Low- versus high-dose botulinum toxin A injection for the treatment of upper limb spasticity in pediatric patients with cerebral palsy: A systematic review and meta-analysis

INTRODUCTION

Cerebral palsy (CP) is a lifelong neurological condition that affects posture, mobility, and muscle tone. CP presents in three main forms: Spastic type, dyskinetic type, and ataxic and mixed type.^[1] Among these, the spastic type reigns dominant, impacting around 80% of children with CP.^[2-4]

Spastic CPs’ clinical appearance varies widely, depending on the location and time the brain injury occurred.^[5] While both upper and lower motor neurons can be affected, damage to the upper motor neuron often holds the reins, significantly hindering daily life functions. For pediatric neurologists, tackling this disability takes center stage, leading them to prioritize management options for this specific type of CP. The mainstay of treatment is occupational therapy, physiotherapy, and anti-spastic pharmacotherapy.^[6]

By inhibiting the presynaptic production of acetylcholine from motor endplates of the lower motor nerve at the myoneural junction, Botulinum toxin A (BTX-A) injections directly into the muscle can temporarily reduce spasticity in children with spastic predominating CP.^[6]

The first paper that used BTX-A in children with CP was by Koman et al. in the United States in 1993. The study was conducted on 27 children with CP, and the conclusion indicated that BTX-A injection is a safe method that can improve muscle spasticity and delay surgical interventions.^[7]

In a double-blind, randomized, and placebo-controlled study, Corry et al. found that giving injections to several muscles in the spastic upper extremity of children with CP may improve their tone, range of motion, grasp, and cosmesis. Still, they did not affect their functional ability when picking up coins.^[8]

Despite its established role, the optimal BTX-A dosage remains an ongoing investigation. While some studies advocate for higher doses (8–16 U/kg) for their superior spasticity reduction compared to lower ones (2–6 U/kg), others paint a different picture. Studies indicate that the dosage could not substantially affect upper extremity function as determined by certain assessments such as the Quality of Upper Extremity Skills Test (QUEST). Adding to the complexity, other studies indicate efficacy across all dose ranges (2 U/kg, 6 U/kg, and 8 U/kg) for different clinical patterns of spasticity. Compared to the low dosage 2 U/kg control, therapy with 8 U/kg or 16 U/kg BTX-A in the afflicted upper limb dramatically improved muscular tone and spasticity in one randomized trial.^[9]

Furthermore, a three-month study using the QUEST to compare the dosage of BTX-A in the upper extremities of children with spasticity found no statistically significant difference in upper extremity function between the low-dose and high-dose groups.^[10,11]

In addition, according to another randomized controlled trial (RCT),^[12] all three dosages (8 U/kg, 6 U/kg, and 2 U/kg) substantially decreased spasticity in all three dose groups across all upper-limb clinical characteristics treated.

Navigating this sea of conflicting findings can be daunting for clinicians, caregivers, and patients. This is where our systematic review steps in. To manage spasticity and enhance upper limb mobility and function in children with CP, we aimed to thoroughly examine research on low-dose versus high-dose BTX-A injections. By weighing each approach’s benefits and potential side effects, we hope to equip health-care professionals and families with evidence-based information to guide their decision-making process and pave the way for optimizing spasticity management in this vulnerable population.

MATERIALS AND METHODS

The Preferred Reporting Items for Systematic Reviews and Meta-Analysis checklist was applied to perform and document this study using a specified methodology.

RESULTS

Search

Our comprehensive search through 584 articles yielded only three eligible RCTs on BTX-A dosage for children with CP with upper limb spasticity [Figure 1].^[9,11,12]

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Figure 1:

Flow diagram.

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Risk of bias assessment

Two of the three included RCTs were considered to have a low overall risk of bias, while one’s missing outcome data raised a few concerns. None of the studies showed any evidence of a significant overall risk of bias [Figures 2 and 3].

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Figure 2:

Risk of bias graph.

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Figure 3:

Risk of bias summary. Yellow circle (question mark): Unclear risk of bias, green circle (plus sign): Low risk of bias, empty box: High risk of bias.

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Outcomes

GAS

Two RCTs provide data about GAS.^[9,11] A total of 53 individuals were allocated low doses of BTX-A, and 66 were allocated high doses of BTX-A. Data were reported at follow-up periods of 3 months. Overall, there was no apparent difference between the high and low doses in terms of GAS (standard deviation mean [SDM] = 0.11, 95% confidence interval [CI] [–0.25, 0.48], with P-value of = 0.54) [Figure 4]. Since the funnel plot was symmetric, there was no evidence of publishing bias.

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Figure 4:

Forest plot for Goal Attainment Scaling after 3 months of Botulinum toxin type A injection. SD: Standard deviation, IV: Weighted mean difference, CI: Confidence interval, df: Degrees of freedom, Chi²: Chi-square statistic, P: P-value, I²: I-square heterogeneity statistic, Z: Z statistic.

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MAS

All three RCTs provided data about the MAS.^[9,11,12] A total of 175 individuals were allocated low doses of BTX-A, and 265 were allocated high doses of BTX-A. Data were reported by muscle groups. Overall, low dosage and high dose did not significantly differ from one another in terms of MAS (SDM = −0.01, 95% CI [–0.21, 0.19], with a P-value of = 0.93) [Figure 5]. The funnel plot was asymmetric, which indicates that there is a notable publication bias.

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Figure 5:

Forest plot for Modified Ashworth scale after Botulinum toxin type A injection. SD: Standard deviation, IV: Weighted mean difference, CI: Confidence interval, df: Degrees of freedom, Chi²: Chi-square statistic, P: P-value, I²: I-square heterogeneity statistic, Z: Z statistic.

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AEs

All three RCTs provided data about the AEs.^[9,11,12] Overall, there was no discernible difference between the high and low dosages (OR = 1.12, 95% CI [0.77, 1.62], with a P-value of = 0.55) [Figure 6]. The funnel plot was asymmetric, indicating a notable publication bias.

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Figure 6:

Forest plot for intensity of the adverse events after botulinum toxin type A injection. M-H: Mantel-Haenszel, CI: Confidence interval, df: Degrees of freedom, Chi²: Chi-square statistic, P: P-value, I²: I-square heterogeneity statistic, Z: Z statistic.

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DISCUSSION

The results of this systematic review and meta-analysis, encompassing three RCTs with 512 participants, aimed to compare the efficacy of high-dose (8–16 U/kg) versus low-dose (2–6 U/kg) BTX-A injections in enhancing upper limb mobility and function in pediatric CP patients.

BTX-A functions by inhibiting acetylcholine release at the neuromuscular junction, reducing muscle spasticity and improving motor function. This mechanism is particularly beneficial for managing spasticity in children with CP, as it allows for temporary muscle relaxation, facilitating better movement and potentially enhancing the effectiveness of adjunct therapies such as physiotherapy and occupational therapy.^[6]

Our findings indicate that in terms of functional outcomes assessed using the GAS, there was no significant difference between low-dose and high-dose BTX-A injections. This result suggests that both dosage regimens might provide similar benefits in reaching specific functional goals. Similarly, assessments using the MAS did not show a significant difference between the two dosage groups, indicating similar reductions in muscle tone irrespective of BTX-A dosage. These results align with the previous studies that have failed to demonstrate a clear superiority of high-dose over low-dose BTX-A injections in improving upper limb spasticity.^[11]

It is also essential to note that the incidence of adverse effects did not change significantly between the BTX-A groups receiving high and low doses. The comparable safety profiles of both dosing regimens assure physicians of the relative risk of BTX-A injections in children with CP. This is particularly important as safety is a critical consideration in pediatric treatments.

A recent evidence-based review corroborated that BTX-A injections could improve body function and activity alongside reducing spasticity as measured by MAS.^[15] Moreover, a systematic review supports the idea that using BTX-A injections on the upper limbs of children with CP can yield good outcomes by reducing spasticity. However, the review also emphasized that BTX-A should be combined with occupational or physiotherapy to achieve optimal results. This same study reported that the safe dose with minimal side effects ranged from 0.5 U to 16 U/kg body weight.^[6]

Regarding the effect of BTX-A injections in the lower extremities of children with CP, both low and high doses were associated with improvements in the passive range of motion as measured by the Tardieu scale. In addition, higher doses were found to be safe and well-tolerated, similar to our findings for upper limb treatments.^[16]

In addition to treating spasticity in CP, BTX-A has several other medical indications. These include managing chronic migraines, treating hyperhidrosis (excessive sweating), addressing overactive bladder, and reducing the appearance of facial wrinkles.^[17-20] BTX-A is also used in the treatment of conditions such as cervical dystonia, blepharospasm (uncontrolled blinking), and strabismus (crossed eyes), highlighting its versatility and broad therapeutic potential.^[21]

Finally, the distinction between upper and lower limb spasticity is significant. Lower limb spasticity often involves more widespread and severe spasticity, which might require higher doses of BTX-A, while upper limb spasticity typically requires a more precise, individualized dosing approach. Although further research is necessary, there is potential for the higher doses used to treat lower limb spasticity to be applied to upper limb spasticity, potentially improving outcomes in some cases.

In conclusion, our findings suggest that both low-dose and high-dose BTX-A regimens offer comparable efficacy and safety profiles in managing upper limb spasticity in children with CP. Therefore, factors such as patient tolerance, injection site concerns, and recent treatment outcomes should be considered when choosing a dosing strategy. Moreover, it is important to consider in future studies that higher doses involve greater costs, and as indicated in this paper, higher doses do not necessarily result in better outcomes. This economic consideration is crucial for both health-care providers and patients’ families when planning long-term management strategies for CP. On the other hand, from a long-term perspective, higher doses may prove more cost-effective, as they typically require fewer sessions per year. Furthermore, the higher dose group often experiences a longer sustained duration of improvement compared to the lower dose group, which can alleviate emotional distress for the child and reduce interruptions to family life.^[6]

CONCLUSION

This study provides valuable clinical insights. We have demonstrated that high-dose and low-dose BTX-A did not differ significantly in efficacy or AEs regarding the outcomes we assisted in this review. However, further research is crucial.

RECOMMENDATIONS

Future trials should include larger sample size, longer follow-ups, consistent dose definitions, and comprehensive safety assessments to optimize BTX-A therapy while avoiding adverse effects. Nevertheless, considering the possible limitations, we suggest caution when using this finding.

AUTHORS’ CONTRIBUTIONS

AKB contributed to the study’s design and writing of the final manuscript. LA contributed to the research idea, design of the study, data extraction, statistical analysis/interpretation, risk of bias assessment, and editing of the final manuscript. HMA and HFA contributed to the study’s design, data extraction, risk of bias assessment, and final manuscript writing. SMA and ASA contributed to the data extraction and writing of the final manuscript. All authors have critically reviewed and approved the final draft and are responsible for the manuscript’s content and similarity index.