Neonatal-onset Epilepsy Research Articles

Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy.

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

Michael’s missed genetic diagnosis

AbstractMichael, after whom the Michael Foundation is named, had been diagnosed with neonatal-onset refractory epilepsy that challenged numerous epileptologists at the time. The seizures disappeared in adolescence but a neurodevelopmental disorder with intellectual disability remained. Still, to the best of our knowledge, genetic testing was never considered. Facial photographs of Michael potentially containing the clue to his diagnosis had been published multiple times in the past few decades and are known to a broad audience. Michael passed away in 2023 at the age of 80 years. A post-mortem analysis of Michael’s photographs employing both the human eye and artificial intelligence as well as retrospective anamnesis of Michael’s clinical symptoms revealed Williams–Beuren syndrome to be the by far most likely cause of Michael’s disorder. This diagnosis has implications for affected individuals as well as for the family and relatives and therefore illustrates the importance of genetic testing of neurodevelopmental disorders even in older individuals.

Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders.

SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel Nav1.2 are rare, with clinically heterogeneous expressions that include epilepsy, autism and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relationship to channel function, 81 patients (36 female, 44%, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their Nav1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal onset, n = 27; infant onset, n = 18; and later onset n = 24; and autism without seizures, n = 12) was strongly correlated with a non-seizure severity index (P = 0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (P = 0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland Adaptive Behavior composite score of 49.5 (>3 standard deviations below the norm-referenced mean of the test). Epileptic spasms were significantly more common in infant-onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (P = 0.007). Primary phenotype was also strongly correlated with variant function (P < 0.0001); gain-of-function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy and to severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups, representing: (i) primarily later-onset epilepsy with moderate loss-of-function variants and low severity indices; (ii) mostly infant-onset epilepsy with moderate loss-of-function variants but higher severity indices; and (iii) late-onset and autism only, with the lowest severity indices (mostly zero) and severe/complete loss-of-function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relationship between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on Nav1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance towards clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment

While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n ​= ​1) or G239S variant (n ​= ​2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell patch-clamp electrophysiological experiments in Chinese Hamster Ovary cells transiently-transfected with the cDNAs encoding Kv7.2 subunits carrying the Y141N or G239S variants in homomeric or heteromeric configurations with Kv7.2 subunits, revealed that currents from channels incorporating mutant subunits displayed increased current densities and hyperpolarizing shifts of about 10 ​mV in activation gating; both these functional features are consistent with an in vitro GoF phenotype. The antidepressant drug amitriptyline induced a reversible and concentration-dependent inhibition of current carried by Kv7.2 Y141N and G239S mutant channels. Based on in vitro results, amitriptyline was prescribed in one patient (G239S), prompting a significant improvement in motor, verbal, social, sensory and adaptive behavior skillsduring the two-year-treatment period. Thus, our results suggest that KCNQ2 GoF variants Y141N and G239S cause a mild DD with prominent language deficits in the absence of neonatal seizures and that treatment with the Kv7 channel blocker amitriptyline might represent a potential targeted treatment for patients with KCNQ2 GoF variants.

A novel approach to seizures in neonates.

Recognition of seizures in neonates remains the foremost challenge to overcome. All neonates at risk for seizures, especially the critically ill, should undergo video-EEG monitoring. The initial step toward an accurate diagnosis is the accurate description and interpretation of the electro-clinical phenotype. THE IMPORTANCE OF SEIZURE SEMIOLOGY AND ASSOCIATION WITH ETIOLOGY: The early distinction between acute provoked seizures and neonatal-onset epilepsies serves as the primary determinant for guiding management, treatment choices, and duration. Seizures in neonates should be seen as a symptom, not a disease, and their semiology may suggest the etiology. Neonates with hypoxic-ischemic encephalopathy respond best to phenobarbital, while levetiracetam is a better choice for neonates with congenital heart diseases. Anti-seizure medication can be discontinued after 72h of seizure freedom, before discharge from the hospital. Neonates with epilepsy usually require a personalized, etiology-based approach in terms of choice and duration of treatment. Neonates with channelopathies tend to respond to sodium channel blockers such as carbamazepine, oxcarbazepine, or phenytoin. The surgical option should be considered early in cases of large brain malformations, such as hemimegalencephaly.

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures.

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options.

Epilepsy-associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties.

Pathogenic variants in voltage-gated sodium (NaV) channel genes including SCN2A, encoding NaV1.2, are discovered frequently in neurodevelopmental disorders with or without epilepsy. SCN2A is also a high-confidence risk gene for autism spectrum disorder (ASD) and nonsyndromic intellectual disability (ID). Previous work to determine the functional consequences of SCN2A variants yielded a paradigm in which predominantly gain-of-function variants cause neonatal-onset epilepsy, whereas loss-of-function variants are associated with ASD and ID. However, this framework was derived from a limited number of studies conducted under heterogeneous experimental conditions, whereas most disease-associated SCN2A variants have not been functionally annotated. We determined the functional properties of SCN2A variants using automated patch-clamp recording to demonstrate the validity of this method and to examine whether a binary classification of variant dysfunction is evident in a larger cohort studied under uniform conditions. We studied 28 disease-associated variants and 4 common variants using two alternatively spliced isoforms of NaV1.2 expressed in HEK293T cells. Automated patch-clamp recording provided a valid high throughput method to ascertain detailed functional properties of NaV1.2 variants with concordant findings for variants that were previously studied using manual patch clamp. Many epilepsy-associated variants in our study exhibited complex patterns of gain- and loss-of-functions that are difficult to classify by a simple binary scheme. The higher throughput achievable with automated patch clamp enables study of variants with greater standardization of recording conditions, freedom from operator bias, and enhanced experimental rigor. This approach offers an enhanced ability to discern relationships between channel dysfunction and neurodevelopmental disorders.

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 five 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.

SCN1A gain-of-function mutation causing an early onset epileptic encephalopathy.

Loss-of-function variants in SCN1A cause Dravet syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests separate entities of SCN1A-related disorders due to gain-of-function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain-of-function variant, identified in four individuals at a single center. Individuals carrying the recurrent SCN1A p.R1636Q variant were identified through diagnostic testing. Whole cell voltage-clamp electrophysiological recording in HEK-293 T cells was performed to compare the properties of sodium channels containing wild-type Nav 1.1 or Nav 1.1-R1636Q along with both Nav β1 and Nav β2 subunits, including response to oxcarbazepine. To delineate differences from other SCN1A-related epilepsies, we analyzed electronic medical records. All four individuals had an early onset DEE characterized by focal tonic seizures and additional seizure types starting in the first few weeks of life. Electrophysiological analysis showed a mixed gain-of-function effect with normal current density, a leftward (hyperpolarized) shift of steady-state inactivation, and slower inactivation kinetics leading to a prominent late sodium current. The observed functional changes closely paralleled effects of pathogenic variants in SCN3A and SCN8A at corresponding positions. Both wild type and variant exhibited sensitivity to block by oxcarbazepine, partially correcting electrophysiological abnormalities of the SCN1A p.R1636Q variant. Clinically, a single individual responded to treatment with oxcarbazepine. Across 51 individuals with SCN1A-related epilepsies, those with the recurrent p.R1636Q variants had the earliest ages at onset. The recurrent SCN1A p.R1636Q variant causes a clinical entity with a wider clinical spectrum than previously reported, characterized by neonatal onset epilepsy and absence of prominent movement disorder. Functional consequences of this variant lead to mixed loss and gain of function that is partially corrected by oxcarbazepine. The recurrent p.R1636Q variant represents one of the most common causes of early onset SCN1A-related epilepsies with separate treatment and prognosis implications.

Levetiracetam versus Phenobarbital for Neonatal Seizures: A Retrospective Cohort Study

BackgroundAlthough phenobarbital (PB) is commonly used as a first-line antiseizure medication (ASM) for neonatal seizures, in 2015 we chose to replace it with levetiracetam (LEV), a third-generation ASM. Here, we compared the safety and efficacy of LEV and PB as first-line ASM, considering the years before and after modifying our treatment protocol. MethodsWe conducted a retrospective cohort study of 108 neonates with electroencephalography (EEG)-confirmed seizures treated with first-line LEV or PB in 2012 to 2020. ResultsFirst-line ASM was LEV in 33 (31%) and PB in 75 (69%) neonates. The etiology included acute symptomatic seizures in 69% of cases (30% hypoxic-ischemic encephalopathy, 32% structural vascular, 6% infectious, otherwise metabolic) and neonatal epilepsy in 22% (5% structural due to brain malformation, 17% genetic). Forty-two of 108 (39%) neonates reached seizure freedom following first-line therapy. Treatment response did not vary by first-line ASM among all neonates, those with acute symptomatic seizures, or those with neonatal-onset epilepsy. Treatment response was lowest for neonates with a higher seizure frequency, particularly for those with status epilepticus versus rare seizures (P < 0.001), irrespective of gestational age, etiology, or EEG findings. Adverse events were noted in 22 neonates treated with PB and in only one treated with LEV (P < 0.001). ConclusionsOur study suggests a potential noninferiority and a more acceptable safety profile for LEV, which may thus be a reasonable option as first-line ASM for neonatal seizures in place of PB. Treatment should be initiated as early as possible since higher seizure frequencies predispose to less favorable responses.

The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.

Genetic Testing and Hospital Length of Stay in Neonates With Epilepsy

BackgroundWe evaluated changes in genetic testing for neonatal-onset epilepsy and associated short-term outcomes over an 8-year period among a cohort of patients in the neonatal intensive care unit (NICU) at a single institution before and after the introduction of sponsored genetic epilepsy testing in January 2018. MethodsOur primary outcome was a change in length of stay (LOS) after 2018. We also ascertained severity of illness with the Neonatal Sequential Organ Failure Assessment (nSOFA), type and result of genetic testing, turnaround time to molecular diagnosis (TAT), LOS, antiseizure medications (ASMs), and use of technology at discharge. We compared outcomes using nonparametric tests and difference-in-difference analysis. ResultsFifty-three infants with genetic testing were included; 20 infants were tested after 2018. A total of 4160 infants in the NICU without genetic testing were used as reference. In the genetic testing group, LOS was 25 days (interquartile range [IQR] 5, 49) pre-2018 and 19 days (IQR 6, 19) post-2018 (P < 0.001 when compared with the reference population in the difference-in-difference analysis). TAT decreased from 51 days to 17 days after 2018 (P = 0.003). ASM number decreased from 4 (IQR 2, 5) to 2 post-2018 (IQR 1, 3) (P = 0.02). Over the same time periods there was no significant change in birth weight, maximum nSOFA score, or technology dependence. ConclusionsIn this cohort, changes in genetic testing for neonatal-onset epilepsy were associated with shorter LOS that was not explained by changes in severity of illness, birth weight, or the average LOS in the NICU over time. Validation of these results in a larger, multicenter sample size is warranted.

Neuropathology findings in KCNQ2 neonatal epileptic encephalopathy.

PurposeKCNQ2-epileptic encephalopathy (EE) is a neonatal epilepsy syndrome characterized by a typical clinical presentation and EEG recording, but without any brain or cortical abnormal development on MRI. Most of the patients have a severe developmental impairment. The epileptogenic mechanisms are thought to be the result of the changes of the M-current density causing a change of brain excitability. Although recent studies allow us to better understand the physiopathology of KCNQ2-EE, the neuropathology of this ion channel dysfunction has only been previously described in a single case report. MethodsWe report the neuropathology study of a case of KCNQ2-EE with a typical electro-phenotype due to a de novo heterozygous single nucleotide pathogenic variant in the exon 5 of the KCNQ2 gene (NM_172107.2:c.802C>T; p.Leu268Phe). ResultsAt the macroscopic level, the brain had a normal structure with a normal neocortical gyral pattern. At the histological level, the cortex had a usual six-layer lamination in all lobes but blurred gray-white matter boundaries due to excessive heterotopic neurons in deep white matter were observed. This diffuse mild malformation of cortical development is suggestive of a neuronal migration disorder. ConclusionIn recent years, our understanding of the role of ion channel dysfunctions in early brain development has expanded from the occurrence of EE to brain malformation. Through this rare neuropathological report, we emphasize the role of KCNQ2 channels in the process of cortical development. As for other genetic neonatal onset epilepsies, more reports are needed to further delineate the range of neuropathological abnormalities for KCNQ2-EE.

Neonatal seizures: diagnostic updates based on new definition and classification.

Neonatal seizures are the most common neurological symptoms caused by various etiologies in the neonatal period, but their diagnosis and treatment are challenging because their pathophysiology and electroclinical manifestations differ from those of patients in older age groups. Many seizures present as electrographic-only events without clinical signs or as obscure clinical manifestations that are difficult to distinguish from other neonatal behaviors. Accordingly, a new definition and classification of neonatal seizures was recently proposed by the International League Against Epilepsy Task Force on neonatal seizures, highlighting the role of electroencephalography in diagnosing and treating neonatal seizures. Neonatal seizures are defined as electrographic events with sudden, paroxysmal, and abnormal alteration of activity and divided into electroclinical seizures and electrographic-only seizures according to their clinical signs, thus excluding clinical events without an electrographic correlation. Seizure types are described by their predominant clinical features and divided into motor (automatisms, clonic, epileptic spasms, myoclonic, tonic, and sequential), nonmotor (autonomic and behavioral arrest), and unclassified. Although many neonatal seizures are acute reactive events caused by hypoxic-ischemic encephalopathy or vascular insults, structural, genetic, or metabolic etiologies of neonatal-onset epilepsy should also be thoroughly evaluated to determine their appropriate management.

Cerebrospinal Fluid Ion Analysis in Neonatal Seizures

BackgroundThere is a gap of knowledge regarding cerebrospinal fluid (CSF) ion concentrations in normal and pathological states, particularly during the neonatal period. We aim to compare CSF ion concentrations in newborns with different causes of neonatal-onset epilepsy (NOE) and acute symptomatic seizures (ASS) and controls, to examine their usefulness for diagnostic purposes. MethodsA descriptive retrospective study was conducted from January 2019 to June 2020 in a tertiary hospital. We analyzed CSF K+, Na+, Cl−, and Ca2+ concentrations in frozen samples from patients with neonatal seizures (NS) secondary to NOE and ASS (neonatal arterial ischemic stroke [NAIS] and hypoxic-ischemic encephalopathy). As the control group, we selected CSF samples from newborns who had undergone CSF analysis as part of the diagnostic workup and in whom central nervous system infections had been ruled out, without signs of dehydration, gastroenteritis, or history of seizures. ResultsSixty-eight newborns were included, 16 with NOE, 13 with ASS, and 39 without NS (control group). In comparison with the control group, [K+]CSF was lower in patients with KCNQ2-related epilepsy (P = 0.007), other causes of NOE (P = 0.010), and NAIS (P = 0.002). Changes in [Na+]CSF, [Cl−]CSF, and [Ca2+]CSF were less consistent among subgroups. ConclusionsHere we report for the first time ionic imbalances in the CSF of neonates with NOE and NAIS. No differences were observed between newborns with different causes of NS. Further studies should be undertaken to investigate the physiopathology behind these changes and their impact on biological function.

Disorders of Neuronal Migration/Organization Convey the Highest Risk of Neonatal Onset Epilepsy Compared With Other Congenital Brain Malformations

BackgroundAlthough seizures in neonates are common and often due to acute brain injury, 10-15% are unprovoked from congenital brain malformations. A better understanding of the risk of neonatal-onset epilepsy by the type of brain malformation is essential for counseling and monitoring. MethodsIn this retrospective cohort study, we evaluated 132 neonates with congenital brain malformations and their risk of neonatal-onset epilepsy. Malformations were classified into one of five categories based on imaging patterns on prenatal or postnatal imaging. Infants were monitored with continuous video EEG (cEEG) for encephalopathy and paroxysmal events in addition to abnormal neuroimaging. ResultsSeventy-four of 132 (56%) neonates underwent EEG monitoring, and 18 of 132 (14%) were diagnosed with neonatal-onset epilepsy. The highest prevalence of epilepsy was in neonates with disorders of neuronal migration/organization (9/34, 26%; 95% confidence interval [CI] = 13-44%), followed by disorders of early prosencephalic development (6/38, 16%; 95% CI = 6-31%), complex total brain malformations (2/16, 13%; 95% CI = 2-38%), and disorders of midbrain/hindbrain malformations (1/30, 3%; 95% CI = 0-17%). Of neonates with epilepsy, 5 of 18 (28%) had only electrographic seizures, 13 of 18 (72%) required treatment with two or more antiseizure medicines (ASMs), and 7 of 18 (39%) died within the neonatal period. ConclusionOur results demonstrate that disorders of neuronal migration/organization represent the highest-risk group for early-onset epilepsy. Seizures are frequently electrographic only, require treatment with multiple ASMs, and portend a high mortality rate. These results support American Clinical Neurophysiology Society recommendations for EEG monitoring during the neonatal period for infants with congenital brain malformations.

Stopping Medication for Seizures Prior to NICU Discharge

Source: Glass HC, Soul JS, Chang T, et al Safety of early discontinuation of antiseizure medication after acute symptomatic neonatal seizures. JAMA Neurol. 2021;78(7):817-825; doi:10.1001/jamaneurol.2021.1437Investigators from multiple institutions conducted a prospective observational study to compare outcomes among infants with neonatal seizures whose anti-seizure medications (ASM) were discontinued early (prior to hospital discharge) or maintained following discharge. Study participants were infants with acute symptomatic seizures who were born between July 2015 and March 2018 and were enrolled at 9 Neonatal Seizure Registry (NSRs) centers in the US. Only patients with neonatal seizures documented with continuous conventional electroencephalogram (cEEG) monitoring from a symptomatic cause and who were treated with ASM for the seizures were enrolled. Demographic and clinical data and ASM administration during the neonatal admission were abstracted from the medical record, and participants were followed until 24 months corrected age.The study population was divided into 2 treatment groups based on whether ASM were discontinued prior to hospital discharge or maintained following discharge. The primary study outcome was functional neurodevelopment at 24 months as assessed by the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS), a 50-item questionnaire completed by parents. In typically developing children the mean score is 172 ±10. WIDEA-FS scores among children in the 2 treatment groups were compared with regression analysis. To account for confounding, propensity scores that accounted for multiple patient and clinical characteristics were calculated on study patients and included in regression models. A priori, early discontinuation of ASM was considered to be non-inferior to maintaining therapy after discharge if the difference in mean WIDEA-FS was <-12 points in the propensity score-adjusted analysis. The main secondary outcome was diagnosis of post-neonatal epilepsy. Rates of epilepsy among children in the 2 treatment groups were compared after propensity score adjustment.A total of 303 eligible children were enrolled; 84% were born at ≥37 weeks’ gestation, and 56% were male. Seizure cause was HIE in 43%, ischemic stroke in 26%, intracranial hemorrhage in 18%, and other brain injury in 13%. Overall, 194 (64%) of participants were maintained on ASM after discharge, with 68% of these children treated with phenobarbital. At 24 months, median WIDEA-FS scores were 165 and 161, respectively, for children in the early discontinuation group and those who continued ASM use after discharge. The propensity score-adjusted difference was +4 points (95% CI, -3, +11), meeting the non-inferiority criterion. Among children in the early discontinuation treatment group, 11% developed epilepsy vs 14% of those whose ASM was continued after discharge (adjusted OR, 1.5; 95% CI, 0.7, 3.4).The authors conclude that were no differences in functional neurodevelopment or rate of epilepsy among children with neonatal seizures whose ASM were discontinued before hospital discharge or continued after discharge.Dr Candee has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The majority of acute seizures in the neonatal period are symptomatic and self-limited.1 While infants with a history of neonatal seizures are at risk for postnatal epilepsy, there is typically a period of latency prior to onset. The ideal duration of ASM treatment for neonatal acute symptomatic seizures is unclear. Despite a 2007 retrospective study by Guillet et al showing that seizure recurrence and developmental disabilities were unaffected by phenobarbital prophylaxis,2 a subsequent 2009 NIH-funded attempt at a randomized placebo-controlled clinical trial of prophylactic phenobarbital in neonates was closed early due to low enrollment.3The current comparative effectiveness study included more than 300 neonates with acute symptomatic seizures, all of whom underwent cEEG monitoring, technology not employed during the earlier study by Guillet et al.2 The primary outcomes, functional neurodevelopment and risk of epilepsy, were no different between the group continued on ASM beyond hospital discharge and the group in which therapy was discontinued. Propensity analysis ensured that factors that might influence whether to continue ASM, such as neurological examination or EEG findings, did not unduly influence the study results. The findings strengthen the argument for discontinuation of ASM therapy after 72 hours of seizure freedom, as recommended by the World Health Organization.4 Widespread enactment of this approach could have significant impact on NICU admission duration, cost of care during the first year of life, and long-term cognitive outcome.While a potential weakness of the study is that the primary outcomes were assessed via parent interview using a standardized telephone survey, the study’s applicability is bolstered by the exclusion of neonates with transient reversible causes or neonatal-onset epilepsy syndromes and by the blinding of research staff administering the surveys.ASM treatment beyond hospital discharge is unnecessary for most neonates with acute symptomatic seizures. (See AAP Grand Rounds. 2021;45[1]:6.)5Clearly ASM can neither mitigate preexisting brain pathology underlying most neonatal seizures nor abrogate the subsequent development of epilepsy.6 Follow-up beyond 24 months of age certainly is needed.

Genotypes and clinical features of neonatal-onset genetic epilepsy in 141 patients

Objective: To summarize the genotypes and clinical features of neonatal-onset genetic epilepsy. Methods: Patients (114 cases) with identified gene variants were collected from May 2013 to May 2019 in Peking University First Hospital, retrospectively. The genotype, clinical, electroencephalographic and neuroimaging characteristics were analyzed. Results: A total of 141 neonatal-onset epilepsy patients with identified gene variants were enrolled, including 76 males and 65 females and involving 33 epilepsy genes. Top five genes were KCNQ2 (56 cases), SCN2A (25 cases), STXBP1 (9 cases), CDKL5 (8 cases) and KCNT1 (6 cases), accounting for 73.8% (104/141). The age of seizure onset was 3(1-28) days of age, 71.6% (101/141) were within 1 week of age. The age of genetic diagnosis was 4 months (1 month to 13 years) of age. A total of 130 patients presented focal seizures; 47 patients presented epileptic spasms. Other seizure types included generalized tonic-clonic seizures, clonic seizures, myoclonic seizures, tonic seizures and absence seizures. Fifty-eight patients experienced multiple seizure types. The results of video-electroencephlogram (VEEG) were abnormal in 127 patients and in 62 patients clinical seizures were captured. Global developmental delay was presented in 122 patients. Epilepsy syndromes were diagnosed in 59 patients. Thirteen patients were diagnosed as Ohtahara syndrome (OS), 9 as epilepsy of infancy with migrating focal seizures (EIMFS), 17 as West syndrome (WS), 4 as OS developed to WS, 9 as benign neonatal epilepsy (BNE), 2 as benign familiar neonatal-infantile epilepsy (BFNIE), 2 as benign infantile epilepsy (BIE) and 3 as benign familial infantile epilepsy (BFIE). Sixty-seven patients were diagnosed as unclassified early infantile epileptic encephalopathy (EIEE), 13 patients could not be diagnosed as any epilepsy syndrome, and 2 patients were diagnosed as pyridoxine-dependent epilepsy. Forty-six patients had abnormal neuroimaging including cortical atrophy, corpus callosum dysplasia and cerebellar atrophy, involving 19 genes. Conclusions: Neonatal-onset epilepsy is related to many different genes. Seizure onset age of most patients is within one week after birth. Focal seizures and epileptic spasms are more common. Some patients show abnormal neuroimaging.

Novel Therapeutics for Neonatal Seizures.

Neonatal seizures are a common neurologic emergency for which therapies have not significantly changed in decades. Improvements in diagnosis and pathophysiologic understanding of the distinct features of acute symptomatic seizures and neonatal-onset epilepsies present exceptional opportunities for development of precision therapies with potential to improve outcomes. Herein, we discuss the pathophysiology of neonatal seizures and review the evidence for currently available treatment. We present emerging therapies in clinical and preclinical development for the treatment of acute symptomatic neonatal seizures. Lastly, we discuss the role of precision therapies for genetic neonatal-onset epilepsies and address barriers and goals for developing new therapies for clinical care.

Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review.

Despite expanding next generation sequencing technologies and increasing clinical interest into complex neurologic phenotypes associating epilepsies and developmental/epileptic encephalopathies (DE/EE) with movement disorders (MD), these monogenic conditions have been less extensively investigated in the neonatal period compared to infancy. We reviewed the medical literature in the study period 2000–2020 to report on monogenic conditions characterized by neonatal onset epilepsy and/or DE/EE and development of an MD, and described their electroclinical, genetic and neuroimaging spectra. In accordance with a PRISMA statement, we created a data collection sheet and a protocol specifying inclusion and exclusion criteria. A total of 28 different genes (from 49 papers) leading to neonatal-onset DE/EE with multiple seizure types, mainly featuring tonic and myoclonic, but also focal motor seizures and a hyperkinetic MD in 89% of conditions, with neonatal onset in 22%, were identified. Neonatal seizure semiology, or MD age of onset, were not always available. The rate of hypokinetic MD was low, and was described from the neonatal period only, with WW domain containing oxidoreductase (WWOX) pathogenic variants. The outcome is characterized by high rates of associated neurodevelopmental disorders and microcephaly. Brain MRI findings are either normal or nonspecific in most conditions, but serial imaging can be necessary in order to detect progressive abnormalities. We found high genetic heterogeneity and low numbers of described patients. Neurological phenotypes are complex, reflecting the involvement of genes necessary for early brain development. Future studies should focus on accurate neonatal epileptic phenotyping, and detailed description of semiology and time-course, of the associated MD, especially for the rarest conditions.