Maria Roberta Cilio

• Professor of Pediatric Neurology
• University of California, San Francisco

Purpose of review Neonatal and infantile epilepsies represent a diverse group of disorders with significant neurodevelopmental impact, necessitating early diagnosis, and tailored treatment. Recent advancements in genetic research, phenotyping, and therapeutic development have reshaped the understanding and management of these conditions, making thi...

Objective To employ the neonatal seizure framework developed by the International League Against Epilepsy (ILAE) Neonatal Task force to assess its usefulness in determining the etiology of neonatal seizures. Methods The members of the ILAE Neonatal Task Force evaluated 157 seizures from 146 neonates to determine internal validity and associations...

Objective Few studies have evaluated the efficacy of antiseizure medications (ASMs) according to the etiology of neonatal acute provoked seizures. We aimed to investigate the response to ASMs in term/near term neonates with acute arterial ischemic stroke (AIS), as well as the type of seizure at presentation and the monitoring approach. Methods We...

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 liter...

The challenge of seizure recognition: 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....

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases...

Purpose: Early recognition of seizures in neonates secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications but respond well to sodium channel blockers. Recently, a characteristic ictal amplitude-integrated electroencephalogram (aEEG) pa...

Objective The International League Against Epilepsy (ILAE) Neonatal Seizure Framework was tested by medical personnel. Methods Attendees at the 2016 ILAE European Congress on Epileptology in Prague, the International Video‐EEG Course in Pediatric Epilepsies in Madrid 2017, and a local meeting in Utrecht 2018, were introduced to the proposed ILAE n...

Background: We aim to describe a cohort of patients with KCNQ2-related epilepsy and evaluate the relationship between epileptic activity and developmental outcome. This topic is relevant for the selection of clinical end points in future clinical trials, since cessation of seizures may or may not be the most important outcome. Methods: This retr...

Background and Objective BRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis. Methods Through a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with bi-allelic patho...

The blooming of neonatal neurocritical care over the last decade reflects substantial advances in neuromonitoring and neuroprotection. The most commonly used brain monitoring tools in the neonatal intensive care unit (NICU) are amplitude integrated EEG (aEEG), full multichannel continuous EEG (cEEG), and near-infrared spectroscopy (NIRS). While som...

Neonatal intensive care has expanded from cardiorespiratory care to a holistic approach emphasizing brain health. To best understand and monitor brain function and physiology in the neonatal intensive care unit (NICU), the most commonly used tools are amplitude-integrated EEG, full multichannel continuous EEG, and near-infrared spectroscopy. Each o...

A key goal of neonatal neurocritical care is improved outcomes, and brain monitoring plays an essential role. The recent NEST trial1 reported no outcome benefits using aEEG monitoring compared to clinical seizure identification among neonates treated for seizures. However, the study failed to prove the effects of monitoring on seizure treatment in...

Background While 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 type of brain malformation is essential for counseling and monitoring. Methods In this retrospective cohort study, we evaluated 132 neonate...

Objective To characterize intracranial hemorrhage (ICH) as a seizure etiology in infants born at term and preterm. For term infants, to compare seizure severity and treatment response for multi-site vs single-site ICH and hypoxic-ischemic encephalopathy (HIE) with vs. without ICH. Study design We studied 112 newborn infants with seizures attribute...

Objective To compare key seizure and outcome characteristics between neonates with and without cardiopulmonary disease (CPD). Study design The Neonatal Seizure Registry (NSR-1) is a multicenter, prospectively acquired cohort of neonates with clinical or EEG-confirmed seizures. CPD was defined as congenital heart disease, congenital diaphragmatic h...

Objective Although most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determ...

Objective To determine whether screening continuous EEG monitoring (cEEG) is associated with greater odds of treatment success for neonatal seizures. Methods We included term neonates with acute symptomatic seizures enrolled in the Neonatal Seizure Registry (NSR) , a prospective, multicenter cohort of neonates with seizures. We compared two cEEG a...

Seizures are the most common neurological emergency in the neonatal period and in contrast to those in infancy and childhood, are often provoked seizures with an acute cause and may be electrographic‐only. Hence, neonatal seizures may not fit easily into classification schemes for seizures and epilepsies primarily developed for older children and a...

Objective Early identification of de novo KCNQ2 variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo KCNQ2 pathogenic variants to dissect genotype-phenotype correlations. Methods Patients with de novo KCNQ2 pathogenic variants...

Pathogenic variants in KCNQ2 and KCNQ3, paralogous genes encoding Kv7.2 and Kv7.3 voltage-gated K⁺ channel subunits, are responsible for early−onset developmental/epileptic disorders characterized by heterogeneous clinical phenotypes ranging from benign familial neonatal epilepsy (BFNE) to early−onset developmental and epileptic encephalopathy (DEE...

Background Neonatal seizures are associated with death and neurologic morbidity; however, little is known about how neonates with seizures die. Methods This was a prospective, observational cohort study of neonates with seizures treated at seven sites of the Neonatal Seizure Registry. We characterized mode of death, evaluated the association betwe...

Objective To characterize and determine risk factors for key dimensions of well-being at hospital discharge in families of neonates with acute symptomatic seizures. Study design This prospective, observational cohort study enrolled 144 parent-infant dyads among neonates with acute symptomatic seizures from 9 pediatric hospitals in the Neonatal Sei...

Purpose: Limited data suggest that cannabidiol (CBD) may be effective for treatment of refractory infantile spasms (IS). This study was designed to more rigorously evaluate the efficacy and safety of synthetic CBD in the treatment of IS. Methods: Children six to 36 months of age with IS that failed treatment with both adrenocorticotropic hormone...

Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) is a rare, developmental and epileptic encephalopathy most commonly associated with mutations in KCNT1, a potassium channel. Polymorphous migrating focal seizures begin within 6 months of life and are pharmacoresistant to standard anticonvulsants. Additional therapies are needed to decrease...

The new concept of developmental and epileptic encephalopathy is based on the understanding that many genetic epilepsies are associated with developmental impairment as a direct consequence of the genetic mutation, in addition to the effect of the frequent epileptic activity on brain development. As an example, in infants with KCNQ2 or STXBP1 encep...

Developmental and epileptic encephalopathies are genetic disorders in which both the developmental disability and the frequent epileptic activity are the effect of a specific gene variant. While heterozygous variants in SCN1B have been described in families with generalized epilepsy with febrile seizures plus, Type 1, only three cases of homozygous...

Objective: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. Methods: Patients with NDD and KCNQ3 DNVs were identified...

Background Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population. Objective The objective of...

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Cli...

In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypox...

The aim of this study was to evaluate whether specific etiologies of neonatal seizures have distinct ictal electroclinical features. A systematic review of English articles using the PubMed database since 2004 (last update 9/26/16). Search terms included text words and Medical Subject Headings (MeSH) terms related to neonatal seizures. Eligible art...

Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent...

Although the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy often linked to a pathogenic genetic variant. Historically, studies on neonatal seizures including treatment response and long-term consequences have lumped all etiologies together. However, etio...

The past decade has witnessed a major transformation in our understanding of epilepsies presenting in the neonatal period. Old broad umbrella syndromes, such as Ohtahara syndrome and early myoclonic encephalopathy, are being parsed into new distinct genetic epilepsies based on the underlying etiology. Progress in understanding the genetic basis of...

Background Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox–Gastaut and Dravet syndromes, but most published studies have not extended beyond 12–16 weeks. Objective The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children...

The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own establish...

Objective To evaluate the clinical efficacy and safety of quinidine in patients with KCNT1‐related epilepsy of infancy with migrating focal seizures (EIMFS) in the infantile period and to compare with the effect of quinidine on mutant channels in vitro. Methods We identified 4 patients with EIMFS with onset in the neonatal period, pathogenic varia...

Significance SCN2A , encoding the voltage-gated sodium channel Na v 1.2, has emerged as a major gene implicated in neonatal-, infantile-, and even childhood-onset epilepsies. Many of these epilepsies are also associated with cognitive and behavioral impairments that range in type and severity. The biophysical, neurophysiological, and clinical impac...

Objectives: To assess the prognostic significance of an early normal/mildly abnormal conventional EEG (cEEG) on seizure risk in neonates undergoing therapeutic hypothermia. Methods: We reviewed the video-EEG recordings from a large cohort of neonates treated with therapeutic hypothermia for hypoxic-ischemic encephalopathy from 2008 to 2017 in a...

Whereas the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy, often linked to a pathogenic genetic variant. This defect may disrupt cortical development (e.g., lissencephaly, focal cortical dysplasia), lead to metabolic changes (e.g., pyridoxine-dependent e...

Background: Recurrent and prolonged seizures are harmful for the developing brain, emphasizing the importance of early seizure recognition and effective therapy. Amplitude-integrated electroencephalography (aEEG) has become a valuable tool to diagnose epileptic seizures, and, in parallel, genetic etiologies are increasingly being recognized, chang...

Objective: Although individual neonatal epilepsy syndromes are rare, as a group they represent a sizable subgroup of neonatal seizure etiologies. We evaluated the profile of neonatal epilepsies in a prospective cohort of newborns with seizures. Methods: Consecutive newborns with seizures were enrolled in the Neonatal Seizure Registry (an associa...

Objective: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. Methods: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutat...

Background: The purpose of this study was to characterize seizures among preterm neonates enrolled in the Neonatal Seizure Registry, a prospective cohort of consecutive neonates with seizures at seven pediatric centers that follow the American Clinical Neurophysiology Society's neonatal electroencephalography monitoring guideline. Study design:...

Objective: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. Methods: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved...

Objective: To evaluate treatment responses in benign familial neonatal epilepsy (BFNE). Methods: We recruited patients with BFNE through a multicenter international collaboration and reviewed electroclinical and genetic details, and treatment response. All patients were tested at minimum for mutations/deletions in the KCNQ2, KCNQ3, and SCN2A gen...

Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they...

Rare loss of function variants in 17 epilepsy patients with known HGMD SCN1A variants. (XLSX)

SCN1A domain organization and mutations. The schematic diagram showing the domain organization of the alpha subunit of the voltage-gated sodium ion channel coded by the SCN1A gene and the positions of the missense mutations (shown as orange circles). The complex consists of four homologous domains (I-IV), each containing six transmembrane segments...

List of genes included in the gene panel. (XLSX)

Epileptic encephalopathies are a group of diseases in which epileptic activity itself contributes to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone. These impairments can worsen over time. This concept has been continually redefined since its introduction. A few syndromes are...

Background: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would...

Therapeutic hypothermia (TH) started within six hours from birth has been shown to improve neurodevelopmental outcomes in newborns with moderate-to-severe hypoxic-ischemic encephalopathy. Twenty-nine consecutive newborns treated with whole body cooling at the Bambino Gesú Children's Hospital between March 2011 and December 2012 were included in thi...

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of indivi...

Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repe...

Objectives To describe the antiepileptic drug (AED) treatment of patients with early infantile epileptic encephalopathy due to KCNQ2 mutations during the neonatal phase and the first year of life.Methods We identified 15 patients and reviewed the electroclinical, neuroimaging, and AED treatment data.ResultsSeizure onset was between 1 and 4 days of...

Neonatal seizures have been associated with the later development of postneonatal epilepsy, mainly beginning within the first year of life. Mechanisms of epileptogenesis in the immature brain still need to be fully elucidated but a two-hit hypothesis, showing that an early insult heightens later susceptibility to seizure-induced brain damage, has b...

To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data...

Intractable epilepsies have an extraordinary impact on cognitive and behavioral function and quality of life, and the treatment of seizures represents a challenge and a unique opportunity. Over the past few years, considerable attention has focused on cannabidiol ( CBD ), the major nonpsychotropic compound of Cannabis sativa . Basic research studie...

Neonatal-onset epilepsies are rare conditions, mostly genetically determined, that can have a benign or severe phenotype.(1,2) There is recent recognition of de novo KCNQ2 mutations in patients with severe neonatal-onset epilepsy, with intractable seizures and severe psychomotor impairment, termed KCNQ2 encephalopathy.(3,4) This is a rare condition...

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in...

This retrospective case study describes the sleep-wake cycles of an infant in the neonatal intensive care unit. We analyzed video-electroencephalographic recording of the term infant monitored during treatment with therapeutic hypothermia for hypoxic-ischemic encephalopathy. The continuous video-electroencephalographic recording over a 4-day period...

Mutations in the K(V)7.2 gene encoding for voltage-dependent K(+) channel subunits cause neonatal epilepsies with wide phenotypic heterogeneity. Two mutations affecting the same positively charged residue in the S(4) domain of K(V)7.2 have been found in children affected with benign familial neonatal seizures (R213W mutation) or with neonatal epile...

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in...

Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. We performed exome sequencing in three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We seque...

Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed...

Objective: Stroke is relatively rare in children and the clinical presentation of perinatal stroke is often subtle. In perinatal stroke, multiple, often coexisting, risk factors are involved, varying from maternal and fetal risk factors during pregnancy and delivery, to infectious causes and cardiac diseases as well as medical interventions and con...

To describe the association between electrographically detected seizures and brain injury evaluated by magnetic resonance imaging in newborns treated with hypothermia. A total of 56 newborns treated with hypothermia were monitored using video electroencephalography through cooling and rewarming, and then imaged at a median of 5 days. The electroenc...

Changes in voltage-dependent gating represent a common pathogenetic mechanism for genetically inherited channelopathies, such as benign familial neonatal seizures or peripheral nerve hyperexcitability caused by mutations in neuronal K v 7.2 channels. Mutation-induced changes in channel voltage dependence are most often inferred from macroscopic cur...

Therapeutic hypothermia (TH) is becoming standard of care in newborns with hypoxic-ischemic encephalopathy (HIE). The prognostic value of the EEG and the incidence of seizures during TH are uncertain. To describe evolution of EEG background and incidence of seizures during TH, and to identify EEG patterns predictive for MRI brain injury. A total of...

Understanding the molecular mechanisms underlying voltage-dependent gating in voltage-gated ion channels (VGICs) has been a major effort over the last decades. In recent years, changes in the gating process have emerged as common denominators for several genetically determined channelopathies affecting heart rhythm (arrhythmias), neuronal excitabil...

Despite the availability of over 20 antiepileptic drugs, about 30% of epileptic patients do not achieve seizure control. Thus, identification of additional molecules targeting novel molecular mechanisms is a primary effort in today's antiepileptic drug research. This paper reviews the pharmacological development of retigabine, an antiepileptic drug...

We describe a group of previously normal children who developed severe focal epilepsy after an acute/sub-acute illness resembling encephalitis. This is a retrospective study. An acute phase (encephalitis/encephalopathy period) and a chronic phase (chronic focal resistant epilepsy) were defined. Eight patients were enrolled. The median age at onset...

The anatomic extent of brain stem damage may provide information about clinical outcome and prognosis in children with hypoxic-ischemic encephalopathy and oral motor dysfunction. The aim of this study was to retrospectively characterize the location and extent of brain stem lesions in children with oral motor dysfunction. From January 2005 to Augus...

Neuroprotection is a major health care priority, given the enormous burden of human suffering and financial cost caused by perinatal brain damage. With the advent of hypothermia as therapy for term hypoxic-ischemic encephalopathy, there is hope for repair and protection of the brain after a profound neonatal insult. However, it is clear from the pu...

Parodi S, Vollono C, Baglietto MP, Balestri M, Di Duca M, Landri PA, Ceccherini I, Ottonello G, Cilio MR. Congenital central hypoventilation syndrome: genotype–phenotype correlation in parents of affected children carrying a PHOX2B expansion mutation. Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder. Although most CCHS...

Rett syndrome (RTT) is a progressive neurological disorder characterized by a wide spectrum of phenotypes. Epilepsy is reported to occur in 50-90% of patients with RTT; some develop medically refractory epilepsy. The aim of this study is to investigate the efficacy of levetiracetam (LEV) in drug-resistant patients with RTT. This prospective, pragma...

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (...

Epileptic seizures are the most frequent clinical manifestation of central nervous system dysfunction in the newborn. Current data from animal and human studies suggest that neonatal seizures themselves may lead to worsening brain injury, decrease the threshold for late seizures and result in poor long-term neurological outcome. Studies on the long...

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (...

The K(V)7 (KCNQ) subfamily of voltage-gated K(+) channels consists of five members (K(V)7.1-K(V)7.5) giving rise to non-inactivating, and slowly activating/deactivating currents mainly expressed in cardiac (K(V)7.1) and neuronal (K(V)7.2-K(V)7.5) tissue. In the present study, using the cut-open oocyte voltage clamp, we studied the relation of the i...