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      Off Label Use of Botulinum Toxin in Children under Two Years of Age: A Systematic Review

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          The treatment of children with cerebral palsy with Botulinum Toxin is considered safe and effective, but is only approved for children older than two years of age. The effect of BoNT-A injection on juvenile skeletal muscle especially on neuromuscular junction density, distribution and morphology is poorly delineated and concerns of irreversible damage to the motor endplates especially in young children exist. In contrast, earlier treatment could be appropriate to improve the attainment of motor milestones and general motor development. This review systematically analyzes the evidence regarding this hypothesis. A database search, including PubMed and Medline databases, was performed and all randomized controlled trials (RCTs) comparing the efficacy of Botulinum Toxin in children younger than two years were identified. Two authors independently extracted the data and the methods of all identified trials were assessed. Three RCTs met the inclusion criteria. The results of the analysis revealed an improvement in spasticity of the upper and lower extremities as well as in the range of motion in the joints of the lower limbs. However, evidence of an improvement of general motor development could not be found, as the assessment of this area was not completely specified for this patient group. Based on available evidence it can not be concluded that Botulinum Toxin treatment in children younger than two years improves the achievement of motor milestones. However, there is evidence for the reduction of spasticity, avoiding contractures and delaying surgery. Due to some limitations, the results of this review should be cautiously interpreted. More studies, long-term follow up independent high-quality RCTs with effectiveness analyses are needed.

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          Most cited references 33

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          Prognosis for gross motor function in cerebral palsy: creation of motor development curves.

          Lack of a valid classification of severity of cerebral palsy and the absence of longitudinal data on which to base an opinion have made it difficult to consider prognostic issues accurately. To describe patterns of gross motor development of children with cerebral palsy by severity, using longitudinal observations, as a basis for prognostic counseling with parents and for planning clinical management. Longitudinal cohort study of children with cerebral palsy, stratified by age and severity of motor function and observed serially for up to 4 years during the period from 1996 to 2001. Nineteen publicly funded regional children's ambulatory rehabilitation programs in Ontario. A total of 657 children aged 1 to 13 years at study onset, representing the full spectrum of clinical severity of motor impairment in children with cerebral palsy. Severity of cerebral palsy, classified with the 5-level Gross Motor Function Classification System; function, formally assessed with the Gross Motor Function Measure (GMFM). Based on a total of 2632 GMFM assessments, 5 distinct motor development curves were created; these describe important and significant differences in the rates and limits of gross motor development among children with cerebral palsy by severity. There is substantial within-stratum variation in gross motor development. Evidence-based prognostication about gross motor progress in children with cerebral palsy is now possible, providing parents and clinicians with a means to plan interventions and to judge progress over time. Further work is needed to describe motor function of adolescents with cerebral palsy.
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            Gross muscle morphology and structure in spastic cerebral palsy: a systematic review.

            This systematic review and critical evaluation of the literature was conducted to determine how gross muscle morphology and structure are altered in individuals with spastic cerebral palsy (CP). Electronic databases were searched for articles describing studies of muscle morphological and structural properties in individuals with spastic CP. Data describing muscle fascicle length, belly length, fascicle angle, cross-sectional area, volume, and thickness were extracted and effect sizes were computed for comparisons between individuals with spastic CP and typically developed individuals, between the paretic and non-paretic side in individuals with hemiplegia for all muscles examined, and across the full spectrum of gross motor function in individuals with spastic CP. The final yield consisted of 15 articles that met the inclusion criteria. The main finding of the review was the consistent evidence for reduced muscle belly length, muscle volume, cross-sectional area, and muscle thickness in the comparisons between paretic and typically developed muscle and the paretic and non-paretic muscle across a range of muscles. Given the importance of muscle morphology and structure for generating muscle force, it is likely that the observed alterations that occur secondary to the neural lesion in individuals with spastic CP contribute to muscle weakness and the attendant loss of motor function in spastic CP.
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              Assessment of gross motor development in the WHO Multicentre Growth Reference Study.

              The objective of the Motor Development Study was to describe the acquisition of selected gross motor milestones among affluent children growing up in different cultural settings. This study was conducted in Ghana, India, Norway, Oman, and the United States as part of the longitudinal component of the World Health Organization (WHO) Multicentre Growth Reference Study (MGRS). Infants were followed from the age of four months until they could walk independently. Six milestones that are fundamental to acquiring self-sufficient erect locomotion and are simple to evaluate were assessed: sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone, and walking alone. The information was collected by both the children's caregivers and trained MGRS fieldworkers. The caregivers assessed and recorded the dates when the milestones were achieved for the first time according to established criteria. Using standardized procedures, the fieldworkers independently assessed the motor performance of the children and checked parental recording at home visits. To ensure standardized data collection, the sites conducted regular standardization sessions. Data collection and data quality control took place simultaneously. Data verification and cleaning were performed until all queries had been satisfactorily resolved.

                Author and article information

                Toxins (Basel)
                Toxins (Basel)
                07 January 2013
                January 2013
                : 5
                : 1
                : 60-72
                Center for Musculoskeletal Surgery, Campus Virchow, Charité—University Medicine Berlin, Augustenburger Platz 1, Berlin D-13353, Germany; E-Mails: henriette-charlotte.althuizes@ 123456charite.de (H.C.A.); julia.funk@ 123456charite.de (J.F.F.); richard.placzek@ 123456charite.de (R.P.)
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: claudia.druschel@ 123456charite.de ; Tel.: +49-0-30-450-652245; Fax: +49-0-30-450-552901.
                © 2013 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).



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