21702126
Benign and severe early-life seizures: a round in the first year of life
BackgroundAt the onset, differentiation between abnormal non-epileptic movements, and epileptic seizures presenting in early life is difficult as is clinical diagnosis and prognostic evaluation of the various seizure disorders presenting at this age. Seizures starting in the first year of life including the neonatal period might have a favorable course, such as in infants presenting with benign familial neonatal epilepsy, febrile seizures simplex or acute symptomatic seizures. However, in some cases, the onset of seizures at birth or in the first months of life have a dramatic evolution with severe cerebral impairment. Seizure disorders starting in early life include the “epileptic encephalopathies”, a group of conditions characterized by drug resistant seizures, delayed developmental skills, and intellective disability. This group of disorders includes early infantile epileptic encephalopathy also known as Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, infantile spasms syndrome (also known as West syndrome), severe myoclonic epilepsy in infancy (also known as Dravet syndrome) and, myoclonic encephalopathies in non-progressive disorder.Here we report on seizures manifesting in the first year of life including the neonatal period. Conditions with a benign course, and those with severe evolution are presented. At this early age, clinical identification of seizures, distinction of each of these disorders, type of treatment and prognosis is particularly challenging.The aim of this report is to present the clinical manifestations of each of these disorders and provide an updated review of the conditions associated with seizures in the first year of life.
624857
Pediatric seizures.
On the basis of strong evidence, treatment is highly dependent on the seizure semiology results, electroencephalography (EEG) findings, and origin. • On the basis of moderate evidence and consensus, vigorous use of video EEG recordings and home video cameras should be used to delineate the epileptic syndromes. • On the basis of strong evidence, pediatric epilepsy syndromes have common comorbidities. As a consensus, some pediatric epilepsy centers consider referral to a neuropsychologist to be first-line care in these patients. • On the basis of strong evidence and consensus, antiepileptic drug therapy has its own complications and should be discontinued after an appropriate treatment course. • On the basis of moderate evidence and consensus, uncontrolled seizures put patients at risk for significant morbidity and mortality.
13703459
Instruction manual for the ILAE 2017 operational classification of seizure types
This companion paper to the introduction of the International League Against Epilepsy (ILAE) 2017 classification of seizure types provides guidance on how to employ the classification. Illustration of the classification is enacted by tables, a glossary of relevant terms, mapping of old to new terms, suggested abbreviations, and examples. Basic and extended versions of the classification are available, depending on the desired degree of detail. Key signs and symptoms of seizures (semiology) are used as a basis for categories of seizures that are focal or generalized from onset or with unknown onset. Any focal seizure can further be optionally characterized by whether awareness is retained or impaired. Impaired awareness during any segment of the seizure renders it a focal impaired awareness seizure. Focal seizures are further optionally characterized by motor onset signs and symptoms: atonic, automatisms, clonic, epileptic spasms, or hyperkinetic, myoclonic, or tonic activity. Nonmotor‐onset seizures can manifest as autonomic, behavior arrest, cognitive, emotional, or sensory dysfunction. The earliest prominent manifestation defines the seizure type, which might then progress to other signs and symptoms. Focal seizures can become bilateral tonic–clonic. Generalized seizures engage bilateral networks from onset. Generalized motor seizure characteristics comprise atonic, clonic, epileptic spasms, myoclonic, myoclonic–atonic, myoclonic–tonic–clonic, tonic, or tonic–clonic. Nonmotor (absence) seizures are typical or atypical, or seizures that present prominent myoclonic activity or eyelid myoclonia. Seizures of unknown onset may have features that can still be classified as motor, nonmotor, tonic–clonic, epileptic spasms, or behavior arrest. This “users’ manual” for the ILAE 2017 seizure classification will assist the adoption of the new system.
21037500
Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology
The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names. Because current knowledge is insufficient to form a scientifically based classification, the 2017 Classification is operational (practical) and based on the 1981 Classification, extended in 2010. Changes include the following: (1) “partial” becomes “focal”; (2) awareness is used as a classifier of focal seizures; (3) the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated; (4) new focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional; (5) atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset; (6) focal to bilateral tonic–clonic seizure replaces secondarily generalized seizure; (7) new generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic–atonic, myoclonic–tonic–clonic; and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types.
25346050
Global cognitive function in children with epilepsy: A community‐based study
Purpose: To determine the frequency and determinants of subnormal global cognitive function in a representative, community‐based sample of children prospectively identified at the time of initial diagnosis of epilepsy.
20719640
Incidence, prevalence and aetiology of seizures and epilepsy in children.
AIM
To (1) summarize published, peer-reviewed literature about the incidence and prevalence of epilepsy in children from developed and developing countries around the world, and (2) discuss problems in defining aetiologies of epilepsy in children, and distinguish between seizures and epilepsy.


METHODS
Review of selected literature with particular attention to systematic reviews.


RESULTS
The incidence of epilepsy in children ranges from 41-187/100,000. Higher incidence is reported from underdeveloped countries, particularly from rural areas. The incidence is consistently reported to be highest in the first year of life and declines to adult levels by the end of the first decade. The prevalence of epilepsy in children is consistently higher than the incidence and ranges from 3.2-5.5/1,000 in developed countries and 3.6-44/1,000 in underdeveloped countries. Prevalence also seems highest in rural areas. The incidence and prevalence of specific seizure types and epilepsy syndromes is less well documented. In population-based studies, there is a slight, but consistent, predominance of focal seizures compared with generalized seizures. Only about one third of children with epilepsy can be assigned to a specific epilepsy syndrome, as defined by the most recently proposed system for organization of epilepsy syndromes.


CONCLUSIONS
The incidence and prevalence of epilepsy in children appears to be lower in developed countries and highest in rural areas of underdeveloped countries. The reasons for these trends are not well established. Although focal seizures predominate, the incidence and prevalence of specific epilepsy syndromes is not well documented.
12010529
Residual cognitive effects of uncomplicated idiopathic and cryptogenic epilepsy
We assessed residual cognitive deficits in young people with idiopathic and cryptogenic epilepsy. In the setting of an ongoing prospective study, we invited participants initially diagnosed and enrolled in the cohort 8-9 years earlier to undergo standardized neuropsychological assessment. Sibling controls were invited when available. We analyzed 143 pairs in which cases had idiopathic or cryptogenic epilepsy and both case and control had normal intelligence. Compared with that for siblings, the Full Scale IQ for cases was 3.3 points lower (P=0.01) mainly due to slower processing speed, which was 5.6 points lower (P=0.0004). Word reading (P=0.04) and spelling (P=0.01), but not other scores, were also lower in cases. Remission status and drug use did not influence findings. In young people of normal intelligence with idiopathic or cryptogenic childhood-onset epilepsy, substantial residual effects of epilepsy appear to be confined largely to slower processing speed.
9433381
Epilepsy as a spectrum disorder: Implications from novel clinical and basic neuroscience
Epilepsy is increasingly recognized as a disease that reaches well beyond seizures. Cognitive and psychiatric impairment affect half of all epilepsy patients, and to date there are no specific treatments for these symptoms. It is unclear which of these comorbidities are directly due to seizures and which are due to separable mechanisms that are parallel to those underlying ictal activity. Cellular and molecular mechanisms underlying synaptic modulation are central to both the ictal and nonictal changes in epilepsy. Current diagnostic methods are rapidly advancing to better delineate the nature and extent of ictal activity, and could soon be critical in identifying patterns unique to the cognitive and psychiatric comorbidities.
24050288
Seizures in the Newborn and Young Infants
Abstract: The electro‐clinical features of neonatal seizures were described. Although they were usually secondary to the underlying pathological process, there were a few cases of benign familial convulsions which seemed to be dominantly inherited. In the newborn, clinical seizures occurred mainly in active‐REM sleep in contrast to those in the older children and adults. Atypical seizures were also seen in young infants, although less frequently than in the newborn. There were a considerable number of epilepsies beginning in the first year of life associated with a favorable prognosis. Unclassified epilepsies manifesting as brief generalized motor seizures with normal in‐terictal EEGs showed the most favorable outlook, while infantile spasms and other secondary generalized epilepsies had the worst outcome. Partial seizures were intermediate between the above two.
44482932
The history of the concept of epileptic encephalopathy
The first description of epileptic encephalopathies dates back to Dr. West who, in 1857, described the syndrome that took his name. In addition to West syndrome, in the last century other epileptic syndromes entered into the chapter of epileptic encephalopathies. Henry Gastaut has the virtue of having created the modern concept of epileptic encephalopathy and entering it into the official terminology of the International League Against Epilepsy (ILAE). After the first proposal, it was further defined and refined over time.
14460626
Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005–2009
The International League Against Epilepsy (ILAE) Commission on Classification and Terminology has revised concepts, terminology, and approaches for classifying seizures and forms of epilepsy. Generalized and focal are redefined for seizures as occurring in and rapidly engaging bilaterally distributed networks (generalized) and within networks limited to one hemisphere and either discretely localized or more widely distributed (focal). Classification of generalized seizures is simplified. No natural classification for focal seizures exists; focal seizures should be described according to their manifestations (e.g., dyscognitive, focal motor). The concepts of generalized and focal do not apply to electroclinical syndromes. Genetic, structural–metabolic, and unknown represent modified concepts to replace idiopathic, symptomatic, and cryptogenic. Not all epilepsies are recognized as electroclinical syndromes. Organization of forms of epilepsy is first by specificity: electroclinical syndromes, nonsyndromic epilepsies with structural–metabolic causes, and epilepsies of unknown cause. Further organization within these divisions can be accomplished in a flexible manner depending on purpose. Natural classes (e.g., specific underlying cause, age at onset, associated seizure type), or pragmatic groupings (e.g., epileptic encephalopathies, self‐limited electroclinical syndromes) may serve as the basis for organizing knowledge about recognized forms of epilepsy and facilitate identification of new forms.
12689267
Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome
We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions.
43792451
Recent Advances in Neonatal Seizures
Neonatal seizures are the most important indicators of underlying brain injury. Seizures in a neonate are different from seizures in older children in many aspects including clinical presentation and etiology. The neonatal brain is immature and tends to have a decreased seizure threshold. Neonatal seizures are classified, based on their presentation as, clinical seizures, electroclinical seizures and electroencephalographic seizures; based on the pathophysiology as epileptic and nonepileptic seizures; and also on the basis of the etiology. Hypoxic ischemic encephalopathy is the leading cause of neonatal seizures, followed by intracranial hemorrhage, metabolic causes such as hypoglycemia and hypocalcemia, intracranial infections and strokes. Neonatal epilepsy syndromes are rare. Electroencephalography (EEG) is the gold standard for diagnosis. Amplitude integrated EEG (aEEG) is also used for continuous monitoring. The approach to management consists of initial stabilization of the neonate followed by treatment of potentially correctable injurious processes such as hypocalcemia, hypoglycemia and electrolyte disturbances, etiology specific therapies and antiepileptic drug (AED) therapy. Phenobarbital remains the first line AED therapy. Pharmacokinetic data on newer drugs is limited. Prognosis depends on the etiology, seizure type, neurological examination at discharge and EEG. Long term neurodevelopmental follow up is essential for babies with neonatal seizures.
34220026
Novel KCNQ3 Mutation in a Large Family with Benign Familial Neonatal Epilepsy: A Rare Cause of Neonatal Seizures
Benign familial neonatal seizures (BFNS) present a rare familial epilepsy syndrome caused by genetic alterations in the voltage-gated potassium channels Kv7.2 and Kv7.3, encoded by KCNQ2 and KCNQ3. While most BFNS families carry alterations in KCNQ2, mutations in KCNQ3 appear to be less common. Here, we describe a family with 6 individuals presenting with neonatal focal and generalized seizures. Genetic testing revealed a novel KCNQ3 variant, c.835G>T, cosegregating with seizures in 4 tested individuals. This variant results in a substitution of the highly conserved amino acid valine localized within the pore-forming transmembrane segment S5 (p.V279F). Functional investigations in Xenopus laevis oocytes revealed a loss of function, which supports p.V279F as a pathogenic mutation. When p.V279F was coexpressed with the wild-type (WT) Kv7.2 subunits, the resulting potassium currents were about 10-fold reduced compared to the WT Kv7.3 and Kv7.2 coexpression. Genotype-phenotype correlation shows an incomplete penetrance of p.V279F. Response to antiepileptic treatment was variable, but evaluation of treatment response remained challenging due to the self-limiting character of the disease. The identification of the pathogenic variant helped to avoid unnecessary investigations in affected family members and allowed guided therapy.
10814765
Genetic testing in benign familial epilepsies of the first year of life: Clinical and diagnostic significance
To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal‐infantile seizures (BFNIS), and benign familial infantile seizures (BFIS).
33280415
The variable phenotypes of KCNQ‐related epilepsy
Mutations in KCNQ2 and KCNQ3 were originally described in infants with benign familial neonatal seizures (BFNS). Recently, KCNQ2 mutations have also been shown to cause epileptic encephalopathy. This report describes three infants carrying abnormalities of KCNQ2 and one infant with a KCNQ3 mutation. The different KCNQ2 abnormalities led to different phenotypes and included a novel intragenic duplication, c.419_430dup, in an infant with BFNS, a 0.761Mb 20q13.3 contiguous gene deletion in an infant with seizures at 3 months, and a recurrent de novo missense mutation c.881C>T in a neonate with “KCNQ2‐encephalopathy.” The mutation in KCNQ3, c.989G>A, was novel and occurred in an infant with BFNS. KCNQ‐related seizures often present with tonic/clonic manifestations, cyanosis, or apnea. Certain genotype–phenotype correlations help predict outcome. Similarly affected family members suggests benign familial “KCNQ‐related” epilepsy, whereas neonatal seizures with unexplained multifocal epileptiform discharges or burst suppression on electroencephalography, and acute abnormalities of the basal ganglia/thalami are suggestive of KCNQ2‐encephalopathy, which is often sporadic. 20q13.33 contiguous gene deletion encompassing KCNQ2 may harbor atypical features depending on deletion size. Although the phenotype often guides direct targeted gene testing in these conditions, array CGH should also be considered in suspected sporadic or atypical familial cases to diagnose 20q13.33 deletion.
20845111
Recommendation for a definition of acute symptomatic seizure
Purpose:  To consider the definition of acute symptomatic seizures for epidemiological studies, and to refine the criteria used to distinguish these seizures from unprovoked seizures for specific etiologies.
15951685
Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy.
Preface Since the Proposal for Classification of Epilepsies and Epileptic Syndromes was presented to the General Assembly of the International League Against Epilepsy (ILAE) in 1985, the Commission on Classification and Terminology of the ILAE has refined and revised the Proposal in light of findings and suggestions emanating from experience in use of the 1985 schema. The purpose of the International Classification of Epilepsies and Epileptic Syndromes (ICE) is to supplement the International Classification of Epileptic Seizures (ICES), the revised form of which was accepted by the General Assembly of the ILAE in September 1981. The international epilepsy community contributed experience in use of the ICE, and refinements were introduced at subsequent meetings of the Commission held in Paris in 1986, in Esclimont in 1987, and in Bielefeld in 1988. The members of the Commission were Joseph Roger (Marseille), Chairman, Fritz E. Dreifuss (Charlottesville), Manuel Martinez-Lage (Pamplona), Claudio Munari (Paris), Roger J. Porter (Bethesda), Masakazu Seino (Shizuoka), and Peter Wolf (Bielefeld). Consultants who contributed to the work of the Commission included Jean Bancaud (Paris), Patrick Chauvel (Paris), A. V. DelgadoEscueta (Los Angeles), Jerome Engel, Jr. (Los Angeles), Richard H. Mattson (New Haven), Timothy A. Pedley (New York), J. W i n Penry (WinstonSalem), L. F. Quesney (Montreal), and HeinzGregor Wieser (Zurich). These consultants contributed and discussed video-documented data in patients with defined loci studied with depth electrodes. The present ICE represents a consensus statement compatible with the view of the majority of international epileptologists and believed to be suitable for mutual exchange of ideas. The limitation of the ICES, which is confined to description of individual seizure types, is that the terminology used in daily communication between colleagues consists of descriptions of syndromes. This is also true of diagnostic entries in hospital records and communication between collaborators conducting clinical trials. An epileptic syndrome is an epileptic disorder characterized by a cluster of signs and symptoms customarily occurring together; these include such items as type of seizure, etiology, anatomy, precipitating factors, age of onset, severity, chronicity, diurnal and circadian cycling, and sometimes prognosis. However, in contradistinction to a disease, a syndrome does not necessarily have a common etiology and prognosis. On the other hand, some of the epileptic disorders included in this ICE are diseases, and in others, currently considered syndromes, a common etiology may still be discovered. For the sake of convenience, all these disorders are included in one ICE. It is recognized that even now the ICE is not totally satisfactory. Patients may move from one syndrome to another during the evolution of their epileptic condition; e.g., a child with West syndrome may later satisfy the criteria for the LennoxGastaut syndrome. Thus it may be difficult to decide at any particular time into which particular syndrome and classification the patient belongs, as a result of an evolutionary progression, possibly related to the stage of maturation of the nervous system at the time. While the course may to a large extent be predetermined by the cause, it is as yet not always predictable, and misdiagnoses are always possible. Two divisions continue to be widely used in this ICE to shape the major classes: The first separates epilepsies with generalized seizures (generalized epilepsy) from epilepsies with partial or focal seizures (localization-related, partial or focal epilepsies). The other separates epilepsies of known etiology (symptomatic or “secondary” epilepsies) from those that are idiopathic (primary) and those that are cryptogenic. The term idiopathic derives from the Greek “idios,” meaning self, own, or personal. Idiopathic e p ilepsies and syndromes are described as disorders “not preceded or occasioned by another,” according to the Oxford English Dictionary. There is no
3636386
[Benign infantile convulsions associated with mild gastroenteritis: a clinical analysis and follow-up study].
OBJECTIVE
To study the clinical features and prognosis of benign infantile convulsions associated with mild gastroenteritis (BICE).


METHODS
A retrospective analysis was performed for the clinical data of 436 children with BICE, and among these children, 206 were followed up for 1.5 to 7 years. Some parents were invited to complete the Weiss Functional Defect Scale to evaluate the long-term social function.


RESULTS
The peak age of onset of BICE was 13-24 months, and BICE had a higher prevalence rate in September to February of the following year. Convulsions mainly manifested as generalized tonic-clonic seizures, which often occurred within 24 hours after disease onset and lasted for less than 5 minutes each time. Sometimes they occurred in clusters. During the follow-up of 206 children, only one had epileptiform discharge, and the other children had normal electroencephalographic results. The parents of all the 206 children thought their children had normal intelligence and had no marked changes in character. Based on the Weiss Functional Defect Scale completed by the parents of some BICE children, there was no significant difference in the long-term social function between BICE children and healthy children matched by age and sex.


CONCLUSIONS
BICE mainly occurs in children aged 1-2 years, with the manifestation of transient generalized seizures in most children and cluster seizures in some children. BICE seldom progresses to epilepsy and has good prognosis.
35623825
The Gut–brain Axis: A New Pathogenic View of Neurologic Symptoms – Description of a Pediatric Case
Recent literature data have given emphasis to the relationship between gastrointestinal (GI) disorders and neurologic diseases, underlying a new pathogenic pathway: The so-called “gut–brain axis.” Herein, authors report a case of a 10-month-old male infant, admitted for drug-resistant epilepsy, associated with irritable behavior and GI discomfort, secondary to cow's milk protein allergy. Seizures were described by parents as upward eye movements that were mostly deviated to the right and were associated with slight extension of his neck. They were infrequent at first, but had increased gradually during the course of 3 days (up to 15–20 times/day). No anticonvulsant therapy was effective. Only a cow's milk protein-free diet, accidentally started during a gastroenteritis episode, was effective in stopping seizures. Our case underlines the peculiar vulnerability of the blood–brain barrier under 1 year of age, for which children of this age group experience neurologic manifestations during episodes of systemic inflammation.
6335847
Febrile seizures.
Febrile seizures are the most common form of childhood seizures, affecting 2% to 5% of children. They are considered benign and self-limiting; however, a febrile seizure is a terrifying event for most parents, and is one of the most common causes of trips to the emergency room. A febrile seizure is "an event in infancy or childhood, usually occurring between 3 months and 5 years of age, associated with fever but without evidence of intracranial infection or defined cause." This definition excludes seizures with fever in children who have had a prior afebrile seizure. In 2011, The American Academy of Pediatrics (AAP) published a clinical practice guideline defining a febrile seizure as "a seizure accompanied by fever (temperature ≥ 100.4°F or 38°C by any method), without central nervous system infection, that occurs in infants and children 6 through 60 months of age." Febrile seizures are further classified as simple or complex. This article reviews the evaluation, management, and prognosis of simple and complex seizures, including febrile status epilepticus.
45955065
Recommendations for the management of “febrile seizures” Ad hoc Task Force of LICE Guidelines Commission
Febrile seizures are the most common seizure disorder in childhood, affecting 2–5% of children. Simple febrile seizure is defined as a short (<15 min) generalized seizure, not recurring within 24 h, that occurs during a febrile illness not resulting from an acute disease of the nervous system in a child aged between 6 months and 5 years, with no neurologic deficits and no previous afebrile seizures. These recommendations address the instructions for management of the first febrile seizures, giving criteria for hospital admission, diagnosis, differential diagnosis, and treatment of a prolonged seizure. The authors stressed the benign prognosis of the majority of cases and the risk factors for recurrence of febrile seizures and appearance of epilepsy later on. Both continuous and intermittent anticonvulsant therapy are efficacious in preventing single febrile seizures, but side effects may be so important to overcome the benefits. These treatments are indicated in very selected patients.
20337238
Febrile Seizures: Treatment and Prognosis
Summary: Recent epidemiologic data indicate that the vast majority of children with febrile seizures have a normal long‐term outcome. A precise knowledge of the short‐ and long‐term outcome with or without treatment, and short‐ and long‐term side effects is an important prerequisite for assessing the various treatment strategies. We focus on the impact of short‐term or prophylactic treatment on the short‐ and long‐term outcome of various types of febrile seizures. There is universal agreement that daily prophylaxis with antiepileptic agents should never be used routinely in simple febrile seizures, but only in highly selected cases, if at all. Intermittent diazepam (DZP) prophylaxis at times of fever may or may not reduce the recurrence rate, but it does not appear to improve the long‐term outcome as compared with short‐term seizure control. The treatment may be used to reduce the recurrence rate for a small arbitrarily defined group with multiple simple febrile seizures, complex febrile seizures, especially focal, prolonged or both, febrile status, and when parental anxiety is severe. However, there is no evidence that treatment of simple febrile seizures can prevent the rare cases of later epilepsy, and many children with complex febrile seizures have a benign long‐term outcome, even without treatment. Many prefer a “wait and see” policy. An attractive alternative is to treat new febrile seizures with rectal DZP in solution at seizure onset, given by the parents at home to prevent febrile status. Newer, less well documented short‐term strategies include nasal, oral, or rectal administration of other benzodiazepines. Short‐term seizure control of febrile status and careful parental counseling are the two most important targets of treatment.
39314912
Epidemiology and diagnostic and therapeutic management of febrile seizures in the Italian pediatric emergency departments: A prospective observational study
AIM
Febrile seizures (FS) involve 2-5% of the paediatric population, among which Complex FS (CFS) account for one third of accesses for FS in Emergency Departments (EDs). The aim of our study was to define the epidemiology, the clinical, diagnostic and therapeutic approach to FS and CFSs in the Italian EDs.


METHODS
A multicenter prospective observational study was performed between April 2014 and March 2015. Patients between 1 and 60 months of age, randomly accessing to ED for ongoing FS or reported FS at home were included. Demographic features and diagnostic-therapeutic follow-up were recorded. FS were categorized in simple (<10min), prolonged (10-30min) and status epilepticus (>30min).


RESULTS
The study population consisted of 268 children. Most of the children experienced simple FS (71.65%). Among the 68 (25.37%) patients with complex FS, 11 were 6-12 month-old, accounting for 45.83% of all the infants with FS in the younger age group. No therapy has been administered at home in 76.12% patients; 23.51% of them received endorectal diazepam and only 1 patient received buccal midazolam. At arrival at ED, no therapy was necessary for 70.52% patients; 50.63% received endorectal diazepam and 17.72% an i.v. bolus of midazolam. Blood tests and acid-base balanced were performed respectively in 82.09% of cases. An electroencephalogram at ED was performed in 21.64% of patients. Neuroimagings were done in 3.73% of cases. A neurologic consultation was asked for 36 patients (13.43%).


CONCLUSION
this is the first study assessing epidemiologic characteristics of FS in the Italian pediatric population, evidencing a higher prevalence of CFSs in children younger than 12 months of age and opening a new research scenario on the blood brain barrier vulnerability. On a national level, our study showed the need for a diagnostic standardized work-up to improve the cost/benefit ratio on CFS management.
40485325
Febrile and other occasional seizures.
Seizures with fever that result from encephalitis or meningitis usually occur late in the course of febrile illness, and are focal and prolonged. Febrile seizures are by far the most common affecting 5% of the population, followed by posttraumatic seizures and those observed in the setting of a toxic, infectious, or metabolic encephalopathy. This chapter reviews the clinical presentation of the three most common forms, due to fever, trauma, and intoxication. Febrile seizures carry no cognitive or mortality risk. Recurrence risk is increased by young age, namely before 1 year of age. Febrile seizures that persist after the age of 6 years are usually part of the syndrome of Generalized epilepsy febrile seizures plus. These febrile seizures have a strong link with epilepsy since non-febrile seizures may occur later in the same patient and in other members of the same family with an autosomal dominant transmission. Complex febrile seizures, i.e., with focal or prolonged manifestations or followed by focal defect, are related to later mesial temporal epilepsy with hippocampal sclerosis; risk factors are seizure duration and brain malformation. Prophylactic treatment is usually not required in febrile seizures. Early onset of complex seizures is the main indication for AED prophylaxis. Early posttraumatic seizures, i.e., within the first week, are often focal and indicate brain trauma: contusion, hematoma, 24 hours amnesia, and depressed skull fracture are major factors of posttraumatic epilepsy. Prophylaxis with antiepileptic drugs is not effective. Various psychotropic drugs, including antiepileptics, may cause seizures.
9267524
Mesial temporal lobe epilepsy with childhood febrile seizure
To evaluate the demographic and clinical manifestations of patients with mesial temporal sclerosis and temporal lobe epilepsy (MTS‐TLE) with childhood febrile seizure (FS) and establishing the potential differences as compared to those without FS. We also investigated the surgery outcome in these two groups of patients.
9403148
Generalized epilepsy with febrile seizures plus: Mutation of the sodium channel subunit SCN1B
Abstract—Generalized epilepsy with febrile seizures plus (GEFS+) is an important childhood genetic epilepsy syndrome with heterogeneous phenotypes, including febrile seizures (FS) and generalized epilepsies of variable severity. Forty unrelated GEFS+ and FS patients were screened for mutations in the sodium channel &bgr;-subunits SCN1B and SCN2B, and the second GEFS+ family with an SCN1B mutation is described here. The family had 19 affected individuals: 16 with typical GEFS+ phenotypes and three with other epilepsy phenotypes. Site-specific mutation within SCN1B remains a rare cause of GEFS+, and the authors found no evidence to implicate SCN2B in this syndrome.
140205104
Clinical spectrum of SCN2A mutations
Mutations in SCN2A, the gene encoding α2 subunit of the neuronal sodium channel, are associated with a variety of epilepsies: benign familial neonatal-infantile seizures (BFNIS); genetic epilepsy with febrile seizures plus (GEFS+); Dravet syndrome (DS); and some intractable childhood epilepsies. More than 10 new mutations have been identified in BFNIS, all of them are missense. To date, only one nonsense mutation has been found in a patient with intractable childhood epilepsy and severe mental decline. Recently, microduplication of chromosome 2q24.3 (containing eight genes including SCN2A, SCN3A, and the 3' end of SCN1A) was reported in a family with dominantly inherited neonatal seizures and intellectual disability. Functional studies of SCN2A mutations show that they can cause divergent biophysical defects in Na(V)1.2 and impair cell surface expressions. There is no consistent relationship between genotype and phenotype.
2917373
Neonatal seizures in hypoxic–ischaemic encephalopathy – risks and benefits of anticonvulsant therapy
The risk of seizures is at its highest during the neonatal period, and the most common cause of neonatal seizures is hypoxic–ischaemic encephalopathy (HIE). This enhanced vulnerability is caused by an imbalance in the expression of receptors for excitatory and inhibitory neurotransmission, which is age dependent. There has been progress in detecting the electrophysiological abnormalities associated with seizures using amplitude‐integrated electroencephalography (aEEG). Data from animal studies indicate a variety of risk factors for seizures, but there are limited clinical data looking at the long‐term neurodevelopmental consequences of seizures alone. Neonatal seizures are also associated with increased risk of further epileptic seizures; however, it is less clear whether or not this results from an underlying pathology, and whether or not seizures confer additional risk. Phenobarbital and phenytoin are still the first‐line antiepileptic drugs (AEDs) used to treat neonatal seizures, although they are effective in only one‐third of affected infants. Furthermore, based on findings from animal studies, there are concerns regarding the risks associated with using these AEDs. Clinicians face a difficult challenge because, although seizures can be easily identified using aEEG, treatment options are limited, and there are uncertainties regarding treatment outcomes. There is a need to obtain long‐term follow‐up data, comparing groups of infants treated with or without current therapies. If these analyses indicate a definite benefit of treating neonatal seizures, then novel therapeutic approaches should be developed.
46818810
Neonatal epilepsy genetics.
Neonatal epilepsy genetics is a rapidly expanding field with recent technological advances in genomics leading to an expanding list of genetic disorders associated with neonatal-onset epilepsy. The genetic causes of neonatal epilepsy can be grouped into the following categories: (i) malformations of cortical development, (ii) genetic-metabolic, (iii) genetic-vascular, (iv) genetic-syndromic, and (v) genetic-cellular. Clinically, epilepsy in the neonate shows phenotypic overlap with pathogenic variants in unrelated genes causing similar clinical presentation (locus heterogeneity) and variants in the same gene leading to a wide clinical spectrum ranging from benign familial neonatal seizures to more severe epileptic encephalopathies (variable expressivity). We suggest a diagnostic approach to obtaining a genetic diagnosis with emphasis on clinical features such as electro-clinical phenotype and magnetic resonance imaging findings. Rapid identification of genetic disorders with targeted treatments should be a clinical priority. Achieving a genetic diagnosis can be challenging in a rapidly changing genetic landscape, but is increasingly possible.
3795053
Profile of neonatal epilepsies
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 association of 7 US children's hospitals). Treatment and diagnostic testing were at the clinicians' discretion. Neonates with seizures related to epileptic encephalopathies (without structural brain abnormalities), brain malformations, or benign familial epilepsies were included in this analysis. Results: Among 611 consecutive newborns with seizures, 79 (13%) had epilepsy (35 epileptic encephalopathy, 32 congenital brain malformations, 11 benign familial neonatal epilepsy [BFNE], 1 benign neonatal seizures). Twenty-nine (83%) with epileptic encephalopathy had genetic testing and 24/29 (83%) had a genetic etiology. Pathogenic or likely pathogenic KCNQ2 variants (n = 10) were the most commonly identified etiology of epileptic encephalopathy. Among 23 neonates with brain malformations who had genetic testing, 7 had putative genetic etiologies. Six infants with BFNE had genetic testing; 3 had pathogenic KCNQ2 variants and 1 had a pathogenic KCNQ3 variant. Comorbid illnesses that predisposed to acute symptomatic seizures occurred in 3/35 neonates with epileptic encephalopathy vs 10/32 with brain malformations (p = 0.03). Death or discharge to hospice were more common among newborns with brain malformations (11/32) than those with epileptic encephalopathy (3/35, p = 0.01). Conclusions: Neonatal epilepsy is often due to identifiable genetic causes. Genetic testing is now warranted for newborns with epilepsy in order to guide management and inform discussions of prognosis.
2545445
Inborn Errors of Metabolism and Epilepsy: Current Understanding, Diagnosis, and Treatment Approaches
Inborn errors of metabolism (IEM) are a rare cause of epilepsy, but seizures and epilepsy are frequently encountered in patients with IEM. Since these disorders are related to inherited enzyme deficiencies with resulting effects on metabolic/biochemical pathways, the term “metabolic epilepsy” can be used to include these conditions. These epilepsies can present across the life span, and share features of refractoriness to anti-epileptic drugs, and are often associated with co-morbid developmental delay/regression, intellectual, and behavioral impairments. Some of these disorders are amenable to specific treatment interventions; hence timely and appropriate diagnosis is critical to improve outcomes. In this review, we discuss those disorders in which epilepsy is a dominant feature and present an approach to the clinical recognition, diagnosis, and management of these disorders, with a greater focus on primarily treatable conditions. Finally, we propose a tiered approach that will permit a clinician to systematically investigate, identify, and treat these rare disorders.
4677500
Pyridoxine-dependent epilepsy due to antiquitin deficiency: achieving a favourable outcome
We report 4 pyridoxine-dependent epilepsy patients in which good outcome was determined in three. The 4 patients were male and aged from 7 to 24 years old (from three unrelated Caucasian families). A clinical diagnosis of neonatal pyridoxine-dependent epilepsy was confirmed by biochemical and genetic studies. Clinical evaluation was performed and medical records were reviewed for therapy implementation and management, neurodevelopment outcome, magnetic resonance imaging, and electroencephalography. All were taking pyridoxine treatment and were seizure-free. Elevated urinary alpha-aminoadipic semialdehyde excretion was found in all patients. Antiquitin gene analysis identified a large homozygous deletion in one patient and two heterozygous mutations in the others. Treatment with pyridoxine should be attempted for all cases of infantile and childhood refractory epilepsy, as has been the case over the last 20 years. Currently, urinary alpha-aminoadipic semialdehyde is a reliable biomarker of pyridoxine-dependent epilepsy, even under pyridoxine treatment. Detection of mutations in the antiquitin gene, encoding alphaaminoadipic semialdehyde dehydrogenase, establishes the diagnosis and allows for adequate genetic counselling.
24410195
Normal Neurodevelopmental Outcomes in PNPO Deficiency: A Case Series and Literature Review.
Pyridox(am)ine 5'-phosphate oxidase deficiency results in an early-onset neonatal encephalopathy that can be fatal if not detected and treated early. The condition is rare, can result in preterm delivery, and can mimic hypoxic ischemic encephalopathy. Thus, suspicion of the diagnosis, appropriate investigations, and therapeutic trials with pyridoxal-5'-phosphate are often delayed. In this paper we report four cases of pyridox(am)ine 5'-phosphate oxidase deficiency, two of whom are siblings. Three were treated with pyridoxal-5'-phosphate in the first few days of life and the fourth within the first month. One of the siblings was electively treated from birth until a diagnosis was secured. Our cases demonstrate that early diagnosis and treatment can be associated with normal neurodevelopment in childhood. We suggest that a low threshold for investigating for pyridox(am)ine 5'-phosphate oxidase deficiency and electively treating with pyridoxal-5'-phosphate is considered in any neonate with encephalopathy, including those with presumed hypoxic ischemic encephalopathy in whom the degree of encephalopathy is not expected from perinatal history, cord gases and/or neuroimaging.
24827264
Typical and atypical phenotypes of PNPO deficiency with elevated CSF and plasma pyridoxamine on treatment
Pyridox(am)ine phosphate oxidase (PNPO) deficiency causes severe early infantile epileptic encephalopathy and has been characterized as responding to pyridoxal‐5′‐phosphate but not to pyridoxine. Two males with PNPO deficiency and novel PNPO mutations are reported and their clinical, metabolic, and video‐electroencephalographic (EEG) findings described. The first child showed electro‐clinical responses to pyridoxine and deterioration when pyridoxine was withheld. At last review, he has well‐controlled epilepsy with pyridoxal‐5′‐phosphate monotherapy and an autism spectrum disorder. The second child had a perinatal middle cerebral artery infarct and a myoclonic encephalopathy. He failed to respond to pyridoxine but responded well to pyridoxal‐5′‐phosphate. At the age of 21 months he has global developmental delay and hemiparesis but is seizure‐free with pyridoxal‐5′‐phosphate monotherapy. Plasma and cerebrospinal fluid pyridoxamine levels were increased in both children during treatment with pyridoxine or pyridoxal‐5′‐phosphate. These observations indicate that differential responses to pyridoxine and pyridoxal‐5′‐phosphate treatment cannot be relied upon to diagnose PNPO deficiency.
3283370
Pyridoxine 5′-phosphate oxidase is a novel therapeutic target and regulated by the TGF-β signalling pathway in epithelial ovarian cancer
Pyridoxine 5′-phosphate oxidase (PNPO) is an enzyme that converts pyridoxine 5′-phosphate into pyridoxal 5′-phosphate (PLP), an active form of vitamin B6 implicated in several types of cancer. However, the role of PNPO and its regulatory mechanism in epithelial ovarian cancer (EOC) are unknown. In the present study, PNPO expression in human ovarian tumour tissue and its association with the clinicopathological features of patients with EOC were examined. Further, the biological function of PNPO in EOC cells and in xenograft was evaluated. We demonstrated for the first time that PNPO was overexpressed in human EOC. Knockdown of PNPO induced EOC cell apoptosis, arrested cell cycle at G2/M phase, decreased cell proliferation, migration and invasion. Xenografts of PNPO-shRNA-expressing cells into the nude mouse attenuated tumour growth. PNPO at mRNA and protein levels in EOC cells was decreased after transforming growth factor-β1 (TGF-β1) treatment. The inhibitory effect of TGF-β1 on PNPO expression was abolished in the presence of SB-431542, a TGF-β type I receptor kinase inhibitor. Moreover, we found that TGF-β1-mediated PNPO expression was at least in part through the upregulation of miR-143-3p. These data indicate a mechanism underlying PNPO regulation by the TGF-β signalling pathway. Furthermore, PLP administration reduced PNPO expression and decreased EOC cell proliferation, suggesting a feedback loop between PLP and PNPO. Thus, our findings reveal that PNPO can serve as a novel tissue biomarker of EOC and may be a potential target for therapeutic intervention.
6083419
A novel compound heterozygous variant identified in GLDC gene in a Chinese family with non-ketotic hyperglycinemia
BackgroundNon-ketotic hyperglycinemia (NKH) is a rare, devastating autosomal recessive disorder of glycine metabolism with a very poor prognosis. Currently, few studies have reported genetic profiling of Chinese NKH patients. This study aimed to identify the genetic mutations in a Chinese family with NKH.MethodsA Chinese family of Han ethnicity, with three siblings with NKH was studied. Sanger sequencing and multiplex ligation-dependent probe amplification combined with SYBR green real-time quantitative PCR was used to identify potential mutations in the GLDC, AMT and GCSH genes. The potential pathogenicity of the identified missense mutation was analyzed using SIFT, PolyPhen-2, PROVEAN and MutationTaster software.ResultsAll patients exhibited severe and progressive clinical symptoms, including lethargy, hypotonia and seizures, and had greatly elevated glycine levels in their plasma and CSF. Molecular genetic analysis identified compound heterozygous variants in the GLDC gene in these three siblings, including a novel missense variant c.2680A > G (p.Thr894Ala) in exon 23 and a heterozygous deletion of exon 3, which were inherited respectively from their parents. In silico analysis, using several different types of bioinformatic software, predicted that the novel variant c.2680A > G in the GLDC gene was pathogenic. Moreover, the deletion of exon 3 was identified for the first time in a Chinese population.ConclusionsA novel missense variant and a previously reported deletion in GLDC gene were identified. The two variants of GLDC gene identified probably underlie the pathogenesis of non-ketotic hyperglycinemia in this family, and also enrich the mutational spectrum of GLDC gene.
19343165
Two novel mutations in the BCKDHB gene that cause maple syrup urine disease.
BACKGROUND
Maple syrup urine disease (MSUD) is a rare metabolic disorder of autosomal recessive inheritance caused by decreased activity of branched-chain α-ketoacid dehydrogenase complex (BCKD). Mutations in the three genes (BCKDHA, BCKDHB and DBT) are associated with MSUD. Here, we describe the presenting symptoms, clinical course and gene mutation analysis of a Chinese boy with MSUD.


METHODS
Plasma amino acid analysis was performed by tandem mass spectrometry and the levels of organic acids in urine were measured with gas chromatography-mass spectrometry. The BCKDHB gene was sequenced by Sanger method. Furthermore, the significance of the novel mutations was predicted by Polyphen and Mutationtaster. After diagnosis, the patient was fed with protein-restricted diet to reduce intake of BCAA and was treated with l-carnitine. Metabolic parameters, clinical presentation and mental development were followed up.


RESULTS
The patient was diagnosed as MSUD. Two novel BCKDHB mutations (c.523 T > C and c.478-25_552del100) were identified. In silico analysis predicted that the two mutations were "disease causing". The boy tolerated the treatment well and had symptomatic improvement. He presented with mild hypotonia and had nearly normal DQ scores at the age of 10 months. The two novel mutations resulted in the clinical manifestations of MSUD. Our results may reflect the heterogeneity of the pathogenic variants found in patients with MSUD.
3492619
Acute symptomatic neonatal seizures in preterm neonates: etiologies and treatments.
Acute symptomatic neonatal seizures in preterm newborns are a relevant clinical challenge due to the presence of many knowledge gaps. Etiology-wise, acute symptomatic seizures have an age-specific epidemiology, with intraventricular hemorrhage and its complications representing the first cause in extremely and very preterm neonates, whereas other etiologies have similar occurrence rates as in full-term infants. Specific treatment strategies for the premature neonates are not yet available. Studies suggest a similarly low response rate with even more unfavorable prognosis than in full-term infants. Pharmacodynamic and pharmacokinetic changes are likely under way during the preterm period, with the potential to affect both effectiveness and safety of antiepileptic drugs in these patients. However, due to the lack of clear evidence to guide prioritization of second-line drugs, off-label medications are frequently indicated by review papers and flow-charts, and are prescribed in clinical practice. We therefore conclude by exploring potential future lines of research.
26798425
Drug Treatment of Seizures and Epilepsy in Newborns and Children.
The mainstay of treatment of childhood epilepsy is to administer antiepileptic drugs (AEDs). This article provides an overview of the clinical approach to drug treatment of childhood epilepsy, focusing on general principles of therapy and properties of recently introduced medications. Initiation and cessation of therapy, adverse medication effects, drug interactions, indications for the various AEDs, and off-label use of AEDs are reviewed. The distinct challenges in treatment of epileptic spasms and neonatal seizures are addressed. Finally, ideas for the future of drug treatment of childhood epilepsy are presented, with particular attention to precision medicine.
46794162
Neonatal phenobarbital exposure disrupts GABAergic synaptic maturation in rat CA1 neurons
Phenobarbital is the most commonly utilized drug for the treatment of neonatal seizures. The use of phenobarbital continues despite growing evidence that it exerts suboptimal seizure control and is associated with long‐term alterations in brain structure, function, and behavior. Alterations following neonatal phenobarbital exposure include acute induction of neuronal apoptosis, disruption of synaptic development in the striatum, and a host of behavioral deficits. These behavioral deficits include those in learning and memory mediated by the hippocampus. However, the synaptic changes caused by acute exposure to phenobarbital that lead to lasting effects on brain function and behavior remain understudied.
46866423
A Systematic Review of the Efficacy of Levetiracetam in Neonatal Seizures
Abstract Objective Seizures are the most common neurological complication in neonatal intensive care units. Phenobarbital (PB) remains the first‐line antiepileptic drug (AED) for neonatal seizures despite known neurotoxicity. Levetiracetam (LEV) is a newer AED not approved for neonates. Retrospective and pilot studies have investigated the use of LEV in neonatal seizures. Our objective was to compare the efficacy of LEV to PB in neonatal seizures based upon published data. Methods We searched PubMed to perform a systematic review. We found no studies of LEV with comparison or control groups; therefore, we utilized data from two randomized controlled trials of PB as our comparison group. Results Five studies of LEV met all inclusion/exclusion criteria. The pooled sample size for LEV was 102 (48 received primary LEV, 54 received secondary LEV). The pooled sample size for primary PB was 52. Complete or near‐complete seizure cessation was achieved as follows: primary LEV 37/48 (77%), secondary LEV 34/54 (63%), and primary PB 24/52 (46%). Conclusion Our findings suggest that LEV may be at least as or more effective for neonatal seizures as PB. Our review, though limited, is the first to examine LEV efficacy compared with PB in neonates.
6365027
Epileptic encephalopathy: Use and misuse of a clinically and conceptually important concept
The term epileptic encephalopathy (EE) denotes a process by which epileptic activity adversely affects brain function over and above the underlying etiology. Underlying mechanisms are poorly understood, but recent studies demonstrate that seizures and interictal epileptiform discharges can disrupt distributed neural networks that underpin cognitive functions, both temporarily and permanently. EE is just one of a number of factors that can affect development in epilepsy. The presence and relative contribution of EE to cognitive impairment is often difficult to separate from that of the underlying etiology or even effects of antiepileptic medication (AEM). This difficulty has led to the increasing use of the term EE to encapsulate “severe” epileptic syndromes, or etiologies associated with severe epilepsy and intellectual disability (ID), regardless of evidence that the epileptic process has impacted cognition. The use of the term EE in the literature to describe both the process of cognitive impairment by epileptic activity and as a category for severe epilepsy syndromes is creating confusion. We propose that use of the term EE be restricted to the central concept of a pervasive epileptic process disrupting development, and that the use of EE as a classifier be avoided. A different term is needed to encapsulate the broad and heterogenous group of patients with severe epilepsy and ID, for which the mechanisms may be unknown but are often closely related to the underlying genetic, metabolic, or structural etiology. An improved understanding of the mechanisms by which EE develops is of critical importance, potentially leading to identification of biomarkers for early detection and treatment.
3710797
Current understanding and neurobiology of epileptic encephalopathies
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 considered epileptic encephalopathies: early myoclonic encephalopathy and Ohtahara syndrome in the neonatal period, epilepsy of infancy with migrating focal seizures, West syndrome or infantile spasms, Dravet syndrome during infancy, Lennox-Gastaut syndrome, epileptic encephalopathy with continuous spikes-and-waves during sleep, and Landau-Kleffner syndrome during childhood. The inappropriate use of this term to refer to all severe epilepsy syndromes with intractable seizures and severe cognitive dysfunction has led to confusion regarding the concept of epileptic encephalopathy. Here, we review our current understanding of those epilepsy syndromes considered to be epileptic encephalopathies. Genetic studies have provided a better knowledge of neonatal and infantile epilepsy syndromes, while neuroimaging studies have shed light on the underlying causes of childhood-onset epileptic encephalopathies such as Lennox-Gastaut syndrome. Apart from infantile spasm models, we lack animal models to explain the neurobiological mechanisms at work in these conditions. Experimental studies suggest that neuroinflammation may be a common neurobiological pathway that contributes to seizure refractoriness and cognitive involvement in the developing brain.
44620284
Mental Retardation in Pediatric Candidates for Epilepsy Surgery: The Role of Early Seizure Onset
Summary:  Purpose: We sought to determine whether early age at seizure onset is a risk factor for mental retardation, independent of etiology. Assessment of risk for mental retardation with continued uncontrolled seizures plays a role in considerations of timing for epilepsy surgery. Previous studies have indicated that onset of seizures in the first years of life may be a risk factor for mental retardation, but the etiologies of the epilepsies were not included in the analyses.
2348144
Cognitive outcome after extratemporal epilepsy surgery in childhood
Purpose:  The present study aims to describe the cognitive profile of children with medically refractory extratemporal epilepsies who undergo focal surgery and to identify determinants for preoperative and postoperative cognitive level.
44392104
Early-infantile epileptic encephalopathy with suppression-bursts, Ohtahara syndrome; its overview referring to our 16 cases
Ohtahara syndrome (OS) is characterized by frequent tonic spasms, with or without clustering, of early onset within a few months of life, and a suppression-burst (S-B) pattern in electroencephalography (EEG). Tonic spasms occur in not only waking but also sleeping state in most cases. Partial seizures are observed in about one-third of cases. Brain imagings reveal structural abnormalities including malformations, notably asymmetric lesions in most cases.S-B pattern is persistently observed regardless of circadian cycle. Bursts of 1-3s duration alternate with nearly flat suppression phase of 2-5s at an approximately regular rate; 5-10s of burst-burst interval. Some asymmetry in S-B is noted in about two-thirds of cases. Ictal EEG of tonic spasms shows principally desynchronization with or without initial rapid activity. Tonic spasms appear concomitant with bursts. Characteristic age-dependent evolution from OS to West syndrome (WS) in many cases, and further from WS to Lennox-Gastaut syndrome (LGS) in some, proceed concomitantly with EEG transition from S-B to hypsarrhythmia at around age 3-6 months, and further from hypsarrhythmia to diffuse slow spike-waves at around age 1. Under the inclusive concept of the age-dependent epileptic encephalopathy, OS, WS, and LGS have common characteristics such as age preference, frequent minor generalized seizures, and continuous massive epileptic EEG abnormality. Mutual transition suggests the same pathophysiology among three syndromes and the age factor should be considered as the common denominator responsible for the manifestation of each of their own specific clinico-electrical features. Namely, these syndromes may be the age-specific epileptic reaction to various non-specific exogenous brain insults, acting at the specific developmental stages.
6304812
Ohtahara syndrome with emphasis on recent genetic discovery
Ohtahara syndrome or Early Infantile Epileptic Encephalopathy (EIEE) with Suppression-Burst, is the most severe and the earliest developing age-related epileptic encephalopathy. Clinically, the syndrome is characterized by early onset tonic spasms associated with a severe and continuous pattern of burst activity. It is a debilitating and early progressive neurological disorder, resulting in intractable seizures and severe mental retardation. Specific mutations in at least four genes (whose protein products are essential in lower brain's neuronal and interneuronal functions, including mitochondrial respiratory chains have been identified in unrelated individuals with EIEE and include: (a) the ARX (aristaless-related) homeobox gene at Xp22.13 (EIEE-1 variant); (b) the CDKL5 (SYK9) gene at Xp22 (EIEE-2 variant); (c) the SLC25A22 (GC1) gene at 11p15.5 (EIEE-3 variant); and (d) the Stxbp1 (MUNC18-1) gene at 9q34-1 (EIEE-4 variant). A yet unresolved issue involves the relationship between early myoclonic encephalopathy (EME-ErbB4 mutations) versus the EIEE spectrum of disorders.
40918682
Suppression-burst patterns in intractable epilepsy with focal cortical dysplasia
We report on a patient with early-onset spasms in series and partial seizures associated with focal cortical dysplasia whose EEGs showed suppression-burst patterns during early infancy. These electroclinical characteristics suggested a diagnosis of Ohtahara syndrome, but the EEG findings were atypical because of the lack of suppression-burst patterns during wakefulness. In addition, the patient did not have severe psychomotor retardation. With high-dose pyridoxal phosphate therapy, seizures were suppressed and suppression-burst patterns disappeared at 2 months of age. Focal motor seizures recurred later and they often evolved into epilepsia partialis continua. Patients with early-onset intractable seizures associated with suppression-burst patterns on EEGs have several different etiologies, and these patients should be categorized according to their etiology in addition to their syndromic diagnosis.
207103829
Genetics of epilepsy syndromes starting in the first year of life
Background: Incidence rates of epilepsy in children are highest during the first year of life. Most frequently, epilepsy results from a metabolic or structural defect in the brain. However, some infants have clearly delineated epilepsy syndromes for which no underlying etiology can be identified except for a genetic predisposition. Methods: We reviewed the current knowledge on the genetics of epilepsy syndromes starting in the first year of life. We focus on those epilepsy syndromes without a clear structural or metabolic etiology. Results: Recent molecular studies have led to the identification of the responsible gene defects for several of the monogenetic epilepsy syndromes with onset in the first year of life. Discussion: This knowledge has consequences for clinical practice as it opens new perspectives for genetic testing, improving early diagnosis, and facilitating genetic counseling. This overview of epilepsy syndromes and associated gene defects might serve as a basis for the selection of patients in whom genetic testing can be helpful. AD = autosomal dominant; AED = antiepileptic drug; AR = autosomal recessive; AS = absence seizures; BFIS = benign familial infantile seizures; BFNIS = benign familial neonatal-infantile seizures; BFNS = benign familial neonatal seizures; BMEI = benign myoclonic epilepsy of infancy; CAE = childhood absence epilepsy; DD = developmental delay; EFMR = epilepsy and mental retardation limited to females; EPI = epilepsy; FHM = familial hemiplegic migraine; FIME = familial infantile myoclonic epilepsy; FoS = focal seizures; FS = febrile seizures; GCS = generalized clonic seizures; GEFS+ = generalized epilepsy with febrile seizures plus; GTCS = generalized tonic-clonic seizures; ICCA = infantile convulsions and choreoathetosis; IS = infantile spasms; ISSX = X-linked infantile spasms; MR = mental retardation; MS = myoclonic seizures; PMR = psychomotor retardation; RTT = Rett syndrome; SB = suppression-burst; TLE = temporal lobe epilepsy; TS = tonic seizures; UCS = unilateral clonic seizures.
32046251
A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome).
Early infantile epileptic encephalopathy with suppression-burst pattern (EIEE) is one of the most severe and earliest forms of epilepsy, often evolving into West syndrome; however, the pathogenesis of EIEE remains unclear. ARX is a crucial gene for the development of interneurons in the fetal brain, and a polyalanine expansion mutation of ARX causes mental retardation and seizures, including those of West syndrome, in males. We screened the ARX mutation and found a hemizygous, de novo, 33-bp duplication in exon 2, 298_330dupGCGGCA(GCG)9, in two of three unrelated male patients with EIEE. This mutation is thought to expand the original 16 alanine residues to 27 alanine residues (A110_A111insAAAAAAAAAAA) in the first polyalanine tract of the ARX protein. Although EIEE is mainly associated with brain malformations, ARX is the first gene found to be responsible for idiopathic EIEE. Our observation that EIEE had a longer expansion of the polyalanine tract than is seen in West syndrome is consistent with the findings of earlier onset and more-severe phenotypes in EIEE than in West syndrome.
1113528
De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy
Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy. Using array-based comparative genomic hybridization, we found a de novo 2.0-Mb microdeletion at 9q33.3–q34.11 in a girl with EIEE. Mutation analysis of candidate genes mapped to the deletion revealed that four unrelated individuals with EIEE had heterozygous missense mutations in the gene encoding syntaxin binding protein 1 (STXBP1). STXBP1 (also known as MUNC18-1) is an evolutionally conserved neuronal Sec1/Munc-18 (SM) protein that is essential in synaptic vesicle release in several species. Circular dichroism melting experiments revealed that a mutant form of the protein was significantly thermolabile compared to wild type. Furthermore, binding of the mutant protein to syntaxin was impaired. These findings suggest that haploinsufficiency of STXBP1 causes EIEE.
43913351
Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome
Objective: We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs). Methods: We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara syndrome (OS) and 150 with West syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing. Results: We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay. Conclusions: Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.
13492116
Proteus syndrome associated with hemimegalencephaly and Ohtahara syndrome: Report of two cases
The authors report two cases of Brazilian children with most of the common syndromic features of Proteus syndrome, such as asymmetric overgrowth of tissues, skin abnormalities, hypotonia and mental retardation. In both patients, a refractory epilepsy, compatible with Ohtahara syndrome, as well as hemimegalencephaly, with asymmetric distribution of facial fat, were also diagnosed.
22914424
Are early myoclonic encephalopathy (EME) and the Ohtahara syndrome (EIEE) independent of each other?
BACKGROUND
Early myoclonic encephalopathy (EME) and the Ohtahara syndrome are currently listed as two separate syndromes in the classification of epilepsies. The most prominent differentiating points are the observations that patients with Ohtahara syndrome experience predominantly tonic seizures; their seizures evolve to infantile spasms and the prognosis is often worse than patients with EME.


SUMMARY POINTS
We performed a literature review of published cases. Although syndromes may have distinct courses, the differentiation early on may be impossible as both myoclonus and tonic seizures may coexist. There is also an overlap in the etiologies. Tonic seizures are considered a manifestation of brainstem dysfunction and it is possible that this is more prominent in Ohtahara syndrome. To date, there are 17 autopsy cases (12 presumed to be Ohtahara cases and 5 EME). Evidence of hindbrain pathology was present in all. Tonic seizures or tonic posturing was a feature of all cases. We suggest that the two syndromes may represent a continuum and that the prominence of tonic seizures in the Ohtahara syndrome may be an indication of brainstem dysfunction which may play an important role in the subsequent transition to infantile spasms.
8330110
Epileptic encephalopathies (including severe epilepsy syndromes)
Epileptic encephalopathies represent a group of devastating epileptic disorders that appear early in life and are characterized by pharmacoresistant generalized or focal seizures, persistent severe electroencephalography (EEG) abnormalities, and cognitive dysfunction or decline. The ictal and interictal epileptic discharges are age‐specific and are the main etiologic factors causing cognitive deterioration. This is most obvious in the idiopathic group. In the symptomatic group, the most common causes are structural, congenital, or acquired and rarely some metabolic disorders. In certain cases, clinical and EEG abnormalities persist and may evolve from one type to another as the child grows older. Various factors trigger and sustain the underlying pathophysiologic process and the ongoing epileptic and epileptiform activity during the most critical periods of brain maturation, perpetuating their deleterious effect on the brain. Immune‐mediated mechanisms may have a role, suggested by certain encephalopathies responding to immune‐modulating treatments and by the finding of various autoimmune antibodies. The chance of a better cognitive outcome improves with early diagnosis and treatment that is appropriate and effective. Current antiepileptic drugs are, in general, not effective: we urgently need new trials in this very special epileptic category. This article briefly reviews the most common epileptic encephalopathies and analyzes the most important clinical issues.
27463068
Migrating Partial Seizures in Infancy: A Malignant Disorder with Developmental Arrest
Summary: Fourteen infants of both sexes had a previously unreported epileptic condition characterized by nearly continuous multifocal seizures. The first seizures occurred at a mean age of 3 months, without antecedent risk factors. At 1 to 10 months, the seizures became very frequent. They were partial with variable clinical expression, and the EEG showed that the discharges randomly involved multiple independent sites, moving from one cortical area to another in consecutive seizures. Although their topography varied, the EEG ictal pattern of each seizure was very similar. It consisted of rhythmic alpha or theta activity which spread to involve an increasing area of the cortical surface. Patients regressed developmentally and became quadriplegic with severe axial hypotonia. Three patients died at age 7 months and at age 7 and 8 years, respectively. Seizures were controlled in only 2 patients, and only 3 children resumed psychomotor development. Extensive investigation failed to determine an etiology, and there was no familial recurrence. Neuropathological examination of the brain in two cases showed only severe hippocampal neuronal loss and accompanying gliosis.
24417881
Malignant migrating partial seizures in infancy.
The syndrome of malignant migrating partial seizures in infancy (MMPSI) was first reported in 1995, and is now included among the childhood epileptic syndromes in the revision proposal of the ILAE Commission on classification and terminology. The main clinical features are seizure onset in the first 6 months of life, occurrence of almost continuous migrating polymorphous focal seizures, associated with multifocal ictal EEG discharges, progressive deterioration of psychomotor development combined with frequent evolution of acquired microcephaly, and lack of a significant familial and etiological context. Eventually, children develop major axial hypotonia, pyramidal and extrapyramidal signs with athetotic movements and strabismus. Neuroradiological, biochemical, and genetic investigations thus far have note contributed to our knowledge about this syndrome. Etiology is still unknown, though it appears reasonable to suspect a genetic etiology for MMPSI; a channelopathy may be responsible for the age-dependent cortical neuronal hyperexcitability. Seizures are markedly drug resistant and outcome is generally severe. However, some patients may respond favourably to bromide, stiripentol associated with clonazepam, and, more recently, to levetiracetam. Vagus nerve stimulation and a ketogenic diet have been tried also but with poor or inconclusive results. Based on age at onset, MMPEI may be placed between early epileptic encephalopthies and infantile spasms.
3416849
Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum.
Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100,000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.
25118958
SCN2A encephalopathy
Objective: De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Herein, we define the phenotypic spectrum of SCN2A encephalopathy. Methods: Twelve patients with an SCN2A epileptic encephalopathy underwent electroclinical phenotyping. Results: Patients were aged 0.7 to 22 years; 3 were deceased. Seizures commenced on day 1–4 in 8, week 2–6 in 2, and after 1 year in 2. Characteristic features included clusters of brief focal seizures with multiple hourly (9 patients), multiple daily (2), or multiple weekly (1) seizures, peaking at maximal frequency within 3 months of onset. Multifocal interictal epileptiform discharges were seen in all. Three of 12 patients had infantile spasms. The epileptic syndrome at presentation was epilepsy of infancy with migrating focal seizures (EIMFS) in 7 and Ohtahara syndrome in 2. Nine patients had improved seizure control with sodium channel blockers including supratherapeutic or high therapeutic phenytoin levels in 5. Eight had severe to profound developmental impairment. Other features included movement disorders (10), axial hypotonia (11) with intermittent or persistent appendicular spasticity, early handedness, and severe gastrointestinal symptoms. Mutations arose de novo in 11 patients; paternal DNA was unavailable in one. Conclusions: Review of our 12 and 34 other reported cases of SCN2A encephalopathy suggests 3 phenotypes: neonatal-infantile–onset groups with severe and intermediate outcomes, and a childhood-onset group. Here, we show that SCN2A is the second most common cause of EIMFS and, importantly, does not always have a poor developmental outcome. Sodium channel blockers, particularly phenytoin, may improve seizure control.
40707958
A Proposal for Case Definitions and Outcome Measures in Studies of Infantile Spasms and West Syndrome: Consensus Statement of the West Delphi Group
Summary:  Purpose: To reach a broad consensus on case definitions, outcomes, and outcome measures that will ease future study design and facilitate comparison of data from different studies of infantile spasms and West syndrome.
4519822
ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology
The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self‐limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.
42594846
Latest American and European Updates on Infantile Spasms
Infantile spasms remain a challenging condition to study and treat, and although they form the commonest epilepsy syndrome with onset in infancy, the challenge is broadened by the wide range of potential underlying causes. The field of study remains dynamic, with debates relating to case definitions and organising structures for classification of seizures and epilepsies in general, and a newly proposed genetic and biologic classification specifically for infantile spasms. There have been recent consensus statements, a Delphi process eliciting prioritised quality-of-care indicators, systematic reviews of treatment, and a survey of clinical practice in the USA. There is increasing evidence that longer duration of spasms is associated with poorer neurodevelopmental outcomes. It has taken many years to develop an animal model that reasonably represents infantile spasms, but there are now several animal models, and they are leading to innovative and valuable studies that suggest novel treatments.
20348363
Incidence and Aetiology of Infantile Spasms from 1960 to 1976: a Population Study in Finland
This series of cases of infantile spasms comprised 107 children born between 1960 and 1976 in the county of Uusimaa, Finland. The incidence of the syndrome was 0–38 to 0–42/1000 live births and has remained almost unchanged during those years, although there have been changes in the size of different aetiological groups. The importance of prenatal and perinatal factors, and especially of neonatal hypoglycaemia, as causal factors has decreased, whereas the numbers of cases due to infections and malformations has increased.
22199151
Expansion of the ARX spectrum
We present four patients with ARX mutations and widely variant clinical presentations. Case 1, a female with a known ARX mutation has refractory infantile spasms and severe mental retardation. Case 2, a male presented with a neurodegenerative disorder and has a known ARX mutation likely de novo as mother is not a carrier. Cases 3 and 4, two siblings with a novel variant in ARX, which is not clearly pathogenic, have developmental delay. One of the siblings had a diagnosis of autistic spectrum disorder, failure to thrive with severe feeding difficulties, intracranial hemorrhage, and seizures. There are very few affected females with ARX related infantile spasms. These cases expand the known phenotype of this emerging condition.
20202477
Genetic and biologic classification of infantile spasms.
Infantile spasms constitute an age-dependent epilepsy, highly associated with cognitive impairment, autism, and movement disorders. Previous classification systems focused on a distinction between symptomatic and cryptogenic etiologies, and have not kept pace with recent discoveries of mutations in genes in key pathways of central nervous system development in patients with infantile spasms. Children with certain genetic syndromes are much likelier to manifest infantile spasms, and we review the literature to propose a genetic classification of these disorders. Children demonstrating genetic associations with infantile spasms also manifest phenotypes beyond epilepsy that may be explained by recent advances in the understanding of underlying biological mechanisms. Therefore we propose a biologic classification of genes highly associated with infantile spasms, and articulate models for infantile spasms pathogenesis based on those data. The two best described pathways of pathogenesis involve abnormalities in the gene regulatory network of gamma-aminobutyric acidergic forebrain development and abnormalities in molecules expressed at the synapse. These genetic and biologic classifications are flexible, and they should encourage much needed progress in syndrome recognition, clinical genetic testing, and the development of new therapies targeting specific pathways of pathogenesis.
40756791
Somatic mosaicism for a CDKL5 mutation as an epileptic encephalopathy in males
Somatic Mosaicism for a CDKL5 Mutation as an Epileptic Encephalopathy in Males Julien Masliah-Plachon, St ephane Auvin, Juliette Nectoux, Yann Fichou, Jamel Chelly, and Thierry Bienvenu* Laboratoire de Biochimie et Biologie Mol eculaire, AP-HP, Hôpital Cochin, Paris, France Service de Neurologie P ediatrique et des Maladies M etaboliques, AP-HP, Hôpital Robert Debr e, Paris, France Universit e Paris Descartes, CNRS (UMR 8104), Inserm U567, Institut Cochin, Paris, France
22265615
Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations
Objectives: Heterozygous mutations in STXBP1, encoding the syntaxin binding protein 1, have recently been identified in Ohtahara syndrome, an epileptic encephalopathy with very early onset. In order to explore the phenotypic spectrum associated with STXBP1 mutations, we analyzed a cohort of patients with unexplained early-onset epileptic encephalopathies. Methods: We collected and clinically characterized 106 patients with early-onset epileptic encephalopathies. Mutation analysis of the STXBP1 gene was done using sequence analysis of the exon and intron–exon boundaries and multiplex amplification quantification to detect copy number variations. Results: We identified 4 truncating mutations and 2 microdeletions partially affecting STXBP1 in 6 of the 106 patients. All mutations are predicted to abolish STXBP1 function and 5 mutations were proven to occur de novo. None of the mutation-carrying patients had Ohtahara syndrome. One patient was diagnosed with West syndrome at disease onset, while the initial phenotype of 5 further patients did not fit into a specific recognized epilepsy syndrome. Three of these patients later evolved to West syndrome. All patients had severe to profound mental retardation, and ataxia or dyskinetic movements were present in 5 patients. Conclusion: This study shows that mutations in STXBP1 are not limited to patients with Ohtahara syndrome, but are also present in 10% (5/49) of patients with an early-onset epileptic encephalopathy that does not fit into either Ohtahara or West syndrome and rarely in typical West syndrome. STXBP1 mutational analysis should be considered in the diagnostic evaluation of this challenging group of patients.
10828239
A Prospective Study of the Modified Atkins Diet for Intractable Epilepsy in Adults
Purpose: The ketogenic diet is not typically offered to adults with epilepsy due to the significant lifestyle alterations needed for its use. The modified Atkins diet has been recently demonstrated to be therapeutic for children without the need for an admission, fasting period, weighing of foods, or fluid, calorie, and protein restriction.
205224762
Emerging Antiepileptic Drugs for Severe Pediatric Epilepsies.
The medical management of the epilepsy syndromes of early childhood (eg, infantile spasms, Dravet syndrome, and Lennox-Gastaut syndrome) is challenging; and requires careful evaluation, classification, and treatment. Pharmacologic therapy continues to be the mainstay of management for these children, and as such it is important for the clinician to be familiar with the role of new antiepileptic drugs. This article reports the clinical trial data and personal experience in treating the severe epilepsies of childhood with the recently Food and Drug Administration-approved new antiepileptic drugs (vigabatrin, rufinamide, perampanel, and clobazam) and those in clinical trials (cannabidiol, stiripentol, and fenfluramine). Genetic research has also identified an increasing number of pediatric developmental and seizure disorders that are possibly treatable with targeted drug therapies, focused on correcting underlying neural dysfunction. We highlight recent genetic advances, and how they affect our treatment of some of the genetic epilepsies, and speculate on the use of targeted genetic treatment (precision medicine) in the future.
41553756
The core Dravet syndrome phenotype
Dravet syndrome was described in 1978 by Dravet (1978) under the name of severe myoclonic epilepsy in infancy (SMEI). The characteristics of the syndrome were confirmed and further delineated by other authors over the years. According to the semiologic features, two forms have been individualized: (1) the typical, core, SMEI; and (2) the borderline form, SMEIB, in which the myoclonic component is absent or subtle. Clinical manifestations at the onset, at the steady state, and during the course of the disease are analyzed in detail for the typical Dravet syndrome, and the differential diagnosis is discussed. Onset in the first year of life by febrile or afebrile clonic and tonic–clonic, generalized, and unilateral seizures, often prolonged, in an apparently normal infant is the first symptom, suggesting the diagnosis. Later on, multiple seizure types, mainly myoclonic, atypical absences, and focal seizures appear, as well as a slowing of developmental and cognitive skills, and the appearance of behavioral disorders. Mutation screening for the SCN1A gene confirms the diagnosis in 70–80% of patients. All seizure types are pharmacoresistent, but a trend toward less severe epilepsy and cognitive impairment is usually observed after the age of 5 years.
26058561
Atypical multifocal Dravet syndrome lacks generalized seizures and may show later cognitive decline
To show that atypical multifocal Dravet syndrome is a recognizable, electroclinical syndrome associated with sodium channel gene (SCN1A) mutations that readily escapes diagnosis owing to later cognitive decline and tonic seizures.
13959108
Cryptogenic epileptic syndromes related to SCN1A: twelve novel mutations identified.
BACKGROUND
Sodium channel alpha 1 subunit gene, SCN1A, is the gene encoding the neuronal voltage-gated sodium channel alpha 1 subunit (Na(v)1.1) and is mutated in different forms of epilepsy. Mutations in this gene were observed in more than 70% of patients with severe myoclonic epilepsy of infancy (SMEI) and were also found in different types of infantile epileptic encephalopathy.


OBJECTIVE
To search for disease-causing mutations in SCN1A in patients with cryptogenic epileptic syndromes (ie, syndromes with an unknown cause).


DESIGN
Clinical characterization and molecular genetic analysis of a cohort of patients.


SETTING
University hospitals, rehabilitation centers, and molecular biology laboratories.


PATIENTS
Sixty unrelated patients with cryptogenic epileptic syndromes.


MAIN OUTCOME MEASURES
Samples of DNA were analyzed for mutations and for large heterozygous deletions encompassing the SCN1A gene. A search for microdeletions in the SCN1A gene was also performed in the subset of patients with SMEI/SMEI-borderland who had negative results at the point mutation screening.


RESULTS
No large deletions at the SCN1A locus were found in any of the patients analyzed. In contrast, 13 different point mutations were identified in 12 patients: 10 with SMEI, 1 with generalized epilepsy with febrile seizures plus, and 1 with cryptogenic focal epilepsy. An additional search for SCN1A intragenic microdeletions in the remaining patients with SMEI/SMEI-borderland and no point mutations was also negative.


CONCLUSIONS
These results confirm the role of the SCN1A gene in different types of epilepsy, including cryptogenic epileptic syndromes. However, large deletions encompassing SCN1A were not common disease-causing rearrangements in this group of epilepsies.
75826500
Prognostic Challenges of SCN1A Genetic Mutations: Report on Two Children with Mild Features
Mutations in the gene encoding the α-1 subunit of the voltage-gated sodium channel (SCN1A) are associated with variable but usually severe clinical course, both for the epileptic seizures and the cognitive impairment. The purpose of the present study was to retrospectively review two patients affected by seizures and two different types of SCN1A gene mutations (microdeletion and point mutation). The children (a 4-year-old girl and a 3-year-old boy) were affected by generalized tonic–clonic seizures and myoclonic jerks plus unilateral seizures, respectively. Genetic analyses showed, in the girl, the presence of a 4 MB deletion involving SCN1A and four other genes, and a point mutation in the boy. Both the patients showed a mild clinical course, with a good pharmacological control of the crises and sufficient scholastic performances. At present, the role of the combination of SCN1A mutations and the related clinical manifestations is not very clear. Prognostic counseling is particularly challenging given that, in many cases, the clinical course of these patients is independent of the genotype and its severity is difficult to predict.
4583592
Dravet syndrome: Characteristics, comorbidities, and caregiver concerns
The Dravet Syndrome Foundation (DSF) conducted the largest in-depth survey of parents and caregivers of patients with Dravet syndrome (DS) to date, in order to (1) identify top concerns among caregivers, (2) establish an approximate frequency of characteristics and comorbidities of DS beyond seizures, and (3) provide direction for clinicians and researchers looking to study the effects of DS on the patient and family unit. Two hundred fifty-six responses were received representing a patient age range of 9months to 32years with a median age group of 7-10years (IQR=8). In an open response, caregivers ranked speech/communication, impacts on siblings, and cognitive impairment as their top concerns after seizure control, and nearly two-thirds of caregivers reported having suffered from depression. Some characteristics of DS such as gait issues increased with patient age, while others, including photosensitivity, hypotonia, and ataxia, were present from a young age. Comorbidities such as sleep disturbances and cardiac abnormalities were more frequently reported than in previous studies and some (including bradycardia) were correlated with SCN1A mutation status. This survey supports the concept of Dravet syndrome as a disease of the central nervous system with far-reaching effects and highlights the importance of the patient voice in determining appropriate research objectives. While seizure frequency is a relatively well-understood objective, seizures represent only a portion of parent and caregiver concerns. Studying the characteristics of DS described herein may identify additional outcomes significant for research.
23027990
The genetics of Dravet syndrome
Dravet syndrome (DS), otherwise known as severe myoclonic epilepsy of infancy (SMEI), is an epileptic encephalopathy presenting in the first year of life. DS has a genetic etiology: between 70% and 80% of patients carry sodium channel α1 subunit gene (SCN1A) abnormalities, and truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset. The remaining SCN1A mutations comprise splice‐site and missense mutations, most of which fall into the pore‐forming region of the sodium channel. Mutations are randomly distributed across the SCN1A protein. Most mutations are de novo, but familial SCN1A mutations also occur. Somatic mosaic mutations have also been reported in some patients and might explain the phenotypical variability seen in some familial cases. SCN1A exons deletions or chromosomal rearrangements involving SCN1A and contiguous genes are also detectable in about 2–3% of patients. A small percentage of female patients with a DS‐like phenotype might carry PCDH19 mutations. Rare mutations have been identified in the GABARG2 and SCN1B genes. The etiology of about 20% of DS patients remains unknown, and additional genes are likely to be implicated.
6793868
Dravet Syndrome: Diagnosis and Long-Term Course
Abstract Dravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality. The typical presentation is characterized by hemiclonic or generalized clonic seizures triggered by fever during the first year of life, followed by myoclonic, absence, focal and generalized tonic-clonic seizures. Non-convulsive status epilepticus and epileptic encephalopathy are common. Development is normal in the first year of life, but most individuals eventually suffer from intellectual impairment. Dravet syndrome is associated with mutations in the sodium channel alpha1 subunit gene (SCN1A) in 70-80% of individuals. SCN1A mutation results in inhibition of the GABAergic inhibitory interneurons, leading to excessive neuronal excitation. The “interneuron hypothesis” is the current most accepted pathophysiological mechanism of Dravet syndrome. The mortality rate is increased significantly in Dravet syndrome. Ataxia, a characteristic crouched gait and Parkinson’s symptoms may develop in some individuals. It is likely that Dravet syndrome is underdiagnosed in adults with treatment-resistant epilepsy. Early diagnosis is important to avoid anti-seizure medications that exacerbate seizures.
4994684
From genotype to phenotype in Dravet disease
Dravet syndrome combines clonic generalized, focal or unilateral seizures, beginning within the first year of life, often triggered by hyperthermia whatever its cause, including pertussis vaccination. Long-lasting febrile seizures are frequent in infancy and repeat status epilepticus (SE) has negative prognostic value. Massive myoclonus, rare absences, complex partial seizures and generalized spikes may appear several years later. Myoclonic status may occur in childhood, but acute encephalopathy with febrile SE followed by ischemic lesions and psychomotor impairment, the most severe condition, occurs mainly within the first five years of life. Generalized tonic-clonic and tonic seizures in sleep predominate in adulthood. Non epileptic manifestations appear with age, including intellectual disability, ataxia and crouching gait. Incidence of SUDEP is high, whatever the age. SCN1A haploinsufficiency producing NaV1.1 dysfunction mainly affects GABAergic neurons. In cortical interneurons it explains epilepsy, in cerebellum the ataxia, in basal ganglia and motor neurons the crouching gait, in hypothalamus the thermodysregulation and sleep troubles, and dysfunction in all these structures contributes to psychomotor delay. Valproate, stiripentol, topiramate and bromide are the basis of antiepileptic treatment, whereas inhibitors of sodium channel worsen the condition. Benzodiazepines seem to facilitate acute encephalopathy when given chronically, and they should be restricted to SE. Ketogenic diet is useful in both chronic and acute conditions. Only targeting SCN1A haploinsufficiency and NaV1.1 dysfunction could improve non epileptic manifestations of this condition that deserves being considered as a disease, not only as an epilepsy syndrome.
24177741
A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy.
We recently described mutations of the neuronal sodium-channel alpha-subunit gene, SCN1A, on chromosome 2q24 in two families with generalized epilepsy with febrile seizures plus (GEFS+) type 2. To assess the contribution that SCN1A makes to other types of epilepsy, 226 patients with either juvenile myoclonic epilepsy, absence epilepsy, or febrile convulsions were screened by conformation-sensitive gel electrophoresis and manual sequencing of variants; the sample included 165 probands from multiplex families and 61 sporadic cases. The novel mutation W1204R was identified in a family with GEFS+. Seven other coding changes were observed; three of these are potential disease-causing mutations. Two common haplotypes, with frequencies of .67 and .33, were defined by five single-nucleotide polymorphisms (SNPs) spanning a 14-kb region of linkage disequilibrium. An SNP located 18 bp upstream of the splice-acceptor site for exon 3 was observed in 7 of the 226 patients but was not present in 185 controls, suggesting possible association with a disease mutation. This work has confirmed the role of SCN1A in GEFS+, by identification of a novel mutation in a previously undescribed family. Although a few candidate disease alleles were identified, the patient survey suggests that SCN1A is not a major contributor to idiopathic generalized epilepsy. The SCN1A haplotypes and SNPs identified here will be useful in future association and linkage studies.
42206554
Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus.
Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by the presence of febrile and afebrile seizures. The first gene, GEFS1, was mapped to chromosome 19q and was identified as the sodium-channel beta1-subunit, SCN1B. A second locus on chromosome 2q, GEFS2, was recently identified as the sodium-channel alpha1-subunit, SCN1A. Single-stranded conformation analysis (SSCA) of SCN1A was performed in 53 unrelated index cases to estimate the frequency of mutations in patients with GEFS+. No mutations were found in 17 isolated cases of GEFS+. Three novel SCN1A mutations-D188V, V1353L, and I1656M-were found in 36 familial cases; of the remaining 33 families, 3 had mutations in SCN1B. On the basis of SSCA, the combined frequency of SCN1A and SCN1B mutations in familial cases of GEFS+ was found to be 17%.
3839853
Mortality in Dravet syndrome: A review
INTRODUCTION
Premature mortality is a major issue in Dravet syndrome (DS). To improve understanding of DS premature mortality, we conducted a comprehensive literature search with a particular emphasis on SUDEP.


METHODS
We searched PubMed, Embase, Web of Science, Cochrane, CENTRAL, CINAHL, PsycINFO, Academic Search Premier, and ScienceDirect on the following terms: "Dravet syndrome", "severe myoclonic epilepsy", "SMEI", "mortality", "survivors", "prognosis", and "death". DS cases or cohorts studies reporting mortality were included.


RESULTS
The search yielded 676 articles and 86 meeting abstracts. After removing duplicates and screening titles and abstracts, full text of 73 articles was reviewed. Only 28 articles and six meeting abstracts met inclusion criteria. Five articles and four meeting abstracts were excluded, as the case(s) were also described elsewhere. After checking the references, five additional studies were included. The 30 items reported 177 unique cases. Sudden unexpected death in epilepsy was the likely cause in nearly half of the cases (n=87, 49%), followed by status epilepticus (n=56, 32%). Drowning or accidental death was reported in 14 cases (8%), infections in 9 (5%), other causes in six (3%), and unknown in five (3%). Age at death was reported for 142 of the 177 cases (80%), with a mean age of 8.7±9.8years (SD); 73% died before the age of 10years.


DISCUSSION
Dravet syndrome is characterized by high epilepsy-related premature mortality and a marked young age at death. Sudden unexpected death in epilepsy is the leading reported cause of death in DS, accounting for nearly half of all deaths. The cause of this excess mortality remains elusive but may be explained by epilepsy severity, as well as genetic susceptibility to SUDEP.
38366706
Marked efficacy of combined three‐drug therapy (Sodium Valproate, Topiramate and Stiripentol) in a patient with Dravet syndrome
Dravet syndrome (DS) is an intractable epilepsy syndrome. The three‐drug combination therapy of sodium valproate (VPA), clobazam (CLB) and stiripentol (STP) is recommended worldwide.
3445847
Stiripentol efficacy and safety in Dravet syndrome: a 12‐year observational study
To assess long‐term safety and efficacy of stiripentol as an antiepileptic medication for people with Dravet syndrome.
36901937
Myoclonic status in nonprogressive encephalopathies: An update
Myoclonic status in nonprogressive encephalopathies (MSNE) is an epileptic syndrome in development, characterized by the early onset of continuous diffuse epileptiform abnormalities, accompanied by positive and/or negative phenomena correlated with transient and recurring motor, cognitive, or behavioral disturbances. Outcome of MSNE is poor and may determine progressive neurologic deterioration. MSNE is not easy to recognize and should be distinguished from progressive myoclonic epilepsies and other rarely reported infantile myoclonic epilepsies. The identification of MSNE may guide the diagnostic work‐up, suggesting the presence of a genetic defect, such as Angelman syndrome, hypoxic–ischemic encephalopathy, or brain malformation.