Nigel Paneth

A report: the definition and classification of cerebral palsy April 2006.

For a variety of reasons, the definition and the clawification of cerebral palsy (CP) need to be reconsidered. Modern brain imaging techniques have shed new light on the nature of the underlying brain injury and studies on the neurobiology of and pathology associated with brain development have further explored etiologic mechanisms. It is now recognized that assessing the extent of activity restriction is part of CP evaluation and that people without activity restriction should not be included in the CP rubric. Also, previous definitions have not given sufficient prominence to the non‐motor neurodevelopmental disabilities of performance and behaviour that commonly accompany CP, nor to the progression of musculoskeletal difficulties that often occurs with advancing age. In order to explore this information, pertinent material was reviewed on July 11–13,2004 at an international workshop in Bethesda, MD (USA) organized by an Executive Committee and participated in by selected leaders in the preclinical and clinical sciences. At the workshop, it was agreed that the concept ‘cerebral palsy’ should be retained. Suggestions were made about the content of a revised definition and classification of CP that would meet the needs of clinicians, investigators, health officials, families and the public and would provide a common language for improved communication. Panels organized by the Executive Committee used this information and additional comments from the international community to generate a report on the Definition and Classification of Cerebral Palsy, April 2006. The Executive Committee presents this report with the intent of providing a common conceptualization of CP for use by a broad international audience.

Proposed definition and classification of cerebral palsy, April 2005

Because of the availability of new knowledge about the neurobiology of developmental brain injury, information that epidemiology and modern brain imaging is providing, the availability of more precise measuring instruments of patient performance, and the increase in studies evaluating the efficacy of therapy for the consequences of injury, the need for reconsideration of the definition and classification of cerebral palsy (CP) has become evident. Pertinent material was reviewed at an international symposium participated in by selected leaders in the preclinical and clinical sciences. Suggestions were made about the content of a revised definition and classification of CP that would meet the needs of clinicians, investigators, and health officials, and provide a common language for improved communication. With leadership and direction from an Executive Committee, panels utilized this information and have generated a revised Definition and Classification of Cerebral Palsy. The Executive Committee presents this revision and welcomes substantive comments about it.

Phenobarbital compared with phenytoin for the treatment of neonatal seizures.

BACKGROUND Seizures occur in 1 to 2 percent of neonates admitted to an intensive care unit. The treatment is usually with either phenobarbital or phenytoin, but the efficacy of the two drugs has not been compared directly. METHODS From 1990 to 1995, we studied 59 neonates with seizures that were confirmed by electroencephalography. The neonates were randomly assigned to receive either phenobarbital or phenytoin intravenously, at doses sufficient to achieve free plasma concentrations of 25 microg per milliliter for phenobarbital and 3 microg per milliliter for phenytoin. Neonates whose seizures were not controlled by the assigned drug were then treated with both drugs. Seizure control was assessed by electroencephalographic criteria. RESULTS Seizures were controlled in 13 of the 30 neonates assigned to receive phenobarbital (43 percent) and 13 of the 29 neonates assigned to receive phenytoin (45 percent; P=1.00). When combined treatment is considered, seizure control was achieved in 17 (57 percent) of the neonates assigned to receive phenobarbital first and 18 (62 percent) of those assigned to receive phenytoin first (P=0.67). The severity of the seizures was a stronger predictor of the success of treatment than was the assigned agent. Neonates with mild seizures or with seizures that were decreasing in severity before treatment were more likely to have their seizures end, regardless of the treatment assignment. CONCLUSIONS Phenobarbital and phenytoin are equally but incompletely effective as anticonvulsants in neonates. With either drug given alone, the seizures were controlled in fewer than half of the neonates.

Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants

Echolucent images (EL) of cerebral white matter, seen on cranial ultrasonographic scans of very low birth weight newborns, predict motor and cognitive limitations. We tested the hypothesis that markers of maternal and feto-placental infection were associated with risks of both early (diagnosed at a median age of 7 d) and late (median age = 21 d) EL in a multi-center cohort of 1078 infants <1500 ×g. Maternal infection was indicated by fever, leukocytosis, and receipt of antibiotic; feto-placental inflammation was indicated by the presence of fetal vasculitis (i.e. of the placental chorionic plate or the umbilical cord). The effect of membrane inflammation was also assessed. All analyses were performed separately in infants born within 1 h of membrane rupture (n= 537), or after a longer interval (n= 541), to determine whether infection markers have different effects in infants who are unlikely to have experienced ascending amniotic sac infection as a consequence of membrane rupture. Placental membrane inflammation by itself was not associated with risk of EL at any time. The risks of both early and late EL were substantially increased in infants with fetal vasculitis, but the association with early EL was found only in infants born ≥1 after membrane rupture and who had membrane inflammation (adjusted OR not calculable), whereas the association of fetal vasculitis with late EL was seen only in infants born <1 h after membrane rupture (OR = 10.8;p= 0.05). Maternal receipt of antibiotic in the 24 h just before delivery was associated with late EL only if delivery occurred <1 h after membrane rupture (OR = 6.9;p= 0.01). Indicators of maternal infection and of a fetal inflammatory response are strongly and independently associated with EL, particularly late EL.

Behavioural problems in children who weigh 1000 g or less at birth in four countries.

BACKGROUND The increased survival chances of extremely low-birthweight (ELBW) infants (weighing <1000 g at birth) has led to concern about their behavioural outcome in childhood. In reports from several countries with different assessments at various ages, investigators have noted a higher frequency of behavioural problems in such infants, but cross-cultural comparisons are lacking. Our aim was to compare behavioural problems in ELBW children of similar ages from four countries. METHODS We prospectively studied 408 ELBW children aged 8-10 years, whose parents completed the child behaviour checklist. The children came from the Netherlands, Germany, Canada, and USA. The checklist provides a total problem score consisting of eight narrow-band scales. Of these, two (aggressive and delinquent behaviour) give a broad-band externalising score, three (anxious, somatic, and withdrawn behaviour) give a broad-band internalising score, and three (social, thought, and attention problems) indicate difficulties fitting neither broad-band dimension. For each cohort we analysed scores in ELBW children and those in normal- birthweight controls (two cohorts) or national normative controls (two cohorts). Across countries, we assessed deviations of the ELBW children from normative or control groups. FINDINGS ELBW children had higher total problem scores than normative or control children, but this increase was only significant in European countries. Narrow-band scores were raised only for the social, thought, and attention difficulty scales, which were 0.5-1.2 SD higher in ELBW children than in others. Except for the increase in internalising scores recorded for one cohort, ELBW children did not differ from normative or control children on internalising or externalising scales. INTERPRETATION Despite cultural differences, types of behavioural problems seen in ELBW children were very similar in the four countries. This finding suggests that biological mechanisms contribute to behavioural problems of ELBW children.

EARLY ORIGIN OF CORONARY HEART DISEASE (THE BARKER HYPOTHESIS )

Risk profiles for coronary heart disease are surely among the most valuable products of epidemiology of the past half century. Not only have some important personal determinants of coronary heart disease been uncovered but also methods for their amelioration have been developed, and best of all, in many countries rates of cardiac disease have fallen steadily for 25 years. Yet for some time now quietude has beset this field of research. The main risk factors—raised body weight, cholesterol concentration, and blood pressure; glucose intolerance; smoking; and lack of physical activity—are old discoveries, and much current research seems merely to be fine tuning these standbys. The precise role of variations in coagulation profiles in the pathogenesis of coronary heart disease remains hazy, and factors such as stress and social support seem no more and no less promising and ambiguous than they were decades ago. So the excited welcome given to a totally new set of antecedents is unsurprising. The hypothesis of Professor David Barker and colleagues working in Southampton is that “a babys nourishment before birth and during infancy,” as manifest in patterns of fetal and infant growth, “programmes” the development of risk factors such as raised blood pressure, fibrinogen concentration, and factor VIII concentration and glucose intolerance and hence these are key determinants of coronary heart disease. Since 1987 the group has elaborated this hypothesis in at least 40 papers (many of them in the BMJ) and two books.1 2 Although some evidence comes from comparisons among populations, the most recent approach has been to seek places where infant anthropometric measures were systematically recorded many years ago (Hertfordshire and Preston). Middle aged and elderly survivors have then been searched out for study. This idea is in line with a body of research of the past 50 years on the …

Developing and validating the Communication Function Classification System for individuals with cerebral palsy.

Aim  The purpose of this study was to create and validate the Communication Function Classification System (CFCS) for children with cerebral palsy (CP), for use by a wide variety of individuals who are interested in CP. This paper reports the content validity, interrater reliability, and test–retest reliability of the CFCS for children with CP.

White matter damage in preterm newborns —an epidemiologic perspective

Prior to 1980, white matter abnormalities of the preterm newborn were known exclusively as pathological entities, but now cranial ultrasonography can image white matter abnormalities in life. Ultrasonographic white matter echodensities and echolucencies in low birthweight babies predict later handicap (especially cerebral palsy) more accurately than any other antecedent. With the increased availability of high resolution cranial ultrasonography and the improved skill in obtaining and reading cranial ultrasonograms, rapid gains can be expected in our understanding of white matter disorders. These advances are likely to be made in the diagnosis and classification of white matter disorders and in their epidemiologic and prognostic features, topics explored in this review.

Newborn intensive care and neonatal mortality in low-birth-weight infants: a population study.

We examined the neonatal mortality rates of low-birth-weight infants (501 to 2250 g) born between 1976 and 1978 in three kinds of hospitals in New York City: those with newborn-intensive-care units (Level 3), those with capabilities for the care of most premature infants (Level 2), and those without any special facilities for premature newborns (Level 1). Among 13,560 singleton low-birth-weight infants, the adjusted neonatal mortality rate for Level 3 hospitals was 128.5 per thousand live births - significantly lower (P less than 0.001) than the rates for both level 2 (168.1) and Level 1 units (163.0). The association of level of care with mortality could not be accounted for by differences between groups in social or demographic status, in prenatal care, or in medical complication of pregnancy. We infer that birth at a Level 3 center lowers neonatal mortality in low-birth-weight infants. However, only 34 per cent of the patients in this study were born in such units.

The ELGAN study of the brain and related disorders in extremely low gestational age newborns.

BACKGROUND Extremely low gestational age newborns (ELGANs) are at increased risk for structural and functional brain abnormalities. AIM To identify factors that contribute to brain damage in ELGANs. STUDY DESIGN Multi-center cohort study. SUBJECTS We enrolled 1506 ELGANs born before 28 weeks gestation at 14 sites; 1201 (80%) survived to 2 years corrected age. Information about exposures and characteristics was collected by maternal interview, from chart review, microbiologic and histological examination of placentas, and measurement of proteins in umbilical cord and early postnatal blood spots. OUTCOME MEASURES Indicators of white matter damage, i.e. ventriculomegaly and echolucent lesions, on protocol cranial ultrasound scans; head circumference and developmental outcomes at 24 months adjusted age, i.e., cerebral palsy, mental and motor scales of the Bayley Scales of Infant Development, and a screen for autism spectrum disorders. RESULTS ELGAN Study publications thus far provide evidence that the following are associated with ultrasongraphically detected white matter damage, cerebral palsy, or both: preterm delivery attributed to preterm labor, prelabor premature rupture of membranes, or cervical insufficiency; recovery of microorganisms in the placenta parenchyma, including species categorized as human skin microflora; histological evidence of placental inflammation; lower gestational age at delivery; greater neonatal illness severity; severe chronic lung disease; neonatal bacteremia; and necrotizing enterocolitis. CONCLUSIONS In addition to supporting a potential role for many previously identified antecedents of brain damage in ELGANs, our study is the first to provide strong evidence that brain damage in extremely preterm infants is associated with microorganisms in placenta parenchyma.