Efficacy of Rehabilitation Therapy and Pharmacotherapy on Children with Cerebral Palsy: A Meta-Analysis.

Background: Cerebral palsy (CP) has a serious impact on children's multiple motor functions and life behavior. Rehabilitation therapy or pharmacotherapy alone has been proven to have a good effect on patients' strength and gait. However, the efficacy of rehabilitation combined with pharmacotherapy for CP in children needs to be further explored. This study is aimed at assessing the effectiveness of this combined method on life function and social behavior in children with CP.
Methods: PubMed, China National Knowledge Infrastructure, WanFang Data, EMBASE, and Web of Science databases were searched for all kinds of literature related to the treatment of pediatric CP published between 2000 and 2021. Basic information and experimental data from the literature were screened and extracted, and a meta-analysis was performed using Stata 16.
Results: A total of 605 studies were retrieved, and finally, 10 studies involving 805 pediatric patients were included in the analysis. The analysis results showed that rehabilitation combined with pharmacotherapy could improve the treatment effective rate in children with CP compared with the control group using either alone (RR = 1.184, 95% CI (1.102, 1.273), P < 0.001). In addition, in terms of social behavior, the combined therapy could significantly improve activities of daily living (SMD = 2.94, 95% CI (1.66, 4.22), P < 0.001), motor ability (SMD = 1.86, 95% CI (0.75, 2.96), P = 0.001), adaptability behavior (SMD = 2.82, 95% CI (0.45, 5.18), P = 0.019), language behavior (SMD = 3.08, 95% CI (0.95, 5.22), P = 0.005), social behavior (SMD = 3.78, 95% CI (2.22, 5.35), P < 0.001), and fine motor behavior (SMD = 3.52, 95% CI (1.17, 5.86), P = 0.003).
Conclusion: The current study shows that rehabilitation combined with pharmacotherapy can effectively improve the recovery, quality of life, and social behavior of children with CP.

1. Introduction

Cerebral palsy (CP) is a general term for a series of heterogeneous diseases caused by brain malformations or central nervous system damage [1]. CP patients generally have motor dysfunction and posture disorders affecting muscle tone, speech production, and gait and resulting in permanent nonprogressive central motor dysfunction; and these disorders can lead to difficulty balancing and loss of mobility in patients [1, 2]. Studies have shown that the prevalence of CP in the pediatric population is approximately 0.211% [3], and this disease limits patients' ability to live and is also a major common cause of long-term disability in children. If left untreated, this nonprogressive neurological disorder worsens, and other complications develop with age [4, 5]. Therefore, it is particularly important to treat CP in children so that they can resume their normal daily activities as well as social and recreational activities.

Due to individual differences in the causes of the disease and specific types of the disease, the patient population should be classified first using the International Classification of Function, Disability, and Health, and then targeted treatment should be taken [6]. There are three main methods to treat CP: surgical treatment, rehabilitation therapy, and pharmacotherapy. Impairments are the focus of rehabilitation therapy which can adopt Vojta therapy [7, 8], Bobath therapy [9], and other methods for rehabilitation training. Such training induces activities in the trunk, arms, legs, and other regions to activate the innate movement pattern of the human body, thus repairing muscle and nerve injury and improving postural control and motor ability of CP patients receiving early rehabilitation. In addition to rehabilitation training, there are a wide range of drug interventions to treat different disorders in CP patients. For example, botulinum toxin improves patients' motor ability and increases the range of goal-directed training for gross or fine motor [10, 11]; intrathecal injection of baclofen reduces dystonia and involuntary movements of hands and feet and increases the social participation of children [12, 13]; vitamin D supplementation not only plays a role in skeletal development and mineralization but also aids in language impairment improvement [14, 15]. Numerous studies on pharmacotherapy using botulinum toxin, baclofen, vitamins, and other drugs provide new clinical treatment ideas and some good evidence for clinical research and facilitate the exploration of more safe and effective treatment measures. Whether it is rehabilitation or pharmacotherapy, the common treatment goal is to improve the mobility and behavioral ability of CP patients and improve their quality of life.

In recent years, many studies have confirmed that rehabilitation combined with pharmacotherapy can improve treatment efficiency [16, 17]. However, due to the small sample size of individual studies and the inconsistent results between studies, there is still a lack of systematic evaluation on the effectiveness of rehabilitation combined with pharmacotherapy for CP in children. Therefore, the purpose of this study is to systematically evaluate the efficacy and safety of the combined therapy through meta-analysis and to comprehensively investigate its impact on patients' life function and social behavior.

2. Materials and Methods

2.1. Literature Search and Study Selection

This study was reported according to the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) 2015 statement [18].

Five major databases including PubMed, China National Knowledge Infrastructure, WanFang Data, EMBASE, and Web of Science were searched for literature that met the study topics and was published between January 1, 2000 and July 25, 2021. The keywords used were as follows: “rehabilitation therapy” or “rehabilitation training,” “pharmacotherapy,” “cerebral palsy in children” or “cerebral palsy,” etc. Similar keywords were connected with “or,” and different keywords were connected with “and.” There was no limitation of language.

2.2. Inclusion and Exclusion Criteria of Studies

2.2.1. Screening Criteria

(1) Study subject: patients younger than 18 years old and diagnosed with CP; (2) study type: randomized controlled trials (RCTs) using random number table or other methods; (3) according to different intervention measures, patients were divided into treatment group and control group. The treatment group was treated with drug therapy combined with rehabilitation, and the control group was treated with drug therapy or rehabilitation alone. Drug therapy included oral Chinese medicine, western medicine, or drug injection and other methods, while rehabilitation therapy was defined as nonpharmacological treatment, such as exercise therapy, traditional Chinese acupuncture therapy, guided education, and language therapy; (4) outcome measures: effective rate and score of the comprehensive ability of social life, including activities of daily living, motor ability, social adaptation, language behavior, social behavior, and fine motor.

2.2.2. Exclusion Criteria

(1) Data problems: the required data was missing or could not be extracted. (2) Special sample: study subjects who could not represent the group of children with CP, such as children with disability and other major diseases. (3) Article types: duplicate articles, reviews, case reports, letters, conference abstracts, animal experimental studies, or bioinformatics analysis.

2.3. Literature Screening and Data Extraction

Two investigators independently selected the relevant kinds of literature according to the inclusion and exclusion criteria and excluded duplicates. Then, they read the titles and abstracts. The full text of RCTs that met the previous step of screening would be read to determine whether they were finally included, and then be cross-checked. The inclusion of all literature was jointly decided by two reviewers. In case of different opinions, the disagreement could be resolved through negotiation or by a third party's decision. For duplicate reports or extended reports, the ones with complete data or published recently were selected.

Basic information extracted mainly included first author, year of publication, treatment cycle, subject-related information, interventions, study type, and outcome measures.

2.4. Statistical Analysis

Statistical analysis was performed using Stata 16 software. The heterogeneity of the included studies was assessed by the chi-square test and the I2 statistic. P < 0.05 and I2 > 50% indicated significant heterogeneity among studies, so the random-effects model was used for meta-analysis; conversely, the fixed-effects model was used [19, 20]. Sensitivity analyses were performed by removing each study one by one, aiming to determine the robustness of the pooling study results. Standard mean difference (SMD) was used as a measure for measurement data, and risk ratio (RR) and 95% confidence interval (CI) for categorical variables. P < 0.05 indicated statistically significant difference.

3. Results

3.1. Basic Information of the Included Studies

Combined with the retrieval strategy, we initially retrieved 605 related studies (Figure 1). The number was reduced to 157 after exclusion of literature inconsistent with the topic and repeated literature. The title/abstract and specific content of the remaining studies were further read to exclude studies that did not meet the inclusion criteria. Finally, 10 RCTs were included in this study [16, 17, 21–28]. The flowchart of literature screening is shown in Figure 1.

Figure 1

Literature screening flowchart.

The study characteristics of the included literature were extracted and collected as shown in Table 1. A total of 10 works of literature were included, with 9 in Chinese [16, 17, 21–23, 25–28] and 1 in English [24]. Totally, 805 patients with a mean age ranging from 2 to 9 years old were included. Additionally, the type of intervention in each trial was the same, while specific measures regarding pharmacotherapy and rehabilitation differed. The treatment group was treated with a combination of rehabilitation and pharmacotherapy; for the control group, 4 studies [21-24] received rehabilitation (Bobath method and Vojta therapy), and 6 studies [16, 17, 25–28] used pharmacotherapy (traditional Chinese medicine, botulinum toxin A, citicoline drugs, etc.).

Table 1

The basic characteristics of inclusion in the literature.

Study	Year	Cases treat/con	Age (years)		Sex (male/female)		Treatment measures	Study design	Outcome measures
			Treat group	Con group	Treat group	Con group
Zhu [16]	2018	47/47	4.4 ± 1.1	4.1 ± 1.2	28/19	29/18	Cytidine diphosphate choline, ganglioside + comprehensive rehabilitation6 VS. cytidine diphosphate choline, ganglioside	RCT	①③④⑤⑥⑦
Xie [17]	2021	47/47	4.1 ± 1.2	4.4 ± 1.1	28/19	29/18	Cytidine diphosphate choline + ganglioside + comprehensive rehabilitation3 VS. cytidine diphosphate choline + ganglioside	RCT	①②③④⑤⑥⑦
Xu et al. [21]	2014	43/43	3.5 ± 1.9	3.5 ± 1.8	23/20	25/18	Botulinum toxin type A + Vojta training VS. Vojta training	RCT	②③
Li et al. [22]	2018	39/39	4.5 ± 0.7	4.4 ± 0.5	20/19	18/21	Plasmin capsules + comprehensive rehabilitation training VS. comprehensive rehabilitation training1	RCT	①②③⑥
Zhang et al. [23]	2019	30/30	4.1 ± 0.9	4.0 ± 0.6	14/16	15/15	Chinese medicine antispasmodic prescription + Bobath therapy VS. Bobath therapy	RCT	①③
Schasfoort et al. [24]	2018	41/24	7.3 ± 2.3	7.3 ± 2.3	22/19	15/9	Botulinum toxin type A + intensive physiotherapy VS. intensive physiotherapy	RCT	③
Le [25]	2017	50/50	3.5 ± 1.1	3.0 ± 1.0	32/18	30/20	Cytidine diphosphate choline + comprehensive rehabilitation VS. cytidine diphosphate choline2	RCT	①②⑥
Xie [26]	2016	50/50	2.5 ± 0.5	2.4 ± 0.4	28/22	27/23	Hydrolysate of brain protein, cattle encephalon glycoside and ignotin injection + comprehensive rehabilitation7 VS. hydrolysate of brain protein, cattle encephalon glycoside and ignotin injection	RCT	①②
Zhang and Zhu [27]	2019	40/40	2.6 ± 1.3	3.1 ± 1.0	25/15	29/11	Mecobalamin injection, VB6, compound levodopa, hydrolysate of brain protein + comprehensive rehabilitation4 VS. mecobalamin injection, VB6, compound levodopa, hydrolysate of brain protein	RCT	②③④⑤⑥⑦
Zhao [28]	2019	24/24	2.7 ± 1.5	2.8 ± 1.4	18/6	17/7	Mecobalamin injection, VB6, compound levodopa, hydrolysate of brain protein, VC + comprehensive rehabilitation VS. mecobalamin injection, VB6, compound levodopa, hydrolysate of brain protein, VC	RCT	②③④⑤⑥⑦

Note: Treat: treatment; Con: control; RCT: randomized controlled trial; NR: not reported; ①: effective rate; ②: activity of daily living score after treatment; ③: motor ability score after treatment; ④: social adaptation behavior score after treatment; ⑤: language behavior score after treatment; ⑥: social behavior score after treatment; ⑦: fine motor behavior score after treatment. 1: massage, hydrotherapy, balance training, and Vojta induction therapy; 2: psychological intervention, language, intelligence training, acupuncture and massage, etc.; 3: Botath therapy and Vojta therapy; 4: Botath therapy and Vojta therapy, hyperbaric oxygen therapy, conductive education, acupuncture and massage, and language training; 5: Botath therapy and Vojta therapy, hyperbaric oxygen therapy, conductive education, acupuncture and massage, and language training; 6: Botath therapy and Vojta therapy; 7: hyperbaric oxygen therapy, acupuncture and massage, language training, exercise therapy, and occupational therapy.

3.2. Meta-Analysis Results of Effective Rate

Six studies [16, 17, 22, 23, 25, 26] compared the effective rate between the two groups. No significant heterogeneity was found (I2 = 0.0%, P = 0.919), so the fixed-effects model was used for meta-analysis. According to the pooling of effect sizes, a combination of rehabilitation and pharmacotherapy was more effective than either alone (RR = 1.184, 95% CI (1.102, 1.273), P < 0.001), as shown in Figure 2. Further sensitivity analysis showed that removing each study one by one had little effect on the pooling effect results, as shown in Figure 3. Such outcomes suggested that the results of this study were relatively stable and reliable.

Figure 2

Forest map to compare the effective rate of two groups of children with cerebral palsy after treatment.

Figure 3

Sensitivity analysis of the effective rate of two groups of children with cerebral palsy after treatment.

3.3. Meta-Analysis Results of Prognostic Function Scores

Seven [17, 21, 22, 25–28] studies analyzed patients' postoperative activities of daily living, and 8 [16, 17, 21–24, 27, 28] studies recorded postoperative motor ability score in both groups. The difference in each score between the two groups was analyzed by meta-analysis. The random-effects model was used for analysis on activities of daily living score (I2 = 96.9%, P < 0.05) and motor function score (I2 = 96.8%, P < 0.05). According to the results shown in Figures 4(a) and 4(b), rehabilitation combined with pharmacotherapy could achieve higher scores of activities of daily living (SMD = 2.94, 95% CI (1.66, 4.22), P < 0.001) motor ability score (SMD = 1.86, 95% CI (0.75, 2.96), P = 0.001) in comparison with either alone. Since there was heterogeneity among the included studies, sensitivity analysis was further performed for studies related to these two measures. By removing individual studies one by one, no literature was found to have a significant impact on the overall research results on activities of daily living score daily, as shown in Figure 5(a). Similarly, analysis of the literature on motor function score revealed that the obtained effect size before and after one-by-one removal fluctuated around the overall effect sizes, and no studies were found to have a major impact on the overall effect, as shown in Figure 5(b). Such outcomes suggested that the results of this study were relatively stable and reliable.

Figure 4

Forest map to compare the prognostic function scores of two groups of children with cerebral palsy after treatment. (a) Forest map of activities of daily living score. (b) Forest map of motor function score.

Figure 5

Sensitivity analysis of prognostic function scores of two groups of children with cerebral palsy after treatment. (a) Sensitivity analysis of daily living activities scores. (b) Sensitivity analysis of motor function scores.

3.4. Prognostic Behavior Scores

Meta-analysis was performed on the prognostic behavior scores of the patients, with a higher score indicating a more obvious therapeutic effect. Four studies [16, 17, 27, 28] compared the scores of social adaptation, language behavior, and fine motor between the two groups. Six studies [16, 17, 22, 25, 27, 28] compared social behavior scores between the two groups. Based on the heterogeneity test, the random-effects model was used for analysis of scores of social adaptation (I2 = 98.2%, P ≤ 0.001), language behavior (I2 = 97.6%, P ≤ 0.001), social behavior (I2 = 97.0%, P ≤ 0.001), and fine motor (I2 = 97.8%, P ≤ 0.001). The results showed that rehabilitation combined with pharmacotherapy could significantly improve patients' prognostic behavior, including social adaptation (SMD = 2.82, 95% CI (0.45, 5.18), P = 0.019; Figure 6(a)), language behavior (SMD = 3.08, 95% CI (0.95, 5.22), P = 0.005; Figure 6(b)), social behavior (SMD = 3.78, 95% CI (2.22, 5.35), P < 0.001; Figure 6(c)), and fine motor (SMD = 3.52, 95% CI (1.17, 5.86), P = 0.003; Figure 6(d)). Since there was heterogeneity among the included studies, sensitivity analysis was further performed for studies related to prognostic behavior scores; no literature was found to have a significant effect on the overall study results (Figures 7(a)–7(d)). Therefore, the results of this study were relatively stable and reliable.

Figure 6

Forest map to compare the prognostic behavior scores of two groups of children with cerebral palsy after treatment. (a) Forest map of social adaptation score. (b) Forest map of language behavior score. (c) Forest map of social behavior score. (d) Forest map of fine motor score.

Figure 7

Sensitivity analysis of prognostic behavior scores of two groups of children with cerebral palsy after treatment. (a) Sensitivity analysis of social adaptation score. (b) Sensitivity analysis of language behavior score. (c) Sensitivity analysis of social behavior score. (d) Sensitivity analysis of fine motor score.

4. Discussion

CP leads to serious damage to the physical and mental health of patients, the effect of simple drug treatment is poor, and this disease cannot be fundamentally cured [14]. Many existing treatment methods can develop into different combined treatments, but their safety and efficacy require continuous evaluation and feedback. A report released by the World Health Organization stated that the treatment for disability cases not only focuses on changes in the patient's physiological structure and function after a disease or accident but also emphasizes the participation in social activities that interact with the environment [29]. Compared with single therapeutic manipulation, rehabilitation therapy combined with pharmacotherapy can carry out comprehensive training in many aspects such as physiology, language, movement, and personality. This combined therapy can improve the physiological function and physical activity ability of patients and, therefore, enables them to independently engage in social activities.

Scoring criteria of the specific scales are used for quantification and then to obtain prognosis scores, with a higher score indicating a better effect. All scale scores are presented in the form of numerical values, with the Gross Motor Function Measure (GMFM) [30] and Gesell Developmental Scale (GDS) [31] being used the most. The GDS has a wide range of assessments, including adaptive behavior, fine motor, gross motor, social behavior, and language. The correlative study [28] used 4 scoring scales (GMFM, GDS Gesel, Functional Independence Measure for Children (Wee-FIM) [32], and Pediatric Quality of Life Inventory (PedsQL)) [33] to comprehensively score various indicators and explain the study conclusions. Overall, the repeated scoring of indicators with multiple scales can more accurately reflect the treatment effect of interventions.

Vargus-Adams and Martin proposed 8 important domains for assessing treatment outcomes of CP, including impairment, general health, gross motor skills, self-care/fine motor skills, speech/communication, integration/participation, quality of life, and caregiver issues [34]. In our study, which included 10 RCTs, there were no relevant measures of impairment and caregiver issues; in the integration/participation domain, 6 studies [16, 17, 22, 25, 27, 28] assessed social behavior ability, 4 studies [16, 17, 27, 28] assessed social adaptation; in the other domains, 7 studies [17, 21, 22, 25–28] recorded activities of a daily living score, and 4 studies [16, 17, 27, 28] assessed language function. The indicators mentioned above were analyzed, and the results showed that rehabilitation therapy combined with pharmacotherapy could improve the treatment response rate, daily life ability, motor ability, language ability, social behavior ability, and fine motor of children with CP, providing a new therapeutic idea for such patients.

However, even though the results of this study are stable and reliable, there are still some limitations. First, in this study, the included literature was obtained by searching electronic databases and manually screening literature. The omission of some qualified studies may be caused by the deficiencies in literature search resources and retrieval strategies, thus leading to publication bias. Therefore, it is necessary to comprehensively collect a large number of well-designed and large-sample experiments for future research. Second, in the included experimental studies, the control group and the treatment group were different in drug selection, dosage, frequency, and course of drug use, which may lead to heterogeneity. Third, there is diversity in scoring scales, and the scoring uniformity among various studies is low. Therefore, high-quality scales should be used for repeated scoring as much as possible. Collectively, large-sample, high-quality studies are needed to be carried out to enhance the accuracy and credibility of the findings and to provide a more effective method for the clinical treatment of CP.

5. Conclusion

In summary, this meta-analysis shows that rehabilitation combined with pharmacotherapy has a significant positive effect on daily life function and social behavior of children with CP. Compared with single treatment alone, combined therapy is more effective, and more comprehensively improves the quality of life and social behavior ability of patients, with a high value of clinical promotion.