Neuromuscular mechanisms that contribute to gross motor performance in survivors of childhood acute lymphoblastic leukemia

1 Introduction

Acute lymphoblastic leukemia (ALL) is the most prevalent pediatric cancer, with survival rates exceeding 90 percent [1]. ALL is commonly diagnosed in children younger than 10 years of age and requires medical treatment lasting two to three years. This is a critical time period for the development of gross motor skills, such as jumping. The skill of jumping is required in many childhood physical activities such as playground activities and sports. However, many survivors of childhood ALL (ALL CCS) experience long-term peripheral and central nervous system (CNS) neurotoxic side effects [2–4] that can lead to poor muscle function [5–13], decreased balance proficiency [14–17], impaired gross motor mobility [5, 11] and reduced physical activity levels [18].

The chemotherapy agents most commonly used in ALL treatment include vincristine, methotrexate, mercaptopurine (6-MP), cytarabine, doxorubicin, busulfan, cyclophosphamide, and L-asparaginase. Specifically, vincristine and methotrexate have known short- and long-term neurotoxic side effects that impact the sensory and motor function of distal muscles of the lower extremities [2, 3] and motor processing speed [19]. These physiological changes negatively impact the capacity to acquire and refine muscle activation patterns [6, 11]. As a consequence, muscle activation takes longer [2, 3], motor timing is slower [20], ankle dorsiflexion range of motion is limited [7, 21–23], and agonist and antagonist muscles co-activate during gross motor tasks such as walking [4, 6].

The deficits in the sensory and motor systems in ALL CCS limit the ability to participate in sports or other recreational activities and to keep up with peers [10]. The development of age-appropriate motor skills is necessary to facilitate participation in physical activity and maintain health-related fitness levels [24]. Deficits in gross motor skills can limit engagement in age-appropriate physical activities and can significantly influence the child or adolescent’s quality of life [25]. Additionally, participation in sports and physical activity is associated with improved general health, disease prevention, social behavior, and psychosocial development [25]. Fewer experiences that stimulate neuromuscular input and output can impair balance control and thus impede participation in physical activities [18]. Studies that investigate the mechanisms of neuromuscular function and gross motor performance in ALL CCS are necessary to develop targeted interventions.

The primary purpose of this study was to explore the neuromuscular mechanisms, including the rate of muscle activation and joint torques, that contribute to countermovement jump performance as measured by jump height in ALL CCS compared to age- and sex-matched peers without ALL. The secondary purpose was to explore the clinical measures of muscle extensibility, balance, and mobility and their contribution to jumping performance. We hypothesized that compared to age- and sex-matched controls, ALL CCS would have lower anterior tibialis and gastrocnemius muscle activation rates, decreased joint torques, and reduced jump height during a countermovement jump. Additionally, we hypothesized that ALL CCS would present with impaired gastrocnemius muscle extensibility and poorer balance and mobility performance, measured by the Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition (BOT-2) and Timed Up and Go (TUG) respectively, as compared to controls. The relationships between neuromuscular mechanisms and clinical measures of muscle extensibility, balance, and mobility were explored. We hypothesized that there would be positive correlations between muscle extensibility, rate of muscle activation, and joint torques with jump height, a positive correlation between jump height with BOT-2 scores, and a negative correlation with TUG time.

2 Methods

3 Results

A total of 12 children participated in this study, six ALL CCS (3 males, 3 females), and six age- and sex-matched controls. Descriptive characteristics of individual participants are listed in Table 1. ALL CCS mean age was 11.52±3.27 years, and the control group was 10.92±3.55 years. There were no significant differences in age, height, weight, or reported level of participation, as measured with the CAPE, between the groups. The mean age of diagnosis was 5.93±3.08 years, time on treatment for ALL CCS was 35.16±5.74 months, and time from completion of medical intervention (off-treatment) for the ALL CCS was 27.50±17.24 months.

While performing a countermovement jump, ALL CCS demonstrated a significantly reduced rate of muscle activation of the tibialis anterior muscle as compared to controls (p = 0.030) (Fig. 1), but no significant differences in the rate of activation of the soleus (p = 0.328) or lateral gastrocnemius (p = 0.247) muscles. Of the three lower extremity joints, there were no significant between-group differences in the amount of peak torque that was developed at the ankles (p = 1.00), knees (p = 0.485), or hips (p = 0.818) during the acceleration phase of the countermovement jump (Fig. 2B-D). ALL CCS presented with significantly reduced peak jump height compared to controls (p = 0.041) (Table 2 and Fig. 2A).

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Fig. 1

Rate of muscle activation of ALL CCS (gray bar) and controls (black bar) for the soleus, gastrocnemius, and tibialis anterior muscles. Expressed as the mean and standard error. ^*P < 0.05 for Mann-Whitney U.

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Fig. 2

The jump height (A) and peak joint torque of the hip (B), knee (C), and ankle (D) of the ALL CCS (gray bar) and age- and sex-matched controls (black bar). Expressed as a mean and standard error. ^*P < 0.05 for Mann-Whitney U.

ALL CCS had significantly less gastrocnemius extensibility (p = 0.015) and lower scores on the BOT-2 balance subscale (p = 0.004), and they took longer to complete the TUG (p = 0.002) than the controls (Table 2). There was a strong correlation between the time off-therapy with the BOT-2 balance scale (r_s = 0.93; p = 0.008), but not between the rate of muscle activation of the gastrocnemius muscle, peak jump height, gastrocnemius extensibility, or TUG time. There were moderate correlations between peak jump height with the BOT-2 (r_s = 0.78, p = 0.003) and TUG time (r_s = –0.61, p = 0.037) (Fig. 3). Gastrocnemius extensibility was negatively correlated with the time to complete TUG (r_s = –0.67, p = 0.017).

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Fig. 3

Relationships between jump height versus (A) Timed-Up and Go (TUG) and (B) Bruininks-Oseretsky Test of Motor Proficiency 2 (BOT-2), balance subscale in ALL CCS (filled circles) and controls (open triangles).

This study explored the neuromuscular mechanisms that contribute to countermovement jump performance in ALL CCS compared to age- and sex-matched peers. Our results showed that, compared to peers, this sample of ALL CCS demonstrated deficits in gross motor performance with a decreased jump height, reduced gastrocnemius muscle extensibility, lower BOT-2 balance scores, and increased time to complete the TUG. The neuromuscular deficit of the reduced tibialis anterior rate of muscle activation was also noted in ALL CCS compared to peers. Jump height was significantly correlated with clinical measures of the BOT-2 and TUG.

Jumping is essential to successfully complete many tasks of daily life, play, and sports such as ballet, soccer, volleyball, and basketball. Jump performance is often used as an indicator of athletic potential [36, 37] and requires an ability to rapidly activate the muscles for balance control and coordination. In this study, ALL CCS demonstrated deficits in the ability to achieve jump height similar to their age- and sex-matched peers. This may limit their ability to participate in the same activities as children their own age with typical development. Järvelä et al. (2010) previously identified deficits in vertical jump height in long-term survivors of ALL that were 11 to 21 years post-diagnosis [18]; however, they did not explore the relationships of the deficits in jump performance with clinical measures of extensibility, balance, and mobility.

Potential underlying mechanisms that contribute to the deficits observed in higher-level gross motor tasks such as jump performance are treatment-related side effects, including chemotherapy-induced peripheral neuropathy (CIPN), that result in sensory and motor deficits. CIPN as commonly experienced by ALL CCS limits the somatosensory information received by the CNS [2]. As a result of medical treatment, ALL CCS demonstrate loss of lean muscle mass [38, 39], loss of ankle dorsiflexion range of motion [7, 21–23], delays in cortical processing [19], and demyelination in the motor pathways [3]. Wright et al. (2017) found that the majority of ALL CCS with CIPN that were on average 11.2 + 5.7 years of age had abnormal EMG firing patterns in the anterior tibialis (76%) and the gastrocnemius muscle (94%) during walking [6]. CIPN leads to reduced ankle active and passive dorsiflexion range of motion, a common effect of ALL medical treatment [7, 21–23] that has been described as a significant correlate to jumping performance [40]. However, our results demonstrated that gastrocnemius muscle extensibility did not correlate with jump height in this sample of ALL CCS. One possible reason for the difference may be that we measured the gastrocnemius extensibility with the knee in extension, which may not fully capture the functional length of the muscle during the jumping task. Secondly, the countermovement jump utilizes the stretch-shortening cycle, which is a rapid eccentric contraction followed by a concentric contraction, and may contribute to jump height [41, 42]. At the lowest point of the jump, the knees are flexed and the ankles are dorsiflexed. Assessment and exercise interventions that aim to measure and enhance the stretch-shortening cycle, such as stretching and eccentric and concentric muscle training, could be useful in ALL CCS to improve jump performance.

Balance is an underlying control process that is necessary for smooth, coordinated movement and is essential for walking, running, and jumping. Consistent with previous observations, our findings identified that ALL CCS had poorer balance proficiency as measured by the BOT-2 balance subscale [14–17] and took longer to complete the TUG compared to age- and sex-matched peers [5, 11]. Our results also identified that time off-treatment had a positive correlation with BOT-2 balance performance. Gilchrist and Tanner (2018) reported significant balance deficits in children and adolescents during and after ALL treatment, and these deficits improved with time from completion of medical treatment. However, deficits in balance performance still persisted compared to expected age-related outcomes [14]. Furthermore, balance deficits persist into adulthood, placing ALL CCS at increased risk for falls and early frailty [7]. Previous studies in ALL CCS have examined static or dynamic balance and found deficits in both. However, both components of balance are necessary for executing higher-level motor tasks such as running and jumping [7, 44]. Balance is an important and integral part of daily activities of living. Thus, remediating these deficits early is necessary to avoid the long-term consequences as found in the ALL CCS.

We found that balance and mobility were associated with jump height. Granacher and Gollhofer (2012) suggest that measurements of static and dynamic balance control in children are independent of muscle strength [43]. Our findings of jump height deficits in this sample of ALL CCS may represent a combination of static and dynamic balance deficits in addition to deficits in the ability to generate muscle forces quickly. In numerous published studies, ALL CCS presented with decreased strength of the knee [7–10, 13] and ankle [6, 13]. Therefore, we expected that joint torques of at least one lower extremity joint would differ between ALL CCS and age- and sex-matched peers [45]. Although ALL CCS presented with lower knee and hip torques, no significant differences were detected during the countermovement jump. Therefore, the muscle strength of hip, knee, and ankle extensors may not be the sole contributor to the observed deficits in the countermovement jump height in this ALL CCS sample. Balance impairments in ALL CCS may contribute to poorer jump performance and landing control [46], which could increase the risk of injury. Hence, this study supports the continued need for exploration of jump-related assessments and exercise interventions targeting balance and concentric and eccentric muscle actions in ALL CCS.

The small sample size and absence of specific chemotherapy exposure, secondary medical complications, or measure of peripheral neuropathy in this study limit the ability to assess the effects of individual chemotherapy agents. However, it is important to note that the variety of participants and clinical presentations in this study highlights the importance of individualized assessment and intervention for the spectrum of survivorship in ALL CCS. Further studies with a larger sample size are required to comprehensively examine the neuromuscular mechanisms that contribute to gross motor performance and to address the effects of targeted therapeutic interventions.

5 Conclusions

The results from this study identified that ALL CCS demonstrate neuromuscular impairments that impact jump performance, an essential childhood physical activity. Countermovement jump height was related to balance proficiency and mobility performance. Further research needs to be performed to explore intervention strategies to improve the neuromuscular mechanisms that contribute to high-level gross motor skills in ALL CCS.