Pathophysiology of chronic pain in cerebral palsy: implications for pharmacological treatment and research.

The high prevalence of chronic pain in individuals with cerebral palsy (CP) across the lifespan has been well documented, as has its negative impact on quality of life. However, without an understanding of the underlying (possibly unique) pathophysiology of pain in CP, identification of more effective management options, such as innovative and individualized pharmacological approaches to non-opioid pain treatment, will be significantly hindered. We review, briefly, what is known about chronic pain in CP and present what we need to know with respect to the neurobiology of pain and new developments in pain treatment research that might be applied to CP. WHAT THIS PAPER ADDS: Pain conditions in cerebral palsy have differing mechanisms and will not respond to the same treatments. Novel analgesics under development include inhibitors of ion channels, nerve growth factor, and calcitonin gene-related peptide.

Genes determining the severity of cerebral palsy: the role of single nucleotide polymorphisms on the amount and structure of apolipoprotein E.

AIM: Apolipoprotein E (apoE) influences repair and other processes in the brain, and the apoE4 variant is a risk factor for Alzheimer's disease and for prolonged recovery following traumatic brain injury. We previously reported that specific single nucleotide polymorphisms in the APOE or TOMM40 genes affecting the structure and production of apoE were associated with epilepsy, more impaired hand function and gastrostomy tube feeding in children with cerebral palsy (CP). This study explored how various combinations of the same polymorphisms may affect these clinical manifestations. METHODS: Successful DNA analyses of APOE and TOMM40 were carried out on 227 children. The CP Register of Norway provided details of gross and fine motor function, epilepsy and gastrostomy tube feeding. Possible associations between these clinical manifestations and various combinations of the APOEε2, ε3 or ε4 alleles and of the rs59007384 polymorphism in the TOMM40 gene were explored. RESULTS: Epilepsy, impaired fine motor function and gastrostomy tube feeding were less common in children carrying the combination of rs59007384 GG and APOEε2 or ε3 than in children with other combinations. CONCLUSION: Our findings suggest that specific combinations of genes influence the structure and production of apoE differently and affect the clinical manifestations of CP.

Child apolipoprotein E gene variants and risk of cerebral palsy: estimation from case-parent triads.

OBJECTIVE: To use case-parent triad data to investigate if cerebral palsy (CP) is associated with variants of the APOE gene, the rs59007384 SNP of the TOMM40 gene or combined haplotypes of the two genes. STUDY DESIGN: DNA was analyzed in buccal swabs from 235 children with CP, their parents and a sibling. The relative risks (RR) with 95% confidence intervals (CI) that the children would have a distribution of APOE genotypes, rs59007384 variants or combined haplotypes deviating from Mendelian inheritance were estimated. RESULTS: Children with CP were more likely than expected to carry the APOEε3 allele (RR 7.5; CI: 0.99-53.7 for heterozygotes and 10.3; CI: 1.4-79.6 for homozygotes), and to have the haplotype of APOEε3 and rs59007384 G (RR 2.4; CI: 1-5.7 for heterozygotes, RR 3.7; CI: 1.4-9.5 for homozygotes) whereas the distribution was as expected for rs59007384 alone. In the subgroup analyses the findings were confined to children born preterm. Among siblings the distribution of these genes was as expected according to Mendelian inheritance. CONCLUSION: We speculate that children with APOEε2/APOEε4 alleles are more likely to die following cerebral injury in utero, resulting in a higher than expected proportion of children with CP carrying the APOEε3 allele.

Gene sequences regulating the production of apoE and cerebral palsy of variable severity.

BACKGROUND: The apoE protein is the most important lipid transporter in the brain and has also been shown to have several regulatory functions in the central nervous system. The production of apoE is regulated by a number of genes and increases under certain conditions such as cerebral injury in adults. AIMS: Our aim was to study whether variations in genes regulating the expression of the APOE gene were associated with severity of cerebral palsy (CP). METHODS: Children enrolled in the Cerebral Palsy Register of Norway (CPRN) were invited to participate in this cross-sectional study; 281 of the invited 703 children (40%) returned swabs with buccal cells collected by parents. Six genetic variations thought to affect the production of apoE were genotyped and correlated with clinical data recorded in the CPRN. RESULTS: Compared with children carrying the GG allele, children with genotype GT or TT in a specific genetic variation (rs59007384 located in the nearby TOMM40 gene) had excess risk for worse fine motor function (Odds ratio (OR): 1.82; 95% Confidence interval (CI): 1.10-2.99; p = 0.019) and epilepsy (OR: 2.32; CI: 1.17-4.61; p = 0.016). There was no association between severity of CP and any of the other five genetic variations analyzed. CONCLUSION: Our findings suggest that genetic variations in one of the sequences regulating the expression of APOE, may be associated with worse clinical outcome in children with cerebral palsy.

The apolipoprotein gene and recovery from brain injury among extremely preterm infants.

BACKGROUND: Extremely preterm infants have an increased risk of brain injury and, consequently, are more likely to exhibit signs of motor, cognitive or behavioral impairment. Various factors, including genetic, may influence how the brain responds to an injury, ranging from no to complete recovery. The apolipoprotein E (APOE) gene codes for a protein in the brain involved in maintenance and repair of neurons. OBJECTIVE: To determine whether any of the three APOE alleles are related to improved outcome. METHODS: A total of 87 preterm infants with birth weights less than 1,000 g and no obvious preexisting brain abnormalities were genotyped for the APOE gene; 71 of these were assessed with the Bayley III Scales at a corrected age of 12-15 months. Brain MRI was obtained on a subgroup of 52 infants at term equivalent. RESULTS: No significant relationship was found between the three APOE alleles and developmental outcomes or brain MRI findings. CONCLUSION: APOE does not appear to be related in a direct way to the developmental sequelae of white or gray matter injury in extremely preterm infants.

Adolescents with cerebral palsy: transitioning to adult health care services.

Data from the 2009-2010 US National Survey of Children with Special Health Care Needs were examined to determine the health, developmental and behavioral status of adolescents with cerebral palsy (CP) and to assess how well pediatric health care providers were preparing them for transition to adult health care services. Adolescents with CP had no higher rates of attention deficit hyperactivity disorder, depression, anxiety, oppositional or conduct disorders, or autism spectrum than a comparison group. However, those with CP participated less in sports, clubs, or other organized activities (P < .001). Neither group reported much help in coordinating health services or preparing for transition to adult health care services. Inadequate adult health care services have a direct and unsatisfactory impact on the adult life span. Physicians and other health care providers who include adolescents with CP in their practices should begin discussion and planning for transition to adult health care early in adolescence.

Developmental, emotional and behavioral co-morbidities across the chronic health condition spectrum.

AIMS: Estimate the prevalence of specific developmental, emotional, and behavioral (DEB) problems across selected chronic health conditions; examine the relationship of chronic health conditions to functional activities and participation; determine the potential confounding effect of sociodemographic factors on the prevalence of DEB problems. METHODS: The 2007 National Survey of Children's Health, conducted by the Centers for Disease Control and Prevention, served as the primary data source for this study. A total of 91.642 interviews (66.6% response rate for identified households with children) were performed. Population-based estimates were obtained for variables of interest by assigning sampling weights to each child for whom an interview was completed. RESULTS: Parents were two to 30 times more likely to report DEB problems, such as Attention Deficit/Hyperactivity Disorder, depression, learning problems, and challenging behaviors, for children with chronic health conditions. These children had a greater number and range of difficulties with social interaction and school functioning as well as a lower rate of participation in community activities. Although highest rates of DEB problems were reported for those conditions involving the nervous or sensory systems, children with asthma, diabetes, and musculoskeletal conditions also had a higher rate of problems than children without the conditions. The higher prevalence of DEB problems remained after statistical adjustment for socio-demographic factors. CONCLUSIONS: Children with a spectrum of chronic health conditions are at high risk for DEB problems that affect learning, behavior, and emotional well-being. As part of a comprehensive approach to the management of chronic health conditions, children should be screened for these problems and referred for appropriate further evaluation and remediation. Attention to these common co-morbidities will not only result in enhanced quality of life but will also promote better adherence to medical recommendations and, thereby, optimal disease control.

Neuropsychological recovery and quality-of-life in children and adolescents with growth hormone deficiency following TBI: a preliminary study.

OBJECTIVE: To compare neurocognition and quality-of-life (QoL) in a group of children and adolescents with or without growth hormone deficiency (GHD) following moderate-to-severe traumatic brain injury (TBI). STUDY DESIGNS: Thirty-two children and adolescents were recruited from the TBI clinic at a children's hospital. Growth hormone (GH) was measured by both spontaneous overnight testing and following arginine/glucagon stimulation administration. Twenty-nine subjects participated in extensive neuropsychological assessment. RESULTS: GHD as measured on overnight testing was significantly associated with a variety of neurocognitive and QoL measures. Specifically, subjects with GHD had significantly (p < 0.05) lower scores on measures of visual memory and health-related quality-of-life. These scores were not explained by severity of injury or IQ (p > 0.05). GHD noted in response to provocative testing was not associated with any neurocognitive or QoL measures. CONCLUSIONS: GHD following TBI is common in children and adolescents. Deficits in neurocognition and QoL impact recovery after TBI. It is important to assess potential neurocognitive and QoL changes that may occur as a result of GHD. It is also important to consider the potential added benefit of overnight GH testing as compared to stimulation testing in predicting changes in neurocognition or QoL.

Apolipoprotein E polymorphisms and severity of cerebral palsy: a cross-sectional study in 255 children in Norway.

AIM: The aim of this study was to examine whether the presence of the apolipoprotein E (ApoE) allele APOEε4 is associated with less severe manifestations of cerebral palsy (CP), consistent with the suggested beneficial effect of this allele on neurodevelopment in children. METHOD: ApoE genotyping was performed on buccal epithelial cells from 255 children (141 males 114 females; mean age 12y, SD 2y 3mo, range 9-17y) recorded in the Cerebral Palsy Register of Norway. The main outcome measure of CP severity was the Gross Motor Function Classification System (GMFCS). Secondary outcome measures were fine motor function, epilepsy, and the need for gastrostomy tube feeding (GTF). RESULTS: There was no association between the APOEε4 genotype and GMFCS levels (odds ratio [OR] 1.15; 95% confidence interval [CI] 0.66-1.99). However, the APOEε4 genotype was more often present among children with epilepsy (OR 2.2; 95% CI 1.1-4.2) and/or receiving GTF (OR 2.7; 95% CI 1.1-6.6). Among children with unilateral CP, the presence of APOEε4 was associated with more severe fine motor impairment (OR 2.6; 95% CI 1.3-6.9). INTERPRETATION: Our main hypothesis that APOEε4 would have a protective effect on neurodevelopment was not supported. Instead, subgroup analyses suggested an adverse effect of the APOEε4 genotype on the developing brain after injury.

Factors associated with neonatal intensive care follow-up appointment compliance.

BACKGROUND AND METHODS: Our goal was to identify factors that affect neonatal intensive care unit (NICU) follow-up appointment compliance. Compliant and noncompliant infants discharged from the NICU over 1 year and scheduled for follow-up (133) were compared retrospectively; a prospective telephone survey of noncompliant families was also undertaken. RESULTS: Maternal drug use (odds ratio [OR] = 0.049, 95% confidence interval [CI] = 0.005-0.506), multiple gestation pregnancy (OR = 0.163, 95% CI = 0.050-0.533), male sex (OR = 0.308, 95% CI = 0.112-0.850), and greater distance from the hospital (OR = 0.987, 95% CI = 0.976-0.999) were independently associated with lower appointment compliance. A greater number of days on oxygen was associated with greater odds of compliance (OR = 1.057, 95% CI = 0.976-0.999). Shorter NICU stays (P = .047) and less chronic lung disease (P = .026) were significantly associated with noncompliance by bivariate analysis only. Distance from the hospital and travel expense were the most often self-cited reasons for appointment noncompliance. CONCLUSION: Understanding factors associated with NICU follow-up noncompliance is a starting point for providing targeted intervention.

Changes over time in reducing developmental and behavioral comorbidities of asthma in children.

OBJECTIVE: The purpose of this study was to determine (1) the progress that has been made in reducing the prevalence of asthma and/or reducing its severity over the past decade and (2) the progress that has been made in reducing the developmental and behavioral comorbidities of asthma during this period. METHODS: Rates of asthma, asthma severity, and developmental and behavioral problems among children with asthma were compared between the 2003 and 2007 National Surveys of Children's Health. RESULTS: Asthma rates remained stable between the 2 surveys, but there was a shift from moderate to mild and, to a lesser extent, severe asthma. Comorbid rates of developmental and behavioral problems were about twice as high among children with asthma compared with those without asthma. All problems increased for both groups between the surveys but at a significantly greater pace for repeated grades among children with asthma. CONCLUSIONS: Children with asthma continue to have high rates of comorbid developmental and behavioral problems. Over the past decade, these problems are becoming more, not less frequent. Primary and asthma specialty caregivers should be attuned to these comorbidities and implement methods to screen for, assess, and remediate these problems as early as possible.

Emotional, developmental and behavioural co-morbidities of children with chronic health conditions.

AIM: This study estimated and compared rates of emotional, developmental and behavioural (EDB) problems among children with chronic health conditions. METHODS: Rates of EDB problems were estimated using data from the 2005-2007 National Survey of Children with Special Health Care Needs. The National Survey of Children's Health (NSCH) 2003 was used to provide national estimates as referent values. RESULTS: The overall rate of EDB problems for children with chronic health conditions was 15%, about three times the rate for children in the general US population. The rate of attention deficit disorder/attention-deficit/hyperactivity disorder was 18%, over twice that for children in the general population. Children with migraine or other types of recurrent headaches had the highest rate of EDB problems (47%), about nine times the rate for the NSCH sample; those with arthritis or other joint problems had nearly 30%, about five times the rate for the NSCH. CONCLUSIONS: Chronic health conditions are associated with high rates of EDB problems. Children with recurrent headaches and arthritis have particularly high rates, possibly related to pain associated with these conditions. Chronic health condition management programmes should address both medical treatment as well as EDB co-morbid problems through a multidimensional approach to care.

Traumatic brain injury in children and adolescents: surveillance for pituitary dysfunction.

BACKGROUND: Children who sustain traumatic brain injury (TBI) are at risk for developing hypopituitarism, of which growth hormone deficiency (GHD) is the most common manifestation. OBJECTIVE: To determine the prevalence of GHD and associated features following TBI among children and adolescents. STUDY DESIGN: A total of 32 children and adolescents were recruited from a pediatric TBI clinic. Participants were diagnosed with GHD based on insufficient growth hormone release during both spontaneous overnight testing and following arginine/glucagon administration. RESULTS: GHD was diagnosed in 5/32 participants (16%). Those with GHD exhibited more rapid weight gain following injury than those without GHD and had lower levels of free thyroxine and follicle-stimulating hormone. Males with GHD had lower testosterone levels. CONCLUSIONS: GHD following TBI is common in children and adolescents, underscoring the importance of assessing for GHD, including evaluating height and weight velocities after TBI. Children and adolescents with GHD may further exhibit absence or intermediate function for other pituitary hormones.

Long-term cognition, achievement, socioemotional, and behavioral development of healthy late-preterm infants.

OBJECTIVE: To compare healthy late-preterm infants with their full-term counterparts from age 4 through 15 years for numerous standard cognitive, achievement, socioemotional, and behavioral outcomes. DESIGN: Prospective cohort study. SETTING: National Institute of Child Health and Development Study of Early Child Care and Youth Development, 1991-2007. PARTICIPANTS: A total of 1298 children (53 born at 34-36 weeks' gestational age), and their families, observed from birth through age 15 years. None of the infants had major health problems before or immediately following birth, and all the infants were discharged from the hospital within 7 days. MAIN EXPOSURE: Preterm status: children born late preterm (34-36 weeks) vs those born full term (37-41 weeks). MAIN OUTCOME MEASURES: Eleven standard outcomes measuring cognition, achievement, social skills, and behavioral/emotional problems using the Woodcock-Johnson Psycho-Educational Battery-Revised and the Child Behavior Checklist, administered repeatedly through age 15 years. RESULTS: No consistent significant differences were found between late-preterm and full-term children for these standard measures from ages 4 to 15 years. Through age 15 years, the mean difference of most of these outcomes hovered around 0, indicating, along with small confidence intervals around these differences, that it is unlikely that healthy late-preterm infants are at any meaningful disadvantage regarding these measures. CONCLUSION: Late-preterm infants born otherwise healthy seem to have no real burdens regarding cognition, achievement, behavior, and socioemotional development throughout childhood.

Head injury depth as an indicator of causes and mechanisms.

OBJECTIVE: The goal was to measure differences in the causes, mechanisms, acute clinical presentations, injuries, and outcomes of children <36 months of age with varying "greatest depths" of acute cranial injury. METHODS: Children <36 months of age who were hospitalized with acute head trauma were recruited at multiple sites. Clinical and imaging data were collected, and caregivers underwent scripted interviews. Neurodevelopmental evaluations were completed 6 months after injury. Head trauma causes were categorized independently, and subject groups with varying greatest depths of injury were compared. RESULTS: Fifty-four subjects were enrolled at 9 sites. Twenty-seven subjects underwent follow-up neurodevelopmental assessments 6 months after injury. Greatest depth of visible injury was categorized as scalp, skull, or epidural for 20 subjects, subarachnoid or subdural for 13, cortical for 10, and subcortical for 11. Compared with subjects with more-superficial injuries, subjects with subcortical injuries more frequently had been abused (odds ratio [OR]: 35.6; P < .001), more frequently demonstrated inertial injuries (P < .001), more frequently manifested acute respiratory (OR: 43.9; P < .001) and/or circulatory (OR: 60.0; P < .001) compromise, acute encephalopathy (OR: 28.5; P = .003), prolonged impairments of consciousness (OR: 8.4; P = .002), interhemispheric subdural hemorrhage (OR: 10.1; P = .019), and bilateral brain hypoxia, ischemia, or swelling (OR: 241.6; P < .001), and had lower Mental Developmental Index (P = .006) and Gross Motor Quotient (P < .001) scores 6 months after injury. CONCLUSION: For children <3 years of age, head injury depth is a useful indicator of injury causes and mechanisms.

Risk of childhood asthma in relation to the timing of early child care exposures.

OBJECTIVE: To examine whether early child care exposure influences the risk for development of asthma. STUDY DESIGN: Longitudinal data from 939 children and their families from the National Institute of Child Health and Development Study of Early Child Care and Youth Development were analyzed. Exposure to other children in the primary child care setting as an infant (before 15 months) and as a toddler (16-36 months) were assessed as risk factors for persistent or late-onset asthma by age 15 via logistic regression. RESULTS: The number of children in the child-care environment when the child was a toddler was significantly associated with odds of asthma, even after adjusting for respiratory illnesses and other risk factors (P < .05). The fewer the children exposed to as toddlers, the higher the probability of persistent or late-onset asthma by age 15. CONCLUSIONS: This study supports the theory of a protective effect of exposure to other children at an early age, especially as a toddler, on the risk of asthma. This effect appears to be independent of the number of reported respiratory tract illnesses, suggesting that other protective mechanisms related to the number of children in the child care environment may be involved.

Assessing the relationship between the WNSSP and therapeutic participation in adolescents in low response states following severe traumatic brain injury.

PRIMARY OBJECTIVE: This study examines the relationship between scores on the Western Neuro Sensory Stimulation Profile (WNSSP) and therapeutic participation as it relates to rehabilitation readiness (RR) in adolescents with low response following severe traumatic brain injury (TBI). RESEARCH DESIGN: This is a serial observational design using multiple measures of clinical status and participation. METHODS AND PROCEDURES: Ten children, mean age 16.7 years, who remained in a low response state (30 days or more) were assessed with the WNSSP and videotaped during physical and occupational therapy sessions. Associations were evaluated between WNSSP scores and participation scores related to arousal, awareness and communication. MAIN OUTCOMES AND RESULTS: The WNSSP was only associated with the communication score (p < 0.0001). The arousal and awareness scores had no significant impact on the WNSSP score. CONCLUSIONS: These results suggest that scores on the WNSSP may be related to the return of communication skills in adolescents in low response states as one part of assessing their therapeutic participation and ultimate rehabilitation readiness. This ability may assist in making decisions regarding care planning.

Apolipoprotein E and functional motor severity in cerebral palsy.

Cerebral palsy is attributed to non-progressive disturbances in the developing fetal or infant brain. The APOE ε4 allele has been associated with poor outcome after brain injury in adults but may be protective among very young children. We conducted this study to explore the hypothesis that the APOE ε4 is associated with lowered severity of cerebral palsy. 158 individuals with CP and their parents were genotyped for APOE. Mean age was 9.1 years; 54% were males. 61% were preterm at birth; 34% less than 30 weeks gestation. 30% of the CP subjects had at least one ε4 allele. There was a trend towards significance for subjects with at least one ε4 allele assigned to the low severity group (p = 0.11). The greater number of ε4 alleles, the more likely an individual was in the low severity CP group (p = 0.12). Individuals with brain injury in the perinatal period were almost 5 times more likely to be in the low severity group (p < 0.01). Family analysis via the TDT supported a protective effect of APOE ε4. Further study is needed to confirm that, in contrast to adults, the APOE ε4 allele appears to confer protection and/or facilitate recovery after brain injury in the fetus or newborn, particularly when that injury occurs around term.