Placental contribution to neonatal encephalopathy.

Placental assessment, although currently underused, can inform our understanding of the etiology and timing of Neonatal Encephalopathy (NE). We review our current understanding of the links between placental dysfunction and NE and how this information may inform clinical decisions, now and in the future, emphasizing the four major placental lesions associated with NE. In addition, we discuss maternal and fetal factors that are hypothesized to contribute to specific placental pathologies, especially innate or acquired thrombophilias. We outline the importance of assessing placenta across trimesters and after delivery. As this field continues to evolve, currently available placental histopathological examination methods may need to be combined with advanced prenatal molecular and imaging assessments of placenta and be applied in well-designed studies in large representative populations to better define the links between placental dysfunction and NE.

Does preterm period sleep development predict early childhood growth trajectories?

OBJECTIVE: The current study examined the relationship between sleep state development across the preterm and early post-term periods and subsequent growth trajectories from 1 to 27 months corrected age. STUDY DESIGN: Retrospective analysis of data collected prospectively from 111 preterm infants (⩽34 weeks gestation) who participated in a multi-site longitudinal study. Separate longitudinal parallel process models were calculated for each sleep state (active and quiet sleep) and growth (weight, length and body mass index (BMI) Z-scores) variable to estimate the associations between their developmental trajectories. RESULTS: Significant associations were identified between the trajectories of quiet sleep and weight, active sleep and weight, quiet sleep and BMI, and active sleep and BMI. No statistically meaningful associations were identified between the trajectories of early childhood length and the preterm sleep states. CONCLUSION: Faster preterm period sleep development appears to predict more favorable early childhood growth trajectories, particularly for weight, indicating preterm sleep may be an important biomarker for subsequent growth outcomes.

An analysis of the kangaroo care intervention using neonatal EEG complexity: a preliminary study.

OBJECTIVE: Skin-to-skin contact (SSC) promotes physiological stability and interaction between parents and infants. Temporal analyses of predictability in EEG-sleep time series can elucidate functional brain maturation between SSC and non-SSC cohorts at similar post-menstrual ages (PMAs). METHODS: Sixteen EEG-sleep studies were performed on eight preterm infants who received 8 weeks of SSC, and compared with two non-SSC cohorts at term (N=126) that include a preterm group corrected to term age and a full term group. Two time series measures of predictability were used for comparisons. RESULTS: The SSC premature neonate group had increased complexity when compared to the non-SSC premature neonate group at the same PMA. Discriminant analysis shows that SSC neonates at 40 weeks PMA are closer to the full term neonate non-SSC group than to the premature non-SSC group at the same PMA; suggesting that the KC intervention accelerates neurophysiological maturation of premature neonates. CONCLUSIONS: Based on the hypothesis that EEG-derived complexity increases with neurophysiological maturation as supported by previously published research, SSC accelerates brain maturation in healthy preterm infants as quantified by time series measures of predictability when compared to a similar non-SSC group. SIGNIFICANCE: Times series methods that quantify predictability of EEG sleep in neonates can provide useful information about altered neural development after developmental care interventions such as SSC. Analyses of this type may be helpful in assessing other neuroprotection strategies.

Nonlinear dynamical analysis of the neonatal EEG time series: the relationship between sleep state and complexity.

OBJECTIVE: The complexity of the EEG time series during stages of neonatal sleep states is investigated. The relationship between these sleep states, birth status (i.e. preterm and full-term), and the complexity of the EEG is assessed. METHODS: Dimensional complexity, an estimate of the correlation dimension (D(2)) of the EEG time series, is used as a novel index for quantifying the complexity of the EEG time series during different neonatal sleep states. The dimensional complexity is estimated by using both the Grassberger-Procaccia algorithm and Theiler's modified algorithm. Also, the hypothesis that the neonatal EEG time series contains nonlinear features is investigated and verified in certain sleep states using surrogate data testing. RESULTS: Dimensional complexity of the neonatal EEG time series during active (REM) sleep tends to be higher than during quiet (NREM) sleep; while dimensional complexity of the neonatal EEG time series during indeterminate sleep is virtually at the midpoint of the dimensional complexity range between the active and quiet sleep states. Consequently, there are statistically significant differences between the neonatal EEG time series during different sleep states as measured by dimensional complexity. Also, the birth status (preterm or full-term) of the neonate has an influence on dimensional complexity of the neonatal EEG time series. Further, the surrogate data testing null hypothesis for dimensional complexity cannot be rejected during active sleep. CONCLUSIONS: The neonatal EEG time series tends to have statistically different complexities corresponding to different sleep states. Given that the neonatal EEG time series during active sleep is more complex than during quiet sleep, one can suggest that there is greater activity among cortical circuit elements during active as compared to quiet sleep. Further, active sleep neuronal dynamics are best modeled by a linear stochastic process, while in quiet sleep a nonlinear deterministic model may be more appropriate. SIGNIFICANCE: There has been considerable controversy associated with measures of complexity, such as dimensional analysis, as applied to neonatal EEG data. This paper confirms that there are statistically significant differences in dimensional complexity associated with different states of sleep and that the origin of this complexity shifts from linear stochastic to nonlinear deterministic with transitions from active to quiet sleep, and is further influenced by maturation. This may provide important insight into the organization and structure of neuronal networks during sleep and with brain maturation in the neonatal period.

Nonlinear dynamical analysis of the neonatal EEG time series: the relationship between neurodevelopment and complexity.

OBJECTIVE: To investigate the relationship between the complexity of sleep EEG time series and neurodevelopment for premature or full-term neonates. METHODS: Nonlinear dynamical analysis of neonatal sleep EEG time series is used to compute the correlation dimension D2 which is an index of the complexity of the dynamics of the developing brain. The dimensional complexity is estimated using Theiler's modification of the Grassberger-Procaccia algorithm for two different values of Theiler's w parameter. The hypothesis that neonatal EEG data during sleep contains nonlinear features is verified by means of surrogate data testing. RESULTS: The dimensional complexity of the neonatal EEG increases with neurodevelopment and brain maturation. There is furthermore a statistically significant difference between the dimensional complexity of the EEG for neonates born prematurely when compared to full-term neonates at the same postmenstrual age (PMA). The neonatal EEG time series data used in this study proved to contain nonlinear features where the 'null hypothesis' of surrogate data testing is rejected with p<<0.0001. CONCLUSIONS: A relationship between neurodevelopment and brain maturation and the complexity of the dynamics of the brain as measured by the dimensional complexity of the sleep EEG time series has been established. In particular, the dimensional complexity tends to increase with neurodevelopment and maturation as indicated by their PMA and birth status (premature or full-term). In particular, the brain dynamics of neonates born prematurely is less complex than the brain dynamics of neonates born full-term even at the same PMA. We attribute this to differences in the neurodevelopment between these two cohorts. We propose that the dimensional complexity can be used as an index for quantifying neurodevelopment. SIGNIFICANCE: The dimensional complexity as measured by the correlation dimension of the sleep EEG time series may potentially be a useful measure for quantifying neurodevelopment in neonates. Future work is directed at the analysis of other EEG channels to understand the relationship between complexity in different regions of the brain and maturation and neurodevelopment, along with the utility of complexity to relate to neurodevelopment at older ages as measured by the Bayley score.

Migraine headaches and sleep disturbances in children.

OBJECTIVE: The aim of the present study was to investigate the prevalence of sleep disturbances in children with migraine headaches and to describe individual differences in sleep behaviors based on headache features (eg, frequency, duration, intensity). BACKGROUND: A relationship between migraine headaches and sleep disturbances has been suggested in both children and adults, but there is a lack of research examining the relationship between specific headache features and the range of sleep behaviors in children. METHODS: One hundred eighteen children, aged 2 to 12 years (mean, 9.1; standard deviation, 2.3) were evaluated for headaches at two pediatric neurology departments. Parents completed the Children's Sleep Habits Questionnaire and a standardized questionnaire regarding headache characteristics. RESULTS: Parents reported a high rate of sleep disturbances in children, including sleeping too little (42%), bruxism (29%), child co-sleeping with parents (25%), and snoring (23%). Children with migraine headaches experienced more sleep disturbances compared to published healthy control norms. After controlling for child demographics, we found that the frequency and duration of migraine headaches predicted specific sleep disturbances, including sleep anxiety, parasomnias, and bedtime resistance. CONCLUSIONS: Children with migraine headaches have a high prevalence of sleep disturbances. The direction of the relationship between headaches and sleep is unknown. Regardless, interventions targeting sleep habits may improve headache symptoms, and effective treatment of headaches in children may positively impact sleep.

Controversies regarding neonatal seizure recognition.

Recognition and classification of neonatal seizures remain problematic, particularly when clinicians rely only on clinical criteria. Physicians should utilize synchronized video-EEG-polygraphic recordings to correlate suspicious behaviors with electrographic seizures, to help limit misdiagnosis and overtreatment of either normal or abnormal nonepileptic behaviors. Since neonatal seizures, particularly status epilepticus, predict an increased risk for later epilepsy and other neurological sequelae, accurate diagnoses are needed for aggressive antiepileptic drug use in the NICU, as well as family counseling and anticipatory medical care after discharge. Neurophysiological documentation of neonatal seizures also must be integrated with an appreciation of pathophysiological mechanisms responsible for brain lesions that cause seizures. Maternal-fetal-placental diseases, as well as genetic vulnerabilities may be responsible for seizures long before diagnosis in the newborn period. Alternatively, the severity of seizures in neonates with perinatal asphyxia or other etiologies may be independently associated with brain injury. Seizures in the newborn are one of the few, neonatal neurological emergencies. While prompt diagnostic and therapeutic plans are necessary, unresolved medical issues continue to challenge the physician's evaluation of the newborn with suspected seizures (table I) [1-3]. Recognition of the seizure state remains the foremost challenge to overcome. Clinical and electroencephalographic manifestations of neonatal seizures vary dramatically from those of older children. This generalization is underscored by the brevity and subtlety of the clinical repertoire of the newborn's neurological examination. Environmental restrictions surrounding the sick infant in an intensive care setting, including confinement within an isolette, intubation and attachment to multiple catheters limit accessibility. Medication alters arousal and muscle tone, which further limit the clinician's ability to consider these clinical neurological signs as surrogate markers of underlying brain disorders. Brain injury from antepartum factors may later be expressed as neonatal seizures, as part of a postnatal, encephalopathic clinical picture which may only be precipitated by stress during the intrapartum and neonatal periods [4]. Alternatively, medical conditions during parturition or after birth may cause seizures, with coincident injury. For medication options to effectively treat seizures, new agents need to be designed for specific etiologies, timing of injury, and the unique cellular/molecular organization of the immature brain. This review addresses the challenges and controversies regarding neonatal seizure recognition in the context of current clinical practices. Experimental models of neonatal seizures elucidate the pathophysiological mechanisms and adverse consequences of seizures on brain development. Since 20% to 50% of children with neonatal seizures experience later epilepsy, diagnostic accuracy is essential [5, 6], particularly for the newborn who suffers a prolonged seizure state.

Automated detection of tracé alternant during sleep in healthy full-term neonates using discrete wavelet transform.

OBJECTIVE: To develop an automated procedure for scoring neonatal sleep states using signal processing which are based on visual pattern recognition techniques. METHODS: We are developing an automated computer system to study relationships among multiple non-cerebral physiologic measures and brain activity in newborn infants, and are evaluating the usefulness of a number of different time-frequency domain transforms as potential diagnostic tools. RESULTS: Wavelet transforms yield excellent results in the detection of all twenty tracé alternant quiet sleep segments for 6 full-term healthy infants. CONCLUSIONS: We suggest that this method will be useful for the automated detection of neonatal sleep states, and may help delineate when sleep cycle disturbances occur on either an environmental or disease basis. More accurate physiologic descriptions of neonatal state may improve the clinician's ability to assess functional brain organization for a given post-conceptional age as well as document functional brain maturation at progressively older corrected ages.

Treatment of functional impairment in severe somatoform pain disorder: a case example.

OBJECTIVE: To describe the assessment and treatment of severe functional impairment in a young female adolescent with somatoform pain disorder. METHODS: Treatment included an inpatient hospital admission using a rehabilitation approach and behavior modification program. Standardized assessment of functional impairment and health-related quality of life was performed at baseline and follow-up. Diagnostic evaluation and treatment costs were computed using insurance and hospital billing data. RESULTS: Pre-/postintervention measures of functional disability indicated significant improvement in physical and psychosocial functioning in everyday activities. Although costly, the inpatient admission decreased frequent health care use over the short term. CONCLUSIONS: Delay in diagnosis of somatoform disorders may seriously extend children's disability and require more intensive treatment. Functional disability is a critical measure of treatment outcome in children with severe somatoform disorder. Future research concerning interventions for children with a broad range of recurrent and chronic pain symptoms can be strengthened through a focus on reducing functional disability.

Fetal and neonatal neurologic consultations: identifying brain disorders in the context of fetal-maternal-placental disease.

Pediatric neurologists provide an important consultative role for the fetus or neonate with a suspected brain disorder. Although most consultations are initiated after birth, neonatal neurologic dysfunction may be reflective of fetal brain damage or maldevelopment. Maternal or placental/cord disease states can predispose the fetus or neonate to brain disorders during the antepartum, intrapartum, or early postpartum periods. Neurologists must therefore consider maternal, placental, and fetal conditions on which a neonatal encephalopathy may be superimposed, with or without recent brain injury. This review suggests how the pediatric neurologist can contribute more effectively to fetal and neonatal neurologic evaluations regarding etiologies and mechanisms of brain injury; their role will enhance diagnostic services composed of maternal-fetal specialists, placental and pediatric pathologists, neonatologists, neurosurgeons, geneticists, and other pediatric subspecialists. Selected examples of structural markers during fetal life, and functional markers during neonatal life, illustrate the wide spectrum of disease states that are highly dependent on the timing and location of brain injury. The pediatric neurologist has the opportunity to integrate these complementary lines of investigation into a responsive consultative opinion, which is both medically accurate and ethical, responsible to the welfare of the mother and child.

Perinatal asphyxia: timing and mechanisms of injury in neonatal encephalopathy.

This article summarizes the recent medical literature regarding perinatal asphyxia with respect to timing and mechanisms of injury for neonates who were clinically diagnosed with an encephalopathy in the newborn period. Multiple mechanisms of injury are reviewed, including genetic vulnerability, acquired inflammatory responses, and clotting defects that can lead to ischemic-induced brain damage. Before effective treatments for fetal and neonatal brain disorders can be developed, accurate and timely diagnoses of fetal or neonatal brain injury must be achieved. Specific subsets of children can then benefit from neuroprotective strategies that can target the specific developmental aspects of brain adaptation or plasticity relative to the specific etiology and timing of injury after asphyxia.

Effects of prenatal cocaine/crack and other drug exposure on electroencephalographic sleep studies at birth and one year.

OBJECTIVE: Little is known about the neurophysiologic effects of prenatal cocaine/crack use. The aim of this study, designed to overcome methodologic limitations of previous research, was to investigate the effects of prenatal cocaine use on electroencephalographic (EEG) sleep patterns, a marker of central nervous system development. METHODS: In a longitudinal study of prenatal cocaine/crack exposure, women were interviewed at the end of each trimester about cocaine, crack, alcohol, tobacco, marijuana, and other drug use. Two-hour paper- and computer-generated EEG sleep recordings were obtained on a sample of the full-term infants on the second day of life and at 1 year postpartum. Eligible newborns were full-term, had received no general anesthesia, and had a 5-minute Apgar score >5. All infants whose mothers used one or more lines of cocaine during their first trimester or any crack (n = 37) were selected. A comparison group was chosen randomly from the group of women who did not use cocaine or crack during their pregnancy (n = 34). RESULTS: Women who used cocaine/crack during the first trimester were older, less educated, less likely to be working, and used more tobacco, alcohol, marijuana, and other illicit drugs than women who did not use cocaine/crack during the first trimester. There were no differences in infant birth weight, length, head circumference, or gestational age between the two exposure groups. After controlling for the significant covariates, prenatal cocaine exposure was associated with less well developed spectral correlations between homologous brain regions at birth, and with lower spectral EEG power values at 1 year of age. Prenatal alcohol, marijuana, and tobacco use were found to affect state regulation and cortical activities. CONCLUSIONS: These results indicate that the neurotoxic effects of prenatal cocaine/crack use can be detected with quantitative EEG measures.

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.

Late follow-up of femoral head avascular necrosis managed by intertrochanteric osteotomy & bone grafting.

A prospective study was carried out on fifty hips in forty-eight patients with Ficat stage III (Steinberg stage IV) avascular necrosis (head deformity evident on plain x-ray) involving the supero-ventral segment. Mean age was 33 +/- 8 years (mean and standard deviation). There were thirty-six male and twelve female patients. Followup was 3-14 years (mean 8 years). This study precluded patients who were more than 45 years old, had an underlying condition requiring continued chemotherapy or cortisone, who had extensive dorsal (posterior) head segment involvement or those who were poorly motivated. Avascular necrosis was associated with alcohol in 35% of hips, trauma in 26% and 39% were idiopathic. One pregnancy related case was included in the latter subgroup. Curettage of the avascular segment and impaction of the bone graft was performed via subcapital fenestration of the anterior femoral neck. Pain was the presenting symptom in all cases. The mean pre-operative Harris hip score was 36 points and the mean score at last assessment was 87 points. Seven hips (14%) failed, failure implied conversion to a hip replacement or a Harris hip score of less than 70 points. Failures were seen within the first 3 years after osteotomy. Kaplan Meyer Survivorship analysis demonstrated an overall survivorship probability of 86% at 14 years. One patient died 10 years post surgery, the head was retrieved for histological study. Statistical study (Mann-Whitney U test) was carried out to determine factors related to failure. Of significance were age of the patient at time of osteotomy, contralateral hip involvement and size of the lesion. X ray studies of the femoral head included measurement of the necrotic angle, evaluation of restoration and maintenance of head contour and graft incorporation or stabilisation. Subsequent CAT scan studies enabled accurate quantification and siting of the avascular segment. Secondary x ray degenerative changes of the joint tended to manifest with time but these changes had little bearing on the clinical outcome. Osteotomy does have a measure of unpredictability, but in the appropriate case a high incidence of satisfactory results would be anticipated.

Applying classifications of sleep disorders to children with neurologic conditions.

Information concerning sleep ontogeny and sleep disorders in children is required by many pediatric specialists. Pediatric neurologists, for instance, frequently are called upon to assist in the evaluation of children with undiagnosed symptoms and signs during sleep, as well as to care for children and adolescents with specific neurologic diseases who also experience sleep disturbances. This review discusses pediatric sleep disturbances with specific reference to sleep in children with neurologic conditions.

Understanding sleep ontogeny to assess brain dysfunction in neonates and infants.

The ontogenetic framework onto which a child's sleep is constructed undergoes significant developmental alterations during early life. Sleep state behaviors, in large part, reflect continuities from fetal through neonatal time periods. Major changes in sleep organization subsequently occur throughout infancy. Maturational expressions of sleep behaviors must be understood by the pediatric neurologist before specific physiologic phenomena can be assessed as transient sleep disturbances or clinically relevant sleep disorders. The first part of this two-part review article focuses on the major aspects of developmental sleep physiology in the first few months of life. Recognition of age-specific electroencephalographic/polysomnographic patterns will facilitate the child neurologist's evaluation of the newborn with suspected seizures and interictal encephalopathies, as well as the prediction of neurologic sequelae.

Neonates with electrically confirmed seizures and possible placental associations.

Placental specimens were reviewed from 73 singleton pregnancies of women whose offspring received electroencephalogram (EEG) studies in the neonate period. A group of 43 neonates (postconception age [PCA] 23-44 weeks) with electrically confirmed seizures in the immediate neonate period were compared with 30 healthy preterm and term infants of comparable PCA who had no electrographic seizures. Pathologic placental changes were separated: Group A consisted of chorioamnionitis, edema, meconium staining, and/or retroplacental hematoma. Group B consisted of abnormal villous maturation, infarction, and/or chronic villitis. Logistic regression analyses calculated the odds ratio of having Group A or Group B placental lesions in each neonate group as a function of increasing PCA. For the seizure group, the odds of having Group B with or without Group A placental lesions increased by a factor of 1.2 for each postconception week up to 43 weeks PCA. For a 15-week interval the odds of having Group B lesions for the seizure group increased by a factor of 12.1 (P < 0.007). Ratios were not significant for Group A lesions alone in the seizure group or for either Group B or Group A findings in the neonate group without seizures. Pathophysiologic events in utero leading to Group B rather than Group A findings are associated with electrically confirmed seizures in near-term and term infants. Group A lesions were considered more likely to have intrapartum or peripartum associations, whereas Group B lesions were considered more likely to have antepartum associations.

Effects of prenatal substance exposure: altered maturation of visual evoked potentials.

We investigated the effects of prenatal substance use on visual evoked potentials (VEPs). Seventy-four children were tested at birth and 1 month of age with binocular flash VEPs and at 4, 8, and 18 months of age with binocular pattern VEPs. Regressions were run by trimester to assess the independent effects of substance exposure. Variables included in the regression model were alcohol, marijuana, tobacco, other drug use for each trimester, maternal age, education, income, race, marital status, infant sex, birthweight, and Dubowitz score. Changes in specific components of the binocular VEP were both substance- and trimester-specific. First trimester alcohol use was associated with prolonged P1 wave latencies at 1 month of age. Prolonged P1 wave latencies at birth and 18 months were associated with tobacco use during each of the three trimesters, at 1 and 18 months with third trimester marijuana use, and at 1 and 18 months with first trimester other illicit drug use. Although these women were moderate substance users during pregnancy, their offspring exhibited maturational changes in components of the VEP in the absence of neonatal behavioral disturbances.

Regional differences in spectral EEG measures between healthy term and preterm infants.

State-specific spectral electroencephalographic (EEG) values were compared among 14 bipolar channel derivations between two healthy neonatal cohorts. Fifty-five healthy preterm neonates of < or = 32 weeks gestational age at birth were studied with 24-channel recordings over 3 hours at term conceptional age. These were compared with studies of 45 healthy term neonates. Five spectral measures for each channel (i.e., total spectral EEG, delta, theta, alpha, and beta frequency ranges) were calculated for each minute, which was identified as active or quiet sleep, based on visual analysis. Using multivariate analysis of variance, differences at each channel were assessed between neonatal cohorts for both states and cohorts; higher total EEG spectral values were noted during active sleep; whereas higher delta and theta spectral values were noted during quiet sleep. The term cohort had higher values for spectral theta, alpha, and beta power spectra in multiple channels, most significantly in the left central (i.e., C3O1) and sagittal regions (FzCz, CzPz) during both states (P < .0001, adj r2 > or = .2). Both interhemispheric and intrahemispheric differences in spectral values were present. For a healthy preterm cohort, lower spectral energies are expressed during sleep in specific head regions. Physiologic asymmetries exist in the newborn brain which are unique for the preterm infant, emphasizing functional alterations in brain development. How these asymmetries are altered by prenatal or postnatal stress or disease states needs to be explored.