Off-label use of antiepileptic drugs for the treatment of neonatal seizures

Medically refractory neonatal seizures represent a major therapeutic challenge in neonatal intensive care units. Conventional antiepileptic drugs demonstrate limited efficacy. Previous studies documented a high frequency of off-label drug therapy in neonates. We sought to determine if pediatric neurologists are recommending treatment of neonatal seizures with newer agents, despite a lack of information about their safety or efficacy in this population. Surveys were distributed at the 2007 Annual Meeting of the Child Neurology Society. Responses from 55 pediatric neurologists were analyzed. Seventy-three percent (40/55) recommended treatment of neonatal seizures with one or both of levetiracetam and topiramate; 47% (26/55) recommended levetiracetam; and 55% (30/55) recommended topiramate. Despite an absence of data on neonatal pharmacokinetics of either drug, neurologists made different dosing recommendations for these two drugs (P = 0.003, chi-square test). Respondents considered both agents to be efficacious in the majority of cases; adverse effects were recognized more frequently with topiramate. These results highlight the urgent need for rigorous clinical trials to understand the risks and benefits of new drug therapies for neonatal seizures.     

Autism Spectrum Disorder in a Term Birth Neonatal Intensive Care Unit Population

BackgroundNonspecific perinatal risk factors have been revealed to be associated with the development of autism spectrum disorder. However, term at-risk infants, as a distinct population, are underrepresented in the literature. This study examines the incidence and neonatal risk factors for autism spectrum disorder in term neonatal intensive care unit survivors.MethodsWe performed a retrospective analysis from a single university-practice database of neonates admitted to the neonatal intensive care unit and followed by a single pediatric neurologist. Term infants (≥37 weeks), born between 1991 and 2011, with at least 2 years (or 1 year if found to be neurologically normal) of follow-up were included. Principle outcomes were autism spectrum disorder, cerebral palsy, global developmental delay, and epilepsy.ResultsOne hundred eighty infants were included from a database of 564 neonates. Twelve (6.6%) developed autism spectrum disorder, 53 (29.4%) cerebral palsy, 77 (42.7%) global developmental delay, and 47 (26.1%) epilepsy. Seventy-one (39.4%) developed no adverse outcomes. Nine patients with autism spectrum disorder (75%) were diagnosed with at least one other adverse outcome. No neonatal or perinatal variables were evident to be significantly associated with later autism spectrum disorder.ConclusionsIn term neonatal intensive care unit survivors, autism spectrum disorder occurs at a greater frequency than in the general population and often develops alongside comorbid conditions. This highlights the importance of screening term neonatal intensive care unit survivors for autism spectrum disorder, particularly when comorbidities are present.     

Quo vadis 2010? - carpe diem: challenges and opportunities in pediatric traumatic brain injury

Traumatic brain injury (TBI) in infants and children remains a public health problem of enormous magnitude. It is a complex and heterogeneous condition that presents many diagnostic, therapeutic and prognostic challenges. A number of investigative teams are studying pediatric TBI both in experimental models and in clinical studies at the bedside. This review builds on work presented in a prior supplement to Developmental Neuroscience that was published in 2006, and addresses several active areas of research on this topic, including (1) the application of novel imaging methods, (2) the use of serum and/or CSF biomarkers of injury, (3) advances in neuromonitoring, (4) the development and testing of novel therapies, (5) developments in modeling pediatric TBI, (6) the consideration of a new approach to classification of pediatric TBI, and (7) assessing the potential impact of the development of pediatric and neonatal neurocritical care services on the management and outcome of pediatric TBI.     

Neurodevelopmental outcomes of premature infants at a tertiary care center in Pakistan

The low gestational ages and morbidities of premature neonates in neonatal intensive care units exert a significant impact on neurodevelopmental outcomes. This longitudinal cohort study assessed the neurodevelopmental status of premature neonates after discharge from neonatal intensive care units in resource-limited countries such as Pakistan. Developmental assessment involved the Denver Development Screening Test II. One hundred and ten infants discharged from our neonatal intensive care unit completed follow-up at age 6 months. Overall developmental delay was evident in 32% of infants. Birth weight and gestational age exerted significant impacts on development. The mean gestational age of developmentally normal infants was 34 weeks, whereas that of delayed infants was 30.7 weeks (P < 0.01). The mean birth weight of developmentally normal infants was 2.17 kg vs 1.27 kg in delayed infants (P < 0.01). Neonates who developed complications such as respiratory distress syndrome, intraventricular hemorrhage, thrombocytopenia, hypoglycemia, hyponatremia, or hypothermia in neonatal intensive care units proved to be delayed at age 6 months (P < 0.05). Prematurity and its associated complications are linked to adverse neurodevelopmental outcomes.     

Patterns of cerebral injury in a primate model of preterm birth and neonatal intensive care

Very preterm birth is associated with significant neurodevelopmental morbidity, with 10% to 15% of these infants later developing cerebral palsy and up to 50% experiencing learning disabilities. The nature of the cerebral lesion predisposing these infants to such impairments is not fully understood but is likely related to both cerebral injury and alterations in cerebral development associated with neonatal intensive care. To study the impact of both preterm birth and neonatal intensive care on the immature brain, we are studying a preterm primate model delivered at 125 days of a 184-day gestational period and cared for in a neonatal intensive care unit for 2 to 4 weeks in a fashion highly similar to that for human preterm infants. The most common neuropathology in this model is white-matter damage manifested by reactive astrogliosis or activated microglia and enlarged ventricular size. Subarachnoid, germinal matrix, and intraventricular hemorrhages are also common. These preliminary results support the similarity of this model to both the alterations in cerebral developmental and the pattern of cerebral injury found in human preterm infants. We are now investigating the impact of randomized respiratory therapies on the pattern of cerebral injury. The prematurely born baboon appears to be an accurate and relevant model for the study of preterm human birth.     

Candida tropicalis brain abscess in a neonate: An emerging nosocomial menace

Fungi are a relatively uncommon cause of brain abscess in neonates and early infancy. They are usually associated with predisposing factors like prematurity, low birth weight, use of broad-spectrum antibiotics, and prolonged stay in the intensive care unit. Candida tropicalis (C. tropicalis) is rapidly emerging as a nosocomial threat in the neonatal intensive care settings. This case report describes a neonate with C. tropicalis brain abscess who was diagnosed early and managed aggressively with a favorable outcome. Inadvertent use of intravenous antibiotics can have serious complications such as invasive fungal infection. Correct microbiological diagnosis is the key to successful treatment of deep-seated pyogenic infection. Fungal etiology should always be studied in relevant clinical settings.     

Automated EEG-sleep analyses and neonatal neurointensive care

Clinical applications of neonatal EEG-sleep studies can improve neurointensive care for preterm and fullterm infants. Behavioral and physiologic assessments of neonatal sleep by nursing and physician personnel can result in more developmentally appropriate state regulation for infants, particularly for those who require medical care for many weeks to months in the intensive care unit. Secondly, prediction of altered expressions of EEG-sleep patterns for those children at higher risk for neurological sequelae can anticipate the need for aggressive interventional strategies. The application of digital analyses of specific cerebral and noncerebral physiologic measures for long-term monitoring periods can utilize efficient and novel strategies of automated EEG and sleep state identification which can also assist in daily medical care and prediction of neurodevelopmental outcome.     

The effects of alternative positioning on preterm infants in the neonatal intensive care unit: A randomized clinical trial

There is a paucity of studies that have investigated the developmental benefits of positioning in the neonatal intensive care unit. The purpose of this study was to investigate the effects of a new, alternative positioning device compared to traditional positioning methods used with preterm infants. In this randomized, blinded clinical trial, one hundred preterm infants (born ≤32 weeks gestation) from a level III neonatal intensive care unit in the United States were enrolled at birth. Participants were randomized to be positioned in the alternative positioning device or to traditional positioning methods for their length of stay in the neonatal intensive care unit. Infants were assessed using the NICU Network Neurobehavioral Scale between 35-40 weeks postmenstrual age. Clinical and feeding outcomes were also captured. Linear and logistic regressions were used to investigate differences in neurobehavioral outcome, feeding performance, and medical outcomes. Infants in the alternative positioning arm of the study demonstrated less asymmetry of reflex and motor responses on the NICU Network Neurobehavioral Scale (p = 0.04; adjusted mean difference = 0.90, 95% CI 0.05–1.75) than those positioned using traditional positioning methods. No other significant differences were observed. Reduction in asymmetry among preterm infants is an important benefit of alternative positioning, as symmetrical movement and responses are crucial for early development. However, it will be important to follow this sample of preterm infants to determine the effects of early positioning on neurodevelopmental outcome in childhood.     

Therapies for multiple sclerosis: considerations in the pediatric patient

Current and emerging therapies for multiple sclerosis (MS) offer promise for improved disease control and long-term clinical outcome. To date, these therapies have been evaluated solely in the context of adult MS. However, onset of MS in children is being increasingly recognized, and recent studies have identified a significant impact of MS onset during childhood on cognitive and physical functioning. Optimization of pediatric MS care requires that promising new therapies be made available to children and adolescents, but also that safety and tolerability and potential influence of therapies on the developing immune and neural networks of pediatric patients be closely considered. We propose care algorithms illustrating models for therapy that detail careful monitoring of pediatric patients with MS, provide definitions for inadequate treatment response and treatment escalation, and foster multinational collaboration in future therapeutic trials.     

Treatments with midazolam and lidocaine for status epilepticus in neonates

Status epilepticus (SE) occurs in children of all ages. Recent epidemiologic investigations of SE show heightened morbidity and mortality in newborns and young infants. However, the existing definition of SE in newborns is not precise and not easily applied in clinical investigations or in clinical practice. To evaluate the underlying conditions, clinical features and treatment of SE in neonates in Japan, a retrospective multi-center study was performed. In the initial investigation, questionnaires were sent to pediatric neurologists in 194 neonatal intensive care units of university hospitals, children's hospitals, and general hospitals throughout in Japan. The questionnaires sought information on the background of each case, types of seizures, etiology of SE, treatments, results and adverse effects of treatment for patients less than 1 week old who had prolonged or frequently repeated seizures lasting more than 15 min and who are refractory to treatment with conventional anticonvulsants, such as diazepam (DZP), phenobarbital (PB) or phenytoin (PHT). As a secondary investigation, 65 cases from nine institutes, which completely fulfilled these criteria and were treated with midazolam (MDL) or lidocaine (Lid) to stop seizures were examined more fully. Subtle seizure and generalized tonic-clonic seizure were the most frequent seizure types. Neonatal SE was most frequently associated with hypoxic-ischemic encephalopathy, followed by intraventricular hemorrhage, central nervous system infections, and cerebral infarction. The final treatment outcome was available for 72.7% and 81.3% of MDL- and Lid-treated patients, respectively. Adverse effects of MDL and Lid were identified in 7.3% and 6.3% of patients, respectively. To reveal electroclinical seizures, clinical seizures without ictal discharge or other non-epileptic movements in neonates was important for appropriate treatment. MDL and Lid were useful drugs for the treatment of neonatal SE.     

Neurodevelopmental assessment of the newborn: An opportunity for prediction of outcome

Over the decades, the evolution of neonatology has been a continuum. After intense focus on cardiac and respiratory support, now more time, effort and research are concerned about brain development of the term and preterm infants. There is no single standardized neurodevelopmental assessment tool that can be advocated for infants in the neonatal intensive care unit. The tools that are currently available vary in their physiological bases, pre requisite training and expertise, time allotted to perform and score, and clinical utility and validity. In this communication, we describe the neurobehavioral and sensory capabilities of the neonate. We then compare the commonly used neurobehavioral examinations with an emphasis on premature infants. We envision this effort as an essential step before the development of a universal and comprehensive assessment tool.     

Amplitude-integrated EEG is useful in predicting neurodevelopmental outcome in full-term infants with hypoxic-ischemic encephalopathy: a meta-analysis

Hypoxic ischemic encephalopathy is a common cause of neurological complications resulting in chronic handicapping conditions, such as cerebral palsy. Amplitude-integrated electroencephalography (EEG) has been used in many European countries for more than a decade in the evaluation of infants with hypoxic ischemic encephalopathy but has not been widely used in the United States. The objective of this study was to evaluate the evidence supporting use of amplitude-integrated EEG as a quantitative predictor of neurodevelopmental outcome in full-term infants with hypoxic ischemic encephalopathy. To assess efficacy, the authors performed a meta-analysis of the literature evaluating the use of the amplitude-integrated EEG or cerebral function monitor in full-term infants with hypoxic ischemic encephalopathy and their neurodevelopmental outcome. A total of 8 studies were eligible for the primary meta-analysis. There was an overall sensitivity of 91% (95% CI 87-95) and a negative likelihood ratio of 0.09 (95% CI .06-.15) for amplitude-integrated EEG tracings to accurately predict poor outcome. Amplitude-integrated EEG is a valuable bedside tool for predicting long-term neurodevelopmental outcome in term infants with hypoxic ischemic encephalopathy. This information is useful in structuring communication and care plans for physicians and parents. Early assessment techniques such as amplitude-integrated EEG provide objective means for determining inclusion in clinical studies evaluating therapies for hypoxic ischemic encephalopathy and for predicting which patients are most likely to respond to treatment.     

Active head lifting from supine in early infancy: an indicator for non-optimal cognitive outcome in late infancy

Aim To explore whether active head lifting from supine (AHLS) in early infancy is associated with cognitive outcome in the second year of life. Method The presence of AHLS was always recorded in the notes of infants admitted to our tertiary neonatal intensive care unit. Random sampling was used to pair infants with AHLS with two comparison infants without AHLS whose sex, gestational age, birth year (1993–2009), time of assessment, and developmental test (Griffiths Mental Development Scales, Mental Scale of the Bayley Scales of Infant Development‐II, or cognitive subtest of the Bayley Scales of Infant and Toddler Development‐III) were comparable. Brain injury identified from neonatal cranial ultrasound scans was classified as no – mild or moderate – severe. Z‐scores of cognitive test outcomes were calculated for multivariable analysis. Results Eighty‐seven preterm (34 males, 53 females) and 40 term (17 males, 23 females) infants with AHLS were identified. AHLS was documented at a mean (corrected) age of 7.0 (SD 1.7) and 8.1 (SD 2.2) months respectively. The cognitive assessments were performed at a mean corrected age of 15.7 (SD 1.7) and 23.9 (SD 1.6) months in preterm infants, and 19.1 (SD 2.3) months in term infants. The mean cognitive outcome of preterm and term infants with AHLS was lower than that of infants without AHLS (p=0.002 and p=0.004 respectively). This remained after excluding infants with cerebral palsy with matching comparison infants (p=0.001 in preterm and p=0.001 in term infants). The mean difference was highest (1.35SD) between term male infants and comparison infants (p=0.001). Interpretation AHLS is associated with a less favourable cognitive outcome in the second year of life in preterm as well as in term‐born infants than in comparison infants.     

Transient periventricular echodensities and developmental outcome in preterm infants

The outcome of very low–birth-weight infants is reported in relation to neonatal cerebral ultrasound findings. Routine cerebral ultrasound scans were performed in all 147 very low–birth-weight infants admitted to the authors’ neonatal intensive care unit from January 1995 to June 1997. Group 1 consisted of 22 infants without ultrasound abnormalities, group 2 consisted of 32 infants with transient periventricular echodensities, and group 3 consisted of 15 infants with intraventricular hemorrhage. Neurologic status was recorded at follow-up visits at the corrected age of 6 and 12 months, and the infants were evaluated further using the Bayley Scales of Infant Development II. More infants in groups 2 and 3 appeared to have significant and mild motor developmental delays than infants in the control group (group 1) at the corrected age of 1 year (P = 0.001). Furthermore, more infants in group 3 appeared to have significant motor developmental delays than did infants in group 2 at the corrected age of 1 year (15% vs 3%). Infants with transient periventricular echodensities and intraventricular hemorrhage have an increased risk of delayed developmental outcome. Infants with transient periventricular echodensities have a more favorable prognosis than do the infants with intraventricular hemorrhage.     

Invited Review: Factors associated with atypical brain development in preterm infants: insights from magnetic resonance imaging

Preterm birth (PTB) is a leading cause of neurodevelopmental and neurocognitive impairment in childhood and is closely associated with psychiatric disease. The biological and environmental factors that confer risk and resilience for healthy brain development and long-term outcome after PTB are uncertain, which presents challenges for risk stratification and for the discovery and evaluation of neuroprotective strategies. Neonatal magnetic resonance imaging reveals a signature of PTB that includes dysconnectivity of neural networks and atypical development of cortical and deep grey matter structures. Here we provide a brief review of perinatal factors that are associated with the MRI signature of PTB. We consider maternal and foetal factors including chorioamnionitis, foetal growth restriction, socioeconomic deprivation and prenatal alcohol, drug and stress exposures; and neonatal factors including co-morbidities of PTB, nutrition, pain and medication during neonatal intensive care and variation conferred by the genome/epigenome. Association studies offer the first insights into pathways to adversity and resilience after PTB. Future challenges are to analyse quantitative brain MRI data with collateral biological and environmental data in study designs that support causal inference, and ultimately to use the output of such analyses to stratify infants for clinical trials of therapies designed to improve outcome.     

Value of biochemical markers for outcome in term infants with asphyxia

The aim of this study was to define the predictive values of serum and cerebrospinal fluid concentrations of interleukin-6 and neuron-specific enolase and urinary uric acid/creatinine ratio for outcome in term infants with perinatal asphyxia. All biochemical markers were measured simultaneously within the 24-72 hours of life in 21 infants. The infants were monitored with a standardized neurologic and developmental evaluation protocol over the 2 years of life. The overall outcome at 2 years of age was categorized as "favorable" or "adverse". According to Sarnat and Sarnat classification, 12 infants had mild encephalopathy and 9 infants had moderate to severe encephalopathy. Seven of 9 (78%) infants with moderate to severe encephalopathy had adverse outcome. However, all infants with mild encephalopathy had favorable outcome. Interleukin-6 and neuron specific enolase levels in cerebrospinal fluid and serum interleukin-6 levels were significantly correlated with the degree of encephalopathy, as well as the outcome. Interleukin-6 in cerebrospinal fluid (cutoff value, 25.9 pg/mL) had the highest predictive value among the biochemical markers. The predictive factors identified in this study should be examined for their ability in a fresh clinical sample in the neonatal intensive care unit before these markers can be applied to the routine clinical of infants with perinatal asphyxia.     

A systematic review of the effects of early intervention on motor development

We present a systematic review on the effect of early intervention, starting between birth and a corrected age of 18 months, on motor development in infants at high risk for, or with, developmental motor disorders. Thirty-four studies fulfilled the selection criteria. Seventeen studies were performed within the neonatal intensive care unit (NICU) environment. Eight studies had a high methodological quality. They evaluated various forms of intervention. Results indicated that the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) intervention might have a temporary positive effect on motor development. Twelve of the 17 post-NICU studies had a high methodological quality. They addressed the effect of neurodevelopmental treatment (NDT) and specific or general developmental programmes. The results showed that intervention in accordance with the principles of NDT does not have a beneficial effect on motor development. They also indicated that specific or general developmental programmes can have a positive effect on motor outcome. We concluded that the type of intervention that might be beneficial for infants at preterm age differs from the type that is effective in infants who have reached at least term age. Preterm infants seem to benefit most from intervention that aims at mimicking the intrauterine environment, such as NIDCAP intervention. After term age, intervention by means of specific or general developmental programmes has a positive effect on motor development.     

Outcomes in pediatric patients with nonconvulsive status epilepticus

Recognition of nonconvulsive status epilepticus (NCSE) is gaining increasing attention in the assessment and evaluation of critically ill pediatric patients. The underlying cause of NCSE is often the most important factor in determining outcome. However, there is a growing body of literature suggesting that electrical seizure burden in NCSE also contributes to unfavorable outcomes. Determination of impact of NCSE on outcome based on current evidence involves consideration of heterogeneous study settings, study populations, and process of care and outcome measures. In addition, the lack of data on neurocognitive function prior to episodes of NCSE as well as limited long-term neurocognitive assessment data confines precise conclusions about neurocognitive changes.This article is part of a Special Issue entitled “Status Epilepticus”.     

Outcome in neonates with convulsions treated in an intensive care unit

Neurological and developmental outcome was assessed in 131 survivors of neonatal seizures aged 1 to 5 years who had been treated in a single intensive care unit from 1976 to 1979. Half the children had been born at less than 37 weeks' gestational age, and 28% at 31 weeks or less. Fifty-one children were normal on examination, 17 had minor abnormalities, 25 had moderate disabilities, 30 had severe disabilities, 6 had died because of profound neurological deficits, and 2 could not be located. Recurrent nonfebrile seizures had developed in 26 children. Most children with motor handicaps or visual loss were intellectually retarded, but 10 of 15 children with bilateral hearing loss were intellectually normal. Of 77 children whose seizures were caused by a hypoxic-ischemic insult, 41 developed moderate or severe disabilities. As determined by multivariate analysis, significant neonatal predictors of poor outcome in this group included seizures with late onset, tonic seizures, and seizures lasting for many days. Although seizure frequency and neonatal mortality associated with seizures were greatest in very premature infants, the outcome in premature infants who survived was not significantly different from that of term infants.     

Use of the ketogenic diet in the neonatal intensive care unit—Safety and tolerability

Drug‐resistant epilepsy poses a challenge in neonatal patients, especially those in the neonatal intensive care unit (NICU), who have various secondary comorbidities. We present results of four children with a history of drug‐resistant epilepsy for whom a ketogenic diet was initiated and used in the NICU. A nonfasting induction into ketosis over 1–2 weeks was utilized, with gradual increases in the ketogenic ratio every 2–3 days. Data were collected retrospectively from a database, which included medical history, daily progress notes, relevant laboratory data, and imaging and diagnostic information. The ketogenic diet was well tolerated in all cases. The most common side effects observed were constipation, hypoglycemia, and weight loss. Serum β‐hydroxybutyrate levels demonstrated improved reliability as a marker of ketosis when compared to urine ketones in this population. Perceived benefits to the infants included improved seizure control, increased alertness, and decreased need for invasive respiratory support. These cases demonstrate that the use of the ketogenic diet for treatment of neonatal encephalopathy and refractory epilepsy can be undertaken safely in the NICU and is well tolerated by carefully screened neonates and infants.