Quantifying muscle strength, size, and neuromuscular activation in adolescent and young adult survivors of musculoskeletal sarcoma: Identifying correlates and responses to functional strengthening

Abstract

Background:

Medical and surgical treatment for musculoskeletal sarcoma (MSS) place survivors at risk for impairments in muscle properties including muscle strength, muscle size, and neuromuscular activation. The purpose of this study was to explore muscle properties, gross motor performance, and quality of life (QoL) and the changes in response to a 6-week functional strengthening intervention (PT-STRONG) in MSS survivors of childhood cancer (CCS).

Methods:

Eight lower extremity MSS CCS (13–23 years old) performed baseline testing and three completed PT-STRONG. Participants completed measurements of knee extension strength using handheld dynamometry, vastus lateralis (VL) and rectus femoris (RF) muscle thickness using ultrasonography at rest, and neuromuscular activation using electromyography during strength testing and a step-up task. Participants also completed gross motor and QoL assessments.

Results:

Compared with the non-surgical limb, MSS CCS had lower surgical limb knee extension strength, VL muscle thickness, and RF step-up muscle rate of activation (RoA). Compared with normative values, MSS CCS had decreased bilateral knee extension strength, gross motor performance, and physical QoL. Positive correlations among muscle strength, muscle thickness, and gross motor performance were identified. After PT-STRONG, MSS CCSS had improvements in VL muscle thickness, VL and RF step-up RoA, gross motor performance, and physical QoL.

Conclusions:

Positive association between larger muscle thickness with greater knee extension strength, and higher knee extension strength with better gross motor performance indicate that comprehensive physical therapy assessment and interventions that identify and target impairments in muscle properties to guide clinical decision making should be considered for MSS CCS into survivorship.

1. INTRODUCTION

Musculoskeletal sarcomas (MSS) of the bone, such as osteosarcoma and Ewing sarcoma, generally arise from transformed mesenchymal connective tissue cells. MSS most commonly occur by 25 years of age in the long bones of the lower and upper extremities (i.e., femur, tibia, and humerus) or the pelvis [1]. Although MSS account for a small percentage (3.4%) of childhood cancer and affect approximately 750 children and adolescents per year in the USA, these MSS survivors of childhood cancer (CCS) have a high likelihood of recovery and survival [2,3]. Improvements in chemotherapeutic, radiation, and surgical management in MSS CCS have increased long-term survivorship, with a 5-year overall survival rate reaching 70% [2,3]. Due to the complex medical and surgical management, MSS CCS are at risk for impaired muscle properties (muscle strength, muscle size, and neuromuscular activation) of the surgical and non-surgical limbs [4–8], limited gross motor performance [4,5,7–18], and lower health-related quality of life (QoL) [13,16,18–22].

The evolving medical and surgical treatments for MSS have the goal of not only improving survival but also preserving the individual’s long-term physical function and participation in school, work, and recreation. Medical treatments typically consist of six or more months of chemotherapy combined with surgical tumor resection. The chemotherapeutic agents used for MSS affect both cancerous and normal cells and cause short- and long-term side effects in multiple body systems [23–25]. In addition to chemotherapy, MSS CCS undergo a wide surgical resection of the tumor, which may consist of limb amputation, rotationplasty, or limb-sparing surgery (LSS). LSS is the most common surgical procedure for local control for 90% of patients with MSS [26,27]. LSS includes oncologic resection of the bone and/or soft tissue tumor, reconstruction of resected bone segments, and muscular or tendon re-routing [26]. To ensure the entire tumor is removed, the resection of both cancerous tissues and healthy tissues is required [26]. During an LSS surgery, the resected bone segments are reconstructed using an endoprosthesis, hardware, autograft, and/or allograft, and tendons and muscle are re-routed to optimize the functional potential of the limb [26]. For example, the common LSS procedure for a proximal tibial MSS involves resection of the tumor, bone, and surrounding soft tissue, endoprosthetic replacement of the resected tibia and knee joint, reconstruction of the patellar tendon attachment to the endoprosthesis, and a medial gastrocnemius muscle flap [26].

Due to the multimodal medical and surgical treatment, MSS CCS are at risk for impairments in quadriceps muscle strength due to multiple underlying mechanisms beyond surgical loss of muscle such as impairments in muscle size and neuromuscular activation. Specific chemotherapy agents (i.e., doxorubicin), cancer cachexia, pain, immobilization, and disuse have been associated with changes in skeletal muscle properties such as muscle atrophy, weakness, and impaired neuromuscular activation [8,28–31]. MSS CCS are also at risk for alterations in neuromuscular activation due to changes in the knee joint kinematic patterns (i.e. stiff knee gait) that may affect quadriceps rate of muscle activation (RoA) and knee co-contraction index (CCI) [32]. Given that MSS of the lower extremities are most commonly located in the distal femur or proximal tibia, the function of the quadriceps muscles is at high risk for impairment. The vastus lateralis (VL) and rectus femoris (RF) muscles are typically conserved after LSS and are critical to gross motor tasks such as walking, running, and jumping. The VL is the primary extender of the knee, and the biarticular RF performs hip flexion and knee extension, the movements required to kick a ball or climb stairs [33,34]. Therefore, VL and RF muscle properties including muscle strength as measured by hand-held dynamometry (HHD) [35,36], muscle thickness measured by ultrasonography (US) [35,37,38], and neuromuscular activation measured by electromyography (EMG) may relate to gross motor performance in MSS CCS and have yet to be comprehensively explored. In other complex childhood health conditions such as cerebral palsy and acute lymphoblastic leukemia, relationships have been reported among quadriceps muscle thickness, gross motor performance, and QoL [37,39,40].

Previous MSS CCS exercise intervention studies have focused on pre-surgical rehabilitation and increasing physical activity levels during medical treatment [6,41]. Despite the benefits of pre-surgical interventions, significant impairments in muscle strength and gross motor performance persist well beyond medical and surgical treatment [4–6,8–10,12,14–16,39]. Therefore, current efforts are focused on developing exercise interventions to effectively mitigate these declines into survivorship. Functional strength training targets lower extremity muscles that are required to produce functional movements such as walking, rising from a chair, and climbing stairs. Previous studies in healthy children and acute lymphoblastic leukemia CCS using functional strengthening interventions have demonstrated a two times per week 6-week program effectively increased strength and improve gross motor performance [31,42]. Building on this evidence, we sought to determine whether a functional strengthening intervention would be effective in MSS CCS.

Therefore, this study aimed to explore the muscle properties (muscle strength, muscle size, and neuromuscular activation) of the lower extremity that underwent surgery (surgical limb) and the contralateral lower extremity (non-surgical limb) and the relationships among muscle properties, gross motor performance, and QoL in adolescent and young adult MSS CCS. We hypothesized that MSS CCS would present with decreased knee extension strength, smaller muscle thickness, lower VL and RF muscle RoA, and increased knee CCI in the surgical limb compared with the non-surgical limb, and poorer gross motor performance and QoL compared with a normative population. We also hypothesized that muscle size and neuromuscular activation would be correlated with muscle strength and gross motor performance and that a 6-week functional strengthening intervention would increase knee extension strength, increase VL and RF muscle thickness and RoA, decrease knee CCI, and improve gross motor performance.

2. METHODS

2.1. Study Participants

Eight adolescent and young adult MSS CCS participants were recruited from Pediatric Hematology/Oncology Clinics at the University of Maryland Medical Center, Children’s National Hospital, and Johns Hopkins Hospital between July 2018 and June 2022 for participation in this study at the University of Maryland, School of Medicine, Department of Physical Therapy & Rehabilitation Science. Participants were eligible if they were adolescents or young adults between 13 and 26 years old, had a previous diagnosis of osteosarcoma or Ewing sarcoma of the femur or tibia, underwent lower extremity surgery more than 1 year before enrolling in this study, and completed chemotherapy prior to enrollment in this study. Participant exclusion criteria included a diagnosis of a neurological or muscle disorder not related to a diagnosis of MSS, a history of a serious lower-extremity injury or surgery 6 months before the enrollment in the study, or currently pregnant based on participant report. This study was approved by the University of Maryland, Baltimore institutional review board (HP-00078661), and was performed in line with the principles of the Declaration of Helsinki. All participants <18 years of age provided informed assent and caregivers provided informed consent. All participants ≥18 years of age provided informed consent.

2.2. Study Procedures

The initial baseline assessment, performed in a single session, included measurements of knee extension strength, quadriceps muscle thickness, gross motor performance, and QoL. Participants were given the option to participate in the intervention component of this study. The intervention group participants (n = 3) were asked to attend treatment sessions two times per week for 6 weeks (12 sessions in total). The non-intervention group participants were instructed to continue with their usual activity. Post-intervention assessments (post-test) consisted of the identical measures performed at baseline. To maintain consistency and reduce bias in data collection, the same assessor performed baseline and post-test outcome measures for all participants and a different study team member performed all of the intervention sessions.

2.3. Outcome Measures

2.3.1. Muscle Properties

2.3.1.1. Knee extension strength

Knee extension joint force at the distal tibia was measured using an HHD (Lafayette Manual Muscle Testing System model 01165, Lafayette Instrument, Lafayette, IN, USA) in the seated position with both knees flexed to 90° (seated 90°) and in the supine position with both knees supported at 35° of flexion (supine 35°) as measured by a standard goniometer [30,43,44]. The HHD was placed on the anterior tibia 2 cm proximal to the intermalleolar line. The participants were instructed to take a normal inspiration and slow expiration during maximum voluntary isometric contractions (MVIC) with the instructions, “hold the position you are placed in and kick as fast and as hard as you can into the testing device.” Participants performed two familiarization trials of sub-maximal effort followed by three MVIC trials of 5 s each with at least a 30-s but no more than a 2-min rest break between trials. Knee extension force was recorded as the average of the highest two force values in kilograms (kg) [35]. To account for the difference in lever arms for the participant with a transtibial amputation, the surgical limb force was normalized by multiplying the ratio of the length of the non-surgical lower leg divided by the length of the surgical lower leg. Muscle strength measurement of knee extension using HHD has excellent intra-rater and inter-rater reliability [35,45].

2.3.1.2. Muscle Size

Resting quadriceps muscle thickness was measured by two-dimensional B-mode US (GE Logiq v9, GE Healthcare, Milwaukee, WI, USA; Whale Sigma P5, Whale Imaging Inc., Waltham, MA, USA) of the VL at 50% of the distance from the inferior margin of the greater trochanter to the tibial tuberosity and the RF at 40% of the distance from the anterior superior iliac spine to the tibial tuberosity [35]. Images were acquired using a 5- to 12-MHz frequency, 38-mm linear array probe placed parallel to the long axis of the muscle and perpendicular to the skin surface. Three images of each muscle were collected with the participant positioned supine with the hips and knees in neutral positions. The muscles were verified to be at rest using real-time surface EMG (iWorx, Dover, NH, USA). Off-line analysis of muscle thickness was performed using a custom MATLAB code and ImageJ v1.52s (National Institutes of Health, Bethesda, MD, USA) [35]. The muscle thickness was measured using the average of four measurements of the distance between the deep and superficial aponeuroses taken at the left (distal) and the right (proximal) borders of the US images [35]. These methods for VL and RF muscle thickness using US have excellent intra-rater and inter-rater reliability [35].

2.3.1.3. Neuromuscular Activation

Muscle activity was measured during knee extension in supine 35° MVIC and during a step-up task using the iWorx IX-BIO4 EMG system (iWorx, Dover, NH, USA). This position of knee flexion for MVIC testing was selected based on previous evidence for VL and RF EMG activity to be at their greatest [46]. The participants performed the step-up task by standing in front of a standard stair and stepping onto the stair with one limb followed by the other limb. Surface electrodes were placed on the VL, RF, biceps femoris (BF), and semitendinosus (ST) muscles of the limb that was performing the MVIC or step-up task. The electrodes were bipolar, disposable, pre-gelled, 1-cm-diameter, Ag/AgCl self-adhesive, circular snap electrodes with 20 mm interelectrode spacing (Noraxon, Scottsdale, AZ, USA). Before electrode placement, the skin was cleaned with alcohol. For VL, the electrodes were placed at 60% of the distance between ASIS and tibial tuberosity. The electrodes were placed on the muscle belly of RF at 50% of the distance between the anterior superior iliac spine and tibial tuberosity. The electrodes were placed for the BF and ST at 50% of the distance between the ischial tuberosity and the lateral and medial epicondyle, respectively. A reference electrode was positioned on the anterior tibial bone of the ipsilateral limb.

2.3.1.3.1. Muscle RoA

EMG data were analyzed using Visual 3D (C-Motion Research Biomechanics, Germantown, MD, USA) and band-pass filtered 10–500 Hz. EMG data from the two trials corresponding with the two highest torque values for the MVIC and the two trials of the step-up task were averaged and used for analysis. The EMG amplitude was calculated as the root mean square of the EMG signal. The baseline EMG means and standard deviations (SD) were calculated over 500 ms before EMG activity for each contraction [47]. The EMG onset was identified as the time at which the signal increased by at least 2 SD over the baseline mean and verified visually. The RoA was calculated across epochs of 0–50 ms (RoA₅₀), 0–100 ms (RoA₁₀₀), 0–150 ms (RoA₁₅₀), and 0–200 ms (RoA₂₀₀) [47]. The data were normalized to 150 ms around the maximal EMG amplitude, the highest value within the active signal.

2.3.1.3.2. Knee CCI

Knee CCI was calculated for both the MVIC supine 35° and the step-up tasks. A 500-ms window around the maximal EMG amplitude was used to calculate the CCI and normalized to the peak amplitude during this MVIC knee extension task for VL and RF, and during an MVIC knee flexion task in sitting with the knee flexed to 90° for BF and ST [48]. These testing positions selected for normalization were based on knee flexion angles associated with the highest VL, RF, BF, and ST EMG activity [46,49]. CCI between agonist and antagonist muscles was calculated by applying the CCI equation [50]: $\mathit{\text{CCI}}=\left(\frac{2\times I_{\mathit{\text{ant}}}}{I_{\mathit{\text{tot}}}}\right)\times 100$. In this equation, I_ant is the sum of the EMG activity from antagonist muscles and I_tot is the sum of the EMG activity from the agonist and antagonist muscles. A CCI value of 0% represents pure agonist activation and 100% represents total co-contraction [50,51]

2.3.2. Gross Motor Performance

Gross motor performance was assessed using the functional mobility assessment (FMA), which includes the Timed Up and Down Stairs (TUDS), the Timed Up and Go (TUG), and the 9-min Run–Walk (9RW) tests. The FMA is valid and has excellent intra-rater and inter-rater reliability in MSS CCS [52]. Participants performed the TUDS by walking up and down a flight of stairs [53]. Participants performed the TUG by rising from a chair, walking three meters, turning around, returning to the chair, and sitting down [53,54]. A stopwatch was used to record the time for the TUDS and TUG in seconds [53,54]. The 9RW test was performed using standard procedures over a 65-feet walkway and the distance (m) the participant completed in 9 min was recorded [52,55]. These timed tests have established excellent intra-rater, inter-rater, and test–rest reliability [56,57]. At rest and after each timed test, heart rate (HR) was measured using a finger pulse oximeter (Zacurate, Stafford, TX, USA) and rate of perceived exertion was reported using the Borg Scale (6–20) in which 7 is labeled is ‘very, very light’ and 19 as ‘very, very hard’ [58]. The physiological cost index (PCI) was calculated using the data from the 9RW test and the formula: $\mathit{\text{PCI}}=\frac{\left(\mathit{\text{working}}\mathit{\text{HR}}-\mathit{\text{resting}}\mathit{\text{HE}}\right)}{\mathit{\text{speed}}}$. A total FMA score was calculated using the standard procedure [53].

2.3.3. QoL Questionnaire

The Short Form-36, version 2 (SF-36v2) is an established, reliable, and validated measure of health-related QoL [59]. The questionnaire consists of 36 items with eight subscales (physical functioning, role limitations due to physical problems, general health perceptions, vitality, social functioning, role limitations due to emotional problems, general mental health, health transitions) and two composite domains (physical health (PCS) and mental health (MCS)). A higher score on these scales indicates a higher perceived QoL. A score of 50 on the PCS and MCS is representative of the USA general population norm [59].

2.4. PT-STRONG Physical Therapy Intervention

Adolescent and young adult MSS CCS participants assigned to the intervention group were asked to perform in-person exercise sessions with a physical therapist two times per week for six weeks. Each therapy session included: (1) Discussion: session goals of repetitions and sets; (2) Warm-up: the participant walked overground for 5 min (at least 11 of 20 ‘light’ on the Borg scale); (3) Stretching: the participant performed gentle trunk (flexors/extensors, lateral flexors), hip (flexors/extensors, internal/external rotators), knee (flexors/extensors), and ankle (dorsiflexors/plantarflexors) stretching exercises for three repetitions of 10 s each; (4) Strengthening exercises: the participant performed rapid functional strengthening exercises, which included body squats, step-ups, and step-downs. During these exercises, the physical therapist ensured the participant used proper body mechanics. Exercises were progressed by the number of repetitions (six to 15), followed by the number of sets (one to three), and then by the range (squat depth and step height); (5) Cool-down: the participant walked overground for 5 min (11 on the Borg scale). During exercises, the physical therapist provided verbal cues and feedback for proper body position, but only provided hands-on contact to maintain safety, not to physically assist with performing the movement. In each session, the physical therapist advanced the program based on the participant’s progress with a goal of three sets of 15 repetitions for squatting and stepping. The physical therapist kept a weekly log to document the number of sets and repetitions of each exercise performed.

2.5. Statistical Analysis

Statistical analysis was performed using SPSS (IBM Inc., Chicago, IL, USA). Descriptive data are presented as mean ± SD. The normality of the data was assessed using the Shapiro–Wilk test. Differences between limbs at baseline in muscle strength, size, and neuromuscular activation during MVIC and the step-up task were assessed using paired t-tests. Differences between established normative values for knee extension force in seated 90°, the 9RW distance, TUG time, TUDS time, total FMA score, and SF-36v2 PCS and MCS were assessed using a one-sample t-test compared with a standardized population [53,59,60]. Relationships between baseline data were assessed using the Spearman rank correlation coefficient (r_s). The level of significance was set at P≤0.05. The sample size was determined by a priori power analysis and an interim post hoc power analysis that assumed that detecting a sample of n = 5 participants would have sufficient power to detect a moderate-to-large difference between groups for knee extension strength (G*Power v.3.1.9.4, Germany). Differences between baseline and post-test surgical limb outcomes for the intervention group are reported as a percentage change. The minimal detectable change (MDC₉₅) was calculated using the baseline data for surgical limb knee extension force, VL and RF muscle thickness, RoA, knee CCI, TUDS, TUG, and 9RW tests using the formula $MD{C}_{95}=1.95\times \sqrt{2}\times \mathit{\text{SEM}}$, in which SEM is the standard error of the mean [61].

3. RESULTS

3.1. Participants

Eight MSS CCS participants with a mean age of 17.34 ± 3.33 years (five males and three females) were recruited, enrolled, and completed baseline assessments. All participants were survivors of a primary bone sarcoma of the femur (n = 4) or tibia (n = 4), with six having a diagnosis of conventional high-grade osteosarcoma and two participants (participants 4 and 8) having a positive BCOR gene rearrangement, a small round cell sarcoma with similarities to Ewing sarcoma [62]. For medical management, all the participants received a combination of chemotherapy including doxorubicin plus methotrexate, cisplatin, vincristine, and/or Cytoxan. At the time of enrollment in our study, the average time since completion of chemotherapy was 3.55 ± 2.30 years, and since surgery was 4.09 ± 2.00 years. For local control, seven of the eight (87.5%) participants underwent an LSS, and one participant underwent a transtibial amputation. Table 1 summarizes the medical and surgical history of the MSS CCS participants.

Table 1.

Medical and surgical history of study participants.

	Tumor location	Surgery	Time since surgery	Time since completion of chemotherapy	Known complications	PT-STRONG intervention
1	Left proximal femur	Limb salvage fibular allograft	Over 6 years	6.09 years	None	No
2	Right distal femur	Limb salvage expandable endoprosthesis	5.78 years	5.44 years	Significantly limited knee flexion range of motion	Yes
3	Right proximal tibia	Limb salvage endoprosthesis with medial gastrocnemius muscle flap	1.66 years	1.10 years	Right toes amputation due to necrosis	Yes
4	Left proximal tibial	Limb salvage endoprosthesis with medial gastrocnemius muscle flap	1.74 years	0.37 years	None	No
5	Right distal femur	Limb salvage endoprosthesis	5.94 years	5.51 years	None	No
6	Left distal femur	Limb salvage endoprosthesis	1.98 years	1.48 years	Poor wound healing requiring rotational gastrocnemius muscle flap and skin graft	Yes
7	Right distal femur	Limb salvage endoprosthesis	5.53 years	5.16 years	Post-surgical foot drop; uses an ankle-foot orthosis	No
8	Right distal tibia	Transtibial amputation	4.04 years	3.26 years	Wound debridement; uses a prosthetic limb	No

All MSS CCS participants completed the baseline data testing for knee extension strength in seated 90°, VL muscle thickness, gross motor performance, and QoL measures. However, only four of the participants performed strength testing in supine 35°, RF muscle thickness, quadriceps neuromuscular activation measurements as these exploratory outcomes were added to the original study design after further examination of previous findings. The participant with a transtibial amputation did not complete neuromuscular activation measures during the step-up task due to restrictions from the prosthetic sock and socket fitting comfortably over the electrodes. Four of the participants were assigned to the intervention group. Three of the four participants completed >80% of the intervention sessions and these data were analyzed for baseline to post-test changes.

3.2. Muscle Properties

Compared with the non-surgical limb, knee extension force (seated 90°; P<0.001), muscle thickness (vastus lateralis; P<0.001), and rectus femoris RoA_150–200 during the step-up task (P=0.016–0.038) were significantly lower in the surgical limb (Table 2). Compared with normative values [60], MSS CCS demonstrated decreased knee extension force for both the surgical and non-surgical limbs (seated 90°; P<0.001).

Table 2.

Measured muscle properties.

	Surgical limb	Non-surgical limb	n	P
Knee extension force
Seated 90°, kg	10.70 (5.59)	21.34 (6.02)	8	<0.001**
Supine 35°, kg	10.39 (5.36)	14.05 (5.64)	4	0.076
Muscle thickness
Vastus lateralis, cm	1.52 (0.45)	2.19 (0.54)	8	<0.001**
Rectus femoris, cm	1.70 (0.67)	2.56 (0.48)	4	0.126
Neuromuscular activation
MVIC - vastus lateralis
RoA50, s−1	1.00 (0.84)	1.41 (0.90)	4	0.630
RoA100, s−1	0.89 (0.84)	1.18 (0.76)	4	0.716
RoA150, s−1	0.91 (0.78)	1.11 (0.69)	4	0.779
RoA200, s−1	0.79 (0.71)	0.99 (0.51)	4	0.709
MVIC - rectus femoris
RoA50, s−1	0.93 (0.72)	0.93 (0.49)	4	0.998
RoA100, s−1	0.95 (0.69)	0.94 (0.48)	4	0.994
RoA150, s−1	0.98 (0.69)	0.96 (0.49)	4	0.963
RoA200, s−1	0.99 (0.60)	0.94 (0.58)	4	0.925
MVIC - Knee CCI	0.51 (0.28)	0.61 (0.09)	4	0.391
Step-Up - vastus lateralis
RoA50, s−1	5.44 (5.09)	9.35 (2.71)	3	0.312
RoA100, s−1	3.68 (2.34)	6.81 (1.23)	3	0.187
RoA150, s−1	3.25 (1.07)	5.29 (0.96)	3	0.192
RoA200, s−1	2.85 (0.36)	4.13 (0.75)	3	0.159
Step-Up - rectus femoris
RoA50, s−1	8.85 (6.66)	14.41 (1.75)	3	0.276
RoA100, s−1	5.25 (1.90)	8.19 (1.08)	3	0.152
RoA150, s−1	3.52 (0.42)	5.60 (0.51)	3	0.038*
RoA200, s−1	2.64 (0.10)	4.16 (0.25)	3	0.016*
Step-up - Knee CCI	0.79 (0.46)	0.41 (0.14)	3	0.369

Mean (standard deviation (SD)). CCI, co-contraction index; MVIC, maximal voluntary isometric contraction measured in supine with knees flexed to 35°; RoA, rate of muscle activation.

3.3. Gross Motor Performance

Compared with normative values [53], MSS CCS presented with the TUDS (MSS CCS: 17.31 ± 11.41s vs. normative: 6.18 ± 0.8 s; P=0.030), TUG (MSS CCS: 7.63 ± 2.45 s vs. normative: 3.78 ± 0.6 s; P=0.003), 9RW (MSS CCS: 706.53 ± 215.30 m vs. normative: 1268.28 ± 272.19 m; P<0.001), and FMA total scores (MSS CCS: 49.75 ± 2.43 vs. normative: 59.00 ± 3.00; P<0.001).

3.4. QoL

On average, MSS CCS reported scores of 44.52 (4.06) and 57.87 (16.58) on the SF36v2 PCS and MCS scores, respectively. These reported scores are lower than normative values for PCS (P=0.007) and similar to normative values for MCS [59].

3.5. Relationships

Significant relationships were identified between knee extension strength and muscle thickness (r_s = 0.76–0.95; P<0.001–0.03; Figure 1(a)–(d)), surgical limb knee extension strength and the TUDS (r_s = −0.71; P=0.05; Figure 2), and non-surgical limb knee extension strength and the TUG (r_s = −0.71; P=0.05) and 9RW (r_s = 0.76; P=0.03) tests (Figure 3). No significant relationships between gross motor performance and QoL were detected.

Figure 1.

Relationships between knee extension strength and muscle thickness.

Figure 2.

Relationships between surgical limb knee extension strength and the Timed Up and Down Stairs test.

Figure 3.

Relationships between non-surgical limb knee extension strength and the Timed up and Go (open triangles; dotted line) and 9-min Run–Walk (filled circles; solid line) tests.

3.6. PT-STRONG Intervention

Three MSS CCS participants completed 100% of the 12 PT-STRONG intervention sessions. Two of the three participants demonstrated improvements between baseline and post-test in surgical limb knee extension strength at seated 90° and VL muscle thickness (Table 3). The VL muscle thickness increase for Participant no. 6 exceeded the MDC₉₅. On average, the participants that completed PT-STRONG improved in gross motor performance measures by decreasing the time to complete the TUDS by 1.80 s and TUG by 1.86 s and increasing the distance walked on the 9RW by 41.86 m (Table 3). The improved performance on the TUG for Participants no. 3 and no. 6 exceeded the MDC₉₅ (Table 3). On average, the participants that completed PT-STRONG improved SF-36v2 PCS scored by 10.74 points and decreased MCS scores by 14.67 points.

Table 3.

PT-STRONG intervention outcome measures.

		Participant no. 2			Participant no. 3			Participant no. 6
Outcome measure	MD C95	Baseline	Post-test	Difference	Baseline	Post-test	Difference	Baseline	Post-test	Difference
Knee extension force
Seated 90°, kg	1.98	13.02a	10.75a	−17.42%	2.68	2.72	+1.69%	6.26	6.80	+8.67%
Supine 35°, kg	7.39	–	–	–	–	–	–	5.75	6.88	+19.79%
Muscle thickness
Vastus lateralis, cm	0.16	1.34	1.16	−12.90%	1.04	1.09	+4.80%	0.75	0.92	+22.38% *
MVIC - vastus lateralis
RoA50, s−1	1.16	–	–	–	–	–	–	0.71	0.91	+26.85%
RoA100, s−1	1.16	–	–	–	–	–	–	0.46	0.63	+37.46%
RoA150, s−1	1.08	–	–	–	–	–	–	0.33	0.82	+146.50%
RoA200, s−1	0.98	–	–	–	–	–	–	0.25	0.85	+240.04%
MVIC - rectus femoris
RoA50, s−1	0.99	–	–	–	–	–	–	0.44	0.73	+63.05%
RoA100, s−1	0.95	–	–	–	–	–	–	0.38	0.71	+85.61%
RoA150, s−1	0.95	–	–	–	–	–	–	0.49	0.63	+28.80%
RoA200, s−1	0.83	–	–	–	–	–	–	0.51	0.57	+12.52%
MVIC - knee CCI	0.39	–	–	–	–	–	–	0.42	0.19	−55.14%
Step-Up - vastus lateralis
RoA50, s−1	8.10	–	–	–	–	–	–	6.40	15.74	+145.99%
RoA100, s−1	3.73	–	–	–	–	–	–	3.82	9.35	+145.06% *
RoA150, s−1	1.70	–	–	–	–	–	–	2.89	6.48	+124.43% *
RoA200, s−1	0.57	–	–	–	–	–	–	2.63	4.68	+77.97% *
Step-Up - rectus femoris
RoA50, s−1	10.60	–	–	–	–	–	–	9.74	16.24	+66.71%
RoA100, s−1	3.03	–	–	–	–	–	–	5.40	10.18	+88.48% *
RoA150, s−1	0.67	–	–	–	–	–	–	3.51	6.62	+88.82% *
RoA200, s−1	0.16	–	–	–	–	–	–	2.90	4.30	+48.47% *
Step-up - knee CCI	0.73	–	–	–	–	–	–	0.66	0.52	−20.91%
Timed Up and Down Stairs, s	4.03	15.43	12.38	−19.77%	41.92	41.94	+0.05%	15.90	13.55	−14.78%
Timed Up and Go, s	0.87	6.82	6.00	−12.02%	10.52	9.15	−13.02%*	12.33	8.93	−27.58%*
9-min Run-Walk, m	76.13	722.99	789.74	+9.23%	531.57	534.92	+0.63%	401.12	456.59	+13.83%

Bold text indicates improvement in outcome measure. CCI, co-contraction index; MVIC, maximum voluntary isometric contractions; RoA, rate of muscle activation.

^aParticipant no. 2 had limited knee flexion range of motion; therefore, the strength testing was performed at end-range of knee flexion (baseline: 58°; post-test: 60°).

^*The difference between baseline and post-test exceeded the minimally detectable change (MDC₉₅).

Of the three participants that completed the intervention, only Participant no. 6 completed knee extension strength at supine 35° and neuromuscular activation testing. Compared with baseline, this participant demonstrated increased surgical limb knee extension strength in supine 35°, decrease in RF muscle thickness, and increased VL and RF RoA, and decreased knee CCI during MVIC and step-up tasks (Table 3). The increases in VL RoA_50–200 and RF RoA_100–200 during the step-up task exceeded the MDC₉₅ (Table 3).

4. DISCUSSION

This study quantified the muscle properties (muscle strength, muscle size, and neuromuscular activation) of the surgical and non-surgical limbs and assessed relationships among muscle properties, gross motor performance, and QoL in adolescent and young adult MSS CCS. Participants in this study presented with decreased muscle strength, muscle thickness, and RoA in the surgical limb compared with their non-surgical limb and poorer gross motor performance and physical QoL compared with a normative population. At baseline, a positive correlation between muscle strength, muscle size, and gross motor performance was identified. We showed that our 6-week PT-STRONG functional strengthening intervention produced individual improvements in MSS CCS for VL muscle thickness, VL and RF RoA during a step-up task, gross motor performance on the TUG, and physical QoL.

MSS CCS presented with decreased bilateral knee extension strength with significantly less strength in the surgical limb compared with the non-surgical limb, consistent with previously reported data [4–6]. This current study identified a 26.1–49.9% between-limb deficit in knee extension strength. Tsauo et al. [4] reported ratios of muscle strength between MSS CCS surgical and non-surgical limbs ranging from 37.4 to 47.5% for knee extension. Muscle strength deficits have not only been identified in the surgical limb but also have been identified in the non-surgical limb [5,6]. The results of our study identified a 72.7% decrease in surgical limb and a 45.6% decrease in non-surgical limb knee extension compared with a normative population. A case series by Beebe et al. [5] examined four children (aged 9–11 years) and reported a decrease in non-surgical knee force production by 63% compared with normative values. Corr et al. [6] also found knee extension strength deficits in the non-operative limb and these strength deficits declined from baseline to post-surgery and did not recover by 20–22 weeks post-surgery. These findings, along with the results of this study, support that MSS CCS have strength deficits that persist well beyond the initial post-operative period.

The relationships between the properties of skeletal muscle have not been previously defined in MSS CCS. The participants in this study had lower surgical limb VL and RF thickness compared with the non-surgical limb. Both the VL and RF muscle thickness measurements were found to correlate with knee extension strength. These findings are consistent with previous reports in children and adolescents with cerebral palsy and adults with osteoarthritis and after total knee arthroplasty, which are populations with known knee joint kinematic changes and decreased activity levels [37,63–65]. Compared with those without health conditions, children and adolescents with cerebral palsy have lower VL and RF muscle thickness, and positive relationships between muscle thickness and knee extension strength have been reported [37,63]. In adults after total knee arthroplasty RF muscle thickness is lower on the surgical limb compared with the non-surgical limb and control participants, and relationships between higher muscle thickness with greater knee extension muscle strength have been identified [64]. Quadriceps muscle thickness is negatively correlated with pain levels and positively related to patient-reported physical function and gross motor performance, including the TUG test, in adults with osteoarthritis and post-total knee arthroplasty [64,65]. Therefore, utilizing US muscle thickness measurements may be a beneficial alternative for MSS CCS, especially if pain or medical restrictions prevent formal muscle strength testing [38].

The MSS CCS in our study presented with limited gross motor performance and lower physical QoL compared with normative values on the FMA, TUDS, TUG, 9RW, and SF-36v2 PCS. These findings are consistent with previously reported performance on these measures in a larger cohort of MSS CCS [10,39,52]. Marchese et al. [39] identified relationships between hip and knee joint range of motion and performance on the TUDS, TUG, 9RW, and SF-36v2 PCS. Relationships between increased knee extension strength and better gross motor performance were present for the MSS CCS. Surgical limb knee extension strength was correlated with better performance on the TUDS. Non-surgical limb knee extension strength was related to a shorter time to complete the TUG and farther distance walked on the 9RW test. These findings are reflective of the lower extremity demands required for walking and climbing stairs. During walking, adaptive gait deviations (i.e., hip Trendelenburg, vaulting) can compensate for a lack of surgical limb function [5]. Okita et al. [66] reported that MSS CCS who underwent LSS increased bilateral hip, bilateral ankle, and non-surgical limb knee power to increase walking speed. However, the participants in this study performed stair climbing with a reciprocal pattern, which requires the isolated surgical limb to extend to ascend the stairs. Given that these participants also demonstrated decreased bilateral knee extension strength, performing a variety of functional tasks that require muscular challenges to both single and double limbs should be considered. The findings from these assessments could help support the development of physical therapy interventions and goals for MSS CCS.

In response to a 6-week PT-STRONG intervention, individual improvements in VL muscle thickness, VL and RF RoA during a step-up task, gross motor performance on the TUG, and physical QoL but not mental QoL were identified in MSS CCS. These findings add to the evidence that exercise can elicit improvements in these patients. The decreased time to perform the TUG for two of the participants dropped below 10 s, which is the cut-off score sensitive to detecting near-falling risk in older adults with hip osteoarthritis [67]. These participants also decreased their TUG time by greater than 0.87 s, which is the MDC₉₅ calculated from the baseline data. Previous intervention studies in CCS demonstrated positive improvements in knee extension strength [68,69], lower extremity RoA [31], and gross motor performance in response to an exercise intervention [31,69]. In MSS CCS, Winter et al. [41] demonstrated that an individualized exercise intervention can improve post-surgical physical activity levels. Participant no. 2 demonstrated decreased knee extension strength and decreased VL muscle thickness post-intervention. Although the reason for the decline in this participant is unknown, it may be due to the participant’s baseline limitations in knee flexion range of motion, which improved from baseline to post-test. The decreased knee extension force and decreased VL muscle thickness may represent reduced muscle stiffness due to the static and dynamic stretching effects of the intervention, which were not specifically measured in this study [70]. Nonetheless, muscle property and gross motor performance deficits in MSS CCS may be amendable to physical therapy interventions. Specifically, our PT-STRONG intervention included body-weight resisted functional strengthening and rapid squat and step-up tasks that targeted muscle size through hypertrophy and neuromuscular activation through challenging RoA, respectively.

Despite the clinically relevant and sensitive outcome measures used in this study, the small sample size arising from the rarity of MSS diagnosis is a limiting factor in generalizing these findings to the broader population. To this end, while this study identifies that MSS CCS at risk for impairments in muscle properties and gross motor performance that may be responsive to exercise intervention, an expansion of this study is warranted before generalizing these results. The control condition for the exploratory outcomes in this study was the participant’s non-surgical limb, which also demonstrated deficits, therefore greater impairments may have been identified had these participants been compared with healthy controls. For the SF-36v2, the participants in this study were compared with the USA general population (>18 years old). In a study by Mones et al. [71], they reported a mean PCS score of 90.57 and MCS score of 89.33 in a cohort of healthy adolescent controls (n = 174; age = 12–18 years). Therefore, the normative sample used for comparison in this study may be conservative and underrepresent the degree of QoL differences among adolescent MSS CCS and their peers. Additional studies with larger samples of MSS CCS and healthy age- and sex-matched controls should be performed to further explore the dosage of training and the effects of an intervention on muscle properties and gross motor performance.

5. CONCLUSIONS

Adolescent and young adult MSS CCS present with decreased quadriceps muscle strength, muscle size, neuromuscular activation, gross motor performance, and physical QoL, which may be amendable to physical therapy interventions. Due to the interplay between skeletal muscle properties and gross motor performance, comprehensive physical therapy assessments that identify impairments in muscle properties, such as muscle thickness and neuromuscular activation, and interventions that target these impairments may enhance the rehabilitation of MSS CCS well into survivorship. The results of these assessments should be used to guide clinical decision-making to promote physical performance and participation in daily activities.