Consensus definition and diagnostic criteria for neonatal encephalopathy-study protocol for a real-time modified delphi study.

BACKGROUND: 'Neonatal encephalopathy' (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. METHODS: Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. DISCUSSION: A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families. IMPACT: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.

Different cohort, disparate results: Selection bias is a key factor in autopsy cohorts.

INTRODUCTION: Research-oriented autopsy cohorts provide critical insights into dementia pathobiology. However, different studies sometimes report disparate findings, partially because each study has its own recruitment biases. We hypothesized that a straightforward metric, related to the percentage of research volunteers cognitively normal at recruitment, would predict other inter-cohort differences. METHODS: The National Alzheimer's Coordinating Center (NACC) provided data on N = 7178 autopsied participants from 28 individual research centers. Research cohorts were grouped based on the proportion of participants with normal cognition at initial clinical visit. RESULTS: Cohorts with more participants who were cognitively normal at recruitment contained more individuals who were older, female, had lower frequencies of apolipoprotein E ε4, Lewy body disease, and frontotemporal dementia, but higher rates of cerebrovascular disease. Alzheimer's disease (AD) pathology was little different between groups. DISCUSSION: The percentage of participants recruited while cognitively normal predicted differences in findings in autopsy research cohorts. Most differences were in non-AD pathologies. HIGHLIGHTS: Systematic differences exist between autopsy cohorts that serve dementia research. We propose a metric to use for gauging a research-oriented autopsy cohort. It is essential to consider the characteristics of autopsy cohorts.

Interobserver Reliability for Identifying Specific Patterns of Placental Injury as Defined by the Amsterdam Classification.

CONTEXT.­: Placental pathology is an essential tool for understanding neonatal illness. The recent Amsterdam international consensus has standardized criteria and terminology, providing harmonized data for research and clinical care. OBJECTIVE.­: To evaluate the interobserver reliability of these criteria between pathologists at different levels of experience using digitally scanned slides from placentas in a birth population including a large proportion of normal deliveries. DESIGN.­: This was a secondary analysis of selected placentas from a large case-control study of placental lesions associated with neonatal encephalopathy. Histologic slides from 80 placentas were digitally scanned and blindly evaluated by 6 pathologists. Interobserver reliability was assessed by positive and negative agreement, Fleiss κ, and interrater correlation coefficients. RESULTS.­: Overall agreement on the diagnosis, grading, and staging of acute chorioamnionitis and villitis of unknown etiology was moderate to good for all observers and good to excellent for a subset of 4 observers. Agreement on the diagnosis and subtyping of fetal vascular malperfusion was poor to fair for all observers and fair to moderate for the subset of 4 pathologists. Agreement on accelerated villous maturation was poor. CONCLUSIONS.­: This study critically evaluates interobserver reliability for lesions defined by the Amsterdam consensus using scanned images with a low frequency of pathologic lesions. Although reliability was good to excellent for inflammatory lesions, lower reliability for vascular lesions emphasizes the need to more explicitly define the specific histologic features and boundaries for these patterns.

Brain arteriolosclerosis.

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer's disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.

The epidemiology of FIRS in term and late preterm births.

The definition of FIRS requires systemic inflammation and elevated levels of IL-6 in fetal plasma. That definition does not specify how systemic inflammation is to be recognized, and perinatal measurement of IL-6 is not a standard procedure. FIRS has not been examined in a population-based study that included post-neonatal outcome so its incidence and natural history are not known. The overlap, and similarities and differences, of FIRS as compared with other causes of neonatal encephalopathy, and how these relate to findings in the placenta, have not been jointly examined in a generalizable sample. FIRS has chiefly been discussed in the obstetric literature because of the need for decisions about management of delivery and antibiotic use. If the term "FIRS" is to be employed in other contexts, consensus should be sought as to which clinical, placental, and laboratory findings are most appropriate for identification of perinatal inflammatory processes, infectious or sterile.

The Placenta in Neonatal Encephalopathy: A Case-Control Study.

OBJECTIVE: We assessed whether specific histologic placental lesions were associated with risk for neonatal encephalopathy, a strong predictor of death or cerebral palsy. STUDY DESIGN: Case-control study of singletons with gestational ages ≥35 weeks. Data were abstracted from a prospectively collected database of consecutive births at a hospital in which placental samples from specified sites are collected and stored for all inborn infants. Placentas of infants with neonatal encephalopathy were compared with randomly selected control infants (ratio of 1:3). Placental histologic slides were read by a single experienced perinatal pathologist unaware of case status, using internationally recommended definitions and terminology. Findings were grouped into inflammatory, maternal, or fetal vascular malperfusion (FVM) and other lesions. RESULTS: Placental samples were available for 73 of 87 (84%) cases and 253 of 261 (97%) controls. Delivery complications and gross placental abnormalities were more common in cases, of whom 4 died. Inflammation and maternal vascular malperfusion did not differ, and findings consistent with global FVM were more frequent in case (20%) than control (7%) placentas (P = .001). There was a trend toward more segmental FVM and high-grade FVM (fetal thrombotic vasculopathy) among cases. Some type of FVM was observed in 24% of placentas with neonatal encephalopathy. In infants with both neonatal encephalopathy and placental FVM, more often than in infants with neonatal encephalopathy without FVM, electronic fetal monitoring tracings were considered possibly or definitely abnormal (P = .028). CONCLUSIONS: Vascular malperfusion of subacute or chronic origin on the fetal side of the placenta was associated with increased risk of neonatal encephalopathy.

Does aetiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy influence the outcome of treatment?

Neonatal encephalopathy, a clinical syndrome affecting term-born and late preterm newborn infants, increases the risk of perinatal death and long-term neurological morbidity, especially cerebral palsy. With the advent of therapeutic hypothermia, a treatment designed for hypoxic or ischaemic injury, associated mortality and morbidity rates have decreased. Unfortunately, only about one in eight neonates (95% confidence interval) who meet eligibility criteria for therapeutic cooling apparently benefit from the treatment. Studies of infants in representative populations indicate that neonatal encephalopathy is a potential result of a variety of antecedents and that asphyxial complications at birth account for only a small percentage of neonatal encephalopathy. In contrast, clinical case series suggest that a large proportion of neonatal encephalopathy is hypoxic or ischaemic, and trials of therapeutic hypothermia are specifically designed to include only infants exposed to hypoxia or ischaemia. This review addresses the differences, definitional and methodological, between infants studied and investigations undertaken, in population studies compared with cooling trials. It raises the question if there may be subgroups of infants with a clinical diagnosis of hypoxic-ischaemic encephalopathy (HIE) in whom the pathobiology of neonatal neurological depression is not fundamentally hypoxic or ischaemic and, therefore, for whom cooling may not be beneficial. In addition, it suggests approaches to future trials of cooling plus adjuvant therapy that may contribute to further improvement of care for these vulnerable neonates.

Fetal growth restriction and risk of cerebral palsy in singletons born after at least 35 weeks' gestation.

OBJECTIVE: The objective of the study was to improve the understanding of etiological paths to cerebral palsy (CP) that include fetal growth restriction by examining factors associated with growth restriction that modify CP risk. STUDY DESIGN: In a total population of singletons born at or after 35 weeks, there were 493 children with CP and 508 matched controls for whom appropriateness of fetal growth could be estimated. Fetal growth was considered markedly restricted if birthweight was more than 2 SD below optimal for gender, gestation, maternal height, and parity. We examined maternal blood pressure in pregnancy, smoking, birth asphyxia, and major birth defects recognized by age 6 years as potential modifiers of CP risk in growth-restricted births. RESULTS: More than 80% of term and late preterm markedly growth-restricted singletons were born following a normotensive pregnancy and were at statistically significantly increased risk of CP (odds ratio, 4.81; 95% confidence interval, 2.7-8.5), whereas growth-restricted births following a hypertensive pregnancy were not. Neither a clinical diagnosis of birth asphyxia nor potentially asphyxiating birth events occurred more frequently among growth-restricted than among appropriately grown infants with CP. Major birth defects, particularly cerebral defects, occurred in an increasing proportion of CP with increasing growth deficit. The factor most predictive of CP in growth-restricted singletons was a major birth defect, present in 53% of markedly growth-restricted neonates with later CP. Defects observed in CP were similar whether growth restricted or not, except for an excess of isolated congenital microcephaly in those born growth restricted. The highest observed CP risk was in infants with both growth restriction and a major birth defect (8.9% of total CP in this gestational age group, 0.4% of controls: odds ratio, 30.9; 95% confidence interval, 7.0-136). CONCLUSION: The risk of CP was increased in antenatally growth-restricted singletons born at or near term to normotensive mothers. In growth-restricted singletons, a major birth defect was the dominant predictor, associated with a 30-fold increase in odds of CP. Identification of birth defects in the growth-restricted fetus or neonate may provide significant prognostic information.

Seizures, encephalopathy, and vaccines: experience in the National Vaccine Injury Compensation Program.

OBJECTIVES: To describe the demographic and clinical characteristics of children for whom claims were filed with the National Vaccine Injury Compensation Program (VICP) alleging seizure disorder and/or encephalopathy as a vaccine injury. STUDY DESIGN: The National VICP within the Department of Health and Human Services compensates individuals who develop medical problems associated with a covered immunization. We retrospectively reviewed medical records of children younger than 2 years of age with seizures and/or encephalopathy allegedly caused by an immunization, where a claim was filed in the VICP between 1995 through 2005. RESULTS: The VICP retrieved 165 claims that had sufficient clinical information for review. Approximately 80% of these alleged an injury associated with whole-cell diphtheria, pertussis (whooping cough), and tetanus or tetanus, diphtheria toxoids, and acellular pertussis vaccine. Pre-existing seizures were found in 13% and abnormal findings on a neurologic examination before the alleged vaccine injury in 10%. A final diagnostic impression of seizure disorder was established in 69%, of whom 17% (28 patients) had myoclonic epilepsy, including possible severe myoclonic epilepsy of infancy. Specific conditions not caused by immunization, such as tuberous sclerosis and cerebral dysgenesis, were identified in 16% of subjects. CONCLUSION: A significant number of children with alleged vaccine injury had pre-existing neurologic or neurodevelopmental abnormalities. Among those developing chronic epilepsy, many had clinical features suggesting genetically determined epilepsy. Future studies that include genotyping may allow more specific therapy and prognostication, and enhance public confidence in vaccination.

Neuroimaging in the evaluation of neonatal encephalopathy.

BACKGROUND AND OBJECTIVE: Computed tomography (CT) is still used for neuroimaging of infants with known or suspected neurologic disorders. Alternative neuroimaging options that do not expose the immature brain to radiation include MRI and cranial ultrasound. We aim to characterize and compare the use and findings of neuroimaging modalities, especially CT, in infants with neonatal encephalopathy. METHODS: The Vermont Oxford Network Neonatal Encephalopathy Registry enrolled 4171 infants (≥36 weeks' gestation or treated with therapeutic hypothermia) between 2006 and 2010 who were diagnosed with encephalopathy in the first 3 days of life. Demographic, perinatal, and medical conditions were recorded, along with treatments, comorbidities, and outcomes. The modality, timing, and results of neuroimaging were also collected. RESULTS: CT scans were performed on 933 of 4107 (22.7%) infants, and 100 of 921 (10.9%) of those received multiple CT scans. Compared with MRI, CT provided less detailed evaluation of cerebral injury in areas of prognostic significance, but was more sensitive than cranial ultrasound for hemorrhage and deep brain structural abnormalities. CONCLUSIONS: CT is commonly used for neuroimaging in newborn infants with neonatal encephalopathy despite concerns over potential harm from radiation exposure. The diagnostic performance of CT is inferior to MRI in identifying neonatal brain injury. Our data suggest that using cranial ultrasound for screening, followed by MRI would be more appropriate than CT at any stage to evaluate infants with neonatal encephalopathy.

Biomarkers S100B and neuron-specific enolase predict outcome in hypothermia-treated encephalopathic newborns*.

OBJECTIVES: To evaluate if serum S100B protein and neuron-specific enolase measured during therapeutic hypothermia are predictive of neurodevelopmental outcome at 15 months in children with neonatal encephalopathy. DESIGN: Prospective longitudinal cohort study. SETTING: A level IV neonatal ICU in a freestanding children's hospital. PATIENTS: Term newborns with moderate to severe neonatal encephalopathy referred for therapeutic hypothermia during the study period. INTERVENTIONS: Serum neuron-specific enolase and S100B were measured at 0, 12, 24, and 72 hours of hypothermia. MEASUREMENTS AND MAIN RESULTS: Of the 83 infants enrolled, 15 (18%) died in the newborn period. Survivors were evaluated by the Bayley Scales of Infant Development-II at 15 months. Outcomes were assessed in 49 of 68 survivors (72%) at a mean age of 15.2 ± 2.7 months. Neurodevelopmental outcome was classified by Bayley Scales of Infant Development-II Mental Developmental Index and Psychomotor Developmental Index scores, reflecting cognitive and motor outcomes, respectively. Four-level outcome classifications were defined a priori: normal = Mental Developmental Index/Psychomotor Developmental Index within 1 SD (> 85), mild = Mental Developmental Index/Psychomotor Developmental Index less than 1 SD (70-85), moderate/severe = Mental Developmental Index/Psychomotor Developmental Index less than 2 SD (< 70), or died. Elevated serum S100B and neuron-specific enolase levels measured during hypothermia were associated with increasing outcome severity after controlling for baseline and socioeconomic characteristics in ordinal regression models. Adjusted odds ratios for cognitive outcome were 2.5 (95% CI, 1.3-4.8) for S100B and 2.1 (95% CI, 1.2-3.6) for neuron-specific enolase, and for motor outcome, 2.6 (95% CI, 1.2-5.6) for S100B and 2.1 (95% CI, 1.2-3.6) for neuron-specific enolase. CONCLUSIONS: Serum S100B and neuron-specific enolase levels in babies with neonatal encephalopathy are associated with neurodevelopmental outcome at 15 months. These putative biomarkers of brain injury may help direct care during therapeutic hypothermia.

Antecedents of cerebral palsy and perinatal death in term and late preterm singletons.

OBJECTIVE: To examine the antecedents of cerebral palsy and of perinatal death in singletons born at or after 35 weeks of gestation. METHODS: From a total population of singletons born at or after 35 weeks of gestation, we identified 494 with cerebral palsy and 508 neonates in a matched control group, 100 neonatal deaths, and 73 intrapartum stillbirths (all deaths in selected birth years). Neonatal death and cerebral palsy were categorized as without encephalopathy, after neonatal encephalopathy, or after neonatal encephalopathy considered hypoxic-ischemic. We examined the contribution of potentially asphyxial birth events, inflammation, fetal growth restriction, and birth defects recognized by age 6 years to each of these outcomes and to intrapartum stillbirths. RESULTS: The odds of total cerebral palsy after potentially asphyxial birth events or inflammation were modestly increased (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1-3.2 and OR 2.2, 95% CI 1.0-4.2, respectively). However, potentially asphyxial birth events occurred in 34% of intrapartum stillbirths and 21.6% of cerebral palsy after hypoxic-ischemic encephalopathy. Inflammatory markers occurred in 13.9% and 11.9% of these outcomes, respectively. Growth restriction contributed significantly to all poor outcome groups. Birth defects were recognized in 5.5% of neonates in the control group compared with 60% of neonatal deaths and more than half of cases of cerebral palsy without hypoxic-ischemic encephalopathy. In children with cerebral palsy, a potentially asphyxial birth event, inflammation, or both were experienced by 12.6%, whereas growth restriction, a birth defect, or both were experienced by 48.6% (P<.001). CONCLUSION: Fetal growth restriction and birth defects recognized by age 6 years were more substantial contributors to cerebral palsy and neonatal death than potentially asphyxial birth events and inflammation. LEVEL OF EVIDENCE: : II.

The association of cerebral palsy with birth asphyxia: a definitional quagmire.

AIM: The aim of this study was to investigate whether current literature provides a useful body of evidence reflecting the proportion of cerebral palsy (CP) that is attributable to birth asphyxia. METHOD: We identified 23 studies conducted between 1986 and 2010 that provided data on intrapartum risks of CP. RESULTS: The proportion of CP with birth asphyxia as a precursor (case exposure rate) varied from less than 3% to over 50% in the 23 studies reviewed. The studies were heterogeneous in many regards, including the definitions for birth asphyxia and the outcome of CP. INTERPRETATIONS: Current data do not support the belief, widely held in the medical and legal communities, that birth asphyxia can be recognized reliably and specifically, or that much of CP is due to birth asphyxia. The very high case exposure rates linking birth asphyxia to CP can probably be attributed to several factors: the fact that the clinical picture at birth cannot specifically identify birth asphyxia; the definition of CP employed; and confusion of proximal effects - results - with causes. Further research is needed.