Reference Centiles to Monitor the 6-minute-walk Test in Ambulant Children with Cerebral Palsy and Identification of Effects after Rehabilitation Utilizing Whole-body Vibration

ABSTRACT

Background: Children with cerebral palsy present age-driven development in gross motor skills and walking capacity.

Aims: To precisely monitor the 6-minute walk test (6MWT) in children with CP, GMFCS levels 1 and 2 over 6 months and to assess the effect of a 6-month rehabilitation program including whole-body vibration.

Methods: Retrospective analysis of data of 157 children with CP who received standardized rehabilitation (DRKS00011331). 6MWT was assessed at the start (M0) and end of the training (M6), as well as at a 6-month follow-up (M12). Centiles were created using the lambda-mu-sigma (LMS) method.

Results: We created 6MWT percentiles using data of all 157 children (M0 data). A medium treatment effect size (Cohen’s d = 0.69) was found (M6 and M12 data).

Conclusions: The generated centiles may help monitor 6MWT changes over 6 months. Combining WBV and conventional physiotherapy can significantly improve 6MWT in children with CP.

Abbreviations: 6MWT: 6-Minute Walk Test; CP: Cerebral palsy; ES: effect size; GMFCS: Gross Motor Function Classification System; GMFM-66: Gross Motor Function Measure 66; LOESS: locally weighted scatterplot smoothing; LMS: lambda-mu-sigma; MCID: minimal clinical important difference; SD: standard deviation; SRM: standardized response mean; WBV: whole-body vibration.

KEYWORDS:

• Cerebral palsy
• centile curves
• effect size
• 6-minute walk test
• walking capacity
• whole-body vibration

Introduction

Cerebral palsy (CP) is a significant cause of permanent, but not unchanging physical disability in childhood and adolescence.^1,2 Resulting in muscle paresis, spasticity, as well as loss of selectivity, CP leads to bone deformities, loss of muscle volume, contractures, dependence of patients in daily life, and inevitably high cost of care.³

Children and adolescents with CP, with mobility level 1 or 2 according to the Gross Motor Function Classification System (GMFCS)⁴ often attend school and extracurricular activities next to typically developing peers, experiencing often difficulties related to insufficient walking capacity.^5,6 A literature review revealed that gait training can improve walking capacity in children with CP, while velocity training and whole-body vibration (WBV) can be effective and thus warrants further investigation.^7,8

The 6-minute-walk test (6MWT) is a common^5,9–11 and reliable^12,13 tool to measure walking capacity in children with CP. Reference values on the 6MWT have been assessed and reported among typically developing children in various countries.^14,15 Either height- or age-related reference centiles are an important fundament for further research, but fail to address the needs of patients suffering from chronic conditions limiting or changing the evolution of their walking capacity, such as CP.¹⁶ Fitzgerald et al. compared typically developing children and children with CP and defined ranges of the 6MWT references.¹⁷ Children with CP, GMFCS level 1 walked on average 89 m less and children functioning at GMFCS level 2 walked on average 142 m less, when compared with their typically developing peers. However, there is still a gap of knowledge regarding the efficacy of treatment targeting the walking capacity of children with CP, as well as their responsiveness to treatment.

Currently, Fiss et al. have reported developmental trajectories and reference percentiles for the 6MWT for children with CP, GMFCS 1, 2 and 3.¹⁸ The authors have generated 6MWT reference centiles for each GMFCS level, recommending the use of centiles to measure the effect of interventions on the walking capacity of children with CP, and calculated probabilities for the centile change based on longitudinal data assessed 12 months after the first 6MWT assessment.¹⁸ This method can only roughly estimate the probability for centile change due to expected, age-related natural development. Following the method of Fiss et al.,¹⁸ we will study a real case study:

A boy with bilateral spastic CP GMFCS level 2 participated in a rehabilitation program. The boy’s walking capacity was assessed using the 6MWT, reaching a score of 402 m at the age of 11 years and 6 months. Six months later he reached a score of 498 m with an age of 12 years. Is this 6MWT increase to be interpreted as a therapeutic effect or does it reflect the expected progression of 6MWT at this age under the standard of care?

Using the reference centiles of Fiss et al.,¹⁸ following can be calculated:

• At M0: Z‐score of 6MWT: ‐0.17 and centile of 6MWT: approximately centile 76.

• At M6: Z‐score of 6MWT: 0.26 and centile of 6MWT: approximately centile 91.

According to Fiss et al.,¹⁸ the probability of a centile increase between two assessments 1 year apart for children with GMFCS‐level 2 is

• 25% more than 13 centile increase.

• 10% for more than 27 centile increase.

The reported boy had an increase of 15 centiles over 6 months. With the method of Fiss et al.,¹⁸ it is not possible to specify exactly the probability of a centile increase of 15 (or more) over 6 months. It can be supposed that the probability lies between 10% and 25%. In the Results, the same case will be evaluated again with the method presented in this study.

Our aim was to generate a tool to precisely quantify changes in the walking capacity of ambulant individuals with CP, GMFCS levels 1 and 2, considering the natural development, expected over a period of 6 months. The generation of age-related centiles for the 6MWT of children with CP, GMFCS levels 1 and 2 was needed to achieve this aim. A further aim was to assess the effect of the 6-month neurorehabilitation training “Auf die Beine”¹⁹ on the 6MWT of children with CP, GMFCS levels 1 and 2. “Auf die Beine” combines WBV training and conventional therapy in intervals of home-training and inpatient stay.

Methods

Study Population and Inclusion Criteria

We conducted a monocentric retrospective analysis of prospectively collected data of children with CP with a Gross Motor Function Classification System (GMFCS) levels 1 and 2,²⁰ who participated and completed “Auf die Beine”, a rehabilitation concept of the Center of Prevention and Rehabilitation (University of Cologne, Germany) from January 2006 to December 2017. The data were extracted from the prospective register of the center (www.drks.de, DRKS-ID: DRKS00011331). The study was approved by the Ethics Committee of the Medical Faculty of the University of Cologne. Informed consent from the guardians was obtained prior to data registration.

The age range was set to three to 12 years. GMFCS consists of a 5-point ordinal scale of locomotion. Children with CP GMFCS levels 1 and 2 can walk without support or with limitations, respectively.²⁰ Children with CP GMFCS levels 3–5 present a more impaired mobility level and were not included in the analysis. Further, children with additional genetic diseases, i.e. trisomy 21, or further chronic conditions, such as chronic renal failure, that can significantly influence the walking capacity, were not included in the study.

WBV and the Rehabilitation Program

“Auf die Beine” (translated as: “On your own feet”) is a neuromuscular training program combining intensive, goal-directed interval training during inpatient stays, of in total 3 weeks, and 6-month home-training using whole-body vibration (WBV) and is included in the basic care in Germany. During the initial two-week inpatient stay patients and caregivers were familiarized with WBV training, which they would perform during a 6-month home-training. During the stay, the children further received four to 5 hours of individualized, goal-oriented physiotherapy with and without training apparatus, pool therapy, functional resistance and treadmill training with or without body weight support. The second stay, with a duration of 1 week, takes place 3 months later, in the middle of the 6-month home-training interval. The offered rehabilitation program during this stay is similar to the one of the initial inpatient stay. The rehabilitation program “Auf die Beine” has been previously reported.¹⁹

For the training, a side-alternating WBV platform (System Galileo®, Novotec Medical, Pforzheim, Germany) was used. Side-alternating vibration stimuli provoke spinal reflexes and muscle contractions, inducing involuntary muscle stimulation.²¹ Each WBV session was 3 × 3 min long, inducing high numbers of repetitions.¹⁹ During inpatient stays the children received three 3 × 3 min long WBV sessions per day. Optimal home-training consisted of ten 3 × 3 min long sessions per week. During the inpatient stays, the caregivers were individually trained to conduct the WBV training with their children. Home-training units, including details about every single performed exercise, were documented in a training log by the caregivers. The WBV system was set to provide always training sessions of 3 minutes, keeping a digital record of the performed activity. The digital record may be extracted for controlling in cases of apparent noncompliance.

The vibration frequency was adjusted according to the individual goals set by the parents, the patient and the therapists, respecting the framework of the WHO International Classification of Functioning, Disability and Health (ICF). In detail, we used vibration frequencies of 5–12 Hz for balance and proprioceptive training, 12–20 Hz for muscle function improvement (repetitive contraction, muscle relaxation enabled), and 20–27 Hz (strong involuntary contraction) to increase muscle mass.¹⁹ The amplitude, depending on the child’s dimensions, varied from 0 to ±3.9 mm.¹⁹ We should underline that WBV is a major, but not the only component of the presented rehabilitation program.

Investigation

Walking capacity was measured with the 6-minute walk test (6MWT).¹³ The children were asked to walk as fast as possible without running around a standardized circular 40-m track over a period of 6 minutes. The physiotherapist was following the children during the assessment to assure that the track was consequently followed. Measurements were regarded as complete and were included in the database, only when the patient kept walking, and not running, during the whole investigation without break or fall. Children with CP, GMFCS level II could use their individual orthoses, if regularly used, during the examination. No further assisting devices were used. A stopwatch was used to keep by the assessor track. Standard encouragements were provided approximately every 30 seconds during the test. The 6MWT is also commonly used to assess walking capacity and endurance in patients with CP⁹ with a good validity, test-retest reliability and agreement.^12,22,23

The assessments were performed at baseline (M0), after 6 months (M6) of additional training, and after 12 months (M12) without additional training (6 months of follow-up). For this study, we used a double-baseline design, in which the participating children acted as their own controls, since the changes after the 6-month intensive neuromuscular training (M6 vs. M0) were compared with their performance after a 6-month standard care (physiotherapy, use of orthoses, orthopedic interventions, pharmacotherapy, etc.) period (M12 vs. M6). Only assessments performed using the same aids, e.g. orthoses, etc., in all three investigations (M0, M6, M12) were included in the analysis of the rehabilitation effect under standard care.

The standard of care for children with CP, GMFCS levels 1 and 2 in Germany commonly includes one or two 30–45 min sessions of physiotherapy per week, the use of individually made orthoses, usually foot orthoses for children with GMFCS 1 and ankle-foot orthoses for children with GMFCS level 2.^24,25 Orthopedic interventions in these children are often limited to the surgical treatment of the calcaneal tendon, while pharmacotherapy commonly includes a botulinum neurotoxin A treatment (BoNT-A), for instance in the triceps surae muscles. In our case though, caregivers and children participating in “Auf die Beine” were instructed to avoid elective surgeries and not to receive BoNT-A shortly before recruitment or during the treatment period.

Reference Centiles and Correlations

We used the LMS (lambda-mu-sigma) method to generate age-related 6MWT reference ranges for children and adolescents with CP, GMFCS levels 1 and 2, using only the M0 data.²⁶ The methodology for the calculation of Z-scores, adjustment of the skewness L(a), median value M(a) and the coefficient of variation S(a), as well as the calculation of the difference between two z-scores and their correlation coefficients r, has already been used to generate and publish centile curves for the 1-minute-walk test in ambulant children with CP.²⁷ With the dataset of 86 6MWT assessments (performed at M6 and M12), we calculated r for age between 3 and 12 years and for a 6-month interval.

Correlation coefficients r of the Z-Scores at M6 and M12 were used to calculate the distribution of centile changes. We further applied LOESS regression to the generated correlation coefficients r. Calculation of Z-scores was performed by applying a modified Box-Cox transformation:

(1) $\begin{array}{rl}& Z_{LMS}=\frac{1}{S\left(a\right)\ast L\left(a\right)}\ast \left[{\left(\frac{g}{M\left(a\right)}\right)}^{L\left(a\right)}-1\right]\\ & \mathrm{f}\mathrm{o}\mathrm{r}\mathrm{S}(\mathrm{a}),\mathrm{L}(\mathrm{a})\mathrm{a}\mathrm{n}\mathrm{d}\mathrm{M}(\mathrm{a})\ne 0\end{array}$(1)

(2) $Z_{LMS}=\frac{\mathrm{l}\mathrm{n}\left(\frac{g}{M\left(a\right)}\right)}{S\left(a\right)}\mathrm{f}\mathrm{o}\mathrm{r}\mathrm{L}(\mathrm{a})=0\mathrm{a}\mathrm{n}\mathrm{d}\mathrm{S}(\mathrm{a}),\mathrm{M}(\mathrm{a})\ne 0$(2)

We calculated r for age a between three to 12 years and for a 6-month interval, using the dataset of the follow-up assessments performed at M6 and M12.

Further, we defined a three-year length section within the age interval from three to 12 years. This section was moved over the complete age interval in steps of 0.1 years. At each step, the correlation coefficient r was calculated with the 6MWT data covered in the moving section. A locally weighted scatterplot smoothing (LOESS) regression was applied to the generated correlation coefficients r.

Finally, we calculated the standard deviation for centile change ∆Z over the age interval from three to 12 years.²⁷ According to Cole, the difference between two Z-scores

(3) $\mathrm{\Delta }Z=Z_2-Z_1$(3)

determined at different time points t₂> t₁ is a measure for centile-crossing development. For the reference population, the following applies:

(4) $\begin{array}{rl}& \mathrm{e}\mathrm{x}\mathrm{p}\mathrm{e}\mathrm{c}\mathrm{t}\mathrm{e}\mathrm{d}\mathrm{v}\mathrm{a}\mathrm{l}\mathrm{u}\mathrm{e}E\left[\mathrm{\Delta }Z\right]=0\\ & \mathrm{s}\mathrm{t}\mathrm{a}\mathrm{n}\mathrm{d}\mathrm{a}\mathrm{r}\mathrm{d}\mathrm{d}\mathrm{e}\mathrm{v}\mathrm{i}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n}\sigma \left(\mathrm{\Delta }Z\right)=\sqrt{2\ast \left(1-r\right)}\end{array}$(4)

where r is the correlation coefficient between Z₂ and Z₁. The following applies to the standard deviation of ΔZ values:

(5) $\mathrm{Z}-\mathrm{s}\mathrm{c}\mathrm{o}\mathrm{r}\mathrm{e}\mathrm{f}\mathrm{o}\mathrm{r}\mathrm{c}\mathrm{e}\mathrm{n}\mathrm{t}\mathrm{i}\mathrm{l}\mathrm{e}\mathrm{c}\mathrm{h}\mathrm{a}\mathrm{n}\mathrm{g}\mathrm{e}=\frac{\mathrm{\Delta }\mathrm{Z}}{\sqrt{(2\ast \left(1-r\right)}}$(5)

Effect Size Estimation and Minimal Clinical Important Difference

We used Cohen’s d to assess the effect size (ES) quantifying differences in the two patient groups before and after the intervention.^27–29 ‘Negligible’ effect was defined when ES<0.20, ‘small’ effect when ES ≥0.20 to <0.50, ‘medium’ effect when ES ≥0.50 to <0.80, and ‘large’ effect when ES≥0.80.

Analysis and Implementation

We analyzed the data using IBM SPSS Statistics for Windows v. 24 (IBM Corp, Armonk, NY, USA) and RStudio v. 1.0.136 in conjunction with R v. 3.2. (R Foundation for Statistical Computing, Vienna, Austria) and the statistical packages GAMLSS (v. 5.0.0), effsize (v. 0.7.1) and pROC (version 1.10.1)^27,30–32 Finally, we exemplary applied the resulting 6MWT reference centiles on the case of the introduction. Shapiro test did not show a normal distribution of the study groups across all assessments, so we compared the changes using the Wilcoxon signed rank test and the clinical effect of the intervention using Cohen’s d.

Results

Study Population

For this study, we included all children with cerebral palsy, that did not suffer from a further syndromic disease and were recruited after completion of the third and before the end of the twelfth year of life. In total, 157 6MWT (73 girls, 84 boys) assessments were performed in children adolescents with CP, GMFCS levels 1 and 2 at M0, and were included for the generation of age-related reference ranges at M0.

Further, complete follow-up measurements at M6 and M12 were available for 78 6MWT (31 girls, 47 boys) assessments and were used to calculate correlations (Figure 1). This subgroup of children (N’ = 78) was used to assess the effectiveness of the provided rehabilitation program, using the reference ranges created using the data of all children who participated in M0 (N = 157). The demographics of the study population, including gender, CP subtypes (unilateral or bilateral spastic, dyskinetic, ataxic or mixed) and GMFCS level, is depicted in Table 1. Results are given as the mean and standard deviation (SD), unless otherwise stated. The characteristics of the two groups did not differ significantly.

Table 1. Characteristics of the study population and evaluation of the effect of the rehabilitation program on the walking capacity assessed by the 6MWT

	Participants in M0	Participants in all three assessments (M0, M6 and M12)
females males	N = 157 73 84	N’ = 78 31 47
GMFCS level 1	57	30
GMFCS level 2	100	48
CP subtype Bil. Spastic Unil. Spastic Dyskinetic Ataxic Mixed	103 33 1 6 14	46 17 0 4 11
Age (y) at M0 Mean Standard deviation	7.13 2.54	7.95 2.16
6MWT at M0 (m) Mean Standard deviation	389.59 126.09	403.62 100.81
6MWT at M6 (m) Mean Standard deviation	N.A.	472.95 111.78
6MWT at M12 (m) Mean Standard deviation	N.A.	480.79 106.28
Height at M0 (m) Mean Standard deviation	119.48 16.62	118.88 15.49
Weight at M0 (kg) Mean Standard deviation	23.28 9.14	22.74 8.30
BMI at M0 (kg/m^2) Mean Standard deviation	15.73 2.58	15.57 2.38
	6MWT M0-M6	6MWT M6-M12
Wilcoxon test V, p	V = 588 p < .001	V = 2010 p = .550
Cohen’s d (CI 95%)	d: 0.69 (medium) (0.43, 0.95)	d: 0.10 (negligible) (0.21, 0.40)

N.A.not applicable

Figure 1. Flowchart of the study population

Reference Centiles and Correlation Coefficients R

The generated age-related 6MWT reference centiles, for both genders, are depicted in Figure 2. The tabulated 6MWT centiles for children with CP are presented in Table 2. The tabulated values of the standard deviation for 6MWT (6 months apart) regardless of sex, GMFCS levels 1 and 2, are depicted in Table 3. For the sake of clarity and comparison with the trajectories of Fiss et al.,¹⁸ we have also generated independent age-related 6MWT centiles for the children with CP, GMFCS levels 1 and 2 separately, as depicted in Figure 3a and 3b.

Table 2. Tabulated 6MWT reference for use with children having cerebral palsy (GMFCS 1 and 2). Distance in meters, age in years. C: centile, L: skewness, M: mean, S: coefficient of variation

Age	C3	C10	C25	C50 = M	C75	C90	C97	L	S
3	101.59	154.57	203.36	251.91	295.91	332.58	366.63	1.587	0.276
3.5	111.88	169.43	222.49	275.48	323.68	363.97	401.47	1.561	0.275
4	122.35	184.36	241.61	298.99	351.40	395.33	436.32	1.535	0.275
4.5	132.89	199.19	260.48	322.17	378.73	426.29	470.76	1.509	0.274
5	143.29	213.57	278.67	344.46	405.02	456.11	504.00	1.483	0.274
5.5	153.35	227.21	295.77	365.37	429.69	484.12	535.28	1.457	0.273
6	162.88	239.82	311.44	384.47	452.25	509.78	563.99	1.431	0.273
6.5	171.72	251.21	325.42	401.45	472.30	532.64	589.64	1.405	0.272
7	179.71	261.15	337.44	415.96	489.46	552.26	611.72	1.379	0.272
7.5	186.69	269.42	347.22	427.69	503.34	568.19	629.76	1.353	0.271
8	192.60	276.00	354.76	436.63	513.93	580.42	643.72	1.327	0.271
8.5	197.70	281.29	360.59	443.45	522.02	589.84	654.57	1.301	0.270
9	202.22	285.66	365.19	448.72	528.29	597.21	663.17	1.275	0.270
9.5	206.30	289.32	368.86	452.84	533.19	603.04	670.07	1.249	0.269
10	210.06	292.46	371.84	456.09	537.08	607.72	675.71	1.223	0.269
10.5	213.61	295.27	374.38	458.80	540.31	611.67	680.54	1.197	0.268
11	217.07	297.93	376.71	461.23	543.22	615.26	684.98	1.171	0.268
11.5	220.47	300.48	378.90	463.48	545.92	618.60	689.16	1.145	0.267
12	223.85	302.99	381.02	465.65	548.51	621.84	693.23	1.119	0.267

Table 3. Tabulated values of the standard deviation of 6MWT Z-score differences (6 months apart), age in years

Age	0.0	0.1	0.2	0.3	0.4	0.5	0.6	0.7	0.8	0.9
3	0.72887	0.73665	0.73679	0.70178	0.70178	0.69862	0.69862	0.71810	0.71574	0.71879
4	0.74165	0.71929	0.71654	0.72379	0.72295	0.72279	0.72923	0.73040	0.73040	0.73040
5	0.73040	0.71758	0.71758	0.71758	0.71784	0.71784	0.71784	0.71784	0.71785	0.71664
6	0.71408	0.67288	0.68558	0.68558	0.65535	0.66104	0.67786	0.67771	0.67487	0.74790
7	0.70745	0.70615	0.73987	0.75042	0.75236	0.75236	0.70876	0.70734	0.70691	0.70691
8	0.70299	0.69083	0.69064	0.71699	0.73365	0.74362	0.74524	0.76275	0.76826	0.76573
9	0.73207	0.76473	0.78972	0.78061	0.78206	0.78347	0.77121	0.76913	0.76913	0.76913
10	0.77092	0.79371	0.79371	0.79371	0.79307	0.79307	0.79307	0.79307	0.79370	0.79692
11	0.80015	0.86762	0.86762	0.86762	0.86762	0.86830	0.86980	0.86992	0.87441	0.87360

Figure 2. Reference curves for 6MWT in children with CP GMFCS levels 1 and 2. The centiles are labeled with the corresponding Z‐scores. The dashed line represents the standard deviation of the difference of 2 GMFM‐66 Z‐scores measured 6 months apart

Figure 3. Reference curves for 6MWT: a. in children with CP GMFCS level 1 and b. in children with CP GMFCS level 2. Centiles presented 5th, 10th, 25th, 50th, 75th, 90th and 95th

The bold-dotted line in Figure 2 depicts the standard deviation (SD) of the difference of two 6MWT Z-scores, respectively, measured 6 months apart. For instance, the 6MWT SD values, evaluated at the first measure, decrease with increasing age until the sixth year of age, followed by a slight increase until 10 years and a fast decrease within the next 4 years, and can be read from the y-axis.

Effect of the Rehabilitation Program “Auf Die Beine” Including WBV

Children with CP, who participated in the rehabilitation program “Auf die Beine” showed significant improvement in the 6MWT at M6 (Wilcoxon signed rank test, p < .001), while no statistically significant changes were revealed at M12 (p = .550). We further applied the reported tool to analyze the effect of the rehabilitation concept Auf die Beine on the 6MWT changes. The analysis of efficacy showed a medium effect size (Cohen’s d = 0.69) for the changes during intervention and a negligible size for the changes in the follow-up (d = 0.1).^27,29 The results are also depicted in Table 1.

Clinical Application

We further demonstrated the use of the presented tool to monitor the walking capacity of individuals with CP, using the case presented in the Introduction. The results are depicted in Figure 4.

Figure 4. Case study. The figure illustrates the use of the tool. First, the two 6MWT scores are entered (two crosses, age₁ = 11 years 6 months, age₂ = 12 years 0 months). The corresponding Z-scores are Z₁ = −0.5 for M0, Z₂ = 0.25 for M6. The age-dependent standard deviation (SD) of the centile change is determined by using the dashed curve (or more preciselyTable 3) and the age of the child at the first 6MWT assessment at M0 (SD = 0.64). Using the formula (Z₂-Z₁)/SD, the Z-score for the centile change can be calculated. It corresponds to a large individual effect size 0.75/0.64 = 1.17

The reported boy with bilateral spastic CP, GMFCS level 2, with 6MWT score 402 m (age: 11 years 6 months) at the beginning (M0) of the rehabilitation, and after 6 months (M6) he scored 498 m (age: 12 years 0 months).

Interpretation: As seen in Figure 4, the Z-scores for the 6MWT at M0 and M6 are estimated as:

Z₁ = −0.5 and Z₂ = +0.25. The age-dependent SD for the centile change is determined by using the dashed curve and the age of the child at the first 6MWT assessment at M0 (SD = 0.64).

Thus, Z-score of centile change = (Z₂-Z₁)/SD = (0.75)/0.64 = 1.17, indicating a large effect size. A Z-score of 1.17 corresponds to the centile of 87.9 in the table of standard normal distribution. Thus, this Z-score corresponds to a probability of 12.1% (=100%-87.9%) for an occurrence of the observed centile change over 6 months under standard of care. Using the method of Fiss et al.,¹⁸ the probability would also roughly lie between 10% and 25%, as presented in the Introduction, validating our finding.

Discussion

For this study, we generated age-related centile curves for the 6MWT in children with CP, GMFCS levels 1 and 2 and we created a tool to precisely quantify their 6MWT score changes within a 6-month period, taking age-expected development into consideration (Figure 2). We implemented the method in a cohort of children with CP who received an intensive 6-month rehabilitation training including WBV and found a clinically significant, medium effect on the 6MWT, which occurred on top of the expected improvement of the walking capacity under standard care. Because the 6MWT assessments were conducted in intervals of 6 months, this 6-month period between at least two 6MWT assessments is needed to use this tool and precisely quantify the effect size of a provided treatment on the child’s walking capacity.

Since our aim was not the generation of centiles to depict the walking capacity of a child at one specific moment, but the creation of the diagnostic tool, we did not differentiate the reference centiles locomotion of the participants according to the GMFCS level (1 or 2) in the presented final tool. For the sake of completeness though, we estimated and presented independent curves for both subgroups of patients (GMFCS levels 1 and 2) (Figure 3a and b). Although the presented curves show an evolution similar to the one reported by Fiss et al.,¹⁸ differences in the methods used to generate the centiles (LMS method vs. quartile regression)¹⁸ do not allow further direct comparisons. Interestingly, the 5th centile of children with CP, GMFCS level 1 shows a less harmonic evolution and a rather abrupt decrease, when generated using quartile regression.¹⁸

Different approaches have been adopted to describe the evolution of the walking capacity in childhood and adolescents among typically developing individuals in various countries.¹⁵ Although age-related centiles are more commonly used,^14,33–35 the first reported reference values for the 6MWT among typically developing children were height-related.³⁶ However, the authors have already discussed, that age showed also a clear association with height and the 6MWT score, and the reason they chose height for the generation of the centiles, was that they regarded the parameter as easier to measure in clinical practice, as well as a way of avoiding discrepancies among different nations.³⁶

Regarding children with CP Fitzgerald et al. studied children with GMFCS levels 1, 2 and 3 and compared them with typically developing individuals.¹⁷ The differences between the four groups were significant.¹⁷ In our study, we presented the curves for the two levels of locomotion independently (GMFCS 1 and 2) (Figure 3a and 3b) but summarized them in one graph for the final tool (Figure 2).

Some authors have reported significant differences in the walking capacity assessed by the 6MWT between typically developing boys and girls.³⁶ We initially differentiated the curves though according to the sex of the children, but the differences were not significant. The inferential analysis also showed no significant differences and thus we decided to simplify the tool by depicting both male and female children in one curve.

Other research groups referring to 6MWT in children with CP or similar conditions also did not perform an analysis based on sex in children,^17,18,37 although Fitzgerald et al. underlined in their study limitations that sex-associated differences should be evaluated in future studies among children with CP.¹⁷ On the other hand, a study examining the walking capacity assessed using the 6MWT in adults with CP showed, that although there was a significant sex-associated difference in the 6MWT performance in the univariate analyses, these differences were outspoken in the multivariate regression analyses, when corrected for height and weight.³⁸ Thus, they conclude that in adults with CP height and weight are actually the variables leading to the seemingly sex-associated differences in the walking capacity.³⁸

Regarding the evolution of the walking capacity in childhood, Lammers et al. reported no relevant changes in the 6MWT of typically developing children after the 12th year of age.³⁵ Our initial analysis, including children with ages up to 18 years revealed a similar plateau. Hence, since our amount of data for children older than 12 years of age was also limited, we restricted our centile curves for children aged up to 12 years.

For this analysis, we did not include a control group of typically developing children. Fiss et al. also did not include a control group.¹⁸ Indeed, a control group could better facilitate data comparisons of children with CP with age-matched typically developing peers, due to the wide variety of neural and musculoskeletal impairments which impact on the walking capacity and the differences in the standard of care they receive. However, the aim of this study was not to generate reference centiles for the 6MWT, but to develop a method to monitor the effect of a treatment vs. the expected progression under standard of care in a period of 6 months in children with CP, GMFCS levels 1 and 2, and thus, a control group is not essential.

In the reported case study, the calculated Z-score for patient change corresponded to a 12.1% probability for an expected 6MWT increase over 6 months. According to the tool of Fiss et al.,¹⁸ the expected value was lying between 10% and 25%, which is also the case, validating our finding.

The children in our study received an intensive 6-month rehabilitation training including vibration-assisted physiotherapy. Using the suggested method, we assessed the training effect on the children’s 6MWT score. The intervention had a significant, medium effect on the walking capacity assessed by the 6MWT at M6. This clinically significant effect occurred on top of the expected improvement of the walking capacity under standard care (M12 vs. M6). Changes in the walking capacity of participants of this specific intervention, measured using the 1-minute-walk test (1MWT) have currently been reported. Those children, also aged from three to 12 years, have shown a clinically relevant, but less significant improvement in the 1MWT score.²⁷ This small difference may also have to do with the nature of the two different scores, since the 1MWT assesses the performance in the first minute of walk, depending mainly on the children’s velocity, while the 6MWT score is strongly influenced by the children’s endurance.

A similar, though shorter intervention was offered to children with cerebral palsy in a Korean rehabilitation center, who participated in a controlled trial, as reported by Lee et al.⁷ The intervention group received whole-body vibration in combination with conventional physiotherapy, while the control group received only conventional physiotherapy. Although the children’s walking capacity was not assessed for a duration of 6 minutes, the children showed a significant improvement in gait speed and stride length, when compared with their normally developing peers. This finding also depicts the positive effect of additional whole-body vibration, combined with conventional physiotherapy, to effectively improve walking capacity in children with CP.

Finally, the grade of suitability of the centile curves for all CP subtypes is still not clear. For instance, one would suggest, that children with ataxic CP comprise a clinically different population to the ones with spastic CP and should be probably evaluated differently. A simple demographic analysis showed indeed, that patients with different types of CP showed a slightly different performance. However, interestingly clinically relevant differences in the walking performance were shown by the children with unilateral CP, rather than by patients with ataxic CP. In detail, children with unilateral CP showed a median age of 6,3 years and median 6MWT of 459 m; children with ataxic CP showed a median age of 6,9 years and median 6MWT of 415 m, while the whole study cohort had a median age 6,5 (mean 7,13 years – Table 1), with median 6MWT score of 390 m (mean 389 m – Table 1). This depicts vividly the vast range of the grade of impairment in children with CP. Indeed, centile curves for each CP type, and every single subtype of the spastic CP, would be ideal to monitor the effect of a treatment within a 6-month period. This would require though the study of cohorts, significantly larger than the one used in this study.

Limitations

For the generation of the centiles we used the patient data of the rehabilitation concept “Auf die Beine”, an intensive rehabilitative program, including intervals of inpatient physiotherapy and home-training in a period of 6 months. Thus, selection bias is a limitation for this study.

We estimated the correlation coefficient r, regarding the development of walking capacity between M6 and M12 as expected progression, under standard care provided in Germany. Inevitably, since all children received intensive rehabilitation for 6 months (M0 to M6), a long-term therapy effect on the walking capacity in the following 6 months cannot be ruled out. Nevertheless, the study of the Z-scores using Wilcoxon signed rank test and of the effect using Cohen’s d showed no significant and clinically negligible changes. Therefore, we would interpret the changes between M6 and M12 as expected progression of the walking capacity, similar to the expected changes among typically developing children.³³ Of course, using the same cohort as a control group before and after the intervention presents a study limitation, that shall also be considered when interpreting the changes between M6 and M12. In particular, it could have been more difficult for the children to increase their performance after the 6-month intervention period, since their starting point at M6 was higher. Indeed, a double-baseline design, including an initial assessment of 6MWT changes under standard of care, followed by the intervention, would be the ideal study design. Unfortunately, the retrospective data acquisition did not allow having the control phase prior to the intervention. Cohen’s d also does not necessarily refer to clinically relevant difference.

The presented method can be used to monitor the evolution of the walking capacity of children with cerebral palsy receiving a standard of care similar to the one provided to patients with CP in Germany. On the other hand, the variability of the care of the individual patients presents a further study limitation.

The SD of the walking capacity assessments depends on both the age and the time period between the assessments. The applied method can evaluate changes in Z-scores only for 6-month time periods.²⁹ For other time periods, we can only estimate whether the 6MWT scores are below, above, or equal to the expected development. Further research shall investigate the development of walking capacity using other time periods.

In this study, we could not identify sex-associated differences in the walking capacity, which may be related to an insufficient cohort size. Probably larger cohorts may better depict such differences. However, since the study aim was to generate a tool using centile curves to assess improvement after treatment of an individual patient, as well as of a cohort, and not simply to monitor natural development, we regard that creating centile curves that refer to both sexes is more practical for the daily clinical routine.

Finally, the length of the track used for the 6MWT may also present a further limitation, since the track commonly used in the literature is a circular 25-m track. Unfortunately, such a track was not available at site. However, international guidelines, such as the ones of the American Thoracic Society, do not focus on the length on the track, but rather suggest that non-circular or oval tracks should be avoided, so that children are not obliged to keep reversing their direction.³⁹

Conclusions

We have generated an assessment tool to quantify changes in the 6MWT in children with CP, GMFCS levels 1 and 2 within a 6-month period, utilizing age-related 6MWT trajectories. The method enables the assessment and monitoring of the effect of an offered treatment on the walking capacity of children with CP, taking into consideration changes related to expected development under standard of care over the studied period of 6 months. We also found a clinically significant, medium effect on the 6MWT of children receiving an intensive 6-month rehabilitation training including vibration-assisted physiotherapy, which occurred on top of the expected improvement of the walking capacity in a 6-month period under standard care.

Acknowledgments

We thank the physical therapists at the UniReha GmbH, Centre of Prevention and Rehabilitation of the University of Cologne for their dedicated and qualitative work. We acknowledge Ida Alperstedt and Angelika Stabrey for database management.

Disclosure Statement

ID is working at the Centre of Prevention and Rehabilitation of the University of Cologne and ES is directing the centre. No further competing interests to declare.

Additional information

Funding

No funding to declare.