Showing papers in "Mental Retardation and Developmental Disabilities Research Reviews in 2002"

The epidemiology of autistic spectrum disorders: is the prevalence rising?

Abstract: For decades after Kanner's original paper on the subject was published in 1943, autism was generally considered to be a rare condition with a prevalence of around 2-4 per 10,000 children. Then, studies carried out in the late 1990s and the present century reported annual rises in incidence of autism in pre-school children, based on age of diagnosis, and increases in the age-specific prevalence rates in children. Prevalence rates of up to 60 per 10,000 for autism and even more for the whole autistic spectrum were reported. Reasons for these increases are discussed. They include changes in diagnostic criteria, development of the concept of the wide autistic spectrum, different methods used in studies, growing awareness and knowledge among parents and professional workers and the development of specialist services, as well as the possibility of a true increase in numbers. Various environmental causes for a genuine rise in incidence have been suggested, including the triple vaccine for measles, mumps and rubella (MMR]. Not one of the possible environmental causes, including MMR, has been confirmed by independent scientific investigation, whereas there is strong evidence that complex genetic factors play a major role in etiology. The evidence suggests that the majority, if not all, of the reported rise in incidence and prevalence is due to changes in diagnostic criteria and increasing awareness and recognition of autistic spectrum disorders. Whether there is also a genuine rise in incidence remains an open question.

The epidemiology of mental retardation: Challenges and opportunities in the new millennium

Abstract: There are a number of problems and challenges in relating the science of epidemiology to mental retardation (MR). These relate to how MR is defined and classified and how these definitions may change over time. These as well as other differences in ascertainment sources and methods need to be considered when comparing MR prevalence over time and place. On the other hand, advances in technology also provide new and efficient methods of data collection both by data linkage and by use of web-based methods to study rare diseases. While prevalence studies have not been individually reviewed, we have examined the range of data including recent studies relating to how prevalence differs according to age, gender, social class and ethnicity. Some problems with available etiological classification systems have been identified. Recent etiological studies, most of which use different classification systems, have been reviewed and explanations have been postulated to account for differences in results. Individual risk factors for MR are considered whilst the option of considering a population as opposed to a high risk strategy to MR prevention is raised. This might well involve improving the social milieu surrounding the occurrence of individual risk factors. The impact of biotechnological advances such as antenatal and neonatal screening and assisted reproduction on MR are discussed. The issue of how inequalities in access to technology may impact on case identification and even have the potential to further widen inequalities is raised. The importance of extending the use of epidemiological tools to study the social, health and economic burden of MR is also emphasized. However, in order to apply to MR the "prevention-intervention-research" cycle, which surely underpins all epidemiology, it is vital to ensure that the methodological challenges we raise are adequately addressed.

Intrauterine infection and prematurity.

Abstract: Intrauterine infection is a major cause of premature labor with and without intact membranes. Intrauterine infection is present in approximately 25% of all preterm births and the earlier the gestational age at delivery, the higher the frequency of intra-amniotic infection. Microorganisms may also gain access to the fetus before delivery. A fetal inflammatory response syndrome elicited in response to microbial products is associated with the impending onset of preterm labor and also with multi-systemic organ involvement in the human fetus and a higher rate of perinatal morbidity. The most common microorganisms involved in intrauterine infections are Ureaplasma urealyticum, Fusobacterium species and Mycoplasma hominis. The role of Chlamydia trachomatis and viruses in preterm labor remain to be determined. Use of molecular microbiology techniques to diagnose intrauterine infection may uncover the role of fastidious microorganisms that have not yet been discovered. Antibiotic administration to patients with asymptomatic bacteriuria is associated with a significant reduction in the rate of preterm birth. However, such benefit has not been demonstrated for patients with bacterial vaginosis, or women who carry Streptococcus agalactia, Ureaplasma urealyticum or Trichomonas vaginalis. Antibiotic administration to patients with preterm premature rupture of membranes is associated with prolongation of pregnancy and a reduction in the rate of clinical chorioamnionitis and neonatal sepsis. The benefit has not been demonstrated in patients with preterm labor and intact membranes. Major efforts are required to determine why some women develop an ascending intrauterine infection and others do not and also what interventions may reduce the deleterious effect of systemic fetal inflammation.

The epidemiology of attention-deficit/hyperactivity disorder (ADHD): A public health view

Abstract: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood. However, basic information about how the prevalence of ADHD varies by race/ethnicity, sex, age, and socio-economic status remains poorly described. One reason is that difficulties in the diagnosis of ADHD have translated into difficulties developing an adequate case definition for epidemiologic studies. Diagnosis depends heavily on parent and teacher reports; no laboratory tests reliably predict ADHD. Prevalence estimates of ADHD are sensitive to who is asked what, and how information is combined. Consequently, recent systematic reviews report ADHD prevalence estimates as wide as 2%-18%. The diagnosis of ADHD is complicated by the frequent occurrence of comorbid conditions such as learning disability, conduct disorder, and anxiety disorder. Symptoms of these conditions may also mimic ADHD. Nevertheless, we suggest that developing an adequate epidemiologic case definition based on current diagnostic criteria is possible and is a prerequisite for further developing the epidemiology of ADHD. The etiology of ADHD is not known but recent studies suggest both a strong genetic link as well as environmental factors such as history of preterm delivery and perhaps, maternal smoking during pregnancy. Children and teenagers with ADHD use health and mental health services more often than their peers and engage in more health threatening behaviors such as smoking, and alcohol and substance abuse. Better methods are needed for monitoring the prevalence and understanding the public health implications of ADHD. Stimulant medication is the treatment of choice for treating ADHD but psychosocial interventions may also be warranted if comordid disorders are present. The treatment of ADHD is controversial because of the high prevalence of medication treatment. Epidemiologic studies could clarify whether the patterns of ADHD diagnosis and treatment in community settings is appropriate. Population-based epidemiologic studies may shed important new light on how we understand ADHD, its natural history, its treatment and its consequences.

Cognitive and neuropsychological outcomes: More than IQ scores

Abstract: Improved survival in preterm infants has broadened interest in cognitive and neuropsychological outcomes. The incidence of major disabilities (moderate/severe mental retardation, neurosensory disorders, epilepsy, cerebral palsy) has remained consistent, but high prevalence/low severity dysfunctions (learning disabilities, ADHD, borderline mental retardation, specific neuropsychological deficits, behavioral disorders) have increased. The follow-up literature contains methodologic problems that make generalizations regarding outcome difficult, and these are discussed. Although mean IQs of former VLBW infants generally are in the low average range and are 3-9 points below normal birth weight peers, these scores mask subtle deficits in: visual-motor and visual-perceptual abilities, complex language functions, academics (reading, mathematics, spelling and writing), and attentional skills. There is an increased incidence of non-verbal learning disabilities, need for special educational assistance, and behavioral disorders in children born prematurely. Males have more problems, and there is a trend for worsening outcome over time, due to emergence of more subtle deficits in response to increased performance demands. In addition to IQ and achievement testing in follow-up, there should be evaluation of executive functions and attention, language, sensorimotor functions, visuospatial processes, memory and learning, and behavioral adjustment.

Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults.

Abstract: White matter damage (WMD) in preterm neonates is strongly associated with adverse outcome. The etiology of white matter injury is not known but clinical data suggest that ischemia-reperfusion and/or infection-inflammation are important factors. Furthermore, antenatal infection seems to be an important risk factor for brain injury in term infants. In order to explore the pathophysiological mechanisms of WMD and to better understand how infectious agents may affect the vulnerability of the immature brain to injury, numerous novel animal models have been developed over the past decade. WMD can be induced by antenatal or postnatal administration of microbes (E. coli or Gardnerella vaginalis), virus (border disease virus) or bacterial products (lipopolysaccharide, LPS). Alternatively, various hypoperfusion paradigms or administration of excitatory amino acid receptor agonists (excitotoxicity models) can be used. Irrespective of which insult is utilized, the maturational age of the CNS and choice of species seem critical. Generally, lesions with similarity to human WMD, with respect to distribution and morphological characteristics, are easier to induce in gyrencephalic species (rabbits, dogs, cats and sheep) than in rodents. Recently, however, models have been developed in rats (PND 1-7), using either bilateral carotid occlusion or combined hypoxia-ischemia, that produce predominantly white matter lesions. LPS is the infectious agent most often used to produce WMD in immature dogs, cats, or fetal sheep. The mechanism whereby LPS induces brain injury is not completely understood but involves activation of toll-like receptor 4 on immune cells with initiation of a generalized inflammatory response resulting in systemic hypoglycemia, perturbation of coagulation, cerebral hypoperfusion, and activation of inflammatory cells in the CNS. LPS and umbilical cord occlusion both produce WMD with quite similar distribution in 65% gestational sheep. The morphological appearance is different, however, with a more pronounced infiltration of inflammatory cells into the brain and focal microglia/macrophage ("inflammatory WMD") in response to LPS compared to hypoperfusion evoking a more diffuse microglial response usually devoid of cellular infiltrates ("ischemic WMD"). Furthermore, low doses of LPS that by themselves have no adverse effects in 7-day-old rats (maturation corresponding to the near term human fetus), dramatically increase brain injury to a subsequent hypoxic-ischemic challenge, implicating that bacterial products can sensitize the immature CNS. Contrary to this finding, other bacterial agents like lipoteichoic acid were recently shown to induce tolerance of the immature brain suggesting that the innate immune system may respond differently to various ligands, which needs to be further explored.

Clinical manifestations and stages of Rett syndrome.

Abstract: The presentation and clinical diagnosis of Rett syndrome at various ages and stages are reviewed. In addition to the classical form, variability in phenotype between different atypical Rett forms is given. Obligatory, supportive, and differential diagnostic criteria are summarized. Long-term follow-up findings in ageing Rett women are addressed.

Neuropathology of Rett syndrome.

Abstract: Rett Syndrome is unlike any other pediatric neurologic disease, and its clinical-pathologic correlation can not be defined with standard histology techniques. Based on hypotheses suggested by careful clinical observations, the nervous system of the Rett child has been explored utilizing morphometry, golgi preparations, computerized tomography, magnetic resonance imaging, chemistry, immunocytochemistry, autoradiography, and molecular biologic techniques. From these many perspectives we conclude that Rett syndrome is not a typical degenerative disorder, storage disorder, nor the result of gross malformation, infectious or neoplastic processes. There remain regions of the brain that have not been studied in detail but the available data suggest that the neuropathology of Rett syndrome can be summarized as follows: the Rett brain is small for the age and the height of the patient; it does not become progressively smaller over three to four decades; it has small dendritic trees in pyramidal neurons of layers III and V in selected lobes (frontal, motor, and temporal); it has small neurons with an increased neuronal packing density; it has an immature expression of microtubular protein-2 and cyclooxygenase; it exhibits a changing pattern of neurotransmitter receptors with an apparent reduction in many neurotransmitters, possibly contributing to some symptomatology. A mutation in Mecp2 causes this unique disorder of brain development. Neuronal mosaicism for normal and mutated Mecp2 produces a consistent phenotype in the classic female patient and a small brain with some preserved islands of function, but with an inability to support hand use and speech. This paper summarizes our current observations about neuropathology of Rett syndrome. MRDD Research Reviews 2002;8:72-76.

Environmental factors associated with a spectrum of neurodevelopmental deficits

Abstract: A number of environmental agents have been shown to demonstrate neurotoxic effects either in human or laboratory animal studies. Critical windows of vulnerability to the effects of these agents occur both preand postnatally. The nervous system is relatively unique in that different parts are responsible for different functional domains, and these develop at different times (e.g., motor control, sensory, intelligence and attention). In addition, the many cell types in the brain have different windows of vulnerability with varying sensitivities to environmental agents. This review focuses on two environmental agents, lead and methylmercury, to illustrate the neurobehavioral and cognitive effects that can result from early life exposures. Special attention is paid to distinguishing between the effects detected following episodes of poisoning and those detected following lower dose exposures. Perinatal and childhood exposure to high doses of lead results in encephalopathy and convulsions. Lower-dose lead exposures have been associated with impairment in intellectual function and attention. At high levels of prenatal exposure, methylmercury produces mental retardation, cerebral palsy and visual and auditory deficits in children of exposed mothers. At lower levels of methylmercury exposure, the effects in children have been more subtle. Other environmental neurotoxicants that have been shown to produce developmental neurotoxicity include polychlorinated biphenyls (PCBs), dioxins, pesticides, ionizing radiation, environmental tobacco smoke, and maternal use of alcohol, tobacco, marijuana and cocaine. Exposure to environmental agents with neurotoxic effects can result in a spectrum of adverse outcomes from severe mental retardation and disability to more subtle changes in function depending on the timing and dose of the chemical agent.

The epidemiology of the epilepsies in children.

Abstract: The epilepsies are a heterogeneous collection of neurological conditions and syndromes characterized by recurrent, unprovoked, paroxysmal seizure activity. There are several types of epileptic seizures and syndromes that are unique to children, including infantile spasms, Lennox-Gastaut syndrome and absence seizures. Febrile seizures and neonatal seizures, while not epilepsy, are relatively common types of seizures in infants and children and are likely markers of risk of later epilepsy. Thus, it is important to consider the epidemiological features of the epilepsies as they occur specifically in infants and children. The purpose of this review is to summarize what is currently known about the epidemiology of the childhood epilepsies and to identify promising areas for further population-based studies. The epilepsies are an important cause of neurological morbidity in children. The average annual rate of new cases (incidence) of epilepsy is approximately 5-7 cases per 10,000 children from birth to age 15 years, and in any given year, about 5 of every 1,000 children will have epilepsy. There is evidence that the incidence of the epilepsies in some populations of children may be decreasing over time, and this possibility merits further investigation. Factors that are known to increase risk of the epilepsies in children include congenital malformations of the central nervous system (CNS), moderate or severe head trauma, CNS infections, certain inherited metabolic conditions, and genetic factors. However, these account for only 25% to 45% of cases, and thus, the etiology of most cases of the epilepsies remains obscure. The paucity of well-controlled etiological studies is due largely to formidable methodological problems in conducting epidemiological studies of the epilepsies. The prognosis for seizure control is generally good, although children with remote symptomatic seizures and those with additional neurological disabilities do less well.

In utero infection and adult schizophrenia.

Abstract: We review emerging evidence indicating that in utero exposure to infection is a risk factor for schizophrenia. It is hypothesized that a prenatal infection increases the liability to schizophrenia in adulthood by adversely affecting the maturation of critical brain structural and functional components implicated in the pathogenesis and pathophysiology of the disorder. Early evidence for a role of in utero infection includes investigations linking schizophrenia with birth during the winter and in urban regions, and ecologic studies demonstrating associations between influenza epidemics and births of pre-schizophrenic patients. The findings of the latter studies are, however, equivocal. To more rigorously address this question, our group has used increasingly sophisticated research designs that incorporate more refined measures of exposure and outcome, and continuous follow-up of treated cases. This work has already yielded several intriguing findings, including associations between schizophrenia and two in utero infections--rubella and respiratory infection. We also describe our ongoing birth cohort investigations that are expected to advance this work further, including studies that utilize maternal serum samples drawn during pregnancy of offspring who were later diagnosed with schizophrenia.

Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm.

Abstract: Only sparse information is available about a possible association between antenatal infection outside the brain and subsequent cognitive limitations among preterm infants. Based on published studies, we provide a theoretical schema that links them via the fetal inflammatory response and neonatal white matter damage. We conclude that the relationship between antenatal infection and cognitive limitations deserves much further attention by researchers interested in the prevention of this undesirable outcome of prematurity.

Systematic review of chorioamnionitis and cerebral palsy.

Abstract: In a recent meta-analysis evaluating the relationship between chorioamnionitis and cerebral palsy, we found that chorioamnionitis is a risk factor for both cerebral palsy and cystic periventricular leukomalacia (cPVL). The current paper extends the meta-analysis by including studies published in the year 2000, and by further evaluating the causes of heterogeneity among individual study results. Using a random effects model, clinical chorioamnionitis was significantly associated with both cerebral palsy (RR 1.9, 95% CI 1.5-2.5) and cPVL (RR 2.6, 95% CI 1.7-3.9). Sources of heterogeneity included widely varying practices in the diagnosis of clinical chorioamnionitis, different gestational age characteristics, and varying study year. We conclude that based on the available literature, chorioamnionitis is a risk factor for both cerebral palsy and cPVL.

The epidemiology of developmental disabilities in low-income countries.

Abstract: Although most of the world's children live in developing countries and may be at high risk for disability, very little is known about the prevalence and causes of developmental disabilities in these countries. This paper discusses methodological difficulties contributing to this lack of knowledge, and provides an overview of what is known about the epidemiology of developmental disabilities in low-income countries. At least some forms of developmental disability appear to be more common in low-income countries than in wealthier countries, despite the probability of higher mortality among children with disabilities in low-income countries. For example, most studies of severe mental retardation in low-income countries report prevalences greater than 5 per 1,000 children, while prevalence estimates from industrialized countries are consistently below this. Major risk factors for developmental disabilities in some low-income countries include specific genetic diseases, a higher frequency of births to older mothers, consanguinity, and specific micronutrient deficiencies and infections. Trauma and toxic exposures are also important risk factors, but their contributions to the etiology of developmental disabilities in low-income countries are not well documented. Though many of the causes of developmental disabilities are understood and preventable, proven methods of prevention are not being fully implemented in developing countries. Epidemiologic studies are needed to raise awareness of the public health impacts of developmental disabilities in low-income countries and to provide a basis for setting priorities and designing efficient interventions.

Patterns of motor disability in very preterm children

Abstract: Motor development in very preterm children differs in several important ways from that of children born at full term. Variability is common, although the anatomic and physiologic bases for that variability are often poorly understood. Motor patterns over the first postnatal year may depend on behaviours learned during often long periods of neonatal intensive care. The normal pattern of development may be modified by disturbances of brain function caused both by the interruption of normal brain maturation ex-utero and the superimposition of focal brain injuries following very preterm birth. Abnormal patterns of development over the first year may evolve into clear neuromotor patterns of cerebral palsy or resolve, as "transient dystonias." Cerebral palsy is associated with identified patterns of brain injury secondary to ischaemic or haemorrhagic lesions, perhaps modified by activation of inflammatory cytokines. Cerebral palsy rates have not fallen as might be expected over the past 10 years as survival has improved, perhaps because of increasing survival at low gestations, which is associated with the highest prevalence of cerebral palsy. Children who escape cerebral palsy are also at risk of motor impairments during the school years. The relationship of these impairments to perinatal factors or to neurological progress over the first postnatal year is debated. Neuromotor abnormalities are the most frequent of the "hidden disabilities" among ex-preterm children and are thus frequently associated with poorer cognitive ability and attention deficit disorders. Interventions to prevent cerebral palsy or to reduce these late disabilities in very preterm children are needed.

The epidemiology of cerebral palsy in term infants.

Abstract: Half of cerebral palsy (CP) arises in infants of normal birthweight; yet, many fewer studies seek to identify risk factors for CP in term and near-term infants than in those born very prematurely. There has been no net decrease in the prevalence of CP in term and near-term infants over recent decades. Potentially asphyxiating birth complications account for a small minority of CP cases. Recent studies suggest that disorders of coagulation and intrauterine exposure to infection or inflammation are associated with risk of CP, and that both can be accompanied by signs of neonatal encephalopathy, the best available predictor of CP in term neonates. Therapeutic interventions directed at preventing interruption of oxygen supply have not been shown to reduce the occurrence of CP. There have not yet been studies examining whether medical interventions directed at infection or coagulation disorder can reduce the frequency of CP.

Neurodevelopmental care in the NICU.

Abstract: Neurodevelopmental care, which is any NICU intervention undertaken to improve neurodevelopmental outcome, includes NICU design, nursing routines, nursing care plans, management of pain, feeding methods and, most importantly, encouraging parental involvement with their NICU infant. Recognition that sensory stimulation can overwhelm preterm infants and increase physiologic signs of stress led to attempts to reduce sensory input. More recent approaches judiciously add back soothing sensory input (e.g., therapeutic touch, soft music). Circadian light/dark cycles and physical activity improve preterm growth. Attention to infant positioning and handling affects physiologic variables and joint mobility, if not functional motor abilities. A highly organized system of care for NICU infants is Als' NIDCAP (i.e., Neonatal Individualized Developmental Care and Assessment Program). Although NIDCAP may reduce need for respiratory support and hospital length of stay, it does not significantly influence neurodevelopmental outcome at 2-3 years. Pain management includes benign interventions (e.g., nonnutritive sucking, oral glucose), but the prolonged use of narcotics must be balanced against the consequences of sedation and dependency. The foremost challenge for NICUs remains parent disenfranchisement. Kangaroo care, which involves parent/infant skin-to-skin contact, improves preterm growth, decreases nosocomial infections and may shorten hospital length of stay. A great deal of work needs to be done to identify and demonstrate efficacy of specific interventions and changes that humanize the NICU, encourage parental involvement, support infant development and optimize preterm neurodevelopmental outcomes.

Measuring functional outcomes after prematurity: Developmental impact of very low birth weight and extremely low birth weight status on childhood disability

Abstract: Our purpose was to describe functional outcomes in essential activities in preschool, school-age, and adolescent children who were born very (<32 weeks gestation) and extremely (<28 weeks gestation) prematurely. Very low birth weight (VLBW; 1000-1499 g), or extremely low birth weight (ELBW;<1000 g) populations are the focus of our analysis. We describe models of disablement and enablement for specifying the complexity of childhood outcomes using a framework of pathophysiology, impairment, functional limitation and functional strengths, disability in social roles and social participation, societal limitations and environmental facilitators. Representative early childhood, preschool, school-age, and adolescent studies were examined in terms of describing children's functional strengths and challenges after VLBW and ELBW survival. In early childhood, disability was assessed by diagnosing neurosensory impairments and delays on developmental testing. Instruments for measuring functional status in essential activities of self-care, mobility, communication and learning are described. Rates of neurosensory disability in the first three years among recent ELBW survivors ranged from 9-26% for cerebral palsy, 1-15% for blindness, 0-9% for deafness, and 6-42% for evolving cognitive disability (MDI <70). Rates of preschool functional limitation were 5-27% motor, 5-30% self-care, and 5-22% communicative. Rates of school-age functional educational disabilities exceeded 50%. Rates of adolescent activity limitation were 13-32% and vocational limitations were 27-71%. By examining the functional strengths and challenges of children with major neurodevelopmental impairments after very or extremely preterm birth, we can examine causal pathways that lessen the risk of severe functional disability. Among children with mild to moderate disability, we can enhance functional outcomes, optimize community participation, and provide quality family supports. In order to assess the changing outcomes of this vulnerable population of survivors, combinations of clinical and survey based methodologies are required.

Secondary conditions in children with disabilities: spina bifida as a case example.

Abstract: This paper examines the concept of secondary conditions and its application in studies of childhood disability focusing on children with spina bifida as a representative group. The "International Classification of Functioning, Disability and Health" (World Health Organization, Geneva, 2001) provides a classification of body function/structure, activities, participation and the environment to document dimensions of human functioning in context. The ICF is of value in the study of secondary conditions in two ways: as a conceptual framework for defining impairments, activity limitations and participation restrictions, and the mediating role of the environment in their expression; and as a taxonomy for coding these dimensions of disability. The ICF can yield a profile of a child's difficulties, and documentation of environmental barriers experienced by that child. Research studies with children and adolescents with spina bifida reveal that physical and mental impairments and limitations in performing activities and participating in communal life are experienced as secondary conditions. The significance of secondary conditions is that they are preventable. Identifying the mechanisms associated with their manifestation is thus an important priority for the development of effective prevention programs.

Associations between MeCP2 mutations, X-chromosome inactivation, and phenotype.

Abstract: Rett syndrome is a neurodevelopmental disorder of early postnatal brain growth in girls. Patients show a normal neonatal period with subsequent developmental regression and a loss of acquired skills (communication and motor skills), deceleration of head growth, and development of typical hand stereotypies. Recent studies have shown that mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2) cause most typical cases of Rett syndrome. The MeCP2 gene encodes a protein that binds methylated cytosine residues of CpG dinucleotides and mediates, with histone deacetylases and transcriptional repressors, the transcription "silencing" of other genes. Girls with Rett syndrome exhibit mosaic expression for the MeCP2 defect at the cellular level, with most patients showing random X-inactivation and approximately equal numbers of cells expressing the normal MeCP2 gene and the mutated MeCP2 gene. In rare cases, females with a MeCP2 mutation escape phenotypic expression of the disorder because of nonrandom X-inactivation and the preferential inactivation of the mutated MeCP2 allele. Nonrandom patterns of X-inactivation may also contribute to the clinical variability often seen in girls with Rett syndrome. The spectrum of clinical phenotype caused by MeCP2 mutations is wide, including milder "preserved speech" variants, the severe congenital Rett variant, and a subset of X-linked recessive mental retardation in boys. Studies have shown that atypical and classical Rett syndrome can caused by the same MeCP2 mutations, indicating clinical phenotype is variable even among girls with the same MeCP2 mutation. The relationship between type of MeCP2 mutation, X-inactivation status, and clinical phenotype of Rett syndrome is complex and likely involves other environmental and polygenic modifiers.

Preterm outcomes research: a critical component of neonatal intensive care.

Abstract: While early preterm outcome studies described the lives of preterm survivors to justify the efforts required to save them, subsequent studies demonstrated their increased incidence of cerebral palsy, mental retardation, sensory impairments, minor neuromotor dysfunction, language delays, visual-perceptual disorders, learning disability and behavior problems compared to fullterm controls. Because infants born at the lower limit of viability require the most resources and have the highest incidence of neurodevelopmental disability, there is concern that resources have gone primarily to neonatal intensive care and are not available for meeting the followup, health, educational and emotional needs of these fragile infants and their families. Despite many methodological concerns, preterm outcome studies have provided insight into risk factors for and causes of CNS injury in preterm infants. Nevertheless, it remains difficult to predict neurodevelopmental outcome for individual preterm infants. Perinatal and neonatal risk factors are inadequate proxies for neurodevelopmental disability. Recent randomized controlled trials with one to five year neurodevelopmental followup have provided valuable information about perinatal and neonatal treatments. Recognizing adverse longterm neurodevelopmental effects of pharmacological doses of postnatal steroids is a sobering reminder of the need for longterm neurodevelopmental followup in all neonatal randomized controlled trials. Ongoing longterm preterm neurodevelopmental studies, analysis of changes in outcomes over time and among centers, and evaluation of the longterm safety, efficacy and effectiveness of many perinatal and neonatal management strategies and proposed neuroprotective agents are all necessary for further medical and technological advances in neonatal intensive care.

Cerebral palsy in very preterm infants: new epidemiological insights.

Abstract: The focus of this review is on new insights from recent epidemiological research on cerebral palsy in preterm infants. These include: 1) a better understanding of issues related to diagnosis and classification; 2) new information about the brain abnormalities underlying cerebral palsy in preterm infants; and 3) a better understanding of biological mechanisms that may underlie previously described epidemiological associations. Ongoing efforts to improve the diagnosis and classification of cerebral palsy have been enhanced by findings from serial examinations of cohorts of very preterm infants. Cranial ultrasonography through the anterior fontanelle of very preterm infants has provided information about grossly evident brain damage, found in about one-half of preterm infants who develop cerebral palsy. Insights into the pathophysiologic basis for certain epidemiologic associations have come from studies of experimental brain damage in animals and clinical studies of neurologic disorders in adults. Much of the current epidemiological research into the causes of cerebral palsy in preterm infants has focused on two potential mechanisms of brain damage. One mechanism involves insufficient cerebral perfusion; the other, cytokine-mediated damage, potentially triggered by events such as maternal infection (e.g., intrauterine or periodontal infection), neonatal infection (e.g., sepsis and necrotizing enterocolitis), and neonatal oxygen- or ventilator-induced lung injury. In addition to the preterm infant's increased exposure to such damaging factors, the high frequency of cerebral palsy in these infants might be due, in part, to insufficient levels of developmentally regulated protective substances, such as thyroid hormone and glucocorticoids. Models of causation currently are being investigated using recently developed methods for quantifying, with small quantities of blood, biomolecules that are suspected to either promote or protect against brain damage in the neonate. Clinical investigations now under way can be expected to identify strategies to be tested in clinical trials that could lower the risk of cerebral palsy in very preterm infants.

Prematurity at birth: trends, racial disparities, and epidemiology.

Abstract: While infant mortality rates have continued to decline in the U.S., low birth weight and preterm rates have dramatically increased. Although the combination of factors that underlies these trends has not been fully described, there is growing concern that an appreciable part of the rise in prematurity rates stems from efforts taken to improve the survival of these high-risk infants. While advancements in medical technology and practice, augmented by improvements in prenatal care use, may have adversely effected prematurity rates and played a role in broadening racial disparities in pregnancy outcomes, they have positively impacted infant survival. Although many risk factors for prematurity have been identified, there are presently few areas for effective prevention. Accordingly, there is little encouragement for a downturn in prematurity rates in the near future. The prospect of continuing growth in the annual number of surviving preterm infants in the U.S. highlights the need for early detection and treatment of developmental problems for these high-risk survivors, and emphasizes the importance of assuring that needed support services are available to these children and their families. MRDD Research Reviews 2002;8:215–220. © 2002 Wiley-Liss, Inc.

MeCP2 and other methyl-CpG binding proteins

Abstract: DNA methylation is an epigenetic modification that is implicated in transcriptional silencing. Recently, it has become increasingly clear that both correct levels and proper interpretation of methylation are important factors for normal development and function of the human organism. One example is the neurological disorder Rett syndrome (RTT), which affects approximately one in 10,000 girls. RTT is caused by mutations in MeCP2, a protein that was identified by its ability to bind specifically to CpG-methylated DNA. Furthermore, MeCP2 represses transcription in a methylation-dependent manner, and it is the founding member of the family of methyl-CpG binding domain (MBD) proteins.

The phenotypic consequences of MECP2 mutations extend beyond Rett syndrome.

Abstract: Although MECP2 was initially identified as the causative gene in classic Rett syndrome (RTT), the gene has now been implicated in several phenotypes that extend well beyond the clinically defined disorder. MECP2 mutations have been found in people with various disorders, including neonatal onset encephalopathy, X-linked recessive mental retardation (MRX), classic and atypical RTT, autism, and Angelman syndrome, as well as mildly affected females and normal carrier females. To make matters more complex, in approximately 20% of classic sporadic RTT cases and more than 50% of affected sister pairs, no mutation in MECP2 has been found. X-chromosome inactivation patterns can clearly affect the phenotypic expression in females, while the effect of the type and position of the mutation is more apparent in the broader phenotype than in RTT. Both males and females are at risk, although an excess of paternally derived mutations are found in most cases of classic RTT. Thus, because of the range of disparate phenotypes, the gene may account for a relatively large portion of mental retardation in the population.

Ophthalmological problems of the premature infant.

Abstract: Preterm infants are more likely than term infants to have significant abnormalities of all parts of the visual system leading to reduced vision. The most common problem is retinopathy of prematurity (ROP). The frequency and severity of this disorder is inversely related to gestational age. Damage ranges from minor to catastrophic. Preterm infants also have higher rates of amblyopia, strabismus, refractive error, and cortical visual impairment. The later problem is largely associated with neonatal brain injury. Years later, these children may develop glaucoma and retinal detachments.

Neuroimaging in the preterm infant.

Abstract: Legislation Nil Related Policies -Nil Other related documents-Nil RESPONSIBILITY Policy Sponsor Neonatology Clinical Care Unit – Neonatal Coordinating Group Initial Endorsement December 2015 Last Reviewed Last Amended Review date December 2018 Do not keep printed versions of guidelines as currency of information cannot be guaranteed. Access the current version from the WNHS website TRANSFER FROM NICU AND DISCHARGE PLANNING CLINICAL GUIDELINES NEONATOLOGY

Infection markers and early signs of neonatal encephalopathy in the term infant.

Abstract: Recent evidence points to an association between intrauterine infection and cerebral palsy (CP) in the preterm as well as the term infant. The mechanisms that link these two conditions are unclear. Chorioamnionitis is a common clinical problem complicating 5-10% of pregnancies, whereas the incidence of CP attributed to intrapartum asphyxia is rare. Chorioamnionitis may result in brain injury as a result of interruption of placental blood flow (asphyxia), or via fever and/ or the cytokine release associated with infection. This review will attempt to establish the link between perinatal infection and brain damage in term infants. The characteristics of the perinatal inflammatory response, the potential mechanisms of brain injury associated with infection, and the clinical characteristics of neonatal encephalopathy will be discussed.

Public health issues related to infection in pregnancy and cerebral palsy.

Abstract: Cerebral palsy is the most common neuromotor developmental disability of childhood, affecting as many as 8,000 to 12,000 children born in the U.S. each year (corresponding to a prevalence rate of between 2 and 3 per 1000 children). Recent improvements in neonatal care have not resulted in a decline in the overall prevalence of cerebral palsy and, in fact, greater numbers of very preterm/very low birth weight infants are surviving with cerebral palsy and other developmental problems. Infection in pregnancy may be an important cause of the disorder. In preterm infants, there appears to be about a 2-fold increased risk for cerebral palsy from chorioamnionitis, and in term infants the estimated increased risk is about 4-fold. Provisionally, chorioamnionitis might account for 12% of spastic cerebral palsy in term infants and 28% of cerebral palsy in preterm infants. Studies of biochemical markers of fetal inflammation typically associated with infection also suggest that an inflammatory response may be an important independent etiologic factor. If a substantial proportion of cerebral palsy is attributable to acute amnionitis infection and/or neonatal sepsis, cerebral palsy should have decreased in the United States after administration of intrapartum antibiotics became widespread in response to publication of public health consensus guidelines for Group B streptococcus in 1996. However, failure to detect declines could have a number of explanations and these explanations illustrate the many public health challenges related to intrauterine infection and cerebral palsy. Given the gaps in our current knowledge about intrauterine infection and cerebral palsy, public health recommendations for timely and specific prevention activities are limited at this time.

Health-related quality of life of preterm children and their caregivers

Abstract: As advances in medical science have extended the limit of viability downward to 23 or 24 weeks gestation, interest has turned from long-term health outcomes to quality of life for survivors. During the last decade, the first studies of the health-related quality of life (HRQOL) of children and young adults who were born extremely preterm were published. Taken from the fields of anthropology, economics, sociology, and psychology, the foundation of HRQOL is formed by theories of functionalism, positive well-being, and utility. HRQOL can be defined as the physical, psychological, and social domains of health, which can be influenced by an individual's experiences and perception. HRQOL instruments are generally composed of multiple domains and measure physical functioning, mental health, and social role functioning in some form. Utilities, or preferences for health outcomes under conditions of uncertainty, are also used. Studies of HRQOL to-date indicate that preterm children have, on average, poorer health than their normal birthweight peers, but the majority do not perceive their quality of life as significantly different than others of their own age. Measures of HRQOL should not replace the traditional measures of morbidity, but should become part of the standard battery of tools used to assess a preterm child's health and well-being. Ultimately, studies of the HRQOL of preterm children should identify aspects of life, physical, psychological, or social, that could be improved with intervention.