Efficacy of baby-CIMT: study protocol for a randomised controlled trial on infants below age 12 months, with clinical signs of unilateral CP

BACKGROUND: Infants with unilateral brain lesions are at high risk of developing unilateral cerebral palsy (CP). Given the great plasticity of the young brain, possible interventions for infants at risk of unilateral CP deserve exploration. Constraint-induced movement therapy (CIMT) is known to be effective for older children with unilateral CP but is not systematically used for infants. The development of CIMT for infants (baby-CIMT) is described here, as is the methodology of an RCT comparing the effects on manual ability development of baby-CIMT versus baby-massage. The main hypothesis is that infants receiving baby-CIMT will develop manual ability in the involved hand faster than will infants receiving baby-massage in the first year of life. METHOD AND DESIGN: The study will be a randomised, controlled, prospective parallel-group trial. Invited infants will be to be randomised to either the baby-CIMT or the baby-massage group if they: 1) are at risk of developing unilateral CP due to a known neonatal event affecting the brain or 2) have been referred to Astrid Lindgren Children’s Hospital due to asymmetric hand function. The inclusion criteria are age 3–8 months and established asymmetric hand use. Infants in both groups will receive two 6-weeks training periods separated by a 6-week pause, for 12 weeks in total of treatment. The primary outcome measure will be the new Hand Assessment for Infants (HAI) for evaluating manual ability. In addition, the Parenting Sense of Competence scale and Alberta Infant Motor Scale will be used. Clinical neuroimaging will be utilized to characterise the brain lesion type. To compare outcomes between treatment groups generalised linear models will be used. DISCUSSION: The model of early intensive intervention for hand function, baby-CIMT evaluated by the Hand Assessment for Infants (HAI) will have the potential to significantly increase our understanding of how early intervention of upper limb function in infants at risk of developing unilateral CP can be performed and measured. TRIAL REGISTRATION: SFO-V4072/2012, 05/22/201

Children with spastic cerebral palsy : Aspects of muscle activity and botulinum toxin a treatment

Backgound: Cerebral Palsy (CP) is a heterogeneous disorder in which movement and posture are always affected. Spasticity is one of the most common symptoms. A spastic muscle prevents normal motor behaviour and is believed to cause secondary contractures. Other motor symptoms include central dyscoordination causing defects in coordination and excecution of motion and excessive co-contraction in antagonist muscles. Muscle activity in antagonist and adjacent muscles during voluntary movements such as maximum voluntary isometric contraction (MVIC) is not completely understood in children with CP nor in children with typical development (TD). Despite a lack of strong evidence from randomised controlled trials and little long-term data, intramuscular injections with botulinum toxin A (BoNT-A) for treatment of increased muscle tone in children with CP has become increasingly popular over the last decade. Aims: The aims of the thesis were to compare the patterns of muscle activation during MVIC in lower extremity muscles and determine whether children with CP have more co-activity than TD children. A further aim was to write a comprehensive review on BoNT-A treatment with recommendations for future research. Further aims were to evaluate the effect of early BoNT-A treatment in toddlers with CP, and to prospectively evaluate any long-term effects of BoNT-A on muscle tone and joint range of motion (ROM) in the lower extremities of children with CP. Methods/Results: Children with diplegic and hemiplegic CP and TD were assessed with surface EMGs. It was found that children with CP display greater variability in muscle onset order, shorter latencies to onset of other muscles than the intended muscle and twice as much co-activity in both antagonist and adjacent muscles, during MVIC compared to TD children. Ninety-four children with CP were prospectively followed for a maximum of 3 years and 7 months during which time they received a maximum of eight injections per muscle of BoNT-A. Outcome measurements included muscle tone and joint range of motion (ROM). BoNT-A injections reduced long-term spasticity in all muscle-groups examined: the gastrocnemius, hamstring, and adductor muscles. Improvement in ROM, however, was only significant after the first injection; after further injections, joint ROM was reduced. Children with CP, under 2 years of age at study start, participated in a randomized trial which compared the effects of one year of early BoNT-A treatment in the gastrocnemius muscle combined with a daily stretching program to a stretching program alone. The effects on ankle and knee ROM, muscle tone in ankle and knee flexors, gross motor function measure (GMFM) and pediatric evaluation of disability inventory (PEDI) were evaluated at one year and at 3.5 years after study commencement. Gait was evaluated with 3D-gait analysis at 5 years of age. Early treatment with BoNT-A significantly increased knee joint ROM and although not significantly, also increased ankle joint dorsiflexion in the BoNT-A group after 1 year. Children in the control group experienced significantly reduced joint ROM at both joint levels at 3.5 years after study commencement. No differences in GMFM or PEDI scores or 3D-gait data were detected comparing the groups. Conclusions: The activation of muscles differs between children with CP and children with TD when performing a voluntary movement and children with CP express twice as much co-activity. Early BoNT-A intervention in toddlers with CP seems to influence muscle tone and contracture development also after 3.5 years. The effect on gait development remain inconclusive.When BoNT-A treatment in older children (mean age 5.5y at treatment start) is evaluated this suggests that BoNT-A can be effective in reducing muscle tone over a longer period, but not in preventing development of contractures in spastic muscles. The dissociation between the effects on muscle tone and ROM indicates that development of contractures is not coupled to increased muscle tone alone, but might be caused by other mechanisms

Long-term effects of selective dorsal rhizotomy in children with cerebral palsy : a systematic review

Aim: To evaluate the long-term effects of selective dorsal rhizotomy (SDR) 10 years or more after the procedure and complications observed any time after SDR in children with cerebral palsy (CP). Method: Embase, PubMed, and the Cochrane Library were searched from their individual dates of inception through 1st June 2018 for full-text original articles in English that described long-term follow-up after SDR in children with CP. The authors independently screened publications to determine whether they met inclusion criteria; thereafter all authors extracted data on patient characteristics, the proportion of the original cohort being followed-up, and the reported outcomes. Results: Of the 199 studies identified, 16 were included in this evaluation: 14 were case series and two studies reported a retrospectively assigned comparison group. Evidence concerning function was limited by study design differences, clinical variability, loss to follow-up, and heterogeneity across trials. Interpretation: At 10 years or more follow-up, available studies generate low-level evidence with considerable bias. No functional improvement of SDR over routine therapy is documented. Furthermore, the long-term effects of SDR with respect to spasticity reduction is unclear, with many studies reporting a high amount of add-on spasticity treatment. More long-term follow-up using robust scientific protocols is required before it can be decided whether the use of SDR as routine therapy for children with CP is to be recommended or not. What this paper adds: Ten years after selective dorsal rhizotomy, available studies supply inconclusive evidence on functional outcomes. The long-term effect on spasticity is uncertain, studies reported a substantial need for add-on treatment. Short- and long-term complications seem frequent but are not reported in a consistent manner

A First Clinical Trial on Botulinum Toxin-A for Chronic Muscle-Related Pain in Cerebral Palsy

Objective: To test if botulinum toxin-A (BoNT-A) is effective in reducing chronic muscle-related pain in adults with spastic cerebral palsy (CP), as compared to placebo. Design: A single-center, double-blind, parallel, randomized placebo-controlled trial. The design included an interim analysis to allow for confirmatory analysis, as well as pilot study outcomes. Setting: Tertiary university hospital. Participants: Adults with spastic CP and chronic pain associated with spastic muscle(s). Intervention: Treatment was one session of electromyographically guided intramuscular injections of either BoNT-A or placebo normosaline. Main Study Outcomes: The primary outcome was the proportion who achieved a reduction of pain intensity of two or more steps on the Numerical Rating Scale 6 weeks after treatment. Results: Fifty individuals were screened for eligibility, of whom 16 were included (10 female, 6 male, mean age = 32 years, SD = 13.3 years). The randomization yielded eight participants per treatment arm, and all completed the study as randomized. The study was stopped at the interim analysis due to a low probability, under a preset threshold, of a positive primary outcome. Four individuals were treatment responders in the BoNT-A group for the primary outcome compared to five responders in the placebo group (p = 1.000). Adverse events were mild to moderate. In exploratory analysis, the BoNT-A group had a trend of continuing reduction of pain at the last follow-up, after the primary endpoint. Conclusions: This study did not find evidence that BoNT-A was superior to placebo at the desired effect size (number needed to treat of 2.5) at 6 weeks after treatment. Trial registration: ClinicalTrials.gov: NCT0243454

Cognition in Children with Arachnoid Cysts

Background: This study aims to evaluate if children with temporal arachnoid cysts (AC) have cognitive symptoms and if neurosurgery improves these. Methods: A prospective case series study including consecutive pediatric patients with temporal AC. The children underwent neuroradiology, neuroopthalmologic evaluation, and a standard electroencephalography (EEG). Additionally, a neuropsychologist performed a standardized set of evaluations, with a one-year follow-up consisting of Weschler Intelligence Scale for Children version IV (WISC-IV), FAS (for verbal fluency), Boston Naming Test (BNT, for visual naming ability) and NEPSY-II (Developmental NEuroPSYchological Assessment) for verbal memory. Results: Fifteen children, 9 boys and 6 girls, were evaluated and 11 underwent surgery. The Full Scale IQ subscore (FSIQ) improved from M = 84.8 to M = 93.0 (p = 0.005). The preoperative Verbal Comprehension Index (VCI) was in the low average range (M = 86.7), improving to a level within the average range (M = 94.7, p = 0.001). Preoperative Perceptual Speed Index (PSI) was in the below average range (M = 81.5), improving to a level within the average range (M = 92.5, p = 0.004). Conclusion: ACs are a common finding in a pediatric neurosurgical setting. Our data suggest that some temporal AC have a negative effect on general cognitive ability and that this impairment can be improved by surgery. We suggest a standardized evaluation, including comprehensive and validated neuropsychological assessment tools, to thoroughly assess symptoms as well as the postoperative outcome

Exploring social participation in young adults with cerebral palsy

Objectives: To describe social outcomes for young adults with cerebral palsy, and to explore associations of social outcomes with their classification levels within the Gross Motor Function, Manual Ability and Communication Function Classification Systems, and with the presence of intellectual disability. Design: A cross-sectional study with a population-based inclusion approach at a neuropaediatric referral centre in Sweden. Subjects: Sixty-one young adults with cerebral palsy, age 20-22 years. Methods: Physical examination and questionnaires on social outcomes including living arrangements, relationships, occupation, personal finances, extent of family support with personal care, and physical examination. Results: Twenty percent of the young adults with cerebral palsy had moved out of the parental home. Forty-three percent were dependent on family support for basic activities of daily living. Seventy-nine percent of those without intellectual disability were employed or studying. The Communication Function Classification Systems, and presence of intellectual disability, demonstrated associations with most social outcomes, followed in significance by Manual Ability Classification System. Conclusion: In this study young adults with cerebral palsy to a high extent lived in the parental home, and more often without employment, compared with their peers. Many were dependent on parental support, financially, and with activities of daily living. Intellectual disability and communication function were important determinants of social participation. Interventions aimed at alleviating the impact of these particular disabilities should be prioritized

Maternal type 1 diabetes, preterm birth, and risk of intellectual disability in the offspring: A nation-wide study in Sweden

Abstract Objective There are few data on long-term neurological or cognitive outcomes in the offspring of mothers with type 1 diabetes (T1D). The aims of this study were to examine if maternal T1D increases the risk of intellectual disability (ID) in the offspring, estimate the amount of mediation through preterm birth, and examine if the association was modified by maternal glycated hemoglobin (HbA1c). Design Population-based cohort study using population-based data from several national registries in Sweden. Setting and participants All offspring born alive in Sweden between the years 1998 and 2015. Main outcome measure The risk of ID was estimated through hazard ratios with 95% confidence intervals (HR, 95% CI) from Cox proportional hazard models, adjusting for potential confounding. Risks were also assessed in mediation analyses and in subgroups of term/preterm births, in relation to maternal HbA1c and by severity of ID. Results In total, 1,406,441 offspring were included. In this cohort, 7,794 (0.57%) offspring were born to mothers with T1D. The risk of ID was increased in offspring of mothers with T1D (HR; 1.77, 1.43–2.20), of which 47% (95% CI: 34–100) was mediated through preterm birth. The HRs were not modified by HbA1c. Conclusion T1D in pregnancy is associated with moderately increased risks of ID in the offspring. The risk is largely mediated by preterm birth, in particular for moderate/severe cases of ID. There was no support for risk-modification by maternal HbA1c

Childhood-onset seizures : A long-term cohort study of use of antiepileptic drugs, and drugs for neuropsychiatric conditions

OBJECTIVE: We conducted a long-term follow-up of a cohort of children with newly diagnosed unprovoked seizures to assess treatment with antiepileptic drugs (AEDs), neuroleptics, antidepressants and medication for attention deficit hyperactivity disorder (ADHD) with special attention to the impact of comorbidities on the use of such medication. METHODS: Our study cohort comprised 769 children (28 days-18 years), living in Stockholm Sweden, with a first unprovoked seizure identified between 2001 and 2006. Information on neurodevelopmental comorbidities and Cerebral Palsy (CP) at seizure onset was collected from medical records. Information on treatment with AEDs, neuroleptics, antidepressants and ADHD medication was retrieved by linkage to the Swedish National Prescription Registry between 2005 and 2014. The association between comorbidities and drug treatments was assessed by odds ratios (OR) with 95 % confidence intervals (CI), adjusted for age and sex. RESULTS: Eight years after the index seizure, 31 % of the children were on AEDs, and this was more common among children with any of the comorbidities studied (OR; 4.0 95 % CI 2.9-5.6) compared to those without such comorbidities, and within this group of comorbidities particularly for those with CP (OR; 5.2 95 % CI: 2.9-9.3). Children with neurodevelopmental comorbidity or CP at baseline were more likely to receive neuroleptics (ORs 8 years after the index seizure; 6.9, 95 % CI: 2.4-19.8), antidepressants (OR; 2.3, 95 % CI: 1.0-5.5) and ADHD medication (OR; 3.6, 95 % CI: 1.8-7.2) than children without the studied comorbidities. CONCLUSION: Children with seizures in combination with neurodevelopmental comorbidities or CP, especially CP, have a more frequent use of AEDs, neuroleptics, antidepressants, and ADHD medication up to 13 years following the initial seizure than children without comorbidity. Our data highlight the treatment burden in children with epilepsy and comorbidities