Association of brain functional connectivity with neurodevelopmental outcomes in healthy full-term newborns.

OBJECTIVE: To study the association between neurodevelopmental outcomes and functional brain connectivity (FBC) in healthy term infants. METHODS: This is a retrospective study of prospectively collected High-density electroencephalography (HD-EEG) from newborns within 72 hours from birth. Developmental assessments were performed at two years of age using the Bayley Scales of Infant Development-III (BSID-III) measuring cognitive, language, motor, and socio-emotional scores. The FBC was calculated using phase synchronization analysis of source signals in delta, theta, alpha, beta, and gamma frequency bands and its association with neurodevelopmental score was assessed with stepwise regression. RESULTS: 47/163 had both HD-EEG and BSID-III scores. The FBC of frontal region was associated with cognitive score in the theta band (corrected p, regression coefficients range: p < 0.01, 1.66-1.735). Language scores were significantly associated with connectivity in all frequency bands, predominantly in the left hemisphere (p < 0.01, -2.74-2.40). The FBC of frontal and occipital brain regions of both hemispheres was related to motor score and socio-emotional development in theta, alpha, and gamma frequency bands (p < 0.01, -2.16-2.97). CONCLUSIONS: Functional connectivity of higher-order processing is already present at term age. SIGNIFICANCE: The FBC might be used to guide interventions for optimizing subsequent neurodevelopment even in low-risk newborns.

Pearls & Oy-sters: Delayed Response to Pyridoxine in Pyridoxine-Dependent Epilepsy.

Inborn errors of metabolism are a diverse group of genetic disorders including many that cause neonatal-onset epilepsy such as pyridoxine-dependent epilepsy (PDE). PDE occurs secondary to biallelic pathogenic variants in ALDH7A1 and can present with refractory neonatal seizures and status epilepticus. Neonatal seizures and encephalopathy are modifiable with pyridoxine (vitamin B6) supplementation. However, the clinical response to pyridoxine supplementation can be delayed. We present the case of a full-term neonate with PDE in which seizure cessation was seen a few hours after intravenous pyridoxine load, but the improvement in EEG background and level of clinical encephalopathy occurred 5 days later. We share this case to provide an example in which clinical improvement in PDE was gradual and required continuation of treatment for several days illustrating the necessity of continuing vitamin B6 supplementation in suspected cases until confirmatory genetic testing is obtained or an alternate cause is found.

Neonatal Botulism: A Case Series Suggesting Varied Presentations.

Infantile botulism is an uncommon diagnosis and rarer still in the neonatal period. We describe three cases of neonatal-onset botulism that presented with symptoms typically (hypotonia, constipation, facial diplegia) or atypically seen in older infants (encephalopathy, seizures, and hypothermia). Our series shows a wider spectrum of clinical presentations in patients with neonatal-onset botulism. Our report also suggests that neonatal-onset botulism should be considered more broadly in the hypotonic infant, especially as the condition is treatable with intravenous botulinum-specific immune globulin.

Focal to bilateral tonic-clonic seizures predict pharmacoresistance in focal cortical dysplasia-related epilepsy.

OBJECTIVE: Focal cortical dysplasia (FCD) is the most common etiology of surgically-remediable epilepsy in children. Eighty-seven percent of patients with FCD develop epilepsy (75% is pharmacoresistant epilepsy [PRE]). Focal to bilateral tonic-clonic (FTBTC) seizures are associated with worse surgical outcomes. We hypothesized that children with FCD-related epilepsy with FTBTC seizures are more likely to develop PRE due to lesion interaction with restricted cortical neural networks. METHODS: Patients were selected retrospectively from radiology and surgical databases from Children's National Hospital. INCLUSION CRITERIA: 3T magnetic resonance imaging (MRI)-confirmed FCD from January 2011 to January 2020; ages 0 days to 22 years at MRI; and 18 months of documented follow-up. FCD dominant network (Yeo 7-network parcellation) was determined. Association of FTBTC seizures with epilepsy severity, surgical outcome, and dominant network was tested. Binomial regression was used to evaluate predictors (FTBTC seizures, age at seizure onset, pathology, hemisphere, lobe) of pharmacoresistance and Engel outcome. Regression was used to evaluate predictors (age at seizure onset, pathology, lobe, percentage default mode network [DMN] overlap) of FTBTC seizures. RESULTS: One hundred seventeen patients had a median age at seizure onset of 3.00 years (interquartile range [IQR] .42-5.59 years). Eighty-three patients had PRE (71%); 34 had pharmacosensitive epilepsy (PSE) (29%). Twenty patients (17%) had FTBTC seizures. Seventy-three patients underwent epilepsy surgery. Multivariate regression showed that FTBTC seizures are associated with an increased risk of PRE (odds ratio [OR] 6.41, 95% confidence interval [CI] 1.21-33.98, p = .02). FCD hemisphere/lobe was not associated with PRE. Percentage DMN overlap predicts FTBTC seizures. Seventy-two percent (n = 52) overall and 53% (n = 9) of patients with FTBTC seizures achieved Engel class I outcome. SIGNIFICANCE: In a heterogeneous population of surgical and non-operated patients with FCD-related epilepsy, the presence of FTBTC seizures is associated with a tremendous risk of PRE. This finding is a recognizable marker to help neurologists identify those children with FCD-related epilepsy at high risk of PRE and can flag patients for earlier consideration of potentially curative surgery. The FCD-dominant network also contributes to FTBTC seizure clinical expression.

Functional brain network properties of healthy full-term newborns quantified by scalp and source-reconstructed EEG.

OBJECTIVE: Identifying the functional brain network properties of term low-risk newborns using high-density EEG (HD-EEG) and comparing these properties with those of established functional magnetic resonance image (fMRI) - based networks. METHODS: HD-EEG was collected from 113 low-risk term newborns before delivery hospital discharge and within 72 hours of birth. Functional brain networks were reconstructed using coherence at the scalp and source levels in delta, theta, alpha, beta, and gamma frequency bands. These networks were characterized for the global and local network architecture. RESULTS: Source-level networks in all the frequency bands identified the presence of the efficient small world (small-world propensity (SWP) > 0.6) architecture with four distinct modules linked by hub regions and rich-club (coefficient > 1) topology. The modular regions included primary, association, limbic, paralimbic, and subcortical regions, which have been demonstrated in fMRI studies. In contrast, scalp-level networks did not display consistent small world architecture (SWP < 0.6), and also identified only 2-3 modules in each frequency band.The modular regions of the scalp-network primarily included frontal and occipital regions. CONCLUSIONS: Our findings show that EEG sources in low-risk newborns corroborate fMRI-based connectivity results. SIGNIFICANCE: EEG source analysis characterizes functional connectivity at the bedside of low-risk newborn infants soon after birth.

Definitive treatment of seizures due to hemimegalencephaly in neonates and young infants by transarterial embolization: technical considerations for 'endovascular embolic hemispherectomy'.

BACKGROUND: This case series describes the technical considerations and effectiveness of 'endovascular embolic hemispherectomy' for the treatment of medically intractable seizures in neonates and young infants with hemimegalencephaly (HME) and in whom surgical hemispherectomy is not a viable option. METHODS: This is a descriptive review of the endovascular technique used to treat consecutive pediatric patients with serial transarterial embolization for intractable seizures due to HME between 2018 and 2022. Clinical presentation, endovascular procedural details and complications, and efficacy were examined. RESULTS: Three infants (13-day-old, 13-week-old and 15-day-old) with HME and intractable seizures underwent a total of 10 transarterial embolizations. Anticipated intraprocedural events included vasospasm and focal subarachnoid hemorrhage in all three infants, effectively controlled endovascularly, and non-target embolization in one infant. No infants had symptomatic intracranial hemorrhage or femoral artery occlusion. EEG background quiescence and seizure cessation was achieved after the final stage of embolization in all patients. All infants were discharged home from the neonatal ICU (median length of stay 36 days, range 27-74 days) and remain seizure-free to date (4 years, 9 months, and 8 months). None have developed hydrocephalus, required surgical hemispherectomy or other neurosurgical interventions. CONCLUSION: Endovascular hemispherectomy can be safely used to provide definitive treatment of HME-related epilepsy in neonates and young infants when intraprocedural events are managed effectively. This less invasive novel approach should be considered a feasible early alternative to surgical hemispherectomy. Further studies are needed to enhance the safety profile and to assess long-term neurodevelopmental outcome and durability of freedom from seizures.

Electroencephalogram in low-risk term newborns predicts neurodevelopmental metrics at age two years.

OBJECTIVE: To determine whether neurodevelopmental biomarkers at 2 years of age are already present in the newborns' EEG at birth. METHODS: Low-risk term newborns were enrolled and studied utilizing EEG prior to discharge from the birth hospital. A 14-channel EEG montage (scalp-level) and source signals were calculated using the EEG. Their spectral power was calculated for each of the five frequency bands. Cognitive, language and motor skills were assessed using the Bayley Scales of Infant Development-III at age 2 years. The relationship between the spectral power in each frequency band and neurodevelopmental scores were quantified using the Spearman's r. The role of gender, gestational age (GA) and delivery mode, if found significant (P < 0.05), were controlled by analyzing partial correlation. RESULTS: We studied 47 newborns and found a significant association between gender, and delivery mode with EEG power. Scalp- and source-level spectral powers were positively associated with cognitive and language scores. At the source level, significant associations were identified in the parietal and occipital regions. CONCLUSIONS: Electrophysiological biomarkers of neurodevelopment at age 2 years are already present at birth in low-risk term infants. SIGNIFICANCE: Low-risk newborns' EEG utility as a screening tool to optimize neurodevelopmental outcome warrants further evaluation.

Encapsulated pheochromocytoma cells secrete potent noncatecholamine factors.

Pheochromocytomas are widely believed to induce cardiomyopathy via hypersecretion of catecholamines, including norepinephrine (NE). NE can have direct cardiomyocyte toxicity and/or can stimulate myocardial remodeling secondary to the induction of hypertension. Yet, the development of cardiomyopathy is not entirely related to catecholamine dose or the extent of hypertension. To explore these effects, we engineered a polymeric encapsulation system to control PC12 cell kinetics and NE release in vitro and in vivo. Primary neonatal rat cardiomyocytes incubated with pheochromocytoma-conditioned media exhibited greater cytoskeletal changes than myocytes cultured with identical doses of NE alone, including more profound dose-dependent decreases in desmin, beta-tubulin, and vinculin and upregulation of dystrophin. Cardiomyocyte contractility was 29 +/- 6% greater at given levels of NE release. Agarose-encapsulated PC12 cells retain cell viability and structural integrity in vivo. These implants induce a 30% greater degree of cardiac enlargement as compared to pumps releasing equivalent doses of NE. Protein level alterations observed in vitro were mirrored in vivo after implantation of encapsulated cells or NE pumps for 28 days. Together, these data suggest that pheochromocytoma-induced cardiomyopathy is not solely a catecholamine-mediated event; rather, the pathogenesis of this dilated cardiomyopathy appears to be dependent upon secondary factors unexamined to date.