Lucas Ravault
email: lucasravault73@orange.fr

Nelly Darbois

Nicolas Pinsault

Methodological Considerations to Investigate Dosage Parameters of Intensive Upper Limb Rehabilitation in Children with Unilateral Spastic Cerebral Palsy: A Scoping Review of RCTs

Keywords: USCP, CP: Unilateral Spastic Cerebral Palsy, Cerebral Palsy, RCT: Randomized Controlled Trial, IMRT: Intensive Motor Rehabilitation Treatment Cerebral palsy, intensive motor rehabilitation, dosage parameter, critical thinking, pediatrics

Purposes:

To identify and synthesize RCTs on the isolated effect of dosage parameters of upper limb Intensive Motor Rehabilitation Treatments (IMRT) of children with Unilateral Spastic Cerebral Palsy (USCP); to identify the most frequent methodological weaknesses. Methods: Searches were conducted until September 2018 in gray and published literature databases and supplemented by exploring the identified studies' references. Inclusion criteria applied: RCT; children aged 1.5 to 19 years with USCP; upper limb IMRT differing only from ≥1/4 dosage parameters between groups. Literature analyses conducted: qualitative and descriptive. Results: We identified 461 studies. Seventeen were included: three presented a rehabilitation dosage distinction between groups in Frequency-Time, four in Intensity-Progressivity, three in Intensity-Restraint, two in Intensity-Environment and five presented ≥3 distinctions above. Conclusions: Inconsistencies were noted between USCP lifelong issues, and the short follow-ups and lack of participation assessments. Confounding factors and misstatements in Intent To Treat (ITT) analyses were identified. A meta-analysis was considered irrelevant.

Introduction

� Unilateral Spastic Cerebral Palsy (USCP) affects nearly 34% of the children presenting Cerebral Palsy (CP); this proportion has increased in Europe since the end of the 2O th century. [START_REF] Sellier | Decreasing prevalence in cerebral palsy: a multi-site European population-based study, 1980 to 2003[END_REF] Between 1.6/1000 and 2.8/1000 births lead to CP depending on the region of the world. This proportion increased with low gestation age, low birth weight, twin or multiple pregnancy, and ethnic variations. [START_REF] Sellier | Decreasing prevalence in cerebral palsy: a multi-site European population-based study, 1980 to 2003[END_REF][START_REF] Panteliadis | Cerebral palsy: a multidisciplinary approach[END_REF] USCP is clinically manifested by spastic hemiplegia with retractions, impaired motor command and control, and varying degrees of sensory, cognitive and epileptic disorders. [START_REF] Panteliadis | Cerebral palsy: a multidisciplinary approach[END_REF][START_REF] Delacy | Profile of associated impairments at age 5 years in Australia by cerebral palsy subtype and Gross Motor Function Classification System level for birth years 1996 to 2005[END_REF][START_REF] Bleyenheuft | Precision grip control, sensory impairments and their interactions in children with hemiplegic cerebral palsy: A systematic review[END_REF][START_REF] Gordon | Pathophysiology of impaired hand function in children with unilateral cerebral palsy[END_REF] These disorders result in a "developmental disregard" [START_REF] Deluca | Intensive pediatric constraint-induced therapy for children with cerebral palsy: randomized, controlled, crossover trial[END_REF] of the hemiplegic upper-limb: "a certain portion of the motor deficit […] is the result not of the damage per se but of a learning phenomenon stemming from the damage, but whose core is the learned suppression of movement". [START_REF] Taub | The learned nonuse phenomenon: implications for rehabilitation[END_REF] These function deficits secondly have a negative impact on the child's level of activity and level of participation. [START_REF] Panteliadis | Cerebral palsy: a multidisciplinary approach[END_REF][START_REF] Klingels | Randomized trial of modified constraint-induced movement therapy with and without an intensive therapy program in children with unilateral cerebral palsy[END_REF] On the other hand, ambulation capacities are almost systematically preserved. [START_REF] Howard | Cerebral palsy in Victoria: motor types, topography and gross motor function[END_REF] In order to potentiate the improvement of motor functions and activities in the short and long term in children with USCP, many systematic reviews recommend motor rehabilitation: (1) early 10 , (2) adapted to the subtype of CP 10 , (3) and intensively [START_REF] Sakzewski | Efficacy of Upper Limb Therapies for Unilateral Cerebral Palsy: A Meta-analysis[END_REF] ; that is often the case for bimanual training, constraint-induced movement therapy, context-focused therapy, goal-directed/functional training, home-programs integration. [START_REF] Sakzewski | Efficacy of Upper Limb Therapies for Unilateral Cerebral Palsy: A Meta-analysis[END_REF][START_REF] Novak | A systematic review of interventions for children with cerebral palsy: state of the evidence[END_REF][START_REF] Chen | Effectiveness of constraint-induced movement therapy on upper-extremity function in children with cerebral palsy: a systematic review and meta-analysis of randomized controlled trials[END_REF][START_REF] Chiu | Constraint-induced movement therapy improves upper limb activity and participation in hemiplegic cerebral palsy: a systematic review[END_REF][START_REF] Dong | Studies comparing the efficacy of constraint-induced movement therapy and bimanual training in children with unilateral cerebral palsy: A systematic review[END_REF] Several systematic and non-systematic reviews focused on the management of USCP, agree on the added value of these intensive motor rehabilitation treatments (IMRT) compared to those considered "conventional" and/or "non-intensive" and/or not fully taking into account the principles of motor learning. [START_REF] Sakzewski | Efficacy of Upper Limb Therapies for Unilateral Cerebral Palsy: A Meta-analysis[END_REF][START_REF] Chen | Effectiveness of constraint-induced movement therapy on upper-extremity function in children with cerebral palsy: a systematic review and meta-analysis of randomized controlled trials[END_REF][START_REF] Chiu | Constraint-induced movement therapy improves upper limb activity and participation in hemiplegic cerebral palsy: a systematic review[END_REF][START_REF] Dong | Studies comparing the efficacy of constraint-induced movement therapy and bimanual training in children with unilateral cerebral palsy: A systematic review[END_REF][START_REF] Durand | At-home and in-group delivery of constraint-induced movement therapy in children with hemiparesis: A systematic review[END_REF][START_REF] Guerrero | Parámetros de dosificación de la terapia de movimiento inducido por restricción en niños con parálisis cerebral hemipléjica[END_REF] However, these scientific works are largely based on studies whose treatment types differ between the intervention and control groups (e.g. Sakzewski's metaanalysis [START_REF] Sakzewski | Efficacy of Upper Limb Therapies for Unilateral Cerebral Palsy: A Meta-analysis[END_REF] includes studies comparing "modified Constraint-Induced Movement Therapy" (m-CIMT) to "Hand-Arm Bimanual Intensive Therapy" (HABIT) [START_REF] Gordon | Bimanual training and constraint-induced movement therapy in children with hemiplegic cerebral palsy: a randomized trial[END_REF] or "Standard Occupational Therapy" [START_REF] Wallen | Modified constraint-induced therapy for children with hemiplegic cerebral palsy: a randomized trial[END_REF] or other various treatments. [START_REF] Sakzewski | Randomized trial of constraintinduced movement therapy and bimanual training on activity outcomes for children with congenital hemiplegia[END_REF] The treatment type can be considered as a cluster of several distinct dosage parameters; comparing different types of treatments is like comparing two combinations of dosage parameters and their interactions. This represents many confounding factors that prevent the analysis of the specific effect of each dosage parameter of these IMRT on motor function.

Other authors have also described "intensive therapies" targeting the trunk and/or upper and/or lower limbs of children without specifying the subtype of CP concerned. They have not been able to conclude on the determinants of their effectiveness: due to a lack of studies and inclusion criteria that are probably too restrictive. [START_REF] Arpino | Efficacy of intensive versus nonintensive physiotherapy in children with cerebral palsy: a meta-analysis[END_REF][START_REF] Myrhaug | Intensive training of motor function and functional skills among young children with cerebral palsy: a systematic review and meta-analysis[END_REF] A recent systematic review of the peer-reviewed literature, based on a standardized dosage terminology [START_REF] Kolobe | Research summit III proceedings on dosing in children with an injured brain or cerebral palsy: executive summary[END_REF] includes only studies comparing groups receiving the same type of treatment and differing by at least one dosage parameter. [START_REF] Cope | The effects of dosage time and frequency on motor outcomes in children with cerebral palsy: A systematic review[END_REF] They suggest, "that higher amounts of therapy time may have a slightly greater benefit than low amounts of therapy for improving motor function" without reaching the clinically significant threshold. The lack of studies on the "frequency" of treatments and the absence of a study on "intensity" prevent the authors from concluding on these subjects. Again, the non-specification of CP subtypes in the inclusion criteria contributes to many confounding factors (e.g. various associated impairments, clinical expressions, inter-study treatments, and child's or family's functional expectations).

There is therefore still a blurred area today as to the relative influence of each dosage parameter on these short-and long-term functional and participation benefits in children with CP. [START_REF] Durand | At-home and in-group delivery of constraint-induced movement therapy in children with hemiparesis: A systematic review[END_REF][START_REF] Cope | The effects of dosage time and frequency on motor outcomes in children with cerebral palsy: A systematic review[END_REF][START_REF] Eliasson | Guidelines for future research in constraint-induced movement therapy for children with unilateral cerebral palsy: an expert consensus[END_REF] Nor is there a synthesis of the methodological limitations of RCTs that would specifically challenge the dosage parameters in this area.

The purposes of this scoping review were: (1) to identify and synthesize RCTs that allowed to question individually the dosage parameters of IMRT of the upper limb of children with USCP, (2) to identify the most frequent methodological limitations of the RCTs on the subject and their report in order to improve the quality of future research, and (3) to discuss the relevance of conducting a systematic review or meta-analysis on the subject.

Method

A scoping review of RCTs was conducted by systematically exploring the existing randomized controlled literature on the following topic: the effects of the dosage parameters of IMRT of the upper limbs on functional and participation skills of children with Unilateral Spastic Cerebral Palsy (USCP). The method was based on Cochrane's guidelines (http://handbook-5-1.cochrane. org/; https://epoc.cochrane.org/resources/epoc-resourcesreview-authors). The protocol was registered on PROSPERO, CRD42018104517 (http://www.crd.york.ac.uk/PROSPERO/dis play_record.php?ID=CRD42018104517).

From the comparison of several reviews and recommendations standardizing the dosage terminology [START_REF] Kolobe | Research summit III proceedings on dosing in children with an injured brain or cerebral palsy: executive summary[END_REF][START_REF] Page | Optimizing terminology for stroke motor rehabilitation: recommendations from the american congress of rehabilitation medicine stroke movement interventions subcommittee[END_REF][START_REF] Gannotti | A path model for evaluating dosing parameters for children with cerebral palsy[END_REF][START_REF] American | ACSM's guidelines for exercise testing and prescription �[END_REF] , we built a critical terminology framework for the dosage parameters as follows:

• Frequency-Time: "How often during a fixed period the regimen is administered" and "the total amount of time that an intervention period occupies".

Search Strategy

Preliminary Research

One reviewer conducted a preliminary exploration of the Pubmed database to assess the number of RCTs that could be included in the scoping review. The arbitrary "relevance" threshold of 10 RCTs was reached.

Systematical and Complementary Research

One reviewer systematically searched the following databases until September 2018: Pubmed, Google Scholar, CENTRAL, PEDro, ScienceDirect, ITCRP, Clinicaltrials, Open gray, Gray literature report, HAL, TEL (systematical phase). In addition, we examined the bibliographic references of reviews, systematic reviews, meta-analyses on the related subject, and included RCTs (complementary phase). We also consulted several experts who had already published on the subject (complementary phase).

Search Terms

The following keywords and Medical Subject Headings (MeSH) terms were combined according to the specificities of each database: S1 (online supplemental material) or on request from the corresponding author.

(i)

Study Selection

Selection Strategy

For the systematical phase, we first collected the studies by reading the titles. Second, we removed the duplicate studies. Then, we compared the remaining studies to the eligibility criteria using successive analyses of the abstracts and full texts.

As soon as their content did not meet the eligibility criteria, they were excluded without further action; studies that met all eligibility criteria were included.

For the complementary phase, we first collected the studies by reading the titles of the bibliographic references. Then, we directly compared the full-texts of the identified studies to the eligibility criteria by proceeding as above.

Eligibility Criteria

Published and gray literatures were explored without time limit.

The following inclusion criteria were applied:

• RCTs written in English or French.

• Children with USCP, aged 18 months to 19 yearstolerating that up to 20% of the children included in the study were less than 18 months old -and with a motor hemiplegia as a minimum clinical criterion. • Outcomes of upper limb functional skills and/or participation.

• Intervention and comparator groups should be exposed to similar IMRT (i.e. IMRT of same "type", or explicitly qualified as "identical", or with a synonym of "identical").

• IMRT should:

○ Be consistent with one of the following IMRT types: Original-Constraint-induced movement therapy (CIMT), Modified-CIMT (mCIMT), Pediatric-CIMT (P-CIMT); Bimanual Intensive Training (BIT); Hand-Arm Bimanual Intensive Therapy (HABIT); HABIT-Including Lower Extremities (HABIT-ILE); Hybrid protocols combining two or more of the previous cited treatments; Forced-use therapy (FUT). Or, be consistent with all the following properties: 3 to 7 training days per week; from 1 to 6 h of rehabilitation time per training day; from 2 to 10 weeks of program duration. ○ Detailed at least one of the following dosage parameters:

(1) Frequency-Time, or Intensity according to (2)progressivity, (3) -restraint, or (4) -environment. ○ Only differed from one group to another for at least one of the four dosage parameters above. ○ Be provided or supervised at least part of the time by a rehabilitation health professional.

The following exclusion criteria were applied:

• Study analyzing the results of several RCTs, or whose design was different from an RCT. • Children diagnosed with "profound multiples disabilities" [START_REF] Avez-Couturier | La douleur chez l'enfant en situation de handicap neurologique: mise au point de la Commission « déficience intellectuelle et handicap » de la Société française de neurologie pédiatrique[END_REF] , or who had recently undergone surgery. • IMRT mainly based on a computer-based training, or combined with bodysuit/garment.

• Any other element that would conflict with the above inclusion criteria.

Charting the Data

Data Extraction

One reviewer extracted data from the included studies into a structured extensive sheet. The main data collected were: authors' names; redaction/publication year; study locations; recruitment, allocation and randomization details; eligibility criteria; risks of bias; outcomes types; outcome assessment modalities and times; participant and group characteristics; intervention types; qualitative and quantitative description of intervention procedures; distinct dosage parameter(s) between the groups; dosage registration methods; main findings; result analysis methods and procedures.

Collating, Summarizing, and Reporting the Results

Data Synthesis

We presented the successive steps of the selection process in a flow chart (Figure 1). One reviewer sorted data collected into an extensive sheet and summarized the most relevant ones in a descriptive table. The descriptive table provided the characteristics and the main findings of the studies (Table 1).

Based on psychometric studies and one systematic review [START_REF] Feldman | Concurrent and construct validity of the pediatric evaluation of disability inventory[END_REF][START_REF] Uswatte | Pediatric arm function test[END_REF][START_REF] Lattre | Prise en charge non chirurgicale du membre supérieur de l'enfant hémiplégique : actualités sur l'évaluation, les traitements médicamenteux et les techniques rééducatives[END_REF][START_REF] Varni | The PedsQL in pediatric cerebral palsy: reliability, validity, and sensitivity of the generic core scales and cerebral palsy module[END_REF][START_REF] Lemmens | Valid and reliable instruments for arm-hand assessment at ICF activity level in persons with hemiplegia: a systematic review[END_REF] each outcome result was attributed and presented according to one of the following ICF levels: body structure, body function, activity capacity, perceived activity performance, actual activity performance, participation.

Data were summarized into three diagrams and one illustration that presented: the number of RCTs by duration of group comparisons follow-up (Figure 2); the percentage of included RCTs evaluating each ICF level (Figure 3); the number of RCTs by distinct dosage parameter(s) between the groups (Figure 4); the significant between-group differences with their ICF levels, according to the distinct dosage parameters between the groups in the included RCTs (Figure 5).

One reviewer critically analyzed data collected on the methodology and implementation of RCT protocols and summarized them in a table providing the qualitative level of evidence (Table 2). Cochrane's Risk of Bias 2.0 tool (Rob 2.0 tool, 2016) was initially used to qualitatively report the level of evidence of the included studies. Based on Peters et al.'s guidelines on scoping review [START_REF] Peters | Guidance for conducting systematic scoping reviews[END_REF] we chose to report only the following information from the Rob 2.0 tool: randomization design, blinding nature, baseline comparability, intent to treat analysis.

Results

Selection Process

Four hundred and thirty-four studies were retained by reading the titles, 399 after removing duplicates, 104 after reading the abstracts and 16 after reading the full-texts. One additional study was included from the complementary selection phase after reading the full-texts. The distribution of studies by database and the exclusion reasons are detailed in Figure 1.

Studies Characteristics

Seventeen RCTs were included: 7 group randomized and 10 individually randomized. Sixteen were published after 2010 and 1 before. We identified three groups of "overlapping studies", with the same original sample of children, or a subdivision of the original sample. Taking into account these overlaps, we collected 17 studies from 13 different samples of children. RCTs were conducted in America (USA [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF] , Canada 41 , Brazil [START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF] ), Asia (South Korea [START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF] , India [START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF] , Iran [START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF][START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF] ), Africa (Egypt [START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF] ) or Europe (Netherlands [START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF] , England. [START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] )

Intervention Characteristics

The included studies provided the following treatments: CIMT [START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF] , P-CIMT [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF] , mCIMT [START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF][START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] , mCIMT with bimanual skills transfer phase [START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF] , HABIT [START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF] , FUT [START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF] , Intensive Motor Learning Therapy (IMLT) [START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF] , Intensive Motor Therapy (IMT) [START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF] and Conventional Therapy (CT). [START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF] HABIT programs lasted 3 to 4 weeks, P-CIMT 26 days, FUT and CT 6 weeks, and mCIMT, mCIMT-BIM, IMLT and IMT from 12 days to 10 weeks.

Participant Characteristics

A total of 364 children were considered, aged from 18 months to 19 years old. Various proportions of cerebral lesion side were observed in RCTs, ranging from 39% [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF] to 89% [START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF] of children with the left cerebral lesion.

Outcome Characteristics

Twenty-five outcome measurement tools were identified. Three outcomes were attributed to body structure level, one to body function, eight to activity capacity, four to actual activity performance, six to perceived activity performance, one to participation, and two were judged as categorization tools -not part of ICF levels. The rationales for allocations were presented in Table S2 (online supplemental material).

Five RCTs presented the between-group comparisons up to the post-treatment assessment [START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF] (i.e. from 1 day to 1 week after the end of treatment depending on the studies), one RCT up to 1 month of follow-up [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF] , two up to 1.5 months [START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF] , two up to 3 months [START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF] , seven up to 6 months [START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] , and none after that. Data are summarized in Figure 2.

ICF Level Exploration

The exploration of ICF levels was presented as a percentage of the included RCTs that assessed or not each ICF level, to highlight gaps. Twelve percent (2/17) of the included RCTs assessed the body structure level [START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF] , 12% (2/17) the body function [START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF] , 88% (15/17) the activity capacity 36-39,41-43,45-52 , 65% (11/17) the Legend.No response: The authors did not response to our contact or we did not find its contact; Duplicate studies deleting after the full-text reading: Duplicate studies with different titles, identified a posteriori by contacting the author. The FUT group showed better pre-post treatment improvements than the CT group in unimanual activity capacity, and global actual activity performance.

(Continued )

perceived activity performance [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] , 71% (12/17) the actual activity performance [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF][START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] , and 12% (2/17) the participation of children. [START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] No RCTs explored all ICF levels. In contrast, with regard to child samples, one sample was examined by three RCTs [START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF] , resulting in a more complete exploration of ICF levels: body structure, activity capacity, actual and perceived activity performance. Data are summarized in Figure 3.

Distinct Dosage Parameters between Groups

The dosage was presented through the number of RCTs that allowed the dosage parameters of the treatments to be questioned individually. Three RCTs isolated relatively the frequency-time parameter [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF] , four RCTs the intensity-progressivity parameter [START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF] , 3 RCTs the intensity-restraint parameter [START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] , and two RCTs the intensity-environment parameter. [START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF] Five RCTs also compared interventions that differed in three or more dosage parameters. [START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF] The rest time given to children was neither studied nor reported. Data are summarized in Figure 4.

Findings of Included Studies

Between-group differences were not considered for three RCTs [START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF] because they were judged irrelevant as they were calculated solely on the basis of the comparison of posttreatment scores.

The majority of the remaining RCTs showed statistically significant between-group differences (10/13) in at least one outcome measure [START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF] for various types of treatment provided. Three-fourths of the RCTs isolating the intensityprogressivity parameter showed significant between-group differences in the body structure [START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF] , and the actual [START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF] and perceived [START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF] activity performance up to 6 months of followup. One-third of the RCTs isolating the intensity-restraint parameter showed a between-group difference in the perceived activity performance up to 6 months of follow-up. [START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF] One-half of the RCTs isolating the intensity-environment parameter showed a between-group difference in the activity capacity up to 3 months of follow-up. [START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF] The three RCTs comparing interventions that differed in Frequency-Time [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF] did not find a significant between-group although the groups showed similar activity improvements. They investigated the management of daily rehabilitation time, or the continuous/per block rehabilitation schedule, for up to 6 months of follow-up. The five RCTs comparing interventions that differed in three or more dosage parameters showed between-group differences in all ICF levels assessed [START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF] ; excepting the following ones: body structure (no significant difference), and participation (not assessed). Data are summarized in Figure 5.

It should be noted that one RCT comparing HABIT that differed in intensity-progressivity showed a likely benefit of the "Structured Practice Group" by a relationship between body structure and activity capacity and actual performance after 6 months of follow-up [START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF] -greater improvements in JTTHF and COPM-Performance were associated with larger hand motor map expansions.

Level of Evidence

The level of evidence criteria revealed that 71% (12/17) of the RCTs had blind assessors 37-39,41,42,46-50,52 and 29% (5/17) did not provide sufficient information. [START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF] 71% (12/17) of the RCTs presented between-group baseline comparability [START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF] , while 18% (3/17) presented pre-treatment between-group differences of the upper limb functioning [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF] , or the age [START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] , and 12% (2/17) did not provide sufficient information. [START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF] Twelve percent (2/17) of the RCTs actually performed an Intent To Treat Analysis [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF] -"subjects allocated to a treatment group […] followed, assessed and analysed as members of the treatment group irrespective of their compliance with the planned course of treatment" (https://www.thefreedictionary.com/). Sixty-five percent (11/17) did not meet the previous ITT definition. [START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] 24% (4/17) did not provide sufficient information to judge the data analysis. [START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF][START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF] The correspondence between the studies and the methodological quality criteria is presented in Table 2.

Strengths and Weaknesses of the Review

In order to question the consistency of the method with the author's objectives, we considered it relevant to focus on a priori high level of evidence study designs: RCTs, which are the standard of excellence for comparing the effects of several treatment modalities. Also, we conducted preliminary research that reached the arbitrary threshold of 10 RCTs for relevance.

The eligibility criteria focused only on children with USCPs, which reduced the confounding factors involved in the variability of the CP subtypes' specific disability profiles. [START_REF] Panteliadis | Cerebral palsy: a multidisciplinary approach[END_REF] Nevertheless, some uncontrollable ones still prevented us from exclusively questioning the impact of each dosage parameter on children's functional and participation skills.

The dosage parameter terminology was based on a critical terminological framework of the dosage developed from standardized and reference models [START_REF] Kolobe | Research summit III proceedings on dosing in children with an injured brain or cerebral palsy: executive summary[END_REF][START_REF] Page | Optimizing terminology for stroke motor rehabilitation: recommendations from the american congress of rehabilitation medicine stroke movement interventions subcommittee[END_REF][START_REF] Gannotti | A path model for evaluating dosing parameters for children with cerebral palsy[END_REF][START_REF] American | ACSM's guidelines for exercise testing and prescription �[END_REF] ensuring transparency and clear peer understanding. Our critique mainly consisted in dividing the "intensity" parameter into three sub-groups to distance us from the Kolobe et al. definition from which Cope and Mohn-Johnsen's systematic review did not find a study. [START_REF] Cope | The effects of dosage time and frequency on motor outcomes in children with cerebral palsy: A systematic review[END_REF] The systematic literature exploration permitted to include the more recent randomized-controlled literature on the subject [START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] and the previous RTCs [START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF][START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF] that were not included in the last two reviews on dosage parameters. [START_REF] Guerrero | Parámetros de dosificación de la terapia de movimiento inducido por restricción en niños con parálisis cerebral hemipléjica[END_REF][START_REF] Cope | The effects of dosage time and frequency on motor outcomes in children with cerebral palsy: A systematic review[END_REF] Only studies written in French or English were reviewed, but this could be offset by the extensive use of English in cerebral palsy research. We could not ignore the reviewer's subjectivity in assigning the "distinction of dosing parameters" to the groups, based on the reporting of dosage in the protocols by the RCT authors. On the other hand, we tried to be transparent about the method and terminology used.

Interpretation of Findings

Level of Evidence

The level of evidence is relatively homogeneous due to the blindness of the evaluators, the presence of baseline comparability and the lack of ITT analyses performed. The randomization design is equally distributed between group-randomization (47% of RCTs [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] ) and individual-randomization (53% of RCTs [START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF][START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF] ). The least satisfied methodological quality criterion is, therefore, the ITT analysis (Table 2). The ITT analysis depends on many uncontrollable factors (e.g. patient adherence to the rehabilitation program, direct or secondary side effects related to the intervention, unexpected events in daily life) fostered by the multidimensional nature of IMRT. Indeed, IMRT �involved � : multiple actors (e.g. children, parents, teachers, carers, care-givers, students), in multiple places (e.g. clinic, home, school), requiring a significant social and temporal commitment (e.g. 24 hours/day of restrained time). It is therefore often complicated to ensure ITT analysis due to frequent loss of follow-up; increasing complexity with increasing followup time.

The lack of consensus on the ITT definition leads in part to a bias in the reports. Many authors reported that they carry out an ITT analysis while the study showed missing outcome data and/or loss of child follow-up. [START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] However, alternatives exist to limit the impact of the attrition bias such as interpolating missing data with known data, as Friel et al. did using the group average. [START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF]

Inconsistencies between Clinical Issues and Research Protocols

Follow-up -We found some inconsistencies between the very long-term clinical challenges, induced by the lifelong motor disabilities of CP 2 , and the too short follow-up of the RCTs analyzed. Indeed, 59% of RCTs (10/17) stopped the assessments before 13 weeks of follow-up [START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF][START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF] , of which 50% (5/10) stopped them at the post-treatment assessment point. [START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF] However, since the 2013 Novak et al.'s recommendations [START_REF] Novak | A systematic review of interventions for children with cerebral palsy: state of the evidence[END_REF] that "additional studies that evaluate long-term outcomes are necessary [because] long-term outcome data are essential for costing and optimizing the outcomes", only 2/6 of the RCTs published after 2015 stopped follow-up before 6 months [START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF] ; including one that supplemented a longer RCT protocol assessing children up to 6 months of follow-up. [START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF] But keeping a critical eye, no studies compared data between groups after this 6-month followup point. The increasing relationship between the prevalence of confounding factors and the duration of follow-up 2 could partly explain this research gap.

Outcomes -The exploration of the diverse ICF levels appears very heterogeneous, the activity level being largely questioned when only 12% of the RCTs (2/17) assessed the body structure [START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF] , the body function [START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF] , or the participation [START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] (Figure 3). One explanation could be that tools commonly considered as assessing the children's participation more often assess the perceived activity performance (e.g. COPM, ABILHAND-Kids, or GAS [START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF] ) through tasks that are too limited to be considered representative of the participation in daily life, as noted by Lemmens et al. (2012). [START_REF] Lemmens | Valid and reliable instruments for arm-hand assessment at ICF activity level in persons with hemiplegia: a systematic review[END_REF] Panteliadis et al. (2018) 2 qualify latter ones as "patient-focused tools" and recommend to combine "focused goal assessment with a wider scan of [Quality of Life]".

It may also be regretted that there are no RCT protocols combining assessment of the body structure level with other ICF levels. Friel et al. (2016) [START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF] were one of the firsts to assess the "critical ingredients that drive motor cortex plasticity [in association] with bimanual training" through the activity ICF level. They obtained encouraging but not statistically significant results between groups. In addition, several recent longitudinal trials initiatives questioning the intensive rehabilitation of children with CP in this way are to be noted [START_REF] Smorenburg | Does corticospinal tract connectivity influence the response to intensive bimanual therapy in children with unilateral cerebral palsy?[END_REF][START_REF] Bleyenheuft | Capturing neuroplastic changes after bimanual intensive rehabilitation in children with unilateral spastic cerebral palsy: a combined DTI, TMS and fMRI pilot study[END_REF] thus opening up this interdisciplinary aspect of research.

Meta-analysis Not Relevant

We are reluctant to conduct a meta-analysis faced with the heterogeneity in the levels of evidence of RCTs (Table 2) and the relative lack of RCTs per dosage parameter (Figure 4) and the persistence of many uncontrollable confounding factors (detailed in the level of evidence paragraph). Other confounding factors justified our choice: (1) the heterogeneity of geographical situations covering four continents, which results in cultural, care accessibility, socio-economic levels, and many other secondary differences; (2) the heterogeneity of participants' characteristics (e.g. large age range, different cerebral lesion side distributions between studies); (3) the heterogeneity of interventions provided (e.g. Various IMRT types between studies, non-uniformity in the management of dosage parameters between studies, the lack of transparency of the environment parameter [START_REF] Myrhaug | Intensive training of motor function and functional skills among young children with cerebral palsy: a systematic review and meta-analysis[END_REF] ) .

Main Findings

For the same reasons that a meta-analysis is not relevant, the main findings of the studies should be tempered in light of the potential selection, attrition, interpretation, and confusion biases detailed in Discussion. Therefore, the main results presented in Figure 5 mainly map and illustrate the authors' interests and research gaps.

Implications for Practice

As presented above in the Main findings chapter, our scoping review reminds us of the need to maintain a critical mind aware of the possible cognitive and methodological biases with which we are constantly confronted.

Standardized evidence-based protocols (e.g. CIMT, mCIMT, P-CIMT, HABIT, mCIMT-BIT) appear to be superior to conventional therapy or alternative intensive rehabilitation treatments (IMLT, ITM). Their extensive research may have gradually led to optimize their dosage management leading to standardized guidelines. [START_REF] Ramey | Handbook of pediatricconstraint induced movement therapy �[END_REF][START_REF] Aarts | The pirate group intervention protocol: description and a case report of a modified constraint-induced movement therapy combined with bimanual training for young children with unilateral spastic cerebral palsy: the pirate group intervention, a case report[END_REF][START_REF] Charles | Development of hand-arm bimanual intensive training (HABIT) for improving bimanual coordination in children with hemiplegic cerebral palsy[END_REF] In addition, the presentation of the main findings of the RCTs according to the dosage parameter distinctions between groups reveals some encouraging results. Despite the management of the Frequency-Time parameter, daily rehabilitation time or the continuous/blocks rehabilitation schedule would not be beneficial to a group [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF] ; the management of the progression of intensity by applying the principles of motor learning seems linked to the improvement of many ICF levels. [START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF] The management of restraint time or the nature of restraint does not seem crucial and presents heterogeneous results. [START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] The Intensity-Environment parameter is poorly explored [START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Rostami | Effects of modified constraint-induced movement therapy in virtual environment on upper-limb function in children with spastic hemiparetic cerebral palsy: A randomised controlled trial[END_REF] , and difficult to isolate because of its uncontrollable multidimensional nature. [START_REF] Myrhaug | Intensive training of motor function and functional skills among young children with cerebral palsy: a systematic review and meta-analysis[END_REF] It is therefore probably premature to recommend that professionals develop their own intensive rehabilitation programs by managing each dosage parameter individually.

However, we strongly recommend, first, that more IMRT be implemented initially based on standardized evidencebased IMRT and, second, that they be managed by the dosage parameter to adapt the original protocols to context-induced specificities and the expectations of children and parents.

Thus, our results are in line with the current systematic literature that recommended IMRT to promote the overall improvement of upper-limb motor function and participation of children with USCP by combining the four dosage parameters' managements as follows:

(1) Frequency-Time: "60 or even 90 hours of continuous intensive rehabilitation" seems correlated to at least 6 months of maintaining functional benefits. [START_REF] Sakzewski | Efficacy of Upper Limb Therapies for Unilateral Cerebral Palsy: A Meta-analysis[END_REF][START_REF] Sakzewski | Comparison of dosage of intensive upper limb therapy for children with unilateral cerebral palsy: how big should the therapy pill be?[END_REF] (2) Intensity-progressivity: To privilege motor learning principle implementation (i.e. shaping, repetition, progressive difficulty, individualized goal-oriented therapy, child-friendly context). 12 (3) Intensity-restraint: At dose-equivalent, no differences between constrained versus unconstrained therapies are observed. 13,14 (4) Intensity-environment: To choose between a home-/clinical-rehabilitation program according to the family contexts and objectives; to integrate into our decision, the ethical benefit of promoting accessibility to the intensive rehabilitation programs by implementing in-groups children programs as recommended in a recent systematic review. [START_REF] Durand | At-home and in-group delivery of constraint-induced movement therapy in children with hemiparesis: A systematic review[END_REF]

Implications for Research

In light of our observations, greater transparency by the authors on the definition of ITT analysis and sincerity in the analysis of the data produced could easily improve the quality and transversality of the sharing of scientific documents.

Interpolation of known values to the missing outcome data could also prevent the attrition bias repercussions.

Given the lack of RCTs allowing to question each of the dosage parameters, especially the Intensity-environment parameter, particular attention in the inclusion criteria could easily limit this gap: by providing the same type of IMRT to both groups; interventions differing only by a single dosage parameter.

Again, we encourage RCTs to evaluate, through a followup of at least 6 months, the multiple ICF levels and to specifically combine body structure assessments -neuroimaging outcomes -with other functional and participation ones. For the participation level, appropriate outcome measures of the quality of life should be used (e.g. PedsQL, KIDSCREEN, CP QOL-Child) in combination with goal assessments (e.g. COPM, GAS) as recommended by Panteliadis et al. [START_REF] Panteliadis | Cerebral palsy: a multidisciplinary approach[END_REF] Finally, the authors never detailed the rest period granted to children. This illustrates the need for authors to further detail their research protocols and dosage parameters using standardized and transparent terminology.

This last observation raises several questions that may be the subject of future research. In effect, USCP induces several biopsycho-social repercussions in children and their families: What are these repercussions? What are their impacts on (intensive) rehabilitation? What are the specific considerations to be taken into account when adapting rehabilitation to the child (and no longer to adapting the child to rehabilitation)?

Figure 1 .

 1 Figure 1. Flow chart of the selection process.Legend.No response: The authors did not response to our contact or we did not find its contact; Duplicate studies deleting after the full-text reading: Duplicate studies with different titles, identified a posteriori by contacting the author.

Figure 2 .

 2 Figure 2. Number of studies by the duration of groups comparison Legend.Post-treatment: Hung (2017); Kumar (2017); Sabour (2013); Chopra (2013); Sung (2005) 1 month: Deluca (2012)1.5 months: Aarts (2010, 3 months: Rostami (2012); El-Kafy (2014) 6 months: Case-Smith (2012); Brandão (2014, 2017); Friel (2016); Kirton (2016); Christmas (2018); Geerdink (2013)

Figure 3 .

 3 Figure 3. Percentage of included assessing each ICF level.

Figure 4 .

 4 Figure 4. Number of RCTs dosage parameter(s) between the groups.

  [START_REF] Page | Optimizing terminology for stroke motor rehabilitation: recommendations from the american congress of rehabilitation medicine stroke movement interventions subcommittee[END_REF]

Table 1 .

 1 Characteristics and main findings of the included studies.

					Distinct dosage parameter
	Sources	Locations	Children characteristics	Treatments	between groups	Main findings
	Deluca 2012; Case-Smith 2012	Virginia, Ohio,	18 USCP 48.06mo (36-72mo) a	P-CIMT	Frequency-Time: -6h/wd, 21 out of 26 days,	No significant between-group difference after 1 month (Deluca et al. 2012) and 6 months (Case-
		Alabama	39% left cerebral lesion		total of 126 h vs.	Smith et al. 2012).
		(USA)			-3h/wd, 21 out of 26 days,
					total of 63 h
	Brandão 2017	Belo Horizonte	20 USCP 9.09y and 8.60y (4-12y) a	HABIT	Frequency-Time: -1x90h of intervention	No significant between-group difference after 1x45h, 2x45h or 1x90h of HABIT. Calculation of
		(Brazil)	56% left cerebral lesion		(6h/wd, 1 block of 15d, no	the power required to find significant between-
					break) vs.	group interactions: requiring 56 to 66 children.
					-2x45h of intervention
					(6h/wd, 2 blocks of 7.5d,
					6mo of break)
	Brandão 2014	New York (USA)	22 USCP; 8.5y and 8.3y (6-13y) a	HABIT	Intensity progressivity: -Structured (increasing	Structured HABIT showed a better pre-post treatment improvement than Unstructured
			70% left cerebral lesion		complexity, shaping, goal-	HABIT in perceived activity performance of
					training) vs.	functional goals (i.e. COPM-Performance); not
					-Unstructured	retained after 6 months.
					("enjoyable" and "playful	No significant between-group difference in
					context")	other outcomes.
	Friel 2016	New York (USA)	20 USCP (18 randomized) 9.9y and 8.9y (NI) a	HABIT	Intensity progressivity: Identical to Brandão et al.	Only Structured HABIT showed increases of the affected hand motor map and motor evoked
			60% left cerebral lesion		2014	potentials amplitudes; greater improvements in
						JTTHF and COPM-Performance were associated
						with larger hand motor map expansions after 6
						months. No significant between-group
						difference in other outcomes.
	Hung 2017	New York (USA)	22 USCP 8.5y and 8.3y (6-13y) a	HABIT	Intensity progressivity: Identical to Brandão et al.	"Only the Structured Practice Group showed better movement quality [, less variable,] with
			70% left cerebral lesion		2014	less trunk involvement and greater elbow
						excursion than the Unstructured Practice
						Group".
	Kumar 2017	Aurangabad (India)	34 USCP 6.67y and 6.56y (4-8y) a	HABIT	Intensity progressivity: -Increasing complexity,	We did not consider between-group data because (1) they were based only on the post-
			40% left cerebral lesion		different manipulation	treatment scores comparison; (2) MAS and
					modalities vs.	MACS data were treated as a "continuous
					-Stable complexity,	quantitative variables" when they were
					constant manipulation	"quantitative categorical variables" with a non-
					modalities	equivalent scoring interval; (3) were not
						confronted to their minimal clinically important
						difference.
	Sabour 2013	Tehran	24 USCP	mCIMT-BIM vs.	Intensity restraint:	We did not consider between-group data
		(Iran)	93.6mo and 94.0mo (60-120mo) a	mCIMT	-Rehabilitation 6h/wd (i.e. 3h with sling restraint, 3h	because they were based only on the post-treatment scores comparison.
			Cerebral lesion side: NI		without) vs.
					-Rehabilitation 6h/wd
					with a sling restraint
	Kirton 2016	Calgary	45 USCP	CIMT	Intensity restraint:	The CIMT group showed a better improvement
		(Canada)	10.34y and 10.57y (6-19y) a	vs. IMLT	-Time restrained: 90% of waking hours vs.	than IMLT group in the perceived activity performance (i.e. COPM-Satisfaction) after 6
			56% left cerebral lesion		-Not restrained	months. Only the CIMT group reached the COPM
						clinically significant gains after 6 months.
	Christmas 2018	Birmingham	62 USCP	mCIMT	Intensity restraint:	The continuous restrained mCIMT was
		(England)	31.5mo and 29.0mo (18-48mo) a		-Continuous short-arm semi-rigid restraint (24h/d	associated with a longer daily therapy time delivered than the Intermittent holding restraint
			Cerebral lesion side: NI		restrained) vs.	(i.e. 60 vs. 30 minutes). No significant between-
					-Intermittent manual	group difference in other outcomes.
					holding restraint (total
					restrained: 1h/d)
	Rostami 2012	Ahvaz (Iran)	14 USCP 74mo (49-100mo) a	mCIMT	Intensity environment: Home-based rehabilitation	The home-based mCIMT showed a better improvement than the clinic-based group in the
			Cerebral lesion side: NI		(0% at the clinic) vs.	global activity capacity after 3 months. No
					Clinic-based rehabilitation	significant between-group difference in other
					(0% at home)	outcomes after 3 months.
	Chopra 2013	New Delhi (India)	30 USCP 5.95y (4-8y) a	mCIMT	Intensity environment: -Activities therapist-	We did not consider pre-post treatment data and between-group data because: (1) no
			57% left cerebral lesion		supervised & guided vs.	standard deviation was provided; (2) the
					-Activities parents-	between-group difference was based only on
					supervised, therapist-	the comparison of post-treatment scores.
					guided
	Sung 2005	Asan (South	31 USCP 33.2mo and 43.2mo (NI) a	FUT vs. CT	≥3 distinct dosage parameters (Type
		Korea)	68% left cerebral lesion		distinction)

Table 1 .

 1 (Continued).

					Distinct dosage parameter
	Sources	Locations	Children characteristics	Treatments	between groups	Main findings
	Aarts 2010, 2011; Geerdink	Ubbergen (Netherlands)	52 USCP Mean age: NI (2.5 to 8y) a	mCIMT-BIM vs. IMLT	≥3 distinct dosage parameters (Type	The mCIMT-BIT group showed better improvements than the IMLT group in the
	2013		44% left cerebral lesion		distinction)	bimanual actual activity performance, and
						perceived activity performance of bimanual
						tasks and functional goals after 8 weeks (Aarts
						et al. 2010) or 6 months (Geerdink et al. 2013).
						No significant between-group difference after 8
						weeks (Aarts et al. 2010, 2011) or 6 months
						(Geerdink et al. 2013) in other outcomes.
	El-Kafy 2014	Le Caire (Egypt)	30 USCP 6.0y and 6.2y (4-8y) a	mCIMT vs. IMT	≥3 distinct dosage parameters (Type	The mCIMT group showed better improvements than the IMT group in isokinetic shoulder flexors
			89% left cerebral lesion		distinction)	performance and bimanual activity capacity
						after 3 months. No significant between-group
						difference in other outcomes.
	USCP: Unilateral Spastic Cerebral Palsy a Mean age (range); NI: No Information; mo: month; y: year; wd: weekday; h: hour; CIMT: Constraint Induced Movement Therapy; P-CIMT: Pediatric-Constraint Induced
	Movement Therapy; mCIMT: modified Constraint Induced Movement Therapy; BIM: Bimanual skills Transfer phase; HABIT: Hand Arm Bimanual Intensive Therapy;
	FUT: Forced Use Therapy; IMLT: Intensive Motor Learning Therapy; IMT: Intensive Motor Therapy; CT: Conventional Therapy; COPM: Canadian Occupational
	Performance Measure; MAS: Modified Aschworth Scale; MACS: Manual Ability Classification System; JTTHF: Jebsen-Taylor Test of Hand Function

L. RAVAULT ET AL.

Acknowledgments

We thank Jean-Philippe Regnaux for his methodological expertise and Katherine Heidrich for her expertise in proofreading. No ethical review was required for this study. The authors have stated that they had no interests which might be perceived as posing a conflict or bias.

Discussion

Summary of Findings

To our knowledge, this scoping review is the first to gather only RCTs that allowed the dosage parameters, of IMRT of the upper limbs provided to children with USCP, to be questioned individually.

The extent exploration of literature databases led us to include 17 RCTs [START_REF] Deluca | Constraintinduced movement therapy (CIMT) for young children with cerebral palsy: effects of therapeutic dosage[END_REF][START_REF] Case-Smith | Multicenter randomized controlled trial of pediatric constraint-induced movement therapy: 6-month follow-up[END_REF][START_REF] Brandão | Comparison of structured skill and unstructured practice during intensive bimanual training in children with unilateral spastic cerebral palsy[END_REF][START_REF] Friel | Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy[END_REF][START_REF] Hung | Structured skill practice during intensive bimanual training leads to better trunk and arm control than unstructured practice in children with unilateral spastic cerebral palsy[END_REF][START_REF] Kirton | Brain stimulation and constraint for perinatal stroke hemiparesis[END_REF][START_REF] Brandão | Does dosage matter? A pilot study of Hand-Arm Bimanual Intensive Training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy[END_REF][START_REF] Sung | Efficacy of forced-use therapy in hemiplegic cerebral palsy[END_REF][START_REF] Kumar | Effect of manipulating object shape, size and weight combined with Hand-Arm Bimanual Intensive Training (HABIT) in improving upper extremity function in children with hemiplegic cerebral palsy-a randomized controlled trial[END_REF][START_REF] Chopra | Supervised V/s unsupervised constraint induced movement therapy in improving upper extremity function in spastic hemiparetic cerebral palsy children[END_REF][START_REF] Sabour | Comparison of Combination of CIMT and BIM training with CIMT alone on fine motor skills of children with hemiplegic cerebral palsy[END_REF][START_REF] Rostami | Effect of treatment environment on modified constraint-induced movement therapy results in children with spastic hemiplegic cerebral palsy: a randomized controlled trial[END_REF][START_REF] El-Kafy | Effect of constraint-induced therapy on upper limb functions: A randomized control trial[END_REF][START_REF] Aarts | Effectiveness of modified constraint-induced movement therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial[END_REF][START_REF] Aarts | Modified Constraint-Induced Movement Therapy combined with Bimanual Training (mCIMT-biT) in children with unilateral spastic cerebral palsy: how are improvements in arm-hand use established?[END_REF][START_REF] Geerdink | Motor learning curve and long-term effectiveness of modified constraint-induced movement therapy in children with unilateral cerebral palsy: A randomized controlled trial[END_REF][START_REF] Christmas | A randomized controlled trial to compare two methods of constraint-induced movement therapy to improve functional ability in the affected upper limb in pre-school children with hemiplegic cerebral palsy: CATCH TRIAL[END_REF] with heterogeneous methodological quality, ranging from very low to relatively high. Some inconsistencies between clinical issues and research protocols are identified; in particular the too short follow-up of the children's outcome evolutions, the lack of assessment of children's participation, and the links between the evolutions of the different ICF levels.

Doubts are expressed about the relevance of conducting a meta-analysis regarding the consequent presence of these selection, attrition, interpretation, and confusion biases. The main findings should, therefore, be qualified in light of this information.

Q4

� The significant between-group differences with their ICF levels, according to the distinct dosage parameters between groups in the included studies.

Disclosure statement

No potential conflict of interest was reported by the authors. �