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.

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.

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.

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.

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.

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.

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.

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.

Prothrombotic risk factors in the evaluation and management of perinatal stroke.

The ischemia in children affected by perinatal stroke has long been thought to be driven by nonhematologic maternal and perinatal events. New information from clinical studies, however, tells us that plasma-phase risk factors, such as factor V Leiden, elevated lipoprotein (a), and mutations in MTHFR, may be important in the pathogenesis of perinatal stroke, if not always in the risk of recurrence. With regard to stroke recurrence, this risk is only about 2% according to the largest follow-up study to date, and certainly less than 5%. Nonetheless, when strokes do recur, they tend to be associated with the presence of plasma-phase risk factors in the affected child, suggesting that a small percentage of children with a first perinatal stroke may benefit from anticoagulation therapy, both to prevent stroke recurrence as well as occurence of a second, non-CNS thrombotic event. Counselling of parents with regard to subsequent pregnancies should always include medical management of systemic maternal disorders, such as diabetes, persistently elevated antiphospholipid antibodies, and inherited maternal hypercoagulability states.

Magnetic resonance imaging evaluation of possible neonatal sinovenous thrombosis.

There are few data on magnetic resonance imaging findings in newborns for whom there is a concern for cerebral sinovenous thrombosis. The study objective was to document findings on magnetic resonance imaging or magnetic resonance venography in cases of suspected neonatal sinovenous thrombosis. A retrospective search of the institutional database was performed to find neonates whose cranial computed tomography raised the suspicion for thrombus. Documented abnormalities were detected on magnetic resonance venography, diffusion-weighted imaging, and T(2)-weighted imaging. Of 15 neonates with suspicious computed tomography studies, 2 had a definite intraluminal clot in the deep venous system; the remainder showed decreased flow-related enhancement within the dural venous sinuses. In all these cases, the sinus was compressed by adjacent subdural hematoma or sutural diastasis. Of the 15 patients, 5 had parenchymal abnormalities (2 of these had definite intraluminal clot). Parenchymal abnormalities were classified as hemorrhage (3/5), cytotoxic edema (3/5), or vasogenic edema (1/5). Intraluminal clot in the newborn is more often identified in the deep than in the superficial venous system. With evidence of venous injury in the absence of identified thrombus, it is possible that either clots dissolve quickly, escaping detection, or that the superficial venous system is vulnerable to mechanical forces during delivery.

Brain malformation and infantile spasms in a SCAD deficiency patient.

This report presents a case of short-chain acyl-coenzyme A (CoA) dehydrogenase deficiency with a previously unreported presentation with brain malformations and infantile spasms. This female infant developed repeated tonic clonic seizures at the age of 3(1/2) months. She subsequently developed West syndrome at the age of 4 months. Her electroencephalogram disclosed hypsarrhythmia, and video-electroencephalographic monitoring confirmed the presence of infantile spasms. Magnetic resonance imaging revealed a small midline frontal meningocele, abnormal cortical gyration, and partial agenesis of the corpus callosum consistent with neuronal migrational disorder. Metabolic evaluation indicated ethylmalonic acidemia. Muscle biopsy with enzymatic assay of short-chain acyl-coenzyme A revealed low enzymatic activity confirming the diagnosis of short-chain acyl-coenzyme A dehydrogenase deficiency. To our knowledge, this is the first report of the coexistence of short-chain acyl-coenzyme A dehydrogenase deficiency, infantile spasms, and brain malformation. We conclude that short-chain acyl-coenzyme A dehydrogenase deficiency should be considered in the differential diagnosis of gyral abnormality, corpus callosal hypoplasia, and infantile spasms.

Proton magnetic resonance spectroscopy and diffusion-weighted imaging in isolated sulfite oxidase deficiency.

Isolated sulfite oxidase deficiency is a rare autosomal recessive disorder of the newborn that can be mistaken for neonatal asphyxia. Diffusion-weighted imaging of the brain demonstrates widespread diffusion restriction, and proton magnetic resonance spectroscopy shows an elevated lactate level, a decrease in the ratio of N-acetylaspartate to creatine, and a rise in the ratio of choline to creatine. This precedes severe cystic encephalomalacia and suggests that the energy failure associated with neuronal dysfunction and myelin disintegration occurs early in isolated sulfite oxidase deficiency.

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.