Divyen K. Shah

Adverse neurodevelopment in preterm infants with postnatal sepsis or necrotizing enterocolitis is mediated by white matter abnormalities on magnetic resonance imaging at term.

OBJECTIVES To test the hypothesis that the impact of postnatal sepsis/necrotizing enterocolitis (NEC) on neurodevelopment may be mediated by white matter abnormality (WMA), which can be demonstrated with magnetic resonance imaging (MRI). STUDY DESIGN A prospective cohort of 192 unselected preterm infants (gestational age <30 weeks), who were evaluated for sepsis and NEC, underwent imaging at term-equivalent age and neurodevelopmental outcome at 2 years corrected age with the Bayley Scales of Infant Development. RESULTS Sixty-eight preterm (35%) infants had 100 episodes of confirmed sepsis, and 9 (5%) infants had confirmed NEC. Coagulase-negative staphylococci accounted for 73% (73/100) of the episodes of confirmed sepsis. Infants with sepsis/NEC had significantly more WMA on MRI at term compared with infants in the no-sepsis/NEC group. They also had poorer psychomotor development that persisted after adjusting for potential confounders but which became nonsignificant after adjusting for WMA. CONCLUSIONS Preterm infants with sepsis/NEC are at greater risk of motor impairment at 2 years, which appears to be mediated by WMA. These findings may assist in defining a neuroprotective target in preterm infants with sepsis/NEC.

Accuracy of Bedside Electroencephalographic Monitoring in Comparison With Simultaneous Continuous Conventional Electroencephalography for Seizure Detection in Term Infants

OBJECTIVE. Our goals were to compare (1) single-channel amplitude-integrated electroencephalography alone, (2) 2-channel amplitude-integrated electroencephalography alone, and (3) amplitude-integrated electroencephalography plus 2-channel electroencephalography with simultaneous continuous conventional electroencephalography for seizure detection in term infants to check the accuracy of limited channels and compare the different modalities of bedside electroencephalography monitoring. METHODS. Infants referred to a tertiary center with clinical seizures underwent simultaneous continuous conventional electroencephalography and 2-channel (C3-P3 and C4-P4) bedside monitoring. Off-line analysis of the continuous conventional electroencephalographic results was performed independently by 2 neurologists. Two experienced neonatal readers reviewed results obtained with amplitude-integrated electroencephalography and 2-channel electroencephalography combined and single-channel and 2-channel amplitude-integrated electroencephalography. All readings were performed independently and then compared. RESULTS. Twenty-one term newborns were monitored. Seizures were detected in 7 patients who had up to 12 electrical seizures, with 1 infant in status epilepticus. Seizures were identified correctly in 6 of 7 patients with amplitude-integrated electroencephalography plus 2-channel electroencephalography. The missed infant had an isolated 12-second seizure. With amplitude-integrated electroencephalography plus 2-channel electroencephalography, 31 of 41 non–status epilepticus seizures were correctly identified (sensitivity, 76%; specificity, 78%; positive predictive value, 78%; negative predictive value, 78%), with a substantial level of interrater agreement. The seizures missed were predominantly slow sharp waves of occipital origin from a single patient (7 of 10 seizures). Nine false-positive results were obtained in 351 hours of recording (1 false-positive result per 39 hours). These were thought to be related to muscle, electrode, and patting artifacts. Use of amplitude-integrated electroencephalography alone (1 or 2 channel) provided low sensitivity (27%–56%) and low interobserver agreement. CONCLUSIONS. Limited-channel bedside electroencephalography combining amplitude-integrated electroencephalography with 2-channel electroencephalography, interpreted by experienced neonatal readers, detected the majority of electrical seizures in at-risk newborn infants.

Reduction in Cerebellar Volumes in Preterm Infants: Relationship to White Matter Injury and Neurodevelopment at Two Years of Age

A substantial number of prematurely born infants will experience later neurodevelopmental challenges. Abnormal development of the cerebellum may be related to some of the impairments exhibited by preterm children. To test the hypothesis that cerebellar development is structurally impaired in preterm infants and associated with adverse outcomes, we studied 83 preterm infants and 13 term controls using volumetric magnetic resonance imaging techniques to obtain cerebellar volumes (CV) at term corrected and subsequent neurodevelopmental assessment at 2 y of age. The preterm group had smaller mean CV at term compared with the term control infants [mean (SD) CV, 22.0 (5.0) versus 23.5 (5.0) cc; mean difference (95% confidence interval), 1.5 (–1.5, 4.4)] although this did not reach statistical significance. Within the preterm group, there was evidence of a reduction in CV related to the presence of white matter injury (WMI) after adjusting for intracranial volume (ICV) [WMI grade 1 versus grade 2: mean (SD) CV, 23.6 (5.0) versus 21.6 (4.5); p = 0.01; WMI grade 1 versus grade 3 and 4: 23.6 (5.0) versus 20.8 (5.6); p = 0.07]. Within the preterm infants, there was no apparent relationship between CV at term and gestational age at birth after adjusting for ICV. At 2 y of age, CV showed a weak correlation with cognitive and motor development, although this was principally mediated by WMI. In conclusion, we found no evidence for a primary impairment in cerebellar development in relation to prematurity, although there was evidence for a secondary effect of cerebral WMI on cerebellar development independent of immaturity.

Electrographic seizures are associated with brain injury in newborns undergoing therapeutic hypothermia

Objective Seizures are common among newborns with hypoxic-ischaemic encephalopathy (HIE) but the relationship between seizure burden and severity of brain injury among neonates receiving therapeutic hypothermia (TH) for HIE is unclear. We tested the hypothesis that seizure burden is associated with cerebral tissue injury independent of amplitude-integrated EEG (aEEG) background activity. Study design Term neonates undergoing 72 h of TH at four centres were selected for study if they had continuous aEEG and MRI. The aEEG with corresponding 2-channel raw EEG (aEEG/EEG), was classified by severity of background and seizure burden; MR images were classified by the severity of tissue injury. Results Of 85 neonates, 52% had seizures on aEEG/EEG. Overall, 35% had high seizure burden, 49% had abnormal aEEG background in the first 24 h and 36% had severe injury on MRI. Seizures were most common on the first day, with significant recurrence during and after rewarming. Factors associated with severe injury on MRI were high seizure burden, poor aEEG background, 10 min Apgar and the need for more than one anticonvulsant. In multivariate logistic regression, high seizure burden was independently associated with greater injury on MRI (OR 5.00, 95% CI 1.47 to 17.05 p=0.01). Neither aEEG background, nor 10 min Apgar score were significant. Conclusions Electrographic seizure burden is associated with severity of brain injury on MRI in newborns with HIE undergoing TH, independent of degree of abnormality on aEEG background. Seizures are common during cooling, particularly on day 1, with a significant rebound on day 4.

Electrographic Seizures in Preterm Infants During the First Week of Life Are Associated With Cerebral Injury

The aim of the study was to determine the incidence of electrographic seizure activity in a prospective cohort of preterm infants and relate it to the presence of cerebral injury. Infants born <30-wk gestation received a median 74 h of continuous 2-channel EEG with amplitude-integrated EEG monitoring in the first week of life. Infants were classified in the abnormal outcome group if they died in the neonatal period and/or had grades 3–4 intraventricular hemorrhage and/or moderate or severe abnormalities on cerebral MRI. Seizures were defined as rhythmic spike and/or wave activity lasting at least 10 s on the raw EEG trace. Eleven of 51 infants monitored had electrographic seizures. These infants were more premature had lower birth weights and a greater proportion had abnormal outcomes. In four infants, seizures preceded ultrasound findings of grades 3–4 intraventricular hemorrhage. Three of the four infants with seizures and concurrent physiologic recordings displayed concurrent rises in heart rate and one showed a fall in respiratory rate. In conclusion, electrographic seizures were more likely to occur in the sicker and more premature infants with abnormal outcomes. Seizures detected on continuous amplitude-integrated EEG monitoring with the raw EEG were associated with poor outcome.

Use of 2-Channel Bedside Electroencephalogram Monitoring in Term-Born Encephalopathic Infants Related to Cerebral Injury Defined by Magnetic Resonance Imaging

OBJECTIVE. Single-channel amplitude-integrated electroencephalography has been shown to be predictive of neurodevelopmental outcome in term infants with hypoxic-ischemic encephalopathy. We describe the relationship of quantifiable electroencephalogram (EEG) measures, obtained using a 2-channel digital bedside EEG monitor from term newborn infants with encephalopathy and/or seizures, to cerebral injury defined qualitatively by MRI. METHODS. Median values of minimum, mean, and maximum EEG amplitude were obtained from term-born encephalopathic infants during a 2-hour seizure-free period obtained within 72 hours of admission. Infants underwent MRI with images qualitatively scored for abnormalities of cortex, white matter, deep nuclear gray matter, and posterior limb of the internal capsule. Eighty-six infants had EEG measures related to qualitative MRI outcomes. RESULTS. The most common diagnosis was hypoxic ischemic encephalopathy (n = 40). For all infants there was a negative relationship between EEG amplitude measures and MRI abnormality scores assessed on a scale from 4 to 15, with a higher score indicating more abnormalities. This relationship was strongest for the minimum amplitude measures in both hemispheres; that is, for every unit increase in score there was a mean drop of 0.41 μv for the left cerebral hemisphere, with 35% of variance explained. This relationship persisted on sub-group analyses for infants with hypoxic-ischemic encephalopathy, infants with other diagnoses and infants monitored after the first 24 hours of life. Using an MRI abnormality score cutoff of 8 or worse for cerebral injury in infants with hypoxic-ischemic encephalopathy, a minimum amplitude of 4 μV showed a higher specificity (80%: left hemisphere), whereas a minimum amplitude of 6 μV showed a higher sensitivity (92%: left hemisphere). CONCLUSIONS. Bedside EEG measures in term-born encephalopathic infants are related to the severity of cerebral injury as defined by qualitative MRI. A minimum amplitude of <4 μV appears useful in predicting outcome.

Amplitude-Integrated Electroencephalography in the Newborn : A Valuable Tool

The use of amplitude-integrated electroencephalography (aEEG) for research and clinical use in the newborn infant has increased over the last 2 decades. However, with this increased use, concerns have been expressed about (1) the accuracy and reliability of the interpretation of aEEG by neonatal clinicians and (2) the lack of evidence of benefit from aEEG monitoring for the infant.1 As early as 1994, Greisen2 noted that lack of knowledge of whether and when to act on the information obtained with aEEG, rather than the technology itself, limited the usefulness of this technique in the newborn. The aims of this commentary are to address these concerns by first reviewing the historical context in which the aEEG was developed and then summarizing current evidence on the use of aEEG in the newborn. aEEG is not a new technology. The cerebral function monitor (CFM) was devised by Dr Douglas Maynard and its clinical potential was explored by Dr Pamela Prior in the 1960s as a means of monitoring cerebral function in adults undergoing bypass surgery and after resuscitation.3,4 With its time-compressed output, the CFM provided a simpler and cheaper means of following trends in cerebral function in the ICU and the operating room without the need for experienced technicians for application, voluminous recordings, and expertise in interpretation for the, then, analog conventional EEG systems. The electrode placement over the parietal areas (P3–P4 in the 10–20 system) was designed so as to be in close proximity to the vulnerable “watershed” regions of the brain in the border zones of arterial blood supply from all 3 cerebral arteries. This position also minimized artifacts from sweating, muscle activity, and eyelid … Address correspondence to Divyen K. Shah, MB, ChB, Washington University, Department of Pediatrics, 8th Floor, NW Tower, 1 Childrens Place, St Louis, MO 63110. E-mail: shah_d{at}kids.wustl.edu

Monitoring of seizures in the newborn

Neonatal seizures are a distinct and not uncommon sign of neurological disease in the newborn, most often occurring in association with hypoxic-ischaemic encephalopathy at term. The diagnosis and monitoring of seizures in the newborn is a considerable challenge, with many suspected clinical seizures having no electrographic correlates, while many electrographic seizures have no clinical correlate. Continuous video-EEG is the gold standard for seizure monitoring, but few centres have the resources or expertise required. Amplitude-integrated EEG can be a helpful monitoring tool in experienced hands, but has potential for error when used by inexperienced staff. Automated seizure detection algorithms show much promise and some cotside systems are already available. The efficiency and accuracy of these systems is likely to improve.

Single versus bihemispheric amplitude-integrated electroencephalography in relation to cerebral injury and outcome in the term encephalopathic infant

Background:  The demand for early diagnosis and prognostication of cerebral injury in the encephalopathic term infant is increasing to facilitate appropriate management. The single‐channel amplitude‐integrated electroencephalogram (S‐aEEG) has been shown to have predictive utility for the severely encephalopathic infant. New bedside aEEG devices with more channels are entering the neonatal environment. Little data are available to compare the utility of two channels (B‐aEEG) with that of an S‐aEEG recording.

Automated electroencephalographic discontinuity in cooled newborns predicts cerebral MRI and neurodevelopmental outcome

Background and hypothesis Prolonged electroencephalographic (EEG) discontinuity has been associated with poor neurodevelopmental outcomes after perinatal asphyxia but its predictive value in the era of therapeutic hypothermia (TH) is unknown. In infants undergoing TH for hypoxic-ischaemic encephalopathy (HIE) prolonged EEG discontinuity is associated with cerebral tissue injury on MRI and adverse neurodevelopmental outcome. Method Retrospective study of term neonates from three UK centres who received TH for perinatal asphyxia, had continuous two channel amplitude-integrated EEG with EEG for a minimum of 48 h, brain MRI within 6 weeks of birth and neurodevelopmental outcome data at a median age of 24 months. Mean discontinuity was calculated using a novel automated algorithm designed for analysis of the raw EEG signal. Results Of 49 eligible infants, 17 (35%) had MR images predictive of death or severe neurodisability (unfavourable outcome) and 29 (59%) infants had electrographic seizures. In multivariable logistic regression, mean discontinuity at 24 h and 48 h (both p=0.01), and high seizure burden (p=0.05) were associated with severe cerebral tissue injury on MRI. A mean discontinuity >30 s/min-long epoch, had a specificity and positive predictive value of 100%, sensitivity of 71% and a negative predictive value of 88% for unfavourable neurodevelopmental outcome at a 10 µV threshold. Conclusions In addition to seizure burden, excessive EEG discontinuity is associated with increased cerebral tissue injury on MRI and is predictive of abnormal neurodevelopmental outcome in infants treated with TH. The high positive predictive value of EEG discontinuity at 24 h may be valuable in selecting newborns with HIE for adjunctive treatments.