Sequential levetiracetam and phenytoin in electroencephalographic neonatal seizures unresponsive to phenobarbital: a multicenter prospective observational study in India.

Background: Although levetiracetam and phenytoin are widely used antiseizure medications (ASM) in neonates, their efficacy on seizure freedom is unclear. We evaluated electroencephalographic (EEG) seizure freedom following sequential levetiracetam and phenytoin in neonatal seizures unresponsive to phenobarbital. Methods: We recruited neonates born ≥35 weeks and aged <72 h who had continued electrographic seizures despite phenobarbital, from three Indian hospitals, between 20 June 2020 and 31 July 2022. The neonates were treated with intravenous levetiracetam (20 mg/kg x 2 doses, second line) followed by phenytoin (20 mg/kg x 2 doses, third line) if seizures persisted. The primary outcome was complete seizure freedom, defined as an absence of seizures on EEG for at least 60 min within 40 min from the start of infusion. Findings: Of the 206 neonates with continued seizures despite phenobarbital, 152 received levetiracetam with EEG. Of these one EEG was missing, 47 (31.1%) were in status epilepticus, and primary outcome data were available in 145. Seizure freedom occurred in 20 (13.8%; 95% CI 8.6%-20.5%) after levetiracetam; 16 (80.0%) responded to the first dose and 4 (20.0%) to the second dose. Of the 125 neonates with persisting seizures after levetiracetam, 114 received phenytoin under EEG monitoring. Of these, the primary outcome data were available in 104. Seizure freedom occurred in 59 (56.7%; 95% CI 46.7%-66.4%) neonates; 54 (91.5%) responded to the first dose and 5 (8.5%) to the second dose. Interpretation: With the conventional doses, levetiracetam was associated with immediate EEG seizure cessation in only 14% of phenobarbital unresponsive neonatal seizures. Additional treatment with phenytoin along with levetiracetam attained seizure freedom in further 57%. Safety and efficacy of higher doses of levetiracetam should be evaluated in well-designed randomised controlled trials. Funding: National Institute for Health and Care Research (NIHR) Research and Innovation for Global Health Transformation (NIHR200144).

The clinical value of amplitude-integrated electroencephalography in a historical cohort with neonatal encephalopathy: A comparison of short-term versus prolonged-period monitoring.

BACKGROUND: To compare the amplitude-integrated electroencephalography (aEEG) monitoring (short-term versus prolonged-period) for neonatal seizure detection and outcome. METHODS: The aEEG monitoring in a historical cohort (n = 88, preterm:42, and term:46) with neonatal encephalopathy between 2010-2022 was re-evaluated for neonatal seizures (electrographic, electro-clinical, and clinical seizures) and EEG background scoring. The cohort was dichotomized: group I (short-period with 6-12 h, n = 36) and group II (prolonged-period with 24-48 h, n = 52). Both monitoring types were evaluated for the diagnostic accuracy of the "patients with seizures" and for outcome characteristics (early death as well as adverse outcomes at 12 months of age). RESULTS: A total of 67 (76 %) neonates of the cohort were diagnosed as "patients with seizures": electrographic-only seizures in 10 (15 %), electro-clinical seizures in 22 (33 %), and clinical-only seizures in 35 (52 %). The aEEG provides the "patients with seizures" in neonates with a 36.5 % rate with both types of monitoring: 17/36 (47.2 %) with short-term and 15/52 (28.8 %) with prolonged-period monitoring. The prolonged period aEEG had higher diagnostic values for seizure detection (sensitivity = 0.73 and negative predictivity value = 0.81). However, the aEEG background scores were similar for both types of aEEG monitoring, respectively (the mean ± SD: 4.73 ± 2.9 versus 4.4 ± 4. p = 0.837). The aEEG scoring was correlated with the magnitude of brain injury documented with MRI, the early death, and the adverse outcome at 12 months of age. CONCLUSIONS: Both aEEG types are valuable for monitoring the "patients with seizures" and outcome characteristics.

Current Evidence: Seizures in Extremely Low Gestational Age Newborns (ELGANs).

Extremely low gestational age newborns (ELGANs) are born at or below 28 weeks of gestational age. Despite improved obstetric care, the incidence of preterm birth continues to rise in advanced countries. Preterm birth remains a major cause of infant mortality, and for infants who survive, neonatal seizures are a significant predictor of later neurologic morbidity. However, little is known about risk factors for neonatal seizures in ELGANs. Understanding the association between neonatal seizures and the development of other neurologic disorders is important given the increasing prevalence of ELGANs. Identifying risk factors that contribute to the development of neonatal seizures in ELGANs may offer insights into novel mechanisms of epileptogenesis in the developing brain and improvements in the prevention or treatment of seizures in preterm infants, including ELGANs. In this literature review, we outline the limitations of epidemiologic studies of neonatal seizures in ELGANs and discuss risk factors for neonatal seizures.

Clinical Experience With Lacosamide as an Adjunct Treatment for Neonatal Seizures: A Retrospective Single-Center Study.

BACKGROUND: Lacosamide (LCM) is a third-generation antiseizure medication (ASM) currently approved for the treatment of focal seizures in children aged greater than one month. There are limited data on its efficacy in the neonatal age group. We describe our experience with LCM as an adjunct ASM for the treatment of neonatal seizures. METHODS: A retrospective chart review over a five-year period (2018 to 2022) was conducted at Le Bonheur Children's Hospital to identify neonates with electroencephalography (EEG)-proven seizures who were treated with LCM. Data were collected on electroclinical seizure characteristics, underlying etiology, ASMs, treatment response, and any adverse effects. RESULTS: A total of 15 neonates with EEG-confirmed seizures who were treated with LCM were included. Ten neonates achieved seizure cessation after LCM was added to their ASM regimen consisting of phenobarbital, levetiracetam, or both. No new treatment-related adverse effects were noted. CONCLUSIONS: LCM is effective as an adjunct treatment for neonatal seizures. Randomized controlled studies are needed to establish its effectiveness and adequate dosing regimen in this population.

Bases neurobiológicas de la epilepsia neonatal y sus comorbilidades / Neurobiological basis of neonatal epilepsy and its co morbilities

Resumen La aparición de convulsiones es frecuente durante el periodo neonatal debido a las características de inma durez funcional del cerebro es este periodo. La aparición de estas convulsiones puede llevar a un diagnóstico de epilepsia neonatal, que suele estar asociado a alteracio nes estructurales del cerebro durante el neurodesarrollo. Aproximadamente el 50% de las personas con epilepsia activa padecen al menos un trastorno médico comórbi do, y esto hace que cambie la evolución de la epilepsia. La presencia de trastornos neurológicos que preceden a la aparición de la epilepsia indica que alteraciones es tructurales y/o funcionales del cerebro subyacentes pue den ser causa de la predisposición a padecer epilepsia y de los procesos comórbidos de manera independiente. En esta revisión describimos los procesos cerebrales estructurales y funcionales que subyacen a la aparición de epilepsia neonatal y sus comorbilidades.

Abstract The occurrence of seizures is frequent during the neonatal period due to the functional immaturity of the brain.The presence of these seizures may lead to a diagnosis of neonatal epilepsy, which is usually as sociated with structural alterations of the brain during neurodevelopment. Approximately 50% of people with active epilepsy have at least one comorbid medical di sorder, and the existence of a comorbid process changes the course of the epilepsy. The presence of neurologic disorders preceding the onset of epilepsy indicates that underlying neurobiological alterations may indepen dently cause the predisposition to epilepsy and comor bid processes. In this review we describe the structural and functional brain processes underlying the onset of neonatal epilepsy and its comorbidities.

Neonatal morbidity and mortality in birth centers in the United States 2018-2021: An observational study of low-risk birthing individuals.

BACKGROUND: Many studies reporting neonatal outcomes in birth centers include births with risk factors not acceptable for birth center care using the evidence-based CABC criteria. Accurate comparisons of outcomes by birth setting for low-risk patients are needed. METHODS: Data from the public Natality Detailed File from 2018 to 2021 were used. Logistic regression, including adjusted and unadjusted odds ratios, compared neonatal outcomes (chorioamnionitis, Apgar scores, resuscitation, intensive care, seizures, and death) between centers and hospitals. Covariates included maternal diabetes, body mass index, age, parity, and demographic characteristics. RESULTS: The sample included 8,738,711 births (8,698,432 (99.53%) in hospitals and 40,279 (0.46%) in birth centers). There were no significant differences in neonatal deaths (aOR 1.037; 95% CI [0.515, 2.088]; p-value 0.918) or seizures (aOR 0.666; 95% CI [0.315, 1.411]; p-value 0.289). Measures of morbidity either not significantly different or less likely to occur in birth centers compared to hospitals included chorioamnionitis (aOR 0.032; 95% CI [0.020, 0.052]; p-value < 0.001), Apgar score < 4 (aOR 0.814, 95% CI [0.638, 1.039], p-value 0.099), Apgar score < 7 (aOR 1.075, 95% CI [0.979, 1.180], p-value 0.130), ventilation >6 h (aOR 0.349; [0.281,0.433], p-value < 0.001), and intensive care admission (aOR 0.356; 95% CI [0.328, 0.386], p-value < 0.001). Birth centers had higher odds of assisted neonatal ventilation for <6 h as compared to hospitals (aOR 1.373; 95% CI [1.293, 1.457], p-value < 0.001). CONCLUSION: Neonatal deaths and seizures were not significantly different between freestanding birth centers and hospitals. Chorioamnionitis, Apgar scores < 4, and intensive care admission were less likely to occur in birth centers.

D-Bifunctional Protein Deficiency Diagnosis-A Challenge in Low Resource Settings: Case Report and Review of the Literature.

D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania's first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the HSD17B4 gene, c788del, p(Pro263GInfs*2), previously identified in another D-BPD patient. WES also identified a variant of the SUOX gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.

Incidence and predictors of neonatal seizures among neonates admitted in Debre Markos Comprehensive Specialized Hospital, Northwest Ethiopia. A prospective follow-up study.

Introduction: Neonatal seizures are the most common neurological problem among newborns. To date, scientific studies on the incidence and predictors of neonatal seizures in African countries, including Ethiopia are scarce. Therefore, this study aimed to assess the incidence and predictors of neonatal seizures among neonates admitted to Debre Markos comprehensive Specialized Hospital. Methods: An institutional-based prospective follow-up study was conducted in Debre Markos comprehensive specialized hospital from February 1, 2022 to January 30, 2023. A systematic random sampling technique was used to select a total of 198 neonates. Data were entered into Epi-Data 4.2 and then exported to STATA version 14.1 for analysis. The Kaplan-Meier survival curve and the log-rank test were computed to explore the descriptive statistics. Variables with a p-value ≤0.2 in bi-variable Cox-regression were selected for multivariable Cox-regression analysis. Finally, a p-value of <0.05 was used to declare the statistical significance of the association with the outcome variable. Results: The overall incidence rate of neonatal seizures was 35 per 1000 person-day observations. The mean follow-up time for this study was 123.4 h. The cumulative survival probability of neonates' at 0 to 24 and 0-72 h was 89.8 % and 81.71 %, respectively. The statistically significant predictors for the incidence of neonatal seizures were perinatal asphyxia (AHR = 10.95; 95%CI: 4.81, 24.93), subgaleal hemorrhage (AHR = 5.17; 95%CI: 2.09, 12.79), and gestational age <37 weeks (AHR = 4.62; 95%CI: 1.62, 13.22). Conclusions: The incidence rate of neonatal seizures in this study was high. Neonates born with gestational age <37 weeks, having perinatal asphyxia, and having subgaleal hemorrhage were statistical predictors for the incidence of neonatal seizures. Thus, healthcare professionals should give special attention to neonates born with gestational age <37 weeks, prevent perinatal asphyxia and subgaleal hemorrhage.

Identifying Metabolic Diseases That Precipitate Neonatal Seizures.

Although a rare cause of neonatal seizures, inborn errors of metabolism (IEMs) remain an essential component of a comprehensive differential diagnosis for poorly controlled neonatal epilepsy. Diagnosing neonatal-onset metabolic conditions proves a difficult task for clinicians; however, routine state newborn screening panels now include many IEMs. Three in particular-pyridoxine-dependent epilepsy, maple syrup urine disease, and Zellweger spectrum disorders-are highly associated with neonatal epilepsy and neurocognitive injury yet are often misdiagnosed. As research surrounding biomarkers for these conditions is emerging and gene sequencing technologies are advancing, clinicians are beginning to better establish early identification strategies for these diseases. In this literature review, the authors aim to present clinicians with an innovative clinical guide highlighting IEMs associated with neonatal-onset seizures, with the goal of promoting quality care and safety.

PYRIDOXINE-dependent epilepsy (PDE): An observational study of neonatal cases on the role of pyridoxine in patients treated with standard anti-seizure medications.

BACKGROUND: The main objective of this study was to evaluate the neurological consequences of delayed pyridoxine administration in patients diagnosed with Pyridoxin Dependent Epilepsies (PDE). MATERIALS AND METHODS: We reviewed 29 articles, comprising 52 genetically diagnosed PDE cases, ensuring data homogeneity. Three additional cases were included from the General Pediatric Operative Unit of San Marco Hospital. Data collection considered factors like age at the first seizure's onset, EEG reports, genetic analyses, and more. Based on the response to first-line antiseizure medications, patients were categorized into four distinct groups. Follow-up evaluations employed various scales to ascertain neurological, cognitive, and psychomotor developments. RESULTS: Our study includes 55 patients (28 males and 27 females), among whom 15 were excluded for the lack of follow-up data. 21 patients were categorized as "Responder with Relapse", 11 as "Resistant", 6 as "Pyridoxine First Approach", and 2 as "Responders". The neurological outcome revealed 37,5 % with no neurological effects, 37,5 % showed complications in two developmental areas, 15 % in one, and 10 % in all areas. The statistical analysis highlighted a positive correlation between the time elapsed from the administration of pyridoxine after the first seizure and worse neurological outcomes. On the other hand, a significant association was found between an extended latency period (that is, the time that elapsed between the onset of the first seizure and its recurrence) and worse neurological outcomes in patients who received an unfavorable score on the neurological evaluation noted in a subsequent follow-up. CONCLUSIONS: The study highlights the importance of early recognition and intervention in PDE. Existing medical protocols frequently overlook the timely diagnosis of PDE. Immediate administration of pyridoxine, guided by a swift diagnosis in the presence of typical symptoms, might improve long-term neurological outcomes, and further studies should evaluate the outcome of PDE neonates promptly treated with Pyridoxine.

KCNQ2 mutations cause unique neonatal behavior arrests without motor seizures: Functional characterization.

OBJECTIVE: KCNQ2 gene mutation usually manifests as neonatal seizures in the first week of life. Nonsense mutations cause a unique self-limited familial neonatal epilepsy (SLFNE), which is radically different from developmental epileptic encephalopathy (DEE). However, the exact underlying mechanisms remain unclear. METHODS: The proband, along with their mother and grandmother, carried the c.1342C > T (p.Arg448Ter) mutation in the KCNQ2 gene. The clinical phenotypes, electroencephalography (EEG) findings, and neurodevelopmental outcomes were comprehensively surveyed. The mutant variants were transfected into HEK293 cells to investigate functional changes. RESULTS: The proband exhibited behavior arrests, autonomic and non-motor neonatal seizures with changes in heart rate and respiration. EEG exhibited focal sharp waves. Seizures were remitted after three months of age. The neurodevelopmental outcomes at three years of age were unremarkable. A functional study demonstrated that the currents of p.Arg448Ter were non-functional in homomeric p.Arg448Ter compared with that of the KCNQ2 wild type. However, the current density and V1/2 exhibited significant improvement and close to that of the wild-type after transfection with heteromeric KCNQ2 + p.Arg448Ter and KCNQ2 + KCNQ3 + p.Arg448Ter respectively. Channel expression on the cell membrane was not visible after homomeric transfection, but not after heteromeric transfection. Retigabine did not affect homomeric p.Arg448Ter but improved heteromeric p. Arg448Ter + KCNQ2 and heteromeric KCNQ2 + Arg448Ter + KCNQ3. CONCLUSIONS: The newborn carrying the p. Arg448Ter mutation presented frequent behavioral arrests, autonomic, and non-motor neonatal seizures. This unique pattern differs from KCNQ2 seizures, which typically manifest as motor seizures. Although p.Arg448Ter is a non-sense decay, the functional study demonstrated an almost-full compensation mechanism after transfection of heteromeric KCNQ2 and KCNQ3.

Código encefalopatía hipóxico-isquémica: revisión sistematizada para entornos con recursos limitados / Hypoxic-ischaemic encephalopathy code: a systematic review for resource-limited settings

Se estima que el 96% de los recién nacidos (RN) con encefalopatía hipóxico-isquémica (EHI) nacen en entornos con recursos limitados (ERL) sin capacidad para ofrecer el estándar asistencial vigente desde hace cerca de 15 años en los países con altos recursos y que incluye hipotermia terapéutica, neuromonitorización continua electroencefalográfica y resonancia magnética, además de un control intensivo de las constantes vitales y del equilibrio homeostático. Esta situación no parece estar cambiando; sin embargo y aún con estas limitaciones, el conocimiento actualmente disponible permite mejorar la asistencia de los pacientes con EHI atendidos en ERL. El propósito de esta revisión sistematizada es ofrecer, bajo el término «código EHI», recomendaciones de prácticas asistenciales basadas en evidencia científica y factibles en ERL, que permitan optimizar la atención del RN con EHI y ayuden potencialmente a reducir los riesgos asociados a la comorbilidad y a mejorar los resultados neuroevolutivos. El contenido del código EHI se agrupó en nueve epígrafes: 1) prevención de la EHI, 2) reanimación, 3) primeras seis horas de vida, 4) identificación y graduación de la EHI, 5) manejo de las convulsiones, 6) otras intervenciones terapéuticas, 7) disfunción multiorgánica, 8) estudios complementarios, y 9) atención a la familia. (AU)

It is estimated that 96% of infants with hypoxic-ischaemic encephalopathy (HIE) are born in resource-limited settings with no capacity to provide the standard of care that has been established for nearly 15 years in high-resource countries, which includes therapeutic hypothermia, continuous electroencephalographic monitoring and magnetic resonance imaging in addition to close vital signs and haemodynamic monitoring. This situation does not seem to be changing; however, even with these limitations, currently available knowledge can help improve the care of HIE patients in resource-limited settings. The purpose of this systematic review was to provide, under the term «HIE Code», evidence-based recommendations for feasible care practices to optimise the care of infants with HIE and potentially help reduce the risks associated with comorbidity and improve neurodevelopmental outcomes. The content of the HIE code was grouped under 9 headings: 1) prevention of HIE, 2) resuscitation, 3) first 6hours post birth, 4) identification and grading of encephalopathy, 5) seizure management, 6) other therapeutic interventions, 7) multiple organ dysfunction, 8) diagnostic tests and 9) family care. (AU)

Comparative Outcomes of Levetiracetam and Phenobarbital Usage in the Treatment of Neonatal Seizures: A Retrospective Analysis.

OBJECTIVES AND AIM: The primary aim of this study was to conduct a comparative analysis of the safety and efficacy of levetiracetam (LEV) and phenobarbital (PB) as first-line treatments for neonatal seizure management. This study was designed to measure and compare the incidence of adverse effects and to determine the discharge and mortality rates associated with the use of these antiseizure medications (ASMs). Through this comparison, this research sought to provide insights to optimise care for neonates experiencing seizures. MATERIALS AND METHODS: This retrospective cohort study evaluated 104 neonates treated for seizures at Zeynep Kamil Hospital from 2015 to 2020 after excluding those on non-PB/LEV antiseizure medications. Seizures were characterised using electroencephalogram (EEG) and categorised according to aetiology and frequency. Treatment efficacy was gauged by seizure cessation, as confirmed using EEG. Adverse effects and demographic data were recorded. Statistical analyses were conducted using SPSS, employing the Shapiro-Wilk, independent t-test, Mann-Whitney U test, and chi-square test, with a significance threshold of p < 0.05. RESULTS: Overall, 104 neonates treated with first-line ASM were evaluated for efficacy; PB was administered in 68.26% of the cases, while LEV was utilised in 31.74%. The total complete response rate was 40.38%, with no significant difference between the PB and LEV groups (p = 0.309). The incidence rate ratios (IRRs) demonstrated that seizure frequency profoundly influenced treatment effectiveness, with IRRs of 2.09 for rare seizures, 3.25 for frequent seizures, and 4.01 for status epilepticus, indicating a higher treatment response rate with increasing seizure frequency. For second-line treatment, among a subset of 62 patients, PB had a slight, non-significant advantage over LEV, with an odds ratio of 1.09, suggesting a marginally better response to LEV. Adverse events were significantly more frequent in the PB group, affecting 19 of 67 neonates (28.36%), compared to only 2 of 71 neonates (2.82%) in the LEV group (p < 0.001). No significant difference was observed in the discharge rates between the two groups (PB, 67.61%; LEV, 75.76%; p = 0.674). Interestingly, the mortality rate was significantly higher in the LEV group (45.45%) than that in the PB group (22.54%; p = 0.045). CONCLUSION: This study underscores LEV's superior safety profile over PB in neonatal seizure management, evidenced by a significantly lower rate of adverse events. PB seems to be more effective in the second-line treatment of neonatal seizures. Despite the lack of significant differences in the discharge rates, the higher mortality rate associated with LEV warrants further investigation. These findings advocate the cautious selection of antiepileptic drugs in neonatal care, with a preference for LEV based on its safety profile.

Hypoxic-ischaemic encephalopathy code: A systematic review for resource-limited settings.

It is estimated that 96% of infants with hypoxic-ischaemic encephalopathy (HIE) are born in resource-limited settings with no capacity to provide the standard of care that has been established for nearly 15 years in high-resource countries, which includes therapeutic hypothermia (TH), continuous electroencephalographic monitoring and magnetic resonance imaging (MRI) in addition to close vital signs and haemodynamic monitoring. This situation does not seem to be changing; however, even with these limitations, currently available knowledge can help improve the care of HIE patients in resource-limited settings. The purpose of this systematic review was to provide, under the term "HIE Code", evidence-based recommendations for feasible care practices to optimise the care of infants with HIE and potentially help reduce the risks associated with comorbidity and improve neurodevelopmental outcomes. The content of the HIE code was grouped under 9 headings: (1) prevention of HIE, (2) resuscitation, (3) first 6h post birth, (4) identification and grading of encephalopathy, (5) seizure management, (6) other therapeutic interventions, (7) multiple organ dysfunction, (8) diagnostic tests and (9) family care.

[Neurobiological basis of neonatal epilepsy and its comorbilities]. / Bases neurobiológicas de la epilepsia neonatal y sus comorbilidades.

The occurrence of seizures is frequent during the neonatal period due to the functional immaturity of the brain.The presence of these seizures may lead to a diagnosis of neonatal epilepsy, which is usually associated with structural alterations of the brain during neurodevelopment. Approximately 50% of people with active epilepsy have at least one comorbid medical disorder, and the existence of a comorbid process changes the course of the epilepsy. The presence of neurologic disorders preceding the onset of epilepsy indicates that underlying neurobiological alterations may independently cause the predisposition to epilepsy and comorbid processes. In this review we describe the structural and functional brain processes underlying the onset of neonatal epilepsy and its comorbidities.

La aparición de convulsiones es frecuente durante el periodo neonatal debido a las características de inmadurez funcional del cerebro es este periodo. La aparición de estas convulsiones puede llevar a un diagnóstico de epilepsia neonatal, que suele estar asociado a alteraciones estructurales del cerebro durante el neurodesarrollo. Aproximadamente el 50% de las personas con epilepsia activa padecen al menos un trastorno médico comórbido, y esto hace que cambie la evolución de la epilepsia. La presencia de trastornos neurológicos que preceden a la aparición de la epilepsia indica que alteraciones estructurales y/o funcionales del cerebro subyacentes pueden ser causa de la predisposición a padecer epilepsia y de los procesos comórbidos de manera independiente. En esta revisión describimos los procesos cerebrales estructurales y funcionales que subyacen a la aparición de epilepsia neonatal y sus comorbilidades.

High Doses of ANA12 Improve Phenobarbital Efficacy in a Model of Neonatal Post-Ischemic Seizures.

Phenobarbital (PB) remains the first-line medication for neonatal seizures. Yet, seizures in many newborns, particularly those associated with perinatal ischemia, are resistant to PB. Previous animal studies have shown that in postnatal day P7 mice pups with ischemic stroke induced by unilateral carotid ligation, the tyrosine receptor kinase B (TrkB) antagonist ANA12 (N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide, 5 mg/kg) improved the efficacy of PB in reducing seizure occurrence. To meet optimal standards of effectiveness, a wider range of ANA12 doses must be tested. Here, using the unilateral carotid ligation model, we tested the effectiveness of higher doses of ANA12 (10 and 20 mg/kg) on the ability of PB to reduce seizure burden, ameliorate cell death (assessed by Fluoro-Jade staining), and affect neurodevelopment (righting reflex, negative geotaxis test, open field test). We found that a single dose of ANA12 (10 or 20 mg/kg) given 1 h after unilateral carotid ligation in P7 pups reduced seizure burden and neocortical and striatal neuron death without impairing developmental reflexes. In conclusion, ANA12 at a range of doses (10-20 mg/kg) enhanced PB effectiveness for the treatment of perinatal ischemia-related seizures, suggesting that this agent might be a clinically safe and effective adjunctive agent for the treatment of pharmacoresistant neonatal seizures.

Early life seizures and epileptic spasms in STXBP1-related disorders.

OBJECTIVE: Individuals with disease-causing variants in STXBP1 frequently have epilepsy onset in the first year of life with a variety of seizure types, including epileptic spasms. However, the impact of early onset seizures and antiseizure medication (ASM) on the risk of developing epileptic spasms and impact on their trajectory are poorly understood, limiting informed and anticipatory treatment, as well as trial design. METHODS: We retrospectively reconstructed seizure and medication histories in weekly intervals for individuals with STXBP1 developmental and epileptic encephalopathy (DEE) with epilepsy onset in the first year of life and quantitatively analyzed longitudinal seizure histories and medication response. RESULTS: We included 61 individuals with early onset seizures, 29 of whom had epileptic spasms. Individuals with neonatal seizures were likely to have continued seizures after the neonatal period (25/26). The risk of developing epileptic spasms was not increased in individuals with neonatal seizures or early infantile seizures (21/41 vs. 8/16, odds ratio [OR] = 1, 95% confidence interval [CI] = .3-3.9, p = 1). We did not find any ASM associated with the development of epileptic spasms following prior seizures. Individuals with prior seizures (n = 16/21, 76%) had a higher risk of developing refractory epileptic spasms (n = 5/8, 63%, OR = 1.9, 95% CI = .2-14.6, p = .6). Individuals with refractory epileptic spasms had a later onset of epileptic spasms (n = 20, median = 20 weeks) compared to individuals with nonrefractory epileptic spasms (n = 8, median = 13 weeks, p = .08). SIGNIFICANCE: We provide a comprehensive assessment of early onset seizures in STXBP1-DEE and show that the risk of epileptic spasms is not increased following a prior history of early life seizures, nor by certain ASMs. Our study provides baseline information for targeted treatment and prognostication in early life seizures in STXBP1-DEE.

Pharmacokinetics and safety of brivaracetam in neonates with repeated electroencephalographic seizures: A multicenter, open-label, single-arm study.

OBJECTIVE: To evaluate the pharmacokinetics (PK), safety, and tolerability of brivaracetam (BRV) in neonates with repeated electroencephalographic seizures not controlled with previous antiseizure medications (ASMs). METHODS: Phase 2/3, multicenter, open-label, single-arm study (N01349/NCT03325439) in neonates with repeated electroencephalographic seizures (lasting ≥10 s) confirmed by video-electroencephalography, and inadequate seizure control with at least one ASM. A screening period (up to 36 h) was followed by a 48-h evaluation period during which patients received 0.5 mg/kg BRV twice daily (b.i.d) intravenously (IV). Patients who benefitted from BRV (investigator's opinion) could continue 0.5 mg/kg b.i.d (IV or oral solution) in an extension period. Outcomes included plasma concentrations of BRV following the first dose (primary), and incidence of treatment-emergent adverse events (TEAEs). RESULTS: Six patients (median [range] postnatal age: 1.5 [1.0, 6.0] days) received ≥1 dose of BRV. All six patients completed the evaluation period; two entered and completed the extension period. Overall (evaluation and extension periods), three patients received one dose of 0.5 mg/kg BRV and three received more than one dose. The median (range) duration of exposure to BRV (IV and oral solution) was 1.5 (1.0, 29.0) days (n = 6). At 0.5-1, 2-4, and 8-12 h following IV BRV administration, the GeoMean (GeoCV) plasma concentrations of BRV were 0.53 mg/L (15.40% [n = 5]), 0.50 mg/L (28.20% [n = 6]), and 0.34 mg/L (13.20% [n = 5]), respectively. Individual and population BRV PK profiles were estimated, and individual PK parameters were calculated using Bayesian feedback. The observed concentrations were consistent with the predicted PK. Three patients experienced four TEAEs, none of which were considered related to BRV. SIGNIFICANCE: BRV plasma concentrations in neonates were consistent with data in older children receiving BRV oral solution, and with data from adults receiving a nominal IV dose of 25 mg b.i.d. BRV was well tolerated, with no drug-related TEAEs reported. PLAIN LANGUAGE SUMMARY: Few drugs are available to treat seizures in newborn babies. Brivaracetam is approved to treat focal-onset seizures in children and adults in Europe (patients 2 years of age and older) and the United States (patients 1 month of age or older). In this study, six newborns with repeated seizures were treated with intravenous brivaracetam. The study doctors took samples of blood from the newborns and measured the levels of brivaracetam. The concentrations of brivaracetam in the newborns' blood plasma were consistent with data from studies in older children and in adults. No brivaracetam-related medical problems were reported.

Symptomatic Subdural Hygroma Following Acinetobacter Meningitis in an Infant.

We present a case of a full-term newborn with prenatal congenital heart disease, admitted to a level III neonatal intensive care unit. After undergoing a surgical palliation procedure, he experienced a complicated recovery, including nosocomial sepsis with isolation of Acinetobacter nosocomialis in both blood and cerebrospinal fluid. Subsequently, he developed focal clonic seizures that were refractory to antiepileptic drugs, and imaging studies revealed the presence of a subdural hygroma. Surgical drainage was performed, resulting in the resolution of the seizures. This report highlights the rare occurrence of Acinetobacter meningitis unrelated to neurosurgery and its progression to subdural hygroma in an infant, emphasizing the importance of recognizing such complications as potential causes of refractory seizures following infectious processes.