Study design
A quasi-randomized, waitlist-controlled, assessor-blinded trial with two groups was conducted. Both groups received an INRS treatment course and four weeks of routine home treatment but in reverse order. The experimental group underwent INRS treatment and, after that, continued home treatment for four weeks. The control group stayed on the waiting list for four weeks receiving routine home treatment after the first evaluation, and then came for INRS treatment (Fig 1).
Figure 1. Timeline of the interventions and assessment procedures
Patients who planned to receive treatment in the tertiary care facilities providing INRS treatment (International Clinic of Rehabilitation or Elita Rehabilitation Center) were considered potential participants. Candidates were selected according to defined inclusion criteria by reviewing their previously obtained medical documentation. The study coordinator remotely (via phone and e-mail) explained the study details to the family and child and re-checked the inclusion-exclusion criteria. If the child and parents were ready to participate and signed the informed consent form, they were randomly assigned to the experimental or control group.
Group allocation was performed using quasi-randomization whereby participants were assigned to the experimental or control group in the order in which they enrolled in the study in the step of 3 (the first 3 participants were assigned to the experimental group, then the next 3 to the control group, then next 3 to the experimental and so on).
All the participants were evaluated three times: at baseline -time T1, after the first period – time T2 (after INRS treatment for the experimental group and routine home treatment for the control group), and in the end – time T3 after groups switched treatments. Evaluations have been performed by certified and trained therapists blinded to group allocation. All data were forwarded to the supervisor on the same day. The study protocol was registered on ClinicalTrials.gov under the identifier: NCT04093180.
Participants
Participant flow is presented in the CONSORT flowchart (Fig 2). Sixty children were preselected as possible participants in the study and underwent the primary screening. Further, 12 children have been excluded from the study due to non-compliance with the study requirements.
Forty-eight children were allocated to one of the groups using quasi-randomization with step 3 until both groups had 24 participants. Two patients were lost to follow-up during home treatment in the experimental group, and one child was excluded due to illness in the control group.
Figure 2. Patient flow
The demographic characteristics of the participants are presented in Table 1. The experimental group included 22 patients, and the control group – 21 children. There was no statistical difference between the groups.
Table 1. Demographic characteristics of the participants.
|
Experimental group
|
Control group
|
Number of children
|
22
|
21
|
Age in years mean (SD)
|
11.5 (3,1)
|
10.8 (3.3)
|
Sex ratio (male/female)
|
12/10
|
18/7
|
Diagnosis
CP: spastic quadriplegia
CP: spastic diplegia
|
18
4
|
17
4
|
GMFCS
Level I
Level II
Level III
Level IV
|
8
11
3
0
|
7
10
4
0
|
MACS
Level I
Level II
Level III
Level IV
|
7
10
5
0
|
6
11
4
0
|
SD – Standard deviation, CP – Cerebral Palsy, GMFCS – Gross Motor Functions Classification System, MACS – Manual Abilities Classification System
Inclusion criteria were: (i) CP, spastic bilateral forms (diagnosis based on the recommendations of the Surveillance of Cerebral Palsy in Europe [18]; (ii) 5 to 12 years of age; (iii) Gross Motor Function Classification System - Levels I-IV; (iv) Manual Ability Classification System – Levels I-IV. Exclusion criteria were: (i) uncontrolled seizures; (ii) severe intellectual disability; (iii) uncooperative behavior; (iv) surgery and Botox injections during the ongoing year.
Intervention
We used the Template for Intervention Description and Replication TIDieR guide to describe Intensive Neurophysiological Rehabilitation System (INRS), also called Professor Kozyavkin Method [19].
The aim of the INRS is to improve the functioning and quality of life of children with CP by enhancing their mobility and self-care functions. Children received an intensive course of treatment, according to INRS, for two weeks. Details of the INRS program were individualized depending on each child's abilities, but, in general, the intervention was not modified during the study.
It included:
-30 minutes of physical therapy aimed at gross motor training is performed daily and includes task-related personalized gross motor exercises, including bimanual activities, postural skills practicing, endurance, mobility, and balance training,
-20 minutes of occupational therapy focused on developing skills necessary for the performance of everyday activities, including play and self-care imitated activities such as tying shoelaces, buttoning, threading beads, and games with the spiky ball,
-5 minutes of spinal manipulative therapy: a variation of the spinal manipulation carried out in lumbar, thoracic, and cervical regions using high-velocity, low-amplitude thrusts techniques,
-60 minutes of full body massage with reflexotherapy using different massage techniques together with isotonic and post-isometric relaxation techniques and applying low current electric stimulation of acupuncture points and myofascial trigger points, reinforced with wax and paraffin application
-15 minutes of joint mobilization when the physical therapist pulls the large and peripheral joint smoothly beyond the range of passive movements by applying pressure to the tissues surrounding the joint,
-20 minutes of computer game therapy when the child is training the movements needed in a functional context with special personalized games; the child can control the game character by moving their body and using special equipment, such as a motion-sensing input device for upper extremities training, dance mat for stepping games, and balance board for balance training,
-15 minutes of gait training on a treadmill with/without suspension,
-15 minutes of strength training (called "mechanotherapy") when muscle strength, endurance, flexibility, and posture are endorsed by applying special devices and technologies, such as suspension-based physical therapy, motorized movement therapy, and cycling,
-30 minutes of group rhythmic gymnastics: adapted active games and dancing movements that are performed in a group of peers and families.
More details about INRS are presented in the manual [12]. INRS treatment was provided by certified medical doctors, physical therapists, and medical nurses experienced in working with children with cerebral palsy. It was provided individually, face to face, with one specialist per child. In the case of group rhythmic gymnastics, there are two staff members for the group. Rehabilitation was provided in the tertiary care facility for about four hours daily for ten days.
The medical staff supervisor has assessed the quality of every component delivery. No adverse events have been reported during the intervention.
Outcome measures
Certified therapists blinded to group allocation measured all outcomes three times. The assessments covered the three domains of ICF.
The primary outcome measure was Gross Motor Function Measure 66 Item Set (GMFM), which has good reliability and responsiveness in children with CP [20]. It uses four targeted item sets to evaluate overall gross motor ability in children with cerebral palsy under five dimensions. The administration of the GMFM starts with a predefined decision item. The child's score on each of these items leads therapists to the item set that is the most suitable for that child.
The secondary outcome measures included the Jebsen-Taylor Hand Function Test, Box and Blocks Test, ABILHAND-Kids Questionnaire, Self-care and Mobility domain of the Pediatric Evaluation of Disability Inventory, and the ankle dorsiflexion passive range of motion.
The Jebsen-Taylor Hand Function Test assesses hand function activities during the performance of activities of daily living [21]. The test quantifies the time it takes for the subject to do the following standardized functional tasks with one hand: turning over cards, picking up small items, simulating feeding, stacking checkers, picking up light cans, and picking up heavy cans. Guidelines specify that testing begins with the non-dominant hand. The writing task was excluded from the assessment due to the age of some participants. Each item is scored according to the time to complete the task. The scores for all items are then summed for a total score for each hand.
Box and Blocks Test is a valid and reliable diagnostic tool that evaluates the level of manual dexterity [22]. The score is the number of blocks the dominant and non-dominant hands carry from one compartment to another in one minute.
ABILHAND-Kids is a measure of manual ability for children with upper limb impairment [23]. The scale measures a person's ability to manage daily activities that require manual ability. The parent is asked to fill in the Ukrainian version of the questionnaire by estimating their child's performance in 21 manual activities on a 3-level scale (impossible, difficult, easy) [24]. A total score is calculated and presented in the logits (the linear measure that expresses the odds of success of the patient in performing tasks).
The Pediatric Evaluation of Disability Inventory (PEDI) is an instrument that measures independence in daily living. It covers daily activities in self-care, mobility, and social functioning among children with CP [25]. For our study, we used self-care and mobility domains. The scaled score was determined using the raw score.
The passive range of ankle dorsiflexion (PROM) was measured with a hand-held goniometer. For each child, we measured both the left and right sides with the knees flexed. A standardized assessment protocol was followed for positioning the patient and the examiner's hand [26].
Sample size
The sample size was calculated based on our previous study of changes in motor functions in children with cerebral palsy after the course of Intensive Neurophysiological Rehabilitation [16]. A mean improvement of the GMFM score from 58.8 to 60.2 with a mean difference (MD) of 1.4 ± 2.9 points was reported. With a 5% of probability of a type I error (α=0.05) and 80% power to detect a possible difference (1-β=0.08), a minimum of 20 participants per group was required. Considering drop-ups during the study, 24 children were allocated to each group.
Statistics
Statistical analysis was performed using SPSS ver. 23 [27]. A null hypothesis rejection was set at p<0.05 for all measurements. Appropriate statistical assumptions of normality and variance homogeneity for each general linear model were tested using the Shapiro-Wilk test before hypothesis testing.
To evaluate changes over time for each variable, the repeated measures analysis of variance tests (ANOVA) with Bonferroni posthoc was performed separately for each group. The effect size was estimated using the value Partial Eta Squared (η2). Values of η2 = 0.01 indicate a small effect; η2 = 0.06 indicates a medium effect; η2 = 0.14 indicates a large effect.
In case of statistically significant change during the treatment in the experimental group, these changes have been compared with the same period (between time T1 and time T2) in the control group using the Analysis of Covariance (ANCOVA) test with time T1 values as a covariate. The effect size was also calculated using η2.
[18] Surveillance of Cerebral Palsy in Europe. http://www.scpenetwork.eu/ Accessed 5 December 2022
[19] Hoffmann TC, Glasziou PP, Boutron I, Milne R, Perera R, Moher D, et al. Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide. BMJ 2014;348.
[20] Russell DJ, Avery LM, Walter SD, Hanna SE, Bartlett DJ, Rosenbaum PL, et al. Development and validation of item sets to improve efficiency of administration of the 66-item Gross Motor Function Measure in children with cerebral palsy. Dev Med Child Neurol 2009;52:e48–54.
[21] Jebsen R, Taylor N, Trieschmann R, Trotter M, Howard L. An objective and standardized test of hand function. Arch Phys Med Rehabil. 1969;50:311-19.
[22] Mathiowetz V, Volland G, Kashman N, Weber K. Adult norms for the Box and Block Test of manual dexterity. Am J Occup Ther. 1985;39(6):386-91.
[23] Arnould C, Penta M, Renders A, Thonnard JL. ABILHAND-Kids: A measure of manual ability in children with cerebral palsy. Neurology. 2004;63(6):1045-52.
[24] Hasiuk M, Arnould C, Kushnir A, Matiushenko O, Kachmar O. Cross-cultural adaptation and validation of the Ukrainian version of the ABILHAND-Kids questionnaire. Disabil Rehabil. 2021;43(4):576-85.
[25] Haley SM, Coster WJ, Ludlow LH, Haltiwanger JT, Andrellos PJ. Pediatric Evaluation of Disability Inventory (PEDI). Boston (MA): PEDI Research Group; 1992.
[26] Norkin CC, White DJ. Measurement of joint motion: a guide to goniometry. 5th ed. Philadelphia: Davis Company, 2016.
[27] SPSS Tutorials. Effect Size – A Quick Guide https://www.spss-tutorials.com/effect-size/ Accessed 29 November 2022.