Restricted diffusion of the callosal splenium is highly specific for seizures in neonates.

BACKGROUND: To determine whether restricted diffusion of the callosal splenium is specific for seizure activity in neonates. METHODS: We performed a retrospective chart review of 123 neonates who had a diagnosis of hypoxic ischemic encephalopathy (HIE) who underwent therapeutic cooling and had magnetic resonance imaging (MRI) within the first 10 days of life. The regions examined for injury include the callosal splenium, cortex, deep gray matter, and subcortical white matter. Neurodevelopmental outcomes were secondarily assessed using the Bayley Scales of Infant Development at 12 to 18 months of age and > 18 months of age. APGAR scores and pH, two important markers of hypoxia/ischemia and encephalopathy, were also analyzed in relation to these outcomes. RESULTS: Approximately 41% of the neonates had at least one abnormal region on brain MRI, and 21% had abnormal signal in the splenium. Clinical and/or electrographic seizures were documented in 32%. Changes in the splenium had a sensitivity of 54%, specificity of 94%, and positive predictive value of 81% for seizure presence. The presence of seizures and splenium lesion was associated poor developmental outcomes at 12 to 18 months of age. APGAR scores at 10 minutes, but not lowest pH was associated with splenial changes. CONCLUSIONS: Restricted diffusion of the callosal splenium is specific for recent seizures in neonates with HIE. Seizures and splenial lesion represent risk factors for poor neurodevelopmental outcomes. Child neurologists and neonatologists should consider splenial signal abnormality in their assessment of neonates at risk for seizures and counsel families about likely outcomes accordingly.

Optical Flow Estimation Improves Automated Seizure Detection in Neonatal EEG.

PURPOSE: Existing automated seizure detection algorithms report sensitivities between 43% and 77% and specificities between 56% and 90%. The algorithms suffer from false alarms when applied to neonatal EEG because of the high degree of nurse handling and rhythmic patting used to soothe neonates. Computer vision technology that quantifies movement in real time could distinguish artifactual motion and improve automated neonatal seizure detection algorithms. METHODS: The authors used video EEG recordings from 43 neonates undergoing monitoring for seizures as part of the NEOLEV2 clinical trial. The Persyst neonatal automated seizure detection algorithm ran in real time during study EEG acquisitions. Computer vision algorithms were applied to extract detailed accounts of artifactual movement of the neonate or people near the neonate though dense optical flow estimation. RESULTS: Using the methods mentioned above, 197 periods of patting activity were identified and quantified, of which 45 generated false-positive automated seizure detection events. A binary patting detection algorithm was trained with a subset of 470 event videos. This supervised detection algorithm was applied to a testing subset of 187 event videos with 8 false-positive events, which resulted in a 24% reduction in false-positive automated seizure detections and a 50% reduction in false-positive events caused by neonatal care patting, while maintaining 11 of 12 true-positive seizure detection events. CONCLUSIONS: This work presents a novel approach to improving automated seizure detection algorithms used during neonatal video EEG monitoring. This artifact detection mechanism can improve the ability of a seizure detector algorithm to distinguish between artifact and true seizure activity.

Cost Efficacy of Rapid Whole Genome Sequencing in the Pediatric Intensive Care Unit.

The diagnostic and clinical utility of rapid whole genome sequencing (rWGS) for critically ill children in the intensive care unit (ICU) has been substantiated by multiple studies, but comprehensive cost-effectiveness evaluation of rWGS in the ICU outside of the neonatal age group is lacking. In this study, we examined cost data retrospectively for a cohort of 38 children in a regional pediatric ICU (PICU) who received rWGS. We identified seven of 17 patients who received molecular diagnoses by rWGS and had resultant changes in clinical management with sufficient clarity to permit cost and quality adjusted life years (QALY) modeling. Cost of PICU care was estimated to be reduced by $184,846 and a total of 12.1 QALYs were gained among these seven patients. The total cost of rWGS for patients and families for the entire cohort (38 probands) was $239,400. Thus, the net cost of rWGS was $54,554, representing $4,509 per QALY gained. This quantitative, retrospective examination of healthcare utilization associated with rWGS-informed medicine interventions in the PICU revealed approximately one-third of a QALY gained per patient tested at a cost per QALY that was approximately one-tenth of that typically sought for cost-effective new medical interventions. This evidence suggests that performance of rWGS as a first-tier test in selected PICU children with diseases of unknown etiology is associated with acceptable cost-per-QALY gained.

Does the first hour of continuous electroencephalography predict neonatal seizures?

OBJECTIVE: Prolonged continuous video-electroencephalography (cEEG) is recommended for neonates at risk of seizures. The cost and expertise required to provide a real-time response to detected seizures often limits its utility. We hypothesised that the first hour of cEEG could predict subsequent seizures. DESIGN AND SETTING: Retrospective multicentre diagnostic accuracy study. PATIENTS: 266 term neonates at risk of seizure or with suspected seizures. INTERVENTION: The first hour of cEEG was graded by expert and novice interpreters as normal, mildly, moderately or severely abnormal; seizures were identified. MAIN OUTCOME MEASURES: Association between abnormalities in the first hour of cEEG and the presence of seizures during total cEEG monitoring. RESULTS: 50/98 (51%) of neonates who developed seizures had their first seizure in the first hour of cEEG monitoring. The 'time-to-event' risk of seizure from 0 to 96 hours was 0.38 (95% CI 0.32 to 0.44) while the risk in the first hour was 0.19 (95% CI 0.15 to 0.24). cEEG background was normal in 48% of neonates, mildly abnormal in 30%, moderately abnormal in 13% and severely abnormal in 9%. Inter-rater agreement for determination of background was very good (weighted kappa=0.81, 95% CI 0.72 to 0.91). When neonates with seizures during the first hour were excluded, an abnormal background resulted in 2.4 times increased risk of seizures during the subsequent monitoring period (95% CI 1.3 to 4.4, p<0.003) while a severely abnormal background resulted in a sevenfold increased risk (95% CI 3.4 to 14.3, p<0.0001). CONCLUSIONS: The first hour of cEEG in at-risk neonates is useful in identifying and predicting whether seizures occur during cEEG monitoring up to 96 hours. This finding enables identification of high-risk neonates who require closer observation.

Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: There are no US Food and Drug Administration-approved therapies for neonatal seizures. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in neonates. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures. METHODS: The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment for neonatal seizures of any cause. The primary outcome measure was complete seizure freedom for 24 hours, assessed by independent review of the EEGs by 2 neurophysiologists. RESULTS: Eighty percent of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam (P < .001; relative risk 0.35 [95% confidence interval: 0.22-0.56]; modified intention-to-treat population). A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. More adverse effects were seen in subjects randomly assigned to phenobarbital (not statistically significant). CONCLUSIONS: In this phase IIb study, phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.

Rapid Whole Genome Sequencing Has Clinical Utility in Children in the PICU.

OBJECTIVES: Genetic disorders are a leading contributor to mortality in the neonatal ICU and PICU in the United States. Although individually rare, there are over 6,200 single-gene diseases, which may preclude a genetic diagnosis prior to ICU admission. Rapid whole genome sequencing is an emerging method of diagnosing genetic conditions in time to affect ICU management of neonates; however, its clinical utility has yet to be adequately demonstrated in critically ill children. This study evaluates next-generation sequencing in pediatric critical care. DESIGN: Retrospective cohort study. SETTING: Single-center PICU in a tertiary children's hospital. PATIENTS: Children 4 months to 18 years admitted to the PICU who were nominated between July 2016 and May 2018. INTERVENTIONS: Rapid whole genome sequencing with targeted phenotype-driven analysis was performed on patients and their parents, when parental samples were available. MEASUREMENTS AND MAIN RESULTS: A molecular diagnosis was made by rapid whole genome sequencing in 17 of 38 children (45%). In four of the 17 patients (24%), the genetic diagnoses led to a change in management while in the PICU, including genome-informed changes in pharmacotherapy and transition to palliative care. Nine of the 17 diagnosed children (53%) had no dysmorphic features or developmental delay. Eighty-two percent of diagnoses affected the clinical management of the patient and/or family after PICU discharge, including avoidance of biopsy, administration of factor replacement, and surveillance for disorder-related sequelae. CONCLUSIONS: This study demonstrates a retrospective evaluation for undiagnosed genetic disease in the PICU and clinical utility of rapid whole genome sequencing in a portion of critically ill children. Further studies are needed to identify PICU patients who will benefit from rapid whole genome sequencing early in PICU admission when the underlying etiology is unclear.

Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization.

Genetic disorders are a leading cause of morbidity and mortality in infants. Rapid whole-genome sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants. We report a retrospective cohort study of acutely ill inpatient infants in a regional children's hospital from July 2016-March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands also received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points. The diagnostic sensitivity of rWGS was 43% (eighteen of 42 infants) and 10% (four of 42 infants) for standard genetic tests (P = .0005). The rate of clinical utility of rWGS (31%, thirteen of 42 infants) was significantly greater than for standard genetic tests (2%, one of 42; P = .0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had a 43% reduction in likelihood of mortality, and one started palliative care. In six of the eleven infants, the changes in management reduced inpatient cost by $800,000-$2,000,000. These findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting.

Neurological Outcomes After Presumed Childhood Encephalitis.

OBJECTIVE: To evaluate factors during acute presumed childhood encephalitis that are associated with development of long-term neurological sequelae. METHODS: A total of 217 patients from Rady Children's Hospital San Diego with suspected encephalitis who met criteria for the California Encephalitis Project were identified. A cohort of 99 patients (40 females, 59 males, age 2 months-17 years) without preexisting neurological conditions, including prior seizures or abnormal brain magnetic resonance imaging scans was studied. Mean duration of follow-up was 29 months. Factors that had a relationship with the development of neurological sequelae (defined as developmental delay, learning difficulties, behavioral problems, or focal neurological findings) after acute encephalitis were identified. RESULTS: Neurological sequelae at follow-up was associated with younger age (6.56 versus 9.22 years) at presentation (P = 0.04) as well as an initial presenting sign of seizure (P = 0.03). Duration of hospital stay (median of 7 versus 15.5 days; P = 0.02) was associated with neurological sequelae. Of the patients with neurological sequelae, a longer hospital stay was associated with patients of an older age (P = 0.04). Abnormalities on neuroimaging (P = 1.00) or spinal fluid analysis (P = 1.00) were not uniquely associated with neurological sequelae. Children who were readmitted after their acute illness (P = 0.04) were more likely to develop neurological sequelae. There was a strong relationship between the patients who later developed epilepsy and those who developed neurological sequelae (P = 0.02). SIGNIFICANCE: Limited data are available on the long-term neurological outcomes of childhood encephalitis. Almost half of our patients were found to have neurological sequelae at follow-up, indicating the importance of earlier therapies to improve neurological outcome.

Epilepsy After Resolution of Presumed Childhood Encephalitis.

OBJECTIVE: To evaluate factors associated with the development of epilepsy after resolution of presumed childhood encephalitis. METHODS: A total of 217 patients with suspected encephalitis who met criteria for the California Encephalitis Project were identified. Evaluable outcome information was available for 99 patients (40 girls, 59 boys, ages 2 months to 17 years) without preexisting neurological conditions, including prior seizures or abnormal brain magnetic resonance imaging scans. We identified factors correlated with the development of epilepsy after resolution of the acute illness. RESULTS: Development of epilepsy was correlated with the initial presenting sign of seizure (P < 0.001). With each additional antiepileptic drug used to control seizures, the odds ratio of developing epilepsy was increased twofold (P < 0.001). An abnormal electroencephalograph (P < 0.05) and longer hospital duration (median of 8 versus 21 days) also correlated with development of epilepsy (P < 0.01). The need for medically induced coma was associated with epilepsy (P < 0.001). Seizures in those patients were particularly refractory, often requiring longer than 24 hours to obtain seizure control. Individuals who required antiepileptic drugs at discharge (P < 0.001) or were readmitted after their acute illness (P < 0.001) were more likely to develop epilepsy. Of our patients who were able to wean antiepileptic drugs after being started during hospitalization, 42% were successfully tapered off within 6 months. CONCLUSIONS: Limited data are available on the risk of developing epilepsy after childhood encephalitis. This is the first study that not only identifies risk factors for the development of epilepsy, but also provides data regarding the success rate of discontinuing antiepileptic medication after resolution of encephalitis.

Acute pediatric encephalitis neuroimaging: single-institution series as part of the California encephalitis project.

PURPOSE: Diagnosing pediatric encephalitis is challenging because of varied clinical presentation, nonspecific neuroimaging features, and rare confirmation of causality. We reviewed acute neuroimaging of children with clinically suspected encephalitis to identify findings that may correlate with etiology and length of stay. METHODS: Imaging of 141 children with clinically suspected encephalitis as part of The California Encephalitis Project from 2005 to 2012 at a single institution was reviewed to compare the extent of neuroimaging abnormalities to patient age, gender, length of stay, and unknown, possible, or confirmed pathogen. Scan review was blinded and categorized by extent and distribution of abnormal findings. RESULTS: Abnormal findings were evident on 23% (22/94) of computed tomography and 50% (67/134) of magnetic resonance imaging studies in the acute setting. Twenty children with normal admission computed tomography had abnormal findings on magnetic resonance imaging performed within 2 days. Length of stay was significantly longer among children with abnormal acute magnetic resonance imaging (P < 0.001) and correlated with increased complexity (Spearman rho = 0.4, P < 0.001) categorized as: no imaging abnormality, meningeal enhancement and/or focal nonenhancing lesion, multifocal lesions, confluent lesions, and lesions plus diffusion restriction, hemorrhage, or hydrocephalus. There was no correlation between neuroimaging findings and an identifiable pathogen (P = 0.8). CONCLUSION: Abnormal magnetic resonance imaging findings are more common than abnormal computed tomography findings in pediatric encephalitis. Increasing complexity of magnetic resonance imaging findings correlated with disease severity as evidenced by longer length of stay, but were not specific for an identifiable pathogen using a standardized diagnostic encephalitis panel.

The role of continuous electroencephalography in childhood encephalitis.

BACKGROUND: Seizures are a known complication of encephalitis. We sought to determine the incidence of seizures and the relative utility of routine and continuous electroencephalography in children with suspected encephalitis. METHODS: Records from all 217 children (ages 0-20 years, enrolled 2004-2011) from our institution who had diagnostic samples sent to the California Encephalitis Project were reviewed. RESULTS: One hundred children (46%) had at least one seizure observed clinically or recorded on electroencephalography. Diffuse abnormalities (e.g., generalized slowing) were more common than focal or epileptiform abnormalities (88.9% vs 63.2% and 57.3%, respectively; P < 0.0001), but focal and epileptiform abnormalities were more correlated with seizures (91.0% [P = 0.04] and 89.2% [P = 0.05], respectively vs 76.9%). Fifty-four patients (25%) had at least 1 day of continuous electroencephalography. When used, continuous electroencephalography recorded a seizure in more than half of patients. Six children had no recognized seizure (clinical or electrographic) before continuous electroencephalography was performed. Twenty-two children (10%) had a seizure recorded by continuous electroencephalography after routine electroencephalography did not record a seizure. Overall, continuous electroencephalography was more likely to capture a seizure, capture a subclinical seizure, or rule out a concerning event as a seizure than routine electroencephalography (all comparisons P < 0.0001). CONCLUSIONS: Children with suspected encephalitis are at high risk for seizures. Continuous electroencephalography is better able than routine electroencephalography to determine whether seizures are present. Further, continuous electroencephalography can guide treatment by classifying a clinical event as seizure or seizure-mimic. Our findings support the expanded use of continuous electroencephalography in children with suspected encephalitis.

Hippocampal volume and memory performance in children with perinatal stroke.

BACKGROUND: Pediatric neurologists and neonatologists often are asked to predict cognitive outcome after perinatal brain injury (including likely memory and learning outcomes). However, relatively few data exist on how accurate predictions can be made. Furthermore, although the consequences of brain injury on hippocampal volume and memory performance have been studied extensively in adults, little work has been done in children. METHODS: We measured the volume of the hippocampus in 27 children with perinatal stroke and 19 controls, and measured their performance on standardized verbal and non-verbal memory tests. RESULTS: We discovered the following: (1) As a group, children with perinatal stroke had smaller left and right hippocampi compared with control children. (2) Individually, children with perinatal stroke demonstrated 1 of 3 findings: no hippocampal loss, unilateral hippocampal loss, or bilateral hippocampal volume loss compared with control children. (3) Hippocampal volume inversely correlated with memory test performance in the perinatal stroke group, with smaller left and right hippocampal volumes related to poorer verbal and non-verbal memory test performance, respectively. (4) Seizures played a significant role in determining memory deficit and extent of hippocampal volume reduction in patients with perinatal stroke. CONCLUSIONS: These findings support the view that, in the developing brain, the left and right hippocampi preferentially support verbal and nonverbal memory respectively, a consistent finding in the adult literature but a subject of debate in the pediatric literature. This is the first work to report that children with focal brain injury incurred from perinatal stroke have volume reduction in the hippocampus and impairments in certain aspects of declarative memory.

The anatomy of amnesia: neurohistological analysis of three new cases.

The most useful information about the anatomy of human memory comes from cases where there has been extensive neuropsychological testing followed by detailed post-mortem neurohistological analysis. To our knowledge, only eight such cases have been reported (four with medial temporal lobe damage and four with diencephalic damage). Here we present neuropsychological and post-mortem neurohistological findings for one patient (NC) with bilateral damage to the medial temporal lobe and two patients (MG, PN) with diencephalic damage due to bilateral thalamic infarction and Korsakoff's syndrome, respectively. All three patients exhibited a similar phenotype of amnesia with markedly impaired declarative memory (anterograde and retrograde) but normal performance on tests of nondeclarative memory (e.g., priming and adaptation-level effects) as well as on tests of other cognitive functions. Patient NC had damage to the hippocampus (dentate gyrus and the CA1 and CA3 fields) and layer III of the entorhinal cortex, but with relative sparing of the CA2 field and the subiculum. Patient MG had damage to the internal medullary lamina and mediodorsal thalamic nuclei. Patient PN had damage to the mammillary nuclei, mammillothalamic tracts, and the anterior thalamic nuclei. These findings illuminate several issues regarding the relation between diencephalic and medial temporal lobe amnesia, the status of recognition memory in amnesia, and the neuroanatomy of memory.

Single-item memory, associative memory, and the human hippocampus.

We tested recognition memory for items and associations in memory-impaired patients with bilateral lesions thought to be limited to the hippocampal region. In Experiment 1 (Combined memory test), participants studied words and then took a memory test in which studied words, new words, studied word pairs, and recombined word pairs were presented in a mixed order. In Experiment 2 (Separated memory test), participants studied single words and then took a memory test involving studied word and new words. In a separate test, they studied word pairs and then took a memory test involving studied word pairs and recombined word pairs. In both experiments, patients were impaired at memory for single items as well as memory for associations, suggesting that the hippocampus is important for both of these memory functions. In Experiment 1, patients appeared to be more impaired at associative memory than item memory. In Experiment 2, patients were similarly impaired at associative memory and item memory. These different findings are considered, including the fact that in Experiment 1 the results depended on the fact that controls produced unexpectedly low false-alarm rates to recombined pairs. We discuss single-item and associative memory from the perspective that the hippocampus and adjacent cortex work cooperatively to signal recognition and that simple dichotomies do not adequately describe the division of labor within the medial temporal lobe.

Item memory, source memory, and the medial temporal lobe: concordant findings from fMRI and memory-impaired patients.

We studied item and source memory with fMRI in healthy volunteers and carried out a parallel study in memory-impaired patients. In experiment 1, volunteers studied a list of words in the scanner and later took an item memory test and a source memory test. Brain activity in the hippocampal region, perirhinal cortex, and parahippocampal cortex was associated with words that would later be remembered (item memory). The activity in these regions that predicted subsequent success at item memory predicted subsequent source memory to a similar degree. In experiment 2, memory-impaired patients with damage thought to be limited to the hippocampal region were given an item memory test and a source memory test, as in experiment 1. The patients were similarly impaired on the item memory test and the source memory test. Together, the findings suggest that medial temporal lobe structures broadly support recognition memory function and that item memory and source memory similarly depend on these structures.

Intact visual perception in memory-impaired patients with medial temporal lobe lesions.

A recent proposal that structures of the medial temporal lobe support visual perception in addition to memory challenges the long-standing idea that the ability to acquire new memories is separable from other cognitive and perceptual functions. In four experiments, we have put this proposal to a rigorous test. Six memory-impaired patients with well characterized lesions of either the hippocampal region or the hippocampal region plus additional medial temporal lobe structures were assessed on difficult tests of visual perceptual discrimination. Across all four experiments, the patients performed as well as controls. The results show that visual perception is intact in memory-impaired patients with damage to the medial temporal lobe even when perception is assessed with challenging tasks. Furthermore, the results support the principle that the ability to acquire new memories is a distinct cerebral function, dissociable from other perceptual and cognitive functions.

The neuroanatomy of remote memory.

In humans and experimental animals, damage to the hippocampus or related medial temporal lobe structures severely impairs the formation of new memory but typically spares very remote memory. Questions remain about the importance of these structures for the storage and retrieval of remote autobiographical memory. We carried out a detailed volumetric analysis of structural brain images from eight memory-impaired patients. Five of the patients had damage limited mainly to the medial temporal lobe. These patients performed normally on tests of remote autobiographical memory. Three patients had medial temporal lobe damage plus significant additional damage to neocortex, and these patients were severely impaired. These findings account for previously reported differences in the recollective ability of memory-impaired patients and demonstrate that the ability to recollect remote autobiographical events depends not on the medial temporal lobe but on widely distributed neocortical areas, especially the frontal, lateral temporal, and occipital lobes.

Quantifying medial temporal lobe damage in memory-impaired patients.

Studies of memory-impaired patients will be most useful when quantitative neuroanatomical information is available about the patients being studied. Toward that end, in the case of medial temporal lobe amnesia, protocols have been developed from histological material that identify the boundaries of relevant structures on magnetic resonance images. Because the size of these structures varies considerably in the normal population, some correction for overall brain size is usually employed when calculating volume measurements. Although different correction procedures have been used to normalize for brain size, there has been little study of how well different methods reduce variability and which methods might be most useful. We measured the volume of the hippocampal region (hippocampus proper, dentate gyrus, and subicular complex) and the volumes of the temporopolar, entorhinal, perirhinal, and parahippocampal cortices in five memory-impaired patients and 30 controls. We then compared three different methods for normalizing the volume measurements: normalization by intracranial volume, normalization by aligning the brain to a standard atlas, and normalization by brain area at the level of the anterior commissure. Normalization by intracranial volume reduced variability in the volume measurements of nearly all brain regions to a greater extent than did normalization by other methods. When normalized by intracranial volume, the patients exhibited a mean reduction in hippocampal volume of about 40% and negligible reductions in the volumes of other medial temporal lobe structures. On the basis of earlier histological analysis of two other patients (L.M. and W.H.), who also had reductions in hippocampal size of about 40%, we suggest that a volume reduction in this range likely indicates a nearly complete loss of hippocampal neurons.