Effect of neonatal seizure burden and etiology on the long-term outcome: data from a randomized, controlled trial.

Background: Neonatal seizures are common, but the impact of neonatal seizures on long-term neurologic outcome remains unclear. We addressed this question by analyzing data from an early-phase controlled trial of bumetanide to treat neonatal seizures. Methods: Neonatal seizure burden was calculated from continuous video-EEG data. Neurologic outcome was determined by standardized developmental tests and post-neonatal seizure recurrence. Results: Of 111 enrolled neonates, 43 were randomized to treatment or control groups. There were no differences in neurologic outcome between treatment and control groups. A subgroup analysis was performed for 84 neonates with acute perinatal brain injury (57 HIE, 18 stroke, 9 ICH), most of whom (70%) had neonatal seizures. There was a significant negative correlation between seizure burden and developmental scores (p<0.01). Associations between seizure burden and developmental scores were stronger in HIE and stroke groups compared with ICH (p<0.05). Conclusion: Bumetanide showed no long-term beneficial or adverse effects, as expected based on treatment duration versus duration of neonatal seizures. For neonates with perinatal brain injury, higher neonatal seizure burden correlated significantly with worse developmental outcome, particularly for ischemic versus hemorrhagic brain injury. These data highlight the need for further investigation of the long-term effects of both neonatal seizure severity and etiology.

Clinical and molecular heterogeneity of syndromic hypothalamic hamartoma.

Two children are presented who have a distinct syndrome of multiple buccolingual frenula, a stiff and short fifth finger with small nails, a hypothalamic hamartoma, mild to moderate neurological impairment, and mild endocrinological symptoms. No variant assessed to be pathogenic or likely pathogenic was detected in the GLI3 gene in either child. This syndrome appears to be distinct from the inherited Pallister-Hall syndrome associated with GLI3 variants, which is characterized by hypothalamic hamartoma, mesoaxial polydactyly, and other anomalies. In the individuals described here, manifestations outside of the central nervous system were milder and the mesoaxial polydactyly, which is common in individuals with Pallister-Hall syndrome, was absent. Instead, these children had multiple buccolingual frenula together with the unusual appearance of the fifth digit. It remains unclear whether these two individuals represent a separate nosologic entity or if they represent a milder manifestation of one of the more severe syndromes associated with a hypothalamic hamartoma.

A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures.

OBJECTIVE: In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to phenobarbital to treat neonatal seizures in the first trial to include a standard-therapy control group. METHODS: A randomized, double-blind, dose-escalation design was employed. Neonates with postmenstrual age 33 to 44 weeks at risk of or with seizures were eligible. Subjects with electroencephalography (EEG)-confirmed seizures after ≥20 and <40mg/kg phenobarbital were randomized to receive additional phenobarbital with either placebo (control) or 0.1, 0.2, or 0.3mg/kg bumetanide (treatment). Continuous EEG monitoring data from ≥2 hours before to ≥48 hours after study drug administration (SDA) were analyzed for seizures. RESULTS: Subjects were randomized to treatment (n = 27) and control (n = 16) groups. Pharmacokinetics were highly variable among subjects and altered by hypothermia. The only statistically significant adverse event was diuresis in treated subjects (48% vs 13%, p = 0.02). One treated (4%) and 3 control subjects died (19%, p = 0.14). Among survivors, 2 of 26 treated subjects (8%) and 0 of 13 control subjects had hearing impairment, as did 1 nonrandomized subject. Total seizure burden varied widely, with much higher seizure burden in treatment versus control groups (median = 3.1 vs 1.2 min/h, p = 0.006). There was significantly greater reduction in seizure burden 0 to 4 hours and 2 to 4 hours post-SDA (both p < 0.01) compared with 2-hour baseline in treatment versus control groups with adjustment for seizure burden. INTERPRETATION: Although definitive proof of efficacy awaits an appropriately powered phase 3 trial, this randomized, controlled, multicenter trial demonstrated an additional reduction in seizure burden attributable to bumetanide over phenobarbital without increased serious adverse effects. Future trials of bumetanide and other drugs should include a control group and balance seizure severity. ANN NEUROL 2021;89:327-340.

The probability of seizures during continuous EEG monitoring in high-risk neonates.

OBJECTIVE: We evaluated the impact of monitoring indication, early electroencephalography (EEG), and clinical features on seizure risk in all neonates undergoing continuous EEG (cEEG) monitoring following a standardized monitoring protocol. METHODS: All cEEGs from unique neonates 34-48 weeks postmenstrual age monitored from 1/2011-10/2017 (n = 291) were included. We evaluated the impact of cEEG monitoring indication (acute neonatal encephalopathy [ANE], suspicious clinical events [SCEs], or other high-risk conditions [OHRs]), age, medication status, and early EEG abnormalities (including the presence of epileptiform discharges and abnormal background continuity, amplitude, asymmetry, asynchrony, excessive sharp transients, and burst suppression) on time to first seizure and overall seizure risk using Kaplan-Meier survival curves and multivariable Cox proportional hazards models. RESULTS: Seizures occurred in 28% of high-risk neonates. Discontinuation of monitoring after 24 hours of seizure-freedom would have missed 8.5% of neonates with seizures. Overall seizure risk was lower in neonates monitored for ANE compared to OHR (P = .004) and trended lower compared to SCE (P = .097). The time course of seizure presentation varied by group, where the probability of future seizure was less than 1% after 17 hours of seizure-free monitoring in the SCE group, but required 42 hours in the OHR group, and 73 hours in the ANE group. The presence of early epileptiform discharges increased seizure risk in each group (ANE: adjusted hazard ratio [aHR] 4.32, 95% confidence interval [CI] 1.23-15.13, P = .022; SCE: aHR 10.95, 95% CI 4.77-25.14, P < 1e-07; OHR: aHR 56.90, 95% CI 10.32-313.72, P < 1e-05). SIGNIFICANCE: Neonates who undergo cEEG are at high risk for seizures, and risk varies by monitoring indication and early EEG findings. Seizures are captured in nearly all neonates undergoing monitoring for SCE within 24 hours of cEEG monitoring. Neonates monitored for OHR and ANE can present with delayed seizures and require longer durations of monitoring. Early epileptiform discharges are the best early EEG feature to predict seizure risk.

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM.

A 17-Year-Old Boy With High-Functioning Autism, Gastrointestinal Illness, and Seizures.

A healthy 17-year-old boy with a high-functioning pervasive developmental disorder presented to the emergency department after having a 4-minute episode of seizure-like activity in the setting of presumed viral gastroenteritis. Within an hour of emergency department arrival, he developed a forehead-sparing facial droop, right-sided ptosis, and expressive aphasia, prompting stroke team assessment and urgent neuroimaging. Laboratory results later revealed a serum sodium of 119 mmol/L. Neurologic deficits self-resolved, and a full physical examination revealed diffuse abdominal tenderness in the lower abdomen with rebound tenderness in the right-lower quadrant. The patient was admitted to the PICU for electrolyte management and monitoring. A computed tomography (CT) scan of the abdomen obtained the following morning revealed the patient's final diagnosis.

HaNDL Syndrome: Case Report and Literature Review.

Headache and Neurologic Deficits with cerebrospinal fluid Lymphocytosis (HaNDL) syndrome is a rare stroke mimicker characterized by moderate to severe headache temporally associated with transient neurologic deficits, typically hemiparesis, hemisensory disturbance, and/or aphasia. Cerebrospinal fluid studies reveal a lymphocytosis and elevated protein. Episodes recur over a period no longer than 3 months. Here we describe the case of a 16-year-old boy who presented with 3 episodes of self-resolving neurologic deficits, papilledema on fundoscopic examination, and leptomeningeal enhancement on magnetic resonance imaging (MRI). We additionally review the 30 previously reported pediatric cases of HaNDL syndrome, with a focus on possible etiologic and pathophysiologic mechanisms of disease. The reported case and literature review highlight the benign episodic nature of this likely underrecognized syndrome as well as the higher than expected frequency of abnormal neuroimaging findings.

Chiari malformations: An important cause of pediatric aspiration.

Chronic aspiration poses a major health risk to the pediatric population. We describe four cases in which work up for chronic aspiration with a brain MRI revealed a Chiari I malformation, a poorly described etiology of pediatric aspiration. All patients had at least one non-specific neurologic symptom but had swallow studies more characteristic of an anatomic than a neurologic etiology. Patients were referred to neurosurgery and underwent posterior fossa decompression with symptom improvement. A high index of suspicion for Chiari malformation should be maintained when the standard work up for aspiration is non-diagnostic, particularly when non-specific neurologic symptoms are present.

A quantitative method for correlating observations of decreased apparent diffusion coefficient with elevated cerebral blood perfusion in newborns presenting cerebral ischemic insults.

In patients presenting with cerebral ischemic injury, the outcome of injured brain tissue quantified as decreased apparent diffusion coefficient (ADC) may depend on associated alterations in cerebral blood perfusion (CBP). This study proposes a non-biased method to quantify associations between ADC and CBP in newborns with global or focal cerebral ischemia. The study population consisted of nine neonates (age: 0 to 3 days) presenting with clinical and imaging evidence of ischemia (seven with global hypoxic ischemia, and two with focal arterial ischemic stroke) with decreased ADC. Six newborns without diffusion abnormalities on magnetic resonance (MR) imaging served as a comparative cohort (age: 0 days to 4 weeks). All patients underwent MR imaging including diffusion weighted imaging (DWI) to determine ADC and axial arterial spin labeling (ASL) to determine CBP. An algorithm was developed that uses the B0 volume from the DWI raw data as a reference, co-registers the ADC and ASL-CBP data to the B0, generates mask filters, and finally performs a statistical analysis to automatically select regions of interest (ROIs) with ADC or ASL-CBP values that deviate significantly from the rest of the brain. If ROIs are identified in this analysis, the algorithm then evaluates correlation based on ROI location and volume. A significant correlation was found between decreased ADC and elevated ASL-CBP with regions of elevated ASL-CBP typically larger than the corresponding ADC abnormality. The association between decreased diffusivity and increased ASL-CBP suggests that, for this cohort, cerebral ischemia is associated with hyperperfusion.

Early cranial ultrasound lesions predict microcephaly at age 2 years in preterm infants.

To assess how well early ultrasound lesions in preterm newborns predict reduced head circumference at 2 years, the investigators followed 923 children born before the 28th week of gestation who were not microcephalic at birth. Six percent of children who had a normal ultrasound scan were microcephalic compared with 15% to 20% who had intraventricular hemorrhage, an echolucent lesion, or ventriculomegaly. The odds ratios (95% confidence intervals) for microcephaly associated with different ultrasound images were intraventricular hemorrhage, 1.5 (0.8-3.0); ventriculomegaly, 3.3 (1.8-6.0); an echodense lesion, 1.6 (0.7-3.5); and an echolucent lesion, 3.1 (1.5-6.2). Ventriculomegaly and an echolucent lesion had very similar low positive predictive values (24% and 27%, respectively) and high negative predictive values (91% and 90%, respectively) for microcephaly. Ventriculomegaly had a higher sensitivity for microcephaly than did an echolucent lesion (24% vs 16%, respectively). Focal white-matter lesion (echolucent lesion) and diffuse white-matter damage (ventriculomegaly) predict an increased risk of microcephaly.

Epilepsy in Prader-Willi syndrome: clinical characteristics and correlation to genotype.

Prader-Willi syndrome (PWS) is a genomic imprinting disease secondary to the loss of a functional paternal copy of 15q11-q13. Unlike its related imprinting disorder, Angelman syndrome, PWS has not been regarded as a risk factor for epilepsy. A retrospective analysis of 92 patients with PWS identified 24 (26%) with seizures. Twenty-two of these (92%) were affected by focal epilepsy and only two (8%) had generalized epilepsy. The most common seizure type was staring spells (67%). Correlation to genotype analysis showed deletions were more common in patients with epilepsy than in patients without epilepsy. The epilepsy syndromes were easy to control with a single antiepileptic drug in most cases. Three patients (11%) had had febrile seizures. These findings suggest that PWS may be a risk factor for epilepsy, which can manifest with focal features. Patients with PWS with a deletion genotype showed a trend toward developing seizures compared with patients with other genotypes in our series, even though this difference did not achieve statistical significance.

Muscle-Eye-Brain disease.

A term female infant was evaluated for global developmental delay, hypotonia, hyporeflexia, diffuse weakness including facial muscles, and visual impairment with optic nerve hypoplasia. In the absence of family history or perinatal concerns, an extensive investigation was performed, including lab studies, muscle biopsy, brain MRI and focused genetic testing. This revealed elevated serum CK, a structurally abnormal brain, and a dystrophic-appearing muscle biopsy with evidence of a glycosylation defect in the alpha-dystroglycan complex. Of the 6 known related genes, testing of the POMGnT1 gene showed three heterozygous missense mutations. Thus her history, examination, biopsy specimen, imaging, laboratory, and genetic studies are all consistent with the diagnosis of Muscle-Eye-Brain (MEB) disease. MEB is one of an emerging spectrum of congenital disorders that involve both central and peripheral nervous systems, described further in this case report.

Increased cerebral blood volume and oxygen consumption in neonatal brain injury.

With the increasing interest in treatments for neonatal brain injury, bedside methods for detecting and assessing injury status and evolution are needed. We aimed to determine whether cerebral tissue oxygenation (StO(2)), cerebral blood volume (CBV), and estimates of relative cerebral oxygen consumption (rCMRO(2)) determined by bedside frequency-domain near-infrared spectroscopy (FD-NIRS) have the potential to distinguish neonates with brain injury from those with non-brain issues and healthy controls. We recruited 43 neonates < or =15 days old and >33 weeks gestational age (GA): 14 with imaging evidence of brain injury, 29 without suspicion of brain injury (4 unstable, 6 stable, and 19 healthy). A multivariate analysis of variance with Newman-Keuls post hoc comparisons confirmed group similarity for GA and age at measurement. StO(2) was significantly higher in brain injured compared with unstable neonates, but not statistically different from stable or healthy neonates. Brain-injured neonates were distinguished from all others by significant increases in CBV and rCMRO(2). In conclusion, although NIRS measures of StO(2) alone may be insensitive to evolving brain injury, increased CBV and rCMRO(2) seem to be useful for detecting neonatal brain injury and suggest increased neuronal activity and metabolism occurs acutely in evolving brain injury.

Cranial ultrasound lesions in the NICU predict cerebral palsy at age 2 years in children born at extremely low gestational age.

Our prospective cohort study of extremely low gestational age newborns evaluated the association of neonatal head ultrasound abnormalities with cerebral palsy at age 2 years. Cranial ultrasounds in 1053 infants were read with respect to intraventricular hemorrhage, ventriculomegaly, and echolucency, by multiple sonologists. Standardized neurological examinations classified cerebral palsy, and functional impairment was assessed. Forty-four percent with ventriculomegaly and 52% with echolucency developed cerebral palsy. Compared with no ultrasound abnormalities, children with echolucency were 24 times more likely to have quadriparesis and 29 times more likely to have hemiparesis. Children with ventriculomegaly were 17 times more likely to have quadriparesis or hemiparesis. Forty-three percent of children with cerebral palsy had normal head ultrasound. Focal white matter damage (echolucency) and diffuse damage (late ventriculomegaly) are associated with a high probability of cerebral palsy, especially quadriparesis. Nearly half the cerebral palsy identified at 2 years is not preceded by a neonatal brain ultrasound abnormality.

Infantile myofibromatosis: a nontraumatic cause of neonatal brachial plexus palsy.

Most injuries to the neonatal brachial plexus occur acutely at birth, and are iatrogenic in origin. However, when weakness is accompanied by atrophy, nontraumatic etiologies should be considered. The differential diagnosis of chronic congenital brachial plexopathy includes cervical bone malformations, humeral osteomyelitis, varicella, and compression from various types of infantile tumors. An illustrative male infant delivered at 37 weeks of gestation with wasted musculature of the left upper arm, ipsilateral Horner's syndrome, and a hemidiaphragm is presented. On further examination, this patient manifested an underlying cervical tumor compressing the brachial plexus. Diagnostic steps leading to the pathologic identification of a solitary cervical myofibroma included physical examination, electromyography, radiographic imaging, and open biopsy. This report emphasizes the importance of differentiating acute from chronic congenital plexus palsy and of recognizing the possibility that infection or neoplasm may underlie the latter.