods

The study received permission from independent research ethics committees at each investigational site. Enrolled subjects were randomly assigned to receive letibotulinumtoxin A injection (study group, n = 70) or onabotulinumtoxin A injection (control group, n = 73) at a ratio of 1:1, and they then received the corresponding investigational products. The random assignment code was generated using a block randomization method. Those codes were sealed until the trial was completed, except in cases of serious adverse events. Participants were ambulatory children (n = 143, 91 boys) with spastic CP (GMFCS levels I–III) who were 2–10 years old and showed dynamic equinus deformity, tip-toe gait. The target muscles were the triceps surae, gastrocnemius, and soleus. In the case of bilateral involvement (n = 95, diplegia or tetraplegia), the investigational product was administered to both legs at a dose of 6 U/kg body weight (3 U/kg for each leg); in the case of unilateral involvement (n = 48, hemiplegia), it was administered to the spastic leg at a dose of 4 U/kg body weight.
For the secondary analyses of this phase III clinical trial, intention-to-treat (ITT) analyses were performed. Continuous variables were presented as means and standard deviations, and categorical variables were presented as frequencies and percentages. Chi-square tests were performed to analyze the efficacy of BoNT injection in terms of injection history, paralysis type, and GMFCS level at 6, 12, and 24 weeks after the injection. Analysis of linear-by-linear associations of the proportion of children in whom the treatment was effective (PRS ≥ 2), which was performed with SPSS software, version 17.0 (SPSS for Windows 12.0, Chicago, IL, USA), and SAS software version 9.4 (SAS Institute, Cary, NC, USA) allowed examination according to GMFCS level. Multivariate logistic regression analyses were performed to identify the factors that affect the outcome of BoNT on observational gait pattern (PRS) and motor function (GMFM-88). The following variables were treated as candidates for the purpose of determining associations with the level of responsiveness to BoNT: (1) age; (2) history of previous BoNT injections (yes vs. none; more than one vs. one or none; more than two vs. two or fewer); (3) baseline total PRS score; (4) baseline GMFM-88 total score; (5) GMFCS level; and (6) paralysis type of CP (i.e., unilateral or bilateral involvement).

Supplementary Materials

The following are available online at www.mdpi.com/2072-6651/9/8/253/s1, Table S1: Multivariate regression analyses of variables on outcome (PRS ≥ 2) at 12 weeks for botulinum toxin injection, previous injection groups: yes vs. none, Table S2: Multivariate regression analyses of variables on outcome (PRS ≥ 2) at 24 weeks for botulinum toxin injection, previous injection groups: yes vs. none.

Acknowledgments

Phase III clinical trial was funded by Hugel.

Author Contributions

Jeong-Yi Kwon, Hyun Jung Chang and Bo Young Hong conceived and designed the experiments; Bo Young Hong, Sang-Jee Lee, Soyoung Lee, Hyun Jung Chang, Joo Hyun Park, Jeong-Yi Kwon performed the experiments; Bo Young Hong analyzed the data; Jeong-Yi Kwon performed important decision making in experiments; Bo Young Hong wrote the paper and it was proofread by Jeong-Yi Kwon, Hyun Jung Chang.

Conflicts of Interest

The authors declare no conflict of interest with respect to the research, authorship, and/or publication of this article.

References

  1. Bax, M.; Goldstein, M.; Rosenbaum, P.; Leviton, A.; Paneth, N.; Dan, B.; Jacobsson, B.; Damiano, D. Executive Committee for the Definition of Cerebral Palsy. Proposed definition and classification of cerebral palsy, April 2005. Dev. Med. Child Neurol. 2005, 47, 571–576. [Google Scholar] [CrossRef] [PubMed]
  2. Kuban, K.C.; Leviton, A. Cerebral palsy. N. Engl. J. Med. 1994, 330, 188–195. [Google Scholar] [CrossRef] [PubMed]
  3. Koman, L.A.; Smith, B.P.; Shilt, J.S. Cerebral palsy. Lancet 2004, 363, 1619–1631. [Google Scholar] [CrossRef]
  4. Mutch, L.; Alberman, E.; Hagberg, B.; Kodama, K.; Perat, M.V. Cerebral palsy epidemiology: Where are we now and where are we going? Dev. Med. Child Neurol. 1992, 34, 547–551. [Google Scholar] [CrossRef] [PubMed]
  5. Yeargin-Allsopp, M.; Van Naarden Braun, K.; Doernberg, N.S.; Benedict, R.E.; Kirby, R.S.; Durkin, M.S. Prevalence of cerebral palsy in 8-year-old children in three areas of the united states in 2002: A multisite collaboration. Pediatrics 2008, 121, 547–554. [Google Scholar] [CrossRef] [PubMed]
  6. Wichers, M.J.; Odding, E.; Stam, H.J.; van Nieuwenhuizen, O. Clinical presentation, associated disorders and aetiological moments in cerebral palsy: A dutch population-based study. Disabil. Rehabil. 2005, 27, 583–589. [Google Scholar] [CrossRef] [PubMed]
  7. Palisano, R.J.; Hanna, S.E.; Rosenbaum, P.L.; Russell, D.J.; Walter, S.D.; Wood, E.P.; Raina, P.S.; Galuppi, B.E. Validation of a model of gross motor function for children with cerebral palsy. Phys. Ther. 2000, 80, 974–985. [Google Scholar] [PubMed]
  8. Hagglund, G.; Andersson, S.; Duppe, H.; Lauge-Pedersen, H.; Nordmark, E.; Westbom, L. Prevention of dislocation of the hip in children with cerebral palsy. The first ten years of a population-based prevention programme. J. Bone Jt. Surg. Br. 2005, 87, 95–101. [Google Scholar]
  9. Feldman, R.G.; Yang, R.R.; Koella, W.P. Spasticity: Disordered Motor Control; Year Book Medical Publishers: Chicago, IL, USA, 1980; pp. 485–495. [Google Scholar]
  10. Hagglund, G.; Wagner, P. Development of spasticity with age in a total population of children with cerebral palsy. BMC Musculoskelet. Disord. 2008, 9, 150. [Google Scholar] [CrossRef] [PubMed]
  11. Goldstein, E.M. Spasticity management: An overview. J. Child Neurol. 2001, 16, 16–23. [Google Scholar] [CrossRef] [PubMed]
  12. Strobl, W.; Theologis, T.; Brunner, R.; Kocer, S.; Viehweger, E.; Pascual-Pascual, I.; Placzek, R. Best clinical practice in botulinum toxin treatment for children with cerebral palsy. Toxins (Basel) 2015, 7, 1629–1648. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Kahraman, A.; Seyhan, K.; Deger, U.; Kutluturk, S.; Mutlu, A. Should botulinum toxin a injections be repeated in children with cerebral palsy? A systematic review. Dev. Med. Child Neurol. 2016, 58, 910–917. [Google Scholar] [CrossRef] [PubMed]
  14. Pirazzini, M.; Rossetto, O.; Eleopra, R.; Montecucco, C. Botulinum neurotoxins: Biology, pharmacology, and toxicology. Pharmacol. Rev. 2017, 69, 200–235. [Google Scholar] [CrossRef] [PubMed]
  15. Koman, L.A.; Mooney, J.F., 3rd; Smith, B.; Goodman, A.; Mulvaney, T. Management of cerebral palsy with botulinum-a toxin: Preliminary investigation. J. Pediatr. Orthop. 1993, 13, 489–495. [Google Scholar] [CrossRef] [PubMed]
  16. Pirazzini, M.; Azarnia Tehran, D.; Leka, O.; Zanetti, G.; Rossetto, O.; Montecucco, C. On the translocation of botulinum and tetanus neurotoxins across the membrane of acidic intracellular compartments. Biochim. Biophys. Acta 2016, 1858, 467–474. [Google Scholar] [CrossRef] [PubMed]
  17. Naidu, K.; Smith, K.; Sheedy, M.; Adair, B.; Yu, X.; Graham, H.K. Systemic adverse events following botulinum toxin a therapy in children with cerebral palsy. Dev. Med. Child Neurol. 2010, 52, 139–144. [Google Scholar] [CrossRef] [PubMed]
  18. Molenaers, G.; Schorkhuber, V.; Fagard, K.; Van Campenhout, A.; De Cat, J.; Pauwels, P.; Ortibus, E.; De Cock, P.; Desloovere, K. Long-term use of botulinum toxin type a in children with cerebral palsy: Treatment consistency. Eur. J. Paediatr. Neurol. 2009, 13, 421–429. [Google Scholar] [CrossRef] [PubMed]
  19. Moeini-Naghani, I.; Hashemi-Zonouz, T.; Jabbari, B. Botulinum toxin treatment of spasticity in adults and children. Semin. Neurol. 2016, 36, 64–72. [Google Scholar] [CrossRef] [PubMed]
  20. Scholtes, V.A.; Dallmeijer, A.J.; Knol, D.L.; Speth, L.A.; Maathuis, C.G.; Jongerius, P.H.; Becher, J.G. Effect of multilevel botulinum toxin a and comprehensive rehabilitation on gait in cerebral palsy. Pediatr. Neurol. 2007, 36, 30–39. [Google Scholar] [CrossRef] [PubMed]
  21. Lidman, G.; Nachemson, A.; Peny-Dahlstrand, M.; Himmelmann, K. Botulinum toxin a injections and occupational therapy in children with unilateral spastic cerebral palsy: A randomized controlled trial. Dev. Med. Child Neurol. 2015, 57, 754–761. [Google Scholar] [CrossRef] [PubMed]
  22. Heinen, F.; Molenaers, G.; Fairhurst, C.; Carr, L.J.; Desloovere, K.; Chaleat Valayer, E.; Morel, E.; Papavassiliou, A.S.; Tedroff, K.; Ignacio Pascual-Pascual, S.; et al. European consensus Table 2006 on botulinum toxin for children with cerebral palsy. Eur. J. Paediatr. Neurol. 2006, 10, 215–225. [Google Scholar] [CrossRef] [PubMed]
  23. Wang, Y.; Gao, B. A dose-response relationship research on botulinum toxin type a local intramuscular injections of lower extremity spasticity in children with cerebral palsy. Childs Nerv. Syst. 2008, 24, 545–547. [Google Scholar] [CrossRef] [PubMed]
  24. Baker, R.; Jasinski, M.; Maciag-Tymecka, I.; Michalowska-Mrozek, J.; Bonikowski, M.; Carr, L.; MacLean, J.; Lin, J.P.; Lynch, B.; Theologis, T.; et al. Botulinum toxin treatment of spasticity in diplegic cerebral palsy: A randomized, double-blind, placebo-controlled, dose-ranging study. Dev. Med. Child Neurol. 2002, 44, 666–675. [Google Scholar] [CrossRef] [PubMed]
  25. Ryll, U.; Bastiaenen, C.; De Bie, R.; Staal, B. Effects of leg muscle botulinum toxin a injections on walking in children with spasticity-related cerebral palsy: A systematic review. Dev. Med. Child Neurol. 2011, 53, 210–216. [Google Scholar] [CrossRef] [PubMed]
  26. Jang, D.H.; Sung, I.Y. The influence of physical therapy and anti-botulinum toxin antibody on the efficacy of botulinum toxin—A injections in children with spastic cerebral palsy. Dev. Neurorehabil. 2014, 17, 414–419. [Google Scholar] [CrossRef] [PubMed]
  27. Herrmann, J.; Geth, K.; Mall, V.; Bigalke, H.; Schulte Monting, J.; Linder, M.; Kirschner, J.; Berweck, S.; Korinthenberg, R.; Heinen, F.; et al. Clinical impact of antibody formation to botulinum toxin a in children. Ann. Neurol. 2004, 55, 732–735. [Google Scholar] [CrossRef] [PubMed]
  28. Kim, K.; Shin, H.I.; Kwon, B.S.; Kim, S.J.; Jung, I.Y.; Bang, M.S. Neuronox versus botox for spastic equinus gait in children with cerebral palsy: A randomized, double-blinded, controlled multicenter clinical trial. Dev. Med. Child Neurol. 2011, 53, 239–244. [Google Scholar] [CrossRef] [PubMed]
  29. Fazzi, E.; Maraucci, I.; Torrielli, S.; Motta, F.; Lanzi, G. Factors predicting the efficacy of botulinum toxin—A treatment of the lower limb in children with cerebral palsy. J. Child Neurol. 2005, 20, 661–666. [Google Scholar] [CrossRef] [PubMed]
  30. Fattal-Valevski, A.; Domenievitz, D.; Giladi, N.; Wientroub, S.; Hayek, S. Long-term effect of repeated injections of botulinum toxin in children with cerebral palsy: A prospective study. J. Child Orthop. 2008, 2, 29–35. [Google Scholar] [CrossRef] [PubMed]
  31. Tedroff, K.; Granath, F.; Forssberg, H.; Haglund-Akerlind, Y. Long-term effects of botulinum toxin a in children with cerebral palsy. Dev. Med. Child Neurol. 2009, 51, 120–127. [Google Scholar] [CrossRef] [PubMed]
  32. Chang, H.J.; Hong, B.Y.; Lee, S.J.; Lee, S.; Park, J.H.; Kwon, J.Y. Efficacy and safety of letibotulinum toxin a for the treatment of dynamic equinus foot deformity in children with cerebral palsy: A randomized controlled trial. Toxins (Basel) 2017, 9, 252. [Google Scholar]
  33. Koman, L.A.; Mooney, J.F., 3rd; Smith, B.P.; 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, 299–303. [Google Scholar] [CrossRef] [PubMed]
  34. Friedman, A.; Diamond, M.; Johnston, M.V.; Daffner, C. Effects of botulinum toxin a on upper limb spasticity in children with cerebral palsy. Am. J. Phys. Med. Rehabil. 2000, 79, 53–59. [Google Scholar] [CrossRef] [PubMed]
  35. Papavasiliou, A.S.; Rapidi, C.A.; Filiopoulos, C.; Rizou, C.; Skouteli, H.N. Evaluation of a multimodal management of prematurity-related spasticity. Pediatr. Neurol. 2006, 35, 400–407. [Google Scholar] [CrossRef] [PubMed]
  36. Yap, R.; Majnemer, A.; Benaroch, T.; Cantin, M.A. Determinants of responsiveness to botulinum toxin, casting, and bracing in the treatment of spastic equinus in children with cerebral palsy. Dev. Med. Child Neurol. 2010, 52, 186–193. [Google Scholar] [CrossRef] [PubMed]
  37. Pascual-Pascual, S.I.; Pascual-Castroviejo, I.; Ruiz, P.J. Treating spastic equinus foot from cerebral palsy with botulinum toxin type a: What factors influence the results?: An analysis of 189 consecutive cases. Am. J. Phys. Med. Rehabil. 2011, 90, 554–563. [Google Scholar] [CrossRef] [PubMed]
  38. Linder, M.; Schindler, G.; Michaelis, U.; Stein, S.; Kirschner, J.; Mall, V.; Berweck, S.; Korinthenberg, R.; Heinen, F. Medium-term functional benefits in children with cerebral palsy treated with botulinum toxin type a: 1-year follow-up using gross motor function measure. Eur. J. Neurol. 2001, 8, 120–126. [Google Scholar] [CrossRef] [PubMed]
  39. Rosenbaum, P.L.; Walter, S.D.; Hanna, S.E.; Palisano, R.J.; Russell, D.J.; Raina, P.; Wood, E.; Bartlett, D.J.; Galuppi, B.E. Prognosis for gross motor function in cerebral palsy: Creation of motor development curves. JAMA 2002, 288, 1357–1363. [Google Scholar] [CrossRef] [PubMed]
  40. Damiano, D.L.; Abel, M.F. Relation of gait analysis to gross motor function in cerebral palsy. Dev. Med. Child Neurol. 1996, 38, 389–396. [Google Scholar] [CrossRef] [PubMed]
  41. Moore, A.P.; Ade-Hall, R.A.; Smith, C.T.; Rosenbloom, L.; Walsh, H.P.; Mohamed, K.; Williamson, P.R. Two-year placebo-controlled trial of botulinum toxin a for leg spasticity in cerebral palsy. Neurology 2008, 71, 122–128. [Google Scholar] [CrossRef] [PubMed]
  42. Dianne, J.R.; Peter, L.R.; Lisa, M.A.; Mary, L. Gross Motor Function Measure (Gmfm-66 & Gmfm-88) User‘s Manual; Mac Keith Press: London, UK, 2002. [Google Scholar]
  43. Alotaibi, M.; Long, T.; Kennedy, E.; Bavishi, S. The efficacy of gmfm-88 and gmfm-66 to detect changes in gross motor function in children with cerebral palsy (cp): A literature review. Disabil. Rehabil. 2014, 36, 617–627. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Differences in physician’s rating scale (PRS) scores at 6 weeks, 12 weeks, and 24 weeks after botulinum toxin injection.
Table 1. Differences in physician’s rating scale (PRS) scores at 6 weeks, 12 weeks, and 24 weeks after botulinum toxin injection.
SubgroupsBaseline—6 Weeks Baseline—12 Weeks Baseline—24 Weeks
PRS < 2PRS ≥ 2pPRS < 2PRS ≥ 2pPRS < 2PRS ≥ 2p
N (%)N (%)N (%)N (%)N (%)N (%)
Pre-injection HistoryNone8 (16.7)40 (83.3)11 (22.9)37 (77.1)20 (41.7)28 (58.3)
Yes29 (30.5)66 (69.5)0.07425 (26.3)70 (71.1)0.65847 (50)47 (50)0.347
0−114 (19.7)57 (80.3)16 (22.5)55 (77.5)28 (39.4)43 (60.6)
>123 (31.9)49 (68.1)0.09520 (27.8)52 (72.2)0.47039 (54.2)32 (44.4)0.110
≤219 (20.2)75 (79.8)24 (25.5)70 (74.5)41 (43.6)52 (55.3)
>218 (36.7)31 (63.3)0.03212 (24.5)37 (75.5)0.89226 (53.1)23 (46.9)0.457
TypeUnilateral14 (29.2%)34 (70.8%)11 (22.9%)37 (77.1%)22 (46.8%)25 (53.2%)
Bilateral23 (24.2%)72 (75.8%)0.52325 (26.3%)70 (73.7%)0.65845 (47.4%)50 (52.6%)0.95
GMFCS levelI22 (24.4%)68 (75.6%)20 (22.2%)70 (77.8%)35 (39.3%)54 (60.7%)
II9 (26.5%)25 (73.5%)10 (29.4%)24 (70.6%)20 (58.8%)14 (41.2%)
III6 (31.6%)13 (68.4%)0.8096 (31.6%)13 (68.4%)0.56212 (63.2%)7 (36.8%)0.05
GMFCS: Gross Motor Function Classification System.
Table
Table 2. Differences in GMFM-88 scores between baseline and at 12 and 24 weeks after botulinum toxin injection according to number of previous injections.
Table 2. Differences in GMFM-88 scores between baseline and at 12 and 24 weeks after botulinum toxin injection according to number of previous injections.
Interval (Weeks)Previous Injection GMFM-Total ScoreGMFM-D ScoreGMFM-E Score
NMeanSDpMeanSDpMeanSDp
12None482.513.4552.214.0213.083.769
Yes951.693.2460.1640.862.8380.0422.754.6540.665
0–1712.113.0351.733.5332.393.404
>1721.823.6100.6120.903.0860.1373.325.1260.206
≤2941.993.1351.563.3552.383.957
>2491.913.7040.8960.843.2620.2163.784.9760.070
24None473.263.9412.494.1334.915.77
Yes942.5664.1590.3441.383.3860.0923.775.4110.247
0–1703.1194.0442.233.9904.305.494
>1712.4804.1320.3561.283.2960.1264.005.6190.749
≤2922.8254.0381.923.8474.105.475
>2492.7454.2180.9131.433.3420.4484.245.7140.881
GMFM: Gross Motor Function Measure, SD: Standard Deviation.
Table
Table 3. Multivariate regression analyses of variables on outcome (PRS ≥ 2) at 12 weeks after botulinum toxin injection, according to the number of previous injections (none or one, two or more).
Table 3. Multivariate regression analyses of variables on outcome (PRS ≥ 2) at 12 weeks after botulinum toxin injection, according to the number of previous injections (none or one, two or more).
VariablesCoeffSEOR95% CI (OR)p 1
Age−0.10840.10380.8970.7321.1000.2960
Gender
 Male−0.10330.39860.9020.4131.9700.7955
 Female1.000
PRS Score−0.19240.09420.8250.6860.9920.0410
GMFCS Level
 I1.000
 II−0.41750.57090.6590.2152.0160.4645
 III0.33370.95641.3960.2149.1000.7272
GMFM Score0.03640.02461.0370.9881.0880.1393
Previous injection
 >1−0.73220.44050.4810.2031.1400.0965
 0–11.000
Type
 Bilateral−0.54900.47370.5780.2281.4620.2465
 Unilateral1.000
1 p Value calculated by logistic regression analysis, GMFCS: Gross Motor Function Classification System, GMFM: Gross Motor Function Measure, OR: Odds Ratio, CI: Confidence Interval.
Table
Table 4. Multivariate regression analyses of effects of variables on outcomes (PRS ≥ 2) at 24 weeks after botulinum toxin injection according to number of previous injections: more than one vs. one or none.
Table 4. Multivariate regression analyses of effects of variables on outcomes (PRS ≥ 2) at 24 weeks after botulinum toxin injection according to number of previous injections: more than one vs. one or none.
VariablesCoeffSEOR95% CI (OR)p 1
Age0.14230.10401.1530.9401.4140.1711
Gender
 Male0.11840.37711.1260.5382.3580.7535
 Female1.000
PRS Score−0.17470.09260.8400.7001.0070.0592
GMFCS Level
 I1.000
 II−0.88340.56840.4130.1361.2590.1201
 III−1.77530.97370.1690.0251.1430.0683
GMFM Score0.00050.02401.0000.9541.0490.9850
Previous injection
 >1−0.88710.42560.4120.1790.9480.0371
 0–11.000
Type
 Bilateral0.18730.42981.2060.5192.8000.6630
 Unilateral1.000
1 p Value calculated by logistic regression analysis, PRS: Physician’s Rating Scale, GMFCS: Gross Motor Function Classification System., OR: Odds Ratio, CI: Confidence Interval.

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MDPI and ACS Style

Hong, B.Y.; Chang, H.J.; Lee, S.-J.; Lee, S.; Park, J.H.; Kwon, J.-Y. Efficacy of Repeated Botulinum Toxin Type A Injections for Spastic Equinus in Children with Cerebral Palsy—A Secondary Analysis of the Randomized Clinical Trial. Toxins 2017, 9, 253. https://doi.org/10.3390/toxins9080253

AMA Style

Hong BY, Chang HJ, Lee S-J, Lee S, Park JH, Kwon J-Y. Efficacy of Repeated Botulinum Toxin Type A Injections for Spastic Equinus in Children with Cerebral Palsy—A Secondary Analysis of the Randomized Clinical Trial. Toxins. 2017; 9(8):253. https://doi.org/10.3390/toxins9080253

Chicago/Turabian Style

Hong, Bo Young, Hyun Jung Chang, Sang-Jee Lee, Soyoung Lee, Joo Hyun Park, and Jeong-Yi Kwon. 2017. "Efficacy of Repeated Botulinum Toxin Type A Injections for Spastic Equinus in Children with Cerebral Palsy—A Secondary Analysis of the Randomized Clinical Trial" Toxins 9, no. 8: 253. https://doi.org/10.3390/toxins9080253

APA Style

Hong, B. Y., Chang, H. J., Lee, S. -J., Lee, S., Park, J. H., & Kwon, J. -Y. (2017). Efficacy of Repeated Botulinum Toxin Type A Injections for Spastic Equinus in Children with Cerebral Palsy—A Secondary Analysis of the Randomized Clinical Trial. Toxins, 9(8), 253. https://doi.org/10.3390/toxins9080253

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