Exposure to Paracetamol in Early Pregnancy and the Risk of Developing Cerebral Palsy: A Case-Control Study Using Serum Samples.

OBJECTIVE: To investigate whether maternal paracetamol use in early pregnancy is associated with cerebral palsy (CP) in offspring. STUDY DESIGN: We conducted a registry and biobank-based case-control study with mother-child pairs. We identified CP cases (n = 322) born between 1995 and 2014 from a nationwide CP-registry. Randomly selected controls (n = 343) and extra preterm controls (n = 258) were obtained from a birth registry. For each mother, a single serum sample from early pregnancy (gestation weeks 10-14) was retrieved from a biobank and analyzed for serum concentrations of paracetamol, categorized into unexposed (<1 ng/ml), mildly exposed (1-100 ng/ml), and highly exposed (>100 ng/ml), and in quartiles. Analyses were performed using logistic regression and adjusted for potential confounders. Separate analyses were conducted including only those children born preterm and only those born term. RESULTS: Of the 923 participants, 36.8% were unexposed, 53.2% mildly exposed, and 10% highly exposed to paracetamol. Overall, prenatal exposure to paracetamol was not associated with CP. Sensitivity and subgroup analyses showed no clear associations between paracetamol and CP across strata of term/preterm birth as well as subtypes of CP. CONCLUSIONS: The present study does not support an association between intrauterine exposure to paracetamol in early pregnancy and the risk of CP. However, it is important to stress that the exposure estimate is based on a single serum sample.

Circulating immune cell populations at rest and in response to acute endurance exercise in young adults with cerebral palsy.

AIM: The aim of this observational study was to determine the immune status and function in young adults with cerebral palsy (CP) in comparison to typically developing individuals. METHOD: Blood samples from 12 individuals with CP (five males, seven females; mean age: 25 years 1 month (5 years 9 months); age range: 19-38 years) and 17 typically developing individuals (eight males, nine females; mean age: 31 years 4 months (6 years 2 months); age range: 20-40 years) were collected before, immediately after, and 1 hour after 45 minutes of frame running or running respectively. Independent t-tests were used to compare heart rate, level of exertion, and baseline cell proportions between groups. Mixed model analysis of variance was utilized to investigate immune cell responses to exercise across groups. RESULTS: Baseline levels of gamma delta (TCRγδ+) T-cells were significantly higher (absolute percentage: +2.65, p = 0.028) in the individuals with CP. Several cell populations showed similar significant changes after exercise in both CP and typically developing groups. Cytotoxic (CD8+) T-cells were only significantly elevated immediately after exercise in the typically developing participants (p < 0.01). Individuals with CP exhibited significantly lower heart rates (-11.1%, p < 0.01), despite similar ratings of perceived exertion. INTERPRETATION: Elevated baseline TCRγδ+ T-cells may indicate low-grade inflammation in adults with CP. Although most of the cell populations showed typical responses to endurance exercise, the absence of response in CD8+ T-cells in individuals with CP may indicate the need for higher intensity during exercise. WHAT THIS PAPER ADDS: TCRγδ+ T-cell baseline levels are elevated in adults with cerebral palsy (CP). The CD8+ T-cell response to exercise was blunted in adults with CP. Exercise intensity is decisive for CD8+ T-cell responses in individuals with CP.

Increased plasma brain-derived neurotrophic factor (BDNF) as a potential biomarker for and compensatory mechanism in mild cognitive impairment: a case-control study.

BACKGROUND: Previous meta-analyses examining the continuum of Alzheimer's disease (AD) concluded significantly decreased peripheral brain-derived neurotrophic factor (BDNF) in AD. However, across different meta-analyses, there remain inconsistent findings on peripheral BDNF levels in individuals with mild cognitive impairment (MCI). This issue has been attributed to the highly heterogenous clinical and laboratory factors. Thus, BDNF's level, discriminative accuracy for identifying all-cause MCI and its subtypes, and its associations with other biomarkers and neurocognitive domains, remain largely unknown. METHODS: To address this heterogeneity, we compared a healthy control cohort (n=56, 45 female) to an MCI cohort (n=40, 28 female), to determine whether plasma BDNF, hs-CRP, and DHEA-S can differentiate healthy from MCI individuals, including two MCI subtypes (amnestic [aMCI] and non-amnestic [non-aMCI]). The associations between BDNF with other biomarkers and neurocognitive tests were examined. Adults with cerebral palsy were included as sensitivity analyses. RESULTS: Compared to healthy controls, BDNF was significantly higher in all-cause MCI, aMCI, and non-aMCI. Furthermore, BDNF had good (AUC=0.84, 95% CI=0.74 to 0.95, p<0.001) and excellent discriminative accuracies (AUC=0.92, 95% CI=0.84 to 1.00, p<0.001) for all-cause MCI and non-amnestic MCI, respectively. BDNF was significantly and positively associated with plasma hs-CRP (ß=0.26, 95% CI=0.02 to 0.50, p=0.038), despite attenuated association upon controlling for BMI (ß=0.15, 95% CI=-0.08 to 0.38, p=0.186). Multiple inverse associations between BDNF and detailed neurocognitive tests were also detected. CONCLUSIONS: These findings suggest BDNF is increased as a compensatory mechanism in preclinical dementia, supporting the neurotrophic and partially the inflammatory hypotheses of cognitive impairment.

Altered distributions and functions of natural killer T cells and γδ T cells in neonates with neonatal encephalopathy, in school-age children at follow-up, and in children with cerebral palsy.

We enumerated conventional and innate lymphocyte populations in neonates with neonatal encephalopathy (NE), school-age children post-NE, children with cerebral palsy and age-matched controls. Using flow cytometry, we demonstrate alterations in circulating T, B and natural killer cell numbers. Invariant natural killer T cell and Vδ2+ γδ T cell numbers and frequencies were strikingly higher in neonates with NE, children post-NE and children with cerebral palsy compared to age-matched controls, whereas mucosal-associated invariant T cells and Vδ1 T cells were depleted from children with cerebral palsy. Upon stimulation ex vivo, T cells, natural killer cells and Vδ2 T cells from neonates with NE more readily produced inflammatory cytokines than their counterparts from healthy neonates, suggesting that they were previously primed or activated. Thus, innate and conventional lymphocytes are numerically and functionally altered in neonates with NE and these changes may persist into school-age.

Commonalities in biomarkers and phenotypes between mild cognitive impairment and cerebral palsy: a pilot exploratory study.

Clinically, individuals with cerebral palsy (CP) experience symptoms of accelerated biological aging. Accumulative deficits in both molecular underpinnings and functions in young adults with CP can lead to premature aging, such as heart disease and mild cognitive impairment (MCI). MCI is an intermediate stage between healthy aging and dementia that normally develops at old age. Owing to their intriguingly parallel yet "inverted" disease trajectories, CP might share similar pathology and phenotypes with MCI, conferring increased risk for developing dementia at a much younger age. Thus, we examined this hypothesis by evaluating these two distinct populations (MCI= 55, CP = 72). A total of nine measures (e.g., blood biomarkers, neurocognition, Framingham Heart Study Score (FHSS) were compared between the groups. Compared to MCI, upon controlling for covariates, delta FHSS, brain-derived neurotrophic factor (BDNF) levels, and systolic blood pressure were significantly lower in CP. Intriguingly, high-sensitivity CRP, several metabolic outcomes, and neurocognitive function were similar between the two groups. This study supports a shared biological underpinning and key phenotypes between CP and MCI. Thus, we proposed a double-hit model for the development of premature aging outcomes in CP through shared biomarkers. Future longitudinal follow-up studies are warranted to examine accelerated biological aging.

Serum trace element and amino acid profile in children with cerebral palsy.

BACKGROUND: The existing data demonstrate that both trace elements and amino acids play a significant role in neurodevelopment and brain functioning. Certain studies have demonstrated alteration of micronutrient status in children with cerebral palsy, although multiple inconsistencies exist. THE OBJECTIVE: of the present study was to assess serum trace element and mineral, as well as amino acid levels in children with cerebral palsy. METHODS: 71 children with cerebral palsy (39 boys and 32 girls, 5.7 ±â€¯2.3 y.o.) and 84 healthy children (51 boys and 33 girls, 5.4 ±â€¯2.3 y.o.) were enrolled in the present study. Serum trace element and mineral levels were assessed using inductively-coupled plasma mass-spectrometry (ICP-MS). Amino acid profile was evaluated by means of high-pressure liquid chromatography (HPLC). RESULTS: Children with cerebral palsy are characterized by significantly lower Cu and Zn levels by 6% and 8%, whereas serum I concentration exceeded the control values by 7%. A tendency to increased serum Mn and Se levels was also observed in patients with cerebral palsy. Serum citrulline, leucine, tyrosine, and valine levels were 15 %, 23 %, 15 %, and 11 % lower than those in healthy controls. Nearly twofold lower levels of serum proline were accompanied by a 44 % elevation of hydroxyproline concentrations when compared to the control values. In multiple regression model serum I, Zn, and hydroxyproline levels were found to be independently associated with the presence of cerebral palsy. Correlation analysis demonstrated a significant correlation between Cu, Mn, Se, I, and Zn levels with hydroxyproline and citrulline concentrations. CONCLUSION: The observed alterations in trace element and amino acid metabolism may contribute to neurological deterioration in cerebral palsy. However, the cross-sectional design of the study does not allow to estimate the causal trilateral relationships between cerebral palsy, altered trace element, and amino acid metabolism.

Cytokine dysregulation in children with cerebral palsy.

AIM: To examine pro- and anti-inflammatory cytokines in children with cerebral palsy (CP) at baseline and in response to endotoxin (lipopolysaccharide), and correlate outcomes compared with age-matched comparisons, to evaluate their ability to mount an immune response. METHOD: Serum cytokines were assessed in 12 children (eight males, four females; mean age 10y 1mo [SD 1y 8mo], 6-16y) with CP against 12 age-matched comparisons (eight males, four females; mean age 9y 1mo [SD 1y 1mo]). Pro- and anti-inflammatory cytokines (interleukin-1ß, interleukin-2, interleukin-6, interleukin-8, interleukin-10, interleukin-18, tumour necrosis factor [TNF]-α, TNF-ß, interferon-γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], vascular endothelial growth factor [VEGF], erythropoietin, and interleukin-1 receptor antagonist) were measured at baseline and in response to in vitro simulation with lipopolysaccharide by multiplex enzyme-linked immunosorbent assay. RESULTS: Significantly higher erythropoietin was found at baseline in children with CP compared with the comparison group. There was a strong response to lipopolysaccharide for interleukin-8, VEGF, TNF-α, and GM-CSF in both children with CP and the comparison group; however, there was significant lipopolysaccharide hyporesponsiveness in children with CP compared with the comparison group for interleukin-1α, interleukin-1ß, interleukin-2, and interleukin-6. INTERPRETATION: Altered cytokine responses in children with CP compared with the comparison group demonstrate an altered inflammatory state that may contribute to ongoing sequelae and could be a target for therapy. WHAT THIS PAPER ADDS: Altered inflammatory responses persist in children with cerebral palsy (CP). Erythropoietin is elevated in children with CP compared with the comparison group. Children with CP have reduced interleukin-1α, interleukin-1ß, interleukin-2, and interleukin-6 inflammatory responses to lipopolysaccharide.

Obesity and cardio-metabolic risk factors among children and adolescents with cerebral palsy / Obesidad y factores de riesgo cardiometabólico en niños y adolescentes con parálisis cerebral

BACKGROUND: obesity and associated cardiometabolic complications are increasing among adults with cerebral palsy (CP). Information in children is scarce, and there is no consensus definition of obesity. OBJECTIVES: to describe the frequency of obesity and metabolic complications in children and adolescents with CP. METHODS: a descriptive, cross-sectional study performed in two outpatient pediatric special needs centers. Demographic, anthropometric (Brooks 2011), and motor function (GMFCS) data, as well as antiepileptic use, were recorded. Fasting triglycerides (TG), total cholesterol (TC), vitamin D (25OHD), glycemia (GLY), and insulinemia levels were measured. The HOMA index was calculated. RESULTS: sixty-five patients were enrolled. Age was 10.8 ± 4.9 years; 63.1 % were male; 81.6 % had GMFCS IV-V; 43.5 % had a gastrostomy; and 83.1 % were on antiepileptics. According to their BMI, 15.4 % were underweight (< 10th percentile) and 10.8 % overweight (> 75th percentile). Overall, 6.1 % had TC ≥ 200 mg/dL, 21.4 % had TG ≥ 110 or 130 mg/dL, 4.6 % had GLY ≥ 100 mg/dL, 16.9 % had HOMA ≥ 3, and 76.9 % had 25OHD < 30 ng/mL. Children with BMI ≥ 75th percentile had higher HOMA and insulin resistance rates than those with BMI < 75th percentile. Elevated TG were associated with high motor impairment and low vitamin D. HOMA was associated to female gender and BMI ≥ 75th percentile. CONCLUSIONS: the frequency of cardiometabolic risk factors was high in this sample of pediatric patients with CP, associated with overweight, low mobility, and vitamin D deficiency. We propose a BMI > 75th percentile as cutoff point for metabolic risk factors

INTRODUCCIÓN: la obesidad y sus complicaciones cardiometabólicas han aumentado en los adultos con parálisis cerebral (PC). La información en la población pediátrica es escasa y no hay consenso en la definición de obesidad. OBJETIVOS: describir la frecuencia de la obesidad y sus complicaciones metabólicas en niños y adolescentes con PC. MÉTODOS: estudio transversal descriptivo realizado en dos centros pediátricos ambulatorios de pacientes con necesidades especiales de atención en salud. Se registraron datos demográficos, antropométricos (curvas de Brooks 2011), función motora (GMFCS) y medicamentos. En muestras sanguíneas en ayunas se midieron: triglicéridos (TG), colesterol total (CT), vitamina D (25OHD), glucemia (GLI) e insulinemia. Se calculó el índice HOMA. RESULTADOS: participaron 65 pacientes con edades de 10,8 ± 4,9 años; el 63,1 % eran varones; el 81,6 % tenían GMFCS IV-V; el 43,5 % estaban gastrostomizados y el 83,1 % tomaban antiepilépticos. Según el IMC, el 15,4 % tenían bajo peso (< percentil 10) y el 10,8 % sobrepeso (≥ p75). Del grupo total, el 6,1 % tenían CT > 200 mg/dL, el 21,4 % TG > 110 o 130 mg/dL, el 4,6 % GLI ≥ 100 mg/dL, el 16,9 % HOMA > 3 y el 76,9 % 25OHD < 30 ng/mL. Los pacientes con IMC ≥ p75 tenían mayor frecuencia de HOMA >3 que aquellos con IMC < p75. La hipertrigliceridemia se asoció a mayor discapacidad motora y a baja vitamina D, y el HOMA al género femenino y a un IMC ≥ p75. CONCLUSIONES: la frecuencia de los factores de riesgo cardiometabólico fue alta en esta muestra de pacientes pediátricos con PC, asociada al género, el sobrepeso, la baja movilidad y la deficiencia de vitamina D. Proponemos un IMC ≥ p75, según las curvas específicas de PC, como punto de corte para el mayor riesgo cardiometabólico

Deep Learning/Artificial Intelligence and Blood-Based DNA Epigenomic Prediction of Cerebral Palsy.

The etiology of cerebral palsy (CP) is complex and remains inadequately understood. Early detection of CP is an important clinical objective as this improves long term outcomes. We performed genome-wide DNA methylation analysis to identify epigenomic predictors of CP in newborns and to investigate disease pathogenesis. Methylation analysis of newborn blood DNA using an Illumina HumanMethylation450K array was performed in 23 CP cases and 21 unaffected controls. There were 230 significantly differentially-methylated CpG loci in 258 genes. Each locus had at least 2.0-fold change in methylation in CP versus controls with a FDR p-value ≤ 0.05. Methylation level for each CpG locus had an area under the receiver operating curve (AUC) ≥ 0.75 for CP detection. Using Artificial Intelligence (AI) platforms/Machine Learning (ML) analysis, CpG methylation levels in a combination of 230 significantly differentially-methylated CpG loci in 258 genes had a 95% sensitivity and 94.4% specificity for newborn prediction of CP. Using pathway analysis, multiple canonical pathways plausibly linked to neuronal function were over-represented. Altered biological processes and functions included: neuromotor damage, malformation of major brain structures, brain growth, neuroprotection, neuronal development and de-differentiation, and cranial sensory neuron development. In conclusion, blood leucocyte epigenetic changes analyzed using AI/ML techniques appeared to accurately predict CP and provided plausible mechanistic information on CP pathogenesis.

C-reactive protein: what to expect after bony hip surgery for nonambulatory children and adolescents with cerebral palsy.

Bony hip reconstruction surgery in children with severe cerebral palsy is associated with high complication rates, usually postoperative chest and urinary tract infections. C-reactive protein (CRP) level is commonly used as an indication of infection; an understanding of its normal postoperative trends is crucial to allow early identification of abnormal levels and possible infection. Our aim was to describe the trends in CRP following bony hip surgery in children who had an uneventful postoperative course, on the basis that the children for whom CRP does not follow this course are likely to have a bacterial infection. A retrospective review was performed of 155 children with CP having bony hip surgery between 2012 and 2016. The median age was 9.9 years (interquartile range: 6.6-12.7). One hundred (64.5%) patients had a Gross Motor Function Classification System rating of V. All CRP levels measured in routine postoperative care were recorded, and medical records were examined for postoperative infective complications. The CRP levels of patients with clinically proven infections were excluded in order to describe what to expect in the absence of infection. Mean CRP peaked on the third postoperative day at 81 mg/l in those who had no postoperative infection. Twenty-five (16.1%) patients had a postoperative infection; their mean CRP was higher on all postoperative days and peaked at 128 mg/l on the third postoperative day. An understanding of the normal postoperative trends in CRP allows identification of those with abnormally raised levels. Postoperative CRP is consistently higher in children with an infective complication. We recommend that the CRP should be routinely checked following bony hip surgery in children with CP, and a careful search for infection undertaken in those with a raised level.

Suboptimal Nutrition and Low Physical Activity Are Observed Together with Reduced Plasma Brain-Derived Neurotrophic Factor (BDNF) Concentration in Children with Severe Cerebral Palsy (CP).

Brain-derived neurotrophic factor (BDNF) is a mediator of exercise and nutrition-induced neural plasticity. In children with cerebral palsy (CP), neuromuscular deficits and mobility impairment have a negative impact on their physical activity level and nutritional status, but whether these children have reduced BDNF concentrations is unknown. Therefore, the aim of the present study was to investigate the plasma BDNF concentration, nutritional status, and physical activity level in children with mild to severe CP. Blood sampling, dietary registration, and questionnaires were completed for children with mild CP (gross motor function classification system (GMFCS) I⁻II, n = 31, age 10.6 ± 0.6 years), severe CP (GMFCS IV⁻V, n = 14, age 10.9 ± 1.1 years) and typically developed (TD) children (n = 22, age 10.9 ± 0.6 years). Children with severe CP had ~40% lower plasma BDNF concentration than TD children (p < 0.05). Furthermore, children with severe CP had lower daily physical activity level than TD children (p < 0.01), and a daily intake of energy, n-3 fatty acids, and dietary fibers that was only ~50% of TD (p > 0.001). Reduced plasma BDNF concentrations were observed in children with severe CP. This may be of significance for optimal neural growth and plasticity. This was observed together with low physical activity levels and a suboptimal intake of energy, n-3 fatty acids, and dietary fibers.

Threshold of metabolic acidosis associated with newborn cerebral palsy: medical legal implications.

Obstetricians and gynecologists belong to 1 of the medical specialties with the highest rate of litigation claims. Among birth injury cases, those cases with cerebral palsy outcomes account for litigation settlements or judgments often in the millions of dollars. In cases of potential perinatal asphyxia, a threshold level of metabolic acidosis (base deficit ≥12 mmol/L) is necessary to attribute neonatal encephalopathy to an intrapartum hypoxic event. With increasing duration or severity of a hypoxic stress resulting in metabolic acidosis, newborn infant umbilical artery base deficit increases. It may be alleged that, as base deficit levels increase beyond 12 mmol/L, there is an increased likelihood and severity of cerebral palsy. As a corollary, it may be claimed that an earlier delivery (by minutes) would reduce the base deficit and prevent or reduce the severity of cerebral palsy. This issue is of relevance to obstetricians as defendants, because retrospective "expert" analysis of cases may suggest that optimal management decisions would have resulted in an earlier delivery. In addressing the association of metabolic acidosis and cerebral palsy, base deficit should be measured as the extracellular component (base deficitextracellular fluid) rather than the commonly used base deficitblood. Studies suggest that, beyond the base deficit threshold of 12 mmol/L, the incidence and severity of cerebral palsy does not significantly increase (until ≥20 mmol/L), although the risk of neonatal death rises markedly. Thus, among most infants with hypoxia-associated neonatal encephalopathy, the occurrence of cerebral palsy is unlikely to be impacted by delivery time variation of few minutes, and this argument should not serve as the basis for medical legal claims.

Maternal concentrations of human chorionic gonadotropin (hCG) and risk for cerebral palsy (CP) in the child. A case control study.

BACKGROUND: Intrauterine conditions may be important in the development of cerebral palsy in the child. The hormone, human chorionic gonadotropin (hCG), is synthesized in the placenta, and hCG plays an important role in placental angiogenesis and development. Thus, maternal hCG concentrations may be an indicator of placental function and thereby the intrauterine environment for the offspring. We studied the associations of maternal concentrations of hCG during pregnancy with cerebral palsy in the child. METHODS: We performed a case-control study nested within a cohort of 29,948 pregnancies in Norway during 1992-1994. Cases were all women within the cohort who gave birth to a singleton child with cerebral palsy diagnosed before five years of age (n = 63). Controls were a random sample of women with a singleton child without cerebral palsy (n = 182). RESULTS: The adjusted odds ratio (OR) for cerebral palsyin the child was 0.78 (95% CI: 0.55-1.10) per log-transformed unit of maternal hCG in the 1 st trimester, and the OR was 1.42 (95% CI: 0.94-2.16) in the 2nd trimester. Thus, women who did not have high hCG concentrations in the 1 st trimester and low hCG concentrations in the 2nd trimester, had increased risk for giving birth to a child with cerebral palsy. Adjustments were made for pregnancy week of serum sampling, maternal age and parity. CONCLUSIONS: The abnormal hCG concentrations in pregnancies with cerebral palsy in the offspring, could suggest placental factors as causes of cerebral palsy.

Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: An individual participant data meta-analysis.

BACKGROUND: Babies born preterm are at an increased risk of dying in the first weeks of life, and those who survive have a higher rate of cerebral palsy (CP) compared with babies born at term. The aim of this individual participant data (IPD) meta-analysis (MA) was to assess the effects of antenatal magnesium sulphate, compared with no magnesium treatment, given to women at risk of preterm birth on important maternal and fetal outcomes, including survival free of CP, and whether effects differed by participant or treatment characteristics such as the reason the woman was at risk of preterm birth, why treatment was given, the gestational age at which magnesium sulphate treatment was received, or the dose and timing of the administration of magnesium sulphate. METHODS AND FINDINGS: Trials in which women considered at risk of preterm birth (<37 weeks' gestation) were randomised to magnesium sulphate or control treatment and where neurologic outcomes for the baby were reported were eligible for inclusion. The primary outcomes were infant death or CP and severe maternal outcome potentially related to treatment. Studies were identified based on the Cochrane Pregnancy and Childbirth search strategy using the terms [antenatal or prenatal] and [magnesium] and [preterm or premature or neuroprotection or 'cerebral palsy']. The date of the last search was 28 February 2017. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. For each prespecified outcome, IPD were analysed using a 1-stage approach. All 5 trials identified were included, with 5,493 women and 6,131 babies. Overall, there was no clear effect of magnesium sulphate treatment compared with no treatment on the primary infant composite outcome of death or CP (relative risk [RR] 0.94, 95% confidence interval (CI) 0.85 to 1.05, 6,131 babies, 5 trials, p = 0.07 for heterogeneity of treatment effect across trials). In the prespecified sensitivity analysis restricted to data from the 4 trials in which the intent of treatment was fetal neuroprotection, there was a significant reduction in the risk of death or CP with magnesium sulphate treatment compared with no treatment (RR 0.86, 95% CI 0.75 to 0.99, 4,448 babies, 4 trials), with no significant heterogeneity (p = 0.28). The number needed to treat (NNT) to benefit was 41 women/babies to prevent 1 baby from either dying or having CP. For the primary outcome of severe maternal outcome potentially related to magnesium sulphate treatment, no events were recorded from the 2 trials providing data. When the individual components of the composite infant outcome were assessed, no effect was seen for death overall (RR 1.03, 95% CI 0.91 to 1.17, 6,131 babies, 5 trials) or in the analysis of death using only data from trials with the intent of fetal neuroprotection (RR 0.95, 95% CI 0.80 to 1.13, 4,448 babies, 4 trials). For cerebral palsy in survivors, magnesium sulphate treatment had a strong protective effect in both the overall analysis (RR 0.68, 95% CI 0.54 to 0.87, 4,601 babies, 5 trials, NNT to benefit 46) and the neuroprotective intent analysis (RR 0.68, 95% CI 0.53 to 0.87, 3,988 babies, 4 trials, NNT to benefit 42). No statistically significant differences were seen for any of the other secondary outcomes. The treatment effect varied little by the reason the woman was at risk of preterm birth, the gestational age at which magnesium sulphate treatment was given, the total dose received, or whether maintenance therapy was used. A limitation of the study was that not all trials could provide the data required for the planned analyses so that combined with low event rates for some important clinical events, the power to find a difference was limited. CONCLUSIONS: Antenatal magnesium sulphate given prior to preterm birth for fetal neuroprotection prevents CP and reduces the combined risk of fetal/infant death or CP. Benefit is seen regardless of the reason for preterm birth, with similar effects across a range of preterm gestational ages and different treatment regimens. Widespread adoption worldwide of this relatively inexpensive, easy-to-administer treatment would lead to important global health benefits for infants born preterm.

Antibody responses to botulinum neurotoxin type A of toxin-treated spastic equinus children with cerebral palsy: A randomized clinical trial comparing two injection schedules.

We have conducted a 26-month-long comparative study involving young patients (2-6years old) with a clinical diagnosis of spastic equinus secondary to cerebral palsy who have been treated with BoNT/A (BOTOX®, Allergan) tri-annually or annually. Serum samples were obtained to determine the presence or absence of blocking antibodies (Abs) by a mouse protection assay (MPA) and levels of anti-BoNT/A Abs by radioimmune assay (RIA). HLA DQ alleles were typed using blood samples to determine the possible association of certain HLA type(s) with the disease or with the Ab status. Blocking Abs were detected in only two out of 18 serum samples of the tri-annual group, but none were found in 20 samples of the annual group. The MPA-positive serum samples gave in RIA significantly higher anti-BoNT/A Ab-binding levels than the MPA-negative samples. On the other hand, when two MPA-positive sample data were excluded, serum samples from tri-annual and annual groups showed similar anti-BoNT/A Ab levels. Linkage of the disorder with a particular HLA DQA1 and DQB1 allele types was not observed due to the small sample size. However, by combining results with other studies on BoNT/A-treated Caucasian patients with cervical dystonia (CD), we found that, among Caucasian patients treated with BoNT/A, DQA1*01:02 and DQB1*06:04 were higher in Ab-positive than in Ab-negative patients. The genetic linkage was on the threshold of corrected significance.

Motor impairment and skeletal mineralization in children with cerebral palsy.

OBJECTIVE: To evaluate the bone mineral density and the effect of motor impairment on bone mineral density in children with cerebral palsy. METHODS: The cross-sectional study was conducted at the Armed Forces Institute of Rehabilitation Medicine, Rawalpindi, Pakistan, from January 2013 to January 2015. Children diagnosed with cerebral palsy were sampled by non-probability purposive sampling from the Cerebral Palsy clinic. On the basis of Gross Motor Function Classification level of motor impairment, the children were divided into mild Cerebral Palsy (level 1 & 2) and moderate to severe Cerebral Palsy (level 3-5) groups. Bone mineral density z-score was measured at lumbar spine with Dual Energy X-Ray Absorptiometry at L1-L4 lumbar vertebra. Data was analysed using SPSS 20. RESULTS: Of the total 108 children selected, 18(16.6%) had to be excluded due to poor nutrition status or deranged serum chemistry, while in 4(3.7%) children Dual Energy X-ray Absorptiometry scan was not done on technical grounds. Of the remaining 86(79.6%) children, 39(45.3%) were males and 47(54.7%) were females. The overall mean age was 6.08±2.89 years and mean bone mineral density z-score was -2.16±0.62. Statistically significant difference was found in bone mineral density z-scores of moderate to severe compared to mild Cerebral Palsy group (p<0.05). Significant difference in bone mineral density z-scores was also found among different levels of Gross Motor Function Classification system of motor impairment (p<0.05). CONCLUSIONS: Cerebral Palsy children had low bone mineral density z-score, especially those who were non-ambulatory.

Bone mineral density and insulin-like growth factor-1 in children with spastic cerebral palsy.

BACKGROUND: Children with cerebral palsy (CP) have significant decrease linear growth rate and low bone mineral density (BMD). AIMS: This study is to evaluate BMD in children with CP and its relation to the levels of insulin-like growth factor-1 (IGF-1). SUBJECTS AND METHODS: This cross-sectional study was carried out on 58 children suffering from spastic CP with the age range 4-12 years compared to 19 controls. All assessed by dual energy x-ray absorptiometry (DXA) to measure BMD, serum level of IGF-1, and serum vitamin D. The patients were classified according to their GMFCS. RESULTS: Fractures were reported in seven (12.1%) of cases. Our study demonstrated that, IGF-1 level and BMD decrease in correlation with the severity of CP. IGF-1correlates positively with serum vitamin D, BMI, and BMD. CP children with severe GMFCS level or who use anticonvulsive drugs are at a high risk for low BMD and low levels of IGF-1. CONCLUSION: Both BMD and IGF-1 were significantly in low children with spastic CP; IGF-1 negatively correlates with the severity of osteopenia in children with spastic. Children with CP who are not independently ambulant or with severe GMFCS level or who use anticonvulsive drugs are at a high risk for developing low BMD.

Bone mineral density and vitamin D status in children with epilepsy, cerebral palsy, and cerebral palsy with epilepsy.

PURPOSE: We aimed to evaluate the relationship between bone mineral density (BMD) disorders and possible risk factors in patients with epilepsy only (EO), cerebral palsy only (CPO), and cerebral palsy-epilepsy (CP + E). METHODS: A total of 122 patients [EO (n = 54), CPO (n = 30), CP + E (n = 38)] and 30 healthy children were evaluated. BMD was only measured in patient groups, not in control subjects. BMD of lumbar vertebrae was determined by dual energy X-ray absorptiometry (DXA). An abnormal BMD was defined as low or low normal BMD. RESULTS: Low BMD rate in EO, CPO, and CP + E group was 3.7, 50, and 39.5 %, respectively. Abnormal BMD values were significantly related to inadequate dietary Ca intake (p = 0.017), severe intellectual disability (p < 0.001), and immobility (p = 0.018). In multivariate regression analysis, the risk of abnormal BMD was higher (3.9-fold) in patients not able to walk independently than the others (p = 0.029). However, serum Ca-Vitamin D levels, insufficient exposure to sunlight, low BMI, and use of AED were not correlated with abnormal BMD. CONCLUSION: Abnormal BMD is a common problem in patients with CP and CP + E. Abnormal BMD was related to the severity of CP, but not to vitamin D levels or AED treatment.

The Effect of Handcycle Ergometer Exercise on Glucose Tolerance in Ambulatory and Non-Ambulatory Adolescents.

PURPOSE: Whole body or leg exercise before a meal can increase insulin sensitivity, but it is unclear whether the same can occur with upper body exercise since a smaller muscle mass is activated. We measured the impact of a single session of handcycle exercise on glucose tolerance and insulin sensitivity. METHODS: Nonambulatory (Non-Amb) adolescents with spina bifida or cerebral palsy (4F/3M), or ambulatory peers (Control, 4F/7M) completed 2 glucose tolerance tests on separate days, preceded by either rest or a 35-min bout of moderate-to-vigorous intermittent handcycle exercise. RESULTS: The Non-Amb group had higher body fat (mean ± SD: 38 ± 12%, Control: 24 ± 9, p = .041) but similar VO2peak (17.7 ± 6.1 ml/kg/min, Control: 21.1 ± 7.9). Fasting glucose and insulin were normal for all participants. Compared with the rest trial, exercise resulted in a reduction in glucose area under the curve (11%, p = .008) without a significant group x trial interaction and no difference in the magnitude of change between groups. Insulin sensitivity was increased 16% (p = .028) by exercise in the Control group but was not significantly changed in the Non-Amb group. CONCLUSION: A single bout of handcycle exercise improves glucose tolerance in adolescents with and without mobility limitations and could therefore help maintain or improve metabolic health.

Serum Leptin as a Nutritional Biomarker in Children with Cerebral Palsy.

Adequate nutrition is crucial for children with cerebral palsy (CCP). However, conventional nutritional assessments may be inadequate for defining undernourished CCP. Leptin, an adipocyte hormone controlling energy expenditure, could be a useful marker. Objectives of this cross-sectional analytic study were to explore correlations between serum leptin level and nutritional status, anthropometric measurements, and biochemical parameters in 86 CCP (aged 9 ± 2 years). Subscapular (SST) and triceps (TST) skinfold thicknesses, weight, and calculated height were obtained. Body mass index and weight-for-height (WH) Z-scores were calculated. Complete blood count and serum levels of leptin and albumin were collected. CCP were classified as undernourished if their WHZ was < -2 according to the World Health Organization criteria. Correlations between anthropometric measurements, biochemical data, and serum leptin levels were evaluated. From 86 CCP, 11 (12%) children were undernourished, and SST, hemoglobin, and hematocrit were significantly lower. Serum leptin levels of nourished and undernourished CCP were 5.4 ± 6.2 and 2.9 ± 1.6 ng/mL (p < 0.001), while the reported value from normal children was 4.9 ng/mL. Serum leptin levels demonstrated a significant correlation with SST and TST (r = 0.83 and 0.72; p < 0.001). Serum leptin was the only marker significantly correlated with WHZ (r = 0.45, p < 0.001) while adjusting for covariates. A serum leptin level of 2.2 ng/mL was the optimal cutoff point for defining adequate nutritional status (WHZ ≥ -2). The measurement of serum leptin should be included in a care scheme of CCP especially during surgical evaluation.