The complex aetiology of cerebral palsy.

Cerebral palsy (CP) is the most prevalent, severe and costly motor disability of childhood. Consequently, CP is a public health priority for prevention, but its aetiology has proved complex. In this Review, we summarize the evidence for a decline in the birth prevalence of CP in some high-income nations, describe the epidemiological evidence for risk factors, such as preterm delivery and fetal growth restriction, genetics, pregnancy infection and other exposures, and discuss the success achieved so far in prevention through the use of magnesium sulfate in preterm labour and therapeutic hypothermia for birth-asphyxiated infants. We also consider the complexities of disentangling prenatal and perinatal influences, and of establishing subtypes of the disorder, with a view to accelerating the translation of evidence into the development of strategies for the prevention of CP.

Early Predictors and Correlates of Communication Function in Children With Cerebral Palsy.

Birth characteristics and developmental milestones were evaluated as early predictors/correlates of communication in children with cerebral palsy. The hypothesis was that maternal report of child's age for vocal play and first words would predict current functional communication. A case series of 215 children, 2 to 17 years (mean age = 8.2 years, SD = 3.9) with cerebral palsy was recruited from medical practices in 3 Michigan cities. Early developmental data were collected by maternal interview. The child's Communication Function Classification System (CFCS) level was obtained from parent. Predictors of less functional communication included gestational age >32 weeks, number of comorbidities, age of first words after age 24 months, and use of communication methods other than speech. Several birth characteristics and developmental language milestones were predictive of later communication performance for children with cerebral palsy. These characteristics and milestones should trigger referrals for communication evaluations, including speech, language, hearing, and/or augmentative and alternative communication.

Recording of Neonatal Seizures in Birth Certificates, Maternal Interviews, and Hospital Discharge Abstracts in a Cerebral Palsy Case-Control Study in Michigan.

We evaluated the recording of neonatal seizures in birth certificates, hospital discharge abstracts, and maternal interviews in 372 children, 198 of them with cerebral palsy, born in Michigan hospitals from 1993 to 2010. In birth certificates, we examined checkbox items "seizures" or "seizure or serious neurologic dysfunction"; in hospital discharge abstracts ICD-9-CM codes 779.0, 345.X, and 780.3; and in maternal interviews a history of seizures or convulsions on day 1 of life recalled 2-16 years later. In 27 neonates, 38 neonatal seizures were recorded in 1 or more sources, 17 in discharge abstracts, 20 in maternal interviews, but just 1 on a birth certificate. The kappa coefficient (κ) between interviews and discharge abstracts was moderate (κ = 0.55), and substantial (κ = 0.63) if mothers noted use of antiepileptics. Agreement was higher (κ = 0.71 vs κ = 0.29) in term births than in preterm births. Birth certificates significantly underreported neonatal seizures.

Comparison of frozen and unfrozen blood spots for gene expression studies.

We studied gene expression in 9 sets of paired newborn blood spots stored for 8-10 years in either the frozen state or the unfrozen state. Fewer genes were expressed in unfrozen spots, but the average correlation coefficient for overall gene expression comparing the frozen and unfrozen state was 0.771 (95% CI, 0.700-0.828).

High correlations in gene expression between paired umbilical cord blood and neonatal blood of healthy newborns on Guthrie cards.

OBJECTIVE: To examine the correlation in genes expressed in paired umbilical cord blood (UCB) and newborn blood (NB). METHOD: Total mRNA and mRNA of three gene sets (inflammatory, hypoxia, and thyroidal response) was assessed using microarray in UCB and NB spotted on Guthrie cards from 7 mother/infant pairs. RESULTS: The average gene expression correlation between paired UCB and NB samples was 0.941 when all expressed genes were considered, and 0.949 for three selected gene sets. CONCLUSION: The high correlation of UCB and NB gene expression suggest that either source may be useful for examining gene expression in the perinatal period.

Gene expression in archived newborn blood spots distinguishes infants who will later develop cerebral palsy from matched controls.

BACKGROUND: Gene expression in archived newborn blood spots remaining from newborn screening may reflect pathophysiological disturbances useful in understanding the etiology of cerebral palsy (CP). METHODS: We quantified the expression of gene sets representing four physiological pathways hypothesized to contribute to CP in archived unfrozen residual newborn blood spot specimens from 53 children with CP and 53 age-, gender-, and gestational age-matched controls. We selected four empirical and three canonical gene sets representing the inflammatory, hypoxic, coagulative, and thyroidal pathways and examined mRNA expression using an 8 × 60,000 oligonucleotide microarray. The log2 fold change of gene expression between matched cases and controls was analyzed using the generally applicable gene set enrichment method. RESULTS: The empirical inflammatory and empirical hypoxic gene sets were significantly downregulated in term-born CP cases (n = 33) as compared with matched controls (P = 0.0007 and 0.0009, respectively), whereas both gene sets were significantly upregulated (P =0.0055 and 0.0223, respectively) in preterm-born CP cases (n = 20). The empirical thyroidal gene set was significantly upregulated in preterm-born CP cases (P = 0.0023). CONCLUSION: The newborn blood spot transcriptome can serve as a platform for investigating distinctive gene expression patterns in children who later develop CP.

Inter-relationships of functional status in cerebral palsy: analyzing gross motor function, manual ability, and communication function classification systems in children.

AIM: To investigate the relationships among the Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS) in children with cerebral palsy (CP). METHOD: Using questionnaires describing each scale, mothers reported GMFCS, MACS, and CFCS levels in 222 children with CP aged from 2 to 17 years (94 females, 128 males; mean age 8 y, SD 4). Children were referred from pediatric developmental/behavioral, physiatry, and child neurology clinics, in the USA, for a case-control study of the etiology of CP. Pairwise relationships among the three systems were assessed using Spearman's correlation coefficients (r(s) ), stratifying by age and CP topographical classifications. RESULTS: Correlations among the three functional assessments were strong or moderate. GMFCS levels were highly correlated with MACS levels (r(s) = 0.69) and somewhat less so with CFCS levels (r(s) = 0.47). MACS and CFCS were also moderately correlated (r(s) = 0.54). However, many combinations of functionality were found. Of the 125 possible combinations of the three five-point systems, 62 were found in these data. INTERPRETATION: Use of all three classification systems provides a more comprehensive picture of the child's function in daily life than use of any one alone. This resulting functional profile can inform both clinical and research purposes.

Cerebral palsy and aging.

Cerebral palsy (CP), the most common major disabling motor disorder of childhood, is frequently thought of as a condition that affects only children. Deaths in children with CP, never common, have in recent years become very rare, unless the child is very severely and multiply disabled. Thus, virtually all children assigned the diagnosis of CP will survive into adulthood. Attention to the adult with CP has been sparse, and the evolution of the motor disorder as the individual moves through adolescence, young adulthood, middle age, and old age is not well understood. Nor do we know what happens to other functional domains, such as communication and eating behavior, in adults with CP. Although the brain injury that initially causes CP by definition does not progressively worsen through the lifetime, the effects of CP manifest differently throughout the lifespan. The aging process must inevitably interact with the motor disorder, but we lack systematic, large-scale follow-up studies of children with CP into adulthood and through adulthood with thorough assessments performed over time. In this paper we summarize what is known of the epidemiology of CP throughout the lifespan, beginning with mortality and life expectancy, then survey what is known of functioning, ability, and quality of life of adults with CP. We conclude by describing a framework for future research on CP and aging that is built around the World Health Organization's International Classification of Functioning, Disability, and Health (ICF) and suggest specific tools and approaches for conducting that research in a sound manner.