Epilepsy in children

doi:10.1016/S0140-6736(06)68182-8

The Lancet

Volume 367, Issue 9509, 11–17 February 2006, Pages 499-524

https://doi.org/10.1016/S0140-6736(06)68182-8 Get rights and content

Summary

10·5 million children worldwide are estimated to have active epilepsy. Over the past 15 years, syndrome-oriented clinical and EEG diagnosis, and better aetiological diagnosis, especially supported by neuroimaging, has helped to clarify the diversity of epilepsy in children, and has improved management. Perinatal and postinfective encephalopathy, cortical dysplasia, and hippocampal sclerosis account for the most severe symptomatic epilepsies. Ion channel defects can underlie both benign age-related disorders and severe epileptic encephalopathies with a progressive disturbance in cerebral function. However, the reasons for age-related expression in children are not understood. Neither are the mechanisms whereby an epileptic encephalopathy originates. Several new drugs have been recently introduced but have provided limited therapeutic benefits. However, treatment and quality of life have improved because the syndrome-specific efficacy profile of drugs is better known, and there is heightened awareness that compounds with severe cognitive side-effects and heavy polytherapies should be avoided. Epilepsy surgery is an important option for a few well-selected individuals, but should be considered with great caution when there is no apparent underlying brain lesion.

Section snippets

Definitions and terminology

Seizures are described with standard terminology,1, 2, 3, 4 and, where possible, classified in specific epilepsy types or syndromes3, 5 (panel 1 and table 1). A syndrome is a complex of signs and symptoms defining a unique epilepsy condition.³ Syndromes are classified on the basis of seizure types, clinical context, neurophysiology, and neuroroimaging.3, 5 Epilepsy can be generalised, if all seizures and electroencephalogram (EEG) abnormalities are generalised, or focal (partial) if clinical

Epidemiology

Worldwide, it is estimated that 10·5 million children under 15 years have active epilepsy, representing about 25% of the global epilepsy population.⁶ Of the 3·5 million people who develop epilepsy annually, 40% are younger than 15 years, and more than 80% live in developing countries.⁶

Population-based studies on childhood-onset epilepsy⁶ indicate annual incidence rates of 61–124 per 100 000 in developing countries, and 41–50 per 100 000 in developed countries.⁶ Incidence falls progressively

Natural history

In children who experience a first unprovoked focal or generalised tonic-clonic seizure, the cumulative risk of recurrence is 42% at 8 years' follow-up, with only 3% of all recurrencies occurring after 5 years.⁹ Multivariable analysis has shown that risk factors for recurrence include a remote symptomatic cause, an abnormal EEG, a seizure occurring when asleep, a history of febrile seizures, and postictal paresis.⁹ Treatment does not change the recurrence rates.10, 11 About 64% of individuals

General aspects of prognosis

Most children with epilepsy can be divided into four main prognostic groups.¹⁵ The first group is the benign epilepsies—eg, benign rolandic epilepsy (20–30% of patients), in which remission occurs after a few years and treatment can often be avoided. The second group is the pharmacosensitive epilepsies—eg, most children with absence epilepsy (30% of patients), in which seizure control is easily achieved by medication and spontaneous remission occurs after a few years. The third one is the

Cause and pathophysiology

Knowledge of the cause and pathophysiology of childhood epilepsy has considerably improved with modern neuroimaging and molecular genetic studies. However, our understanding of the causes and the reasons why specific syndromes appear with precise age-relatedness is still very limited.

Diagnosis

Two-thirds of cases can be assigned to specific syndromes early, after undertaking EEG in all children and neuroimaging where appropriate.99, 100 Of the remaining percentage, about 30% will be assigned to more specific categories within 2 years.¹⁰¹

History taking is the main diagnostic instrument. It should assemble a coherent sequence of manifestations that is made likely by the functional characteristics of the brain, according to age and neurological status. It should include developmental

Differential diagnosis

In children, several non-epileptic paroxysmal events need to be differentiated from epilepsy. Misdiagnosis is frequent and is an important cause of pseudo-refractory epilepsy.¹⁰⁵ Furthermore, cognitive or behavioural symptoms of epilepsy are often interpreted as psychogenical manifestations and sleep-related epileptic seizures as parasomnias.¹⁰⁶

Reflex anoxic seizures and breath-holding spells occur in about 4% of children, and onset is in infancy. Reflex anoxic seizures results from temporary

Structural neuroimaging

CT can detect small calcified lesions or bone scalloping and remodelling. It is indicated in emergency settings, such as status epilepticus or to assess the consequences of head injury prompted by seizures.

MRI is the procedure of choice, although children with uncomplicated febrile convulsions and typical idiopathic epilepsy do not need imaging. Conversely, children with non-idiopathic focal epilepsy should always have an MRI. Seizure semiology and the EEG should guide the imaging study.

Classification and response to treatment of the different epilepsy types

An example of a classification of epilepsy syndromes, with a schematic indication of their main clinical characteristics is shown in table 2. The most important syndromes are reported in the following sections.

Idiopathic focal epilepsies

Idiopathic focal epilepsies are the most frequent epilepsy syndromes in children. They have an age-dependent course and might occur in more than one family member. Response to antiepileptic drugs is usually satisfactory but it is unclear whether treatment changes the outcome. Parents usually accept withholding treatment if it is explained that the disorder is self-limiting and does not induce brain damage. If treatment is necessary, carbamazepine or valproate are preferred.¹²⁶

Benign childhood

Idiopathic generalised epilepsies

Idiopathic generalised epilepsies are frequent and onset is in infancy to adolescence. Idiopathic generalised epilepsies are genetically determined (see section on genetic and molecular basis). Neuroimaging is normal and suggestions that morphological cortical abnormalities might underlie idiopathic generalised epilepsies¹⁵⁶ have not been confirmed.¹⁵⁷ As a result of the overlapping features between different idiopathic generalised epilepsies, the term idiopathic generalised epilepsies with

Epilepsy with seizures precipitated by light stimulation

In visual sensitive (or photosensitive) epilepsies, seizures are precipitated by environmental photic stimuli.¹⁷⁴ The age of onset peaks at 11 years. The term photosensitivity only designates the abnormal EEG response to flickering light,¹⁷⁴ a finding also observed in 4% of healthy children or adolescents.¹⁷⁵ Photic-induced absences, myoclonic seizures, and generalised tonic-clonic seizures are observed in idiopathic generalised epilepsies and in Dravet's syndrome.¹⁷⁶ Single or repeated

The epileptic encephalopathies

Epileptic encephalopathies are conditions in which seizures, the epileptiform abnormalities, or both, contribute to the progressive disturbance in cerebral function.³ About 40% of all epilepsies occurring in the first 3 years of life fit this definition.¹⁸⁴ However, epileptic encephalopathies represents more a concept and an operational category than a syndrome spectrum. Some syndromes such as infantile spasms, severe myoclonic epilepsy, epilepsy with continuous spike and waves during sleep, or

Febrile seizures

Febrile seizures occur during an acute febrile illness for which no cause can be found. This type of seizure affects 2–4% of children aged 3 months to 5 years.²³⁷

Genetic factors are involved with both autosomal dominant and polygenic inheritance. During febrile seizures, most children have respiratory tract infections.²³⁷ There is a substantial risk of occurrence in the 24 h after receiving the diphtheria-pertussis-tetanus vaccine and in the 8–14 days after the measles, mumps, and rubella

Progressive myoclonus epilepsies

Progressive myoclonus epilepsies are a group of syndromes including Lafora disease, Unverricht-Lundborg disease, myoclonus epilepsy with red ragged fibres, early infantile, late infantile, juvenile, and adult ceroid-lipofuscinosis, and sialidosis.²⁴³ The clinical picture includes multifocal and generalised myoclonus, generalised tonic-clonic seizures, or clonic-tonic-clonic seizures, photosensitivity, cognitive deterioration, cerebellar, and extrapyramidal signs. The different syndromes are

Status epilepticus and seizure-induced brain damage

Status epilepticus is a neurological emergency defined as recurrent seizures, lasting for more than 30 min, without interictal resumption of baseline CNS function.¹ About 70% of episodes of status epilepticus are the initial seizure and up to 27% of children with epilepsy will present with one or more episodes,²⁴⁴ although specific syndromes have a different risk.

A pragmatic classification of status epilepticus is made according to the presence or absence of motor manifestations, as a result of

Molecular targets and clinical efficacy of antiepileptic drugs

A spectrum of clinical efficacy is established for most available compounds, although their mechanisms of action are not distinct (table 3) and are poorly understood. The main excitatory neurotransmitter in the CNS is glutamate, which acts on three receptor types (N-methyl-D-aspartate, kainate/AMPA, and metabotropic). The main inhibitory neurotransmitter is γ-aminobutyric acid, which acts on two receptor types. Activation of the GABA-A receptor activates a Cl-permeable ion channel, producing

Search strategy and selection criteria

The information in this report is primarily on the basis of peer-reviewed medical publications from 1980 to 2005. PubMed was used to search for appropriate articles. Selection criteria included a judgment about novelty and importance of studies, and their relevance to the well informed general medical doctor and paediatrician. In the case of treatment studies, only those studies in which efficacy claims were supported by a clinical trial have been cited. The rate of evidence for drug

References (314)

GuerriniR et al.
The genetic and molecular basis of epilepsy
Trends Mol Med
(2003)
HarkinLA et al.
Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus
Am J Hum Genet
(2002)
AsanoE et al.
Surgical treatment of West syndrome
Brain Dev
(2001)
FoxJW et al.
Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia
Neuron
(1998)
HarveyAS et al.
Febrile seizures and hippocampal sclerosis: frequent and related findings in intractable temporal lobe epilepsy of childhood
Pediatr Neurol
(1995)
GuerriniR et al.
Epileptogenic brain malformations: clinical presentation, malformative patterns and indications for genetic testing
Seizure
(2001)
DaboraSL et al.
Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs
Am J Hum Genet
(2001)
ChironC et al.
Randomised trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis
Epilepsy Res
(1997)
KingMA et al.
Epileptology of the first-seizure presentation: a clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients
Lancet
(1998)
BlumeWT et al.
Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology
Epilepsia
(2001)

Epilepsia

(1989)

ForsgrenL

Incidence and prevalence

HauserWA et al.

Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984

Epilepsia

(1993)

TsuboiT

Prevalence and incidence of epilepsy in Tokyo

Epilepsia

(1988)

ShinnarS et al.

The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: an extended follow-up

Pediatrics

(1996)

CamfieldPR et al.

Epilepsy after a first unprovoked seizure in childhood

Neurology

(1985)

ShinnarS et al.

Risk of seizure recurrence following a first unprovoked seizure in childhood: a prospective study

Pediatrics

(1990)

SillanpääM

Long-term outcome of epilepsy

Epileptic Disord

(2000)

SchmidtD et al.

A practical guide to when (and how) to withdraw antiepileptic drugs in seizure-free patients

Drugs

(1996)

BaruzziA et al.

Antiepileptic drug withdrawal in childhood epilepsies: preliminary results of a prospective study

SanderJWAS

Some aspects of prognosis of the epilepsies: a review

Epilepsia

(1993)

KwanP et al.

Early identification of refractory epilepsy

N Engl J Med

(2000)

WallaceRH et al.

Febrile seizures and generalized epilepsy associated with a mutation in the Na⁺-channel b1 subunit gene SCN1B

Nat Genet

(1998)

BerkovicSF et al.

Epilepsia

(2002)

GuerriniR et al.

Chromosomal abnormalities

AugustijnPB et al.

Ring chromosome 20 epilepsy syndrome in children: electroclinical features

Neurology

(2001)

Cited by (354)

Analysis of the role of PANoptosis in seizures via integrated bioinformatics analysis and experimental validation
2024, Heliyon
Epilepsy is recognized as the most common chronic neurological condition among children, and hippocampal neuronal cell death has been identified as a crucial factor in the pathophysiological processes underlying seizures. In recent studies, PANoptosis, a newly characterized form of cell death, has emerged as a significant contributor to the development of various neurological disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. PANoptosis involves the simultaneous activation of pyroptosis, apoptosis, and necroptosis within the same population of cells. However, its specific role in the context of seizures remains to be fully elucidated. Further investigation is required to uncover the precise involvement of PANoptosis in the pathogenesis of seizures and to better understand its potential implications for the development of targeted therapeutic approaches in epilepsy.
In this study, the gene expression data of the hippocampus following the administration of kainic acid (KA) or NaCl was obtained from the Gene Expression Omnibus (GEO) database. The PANoptosis-related gene set was compiled from the GeneCards database and previous literature. Time series analysis was performed to analyze the temporal expression patterns of the PANoptosis-related genes. Gene set variation analysis (GSVA), Gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) were employed to explore potential biological mechanisms underlying PANoptosis and its role in seizures. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were utilized to identify pivotal gene modules and PANoptosis-related genes associated with the pathophysiological processes underlying seizures. To validate the expression of PANoptosis-related genes, Western blotting or quantitative real-time polymerase chain reaction (qRT-PCR) assays were conducted. These experimental validations were performed in human blood samples, animal models, and cell models to verify the expression patterns of the PANoptosis-related genes and their relevance to epilepsy.
The GSVA analysis performed in this study demonstrated that PANoptosis-related genes have the potential to distinguish between the control group and KA-induced epileptic mice. This suggests that the expression patterns of these genes are significantly altered in response to KA-induced epilepsy. Furthermore, the Weighted gene co-expression network analysis (WGCNA) identified the blue module as being highly associated with epileptic phenotypes. This module consists of genes that exhibit correlated expression patterns specifically related to epilepsy. Within the blue module, 10 genes were further identified as biomarker genes for epilepsy. These genes include MLKL, IRF1, RIPK1, GSDMD, CASP1, CASP8, ZBP1, CASP6, PYCARD, and IL18. These genes likely play critical roles in the pathophysiology of epilepsy and could serve as potential biomarkers for diagnosing or monitoring the condition.
In conclusion, our study suggests that the hippocampal neuronal cell death in epilepsy may be closely related to PANoptosis, a novel form of cell death, which provides insights into the underlying pathophysiological processes of epilepsy and helps the development of novel therapeutic approaches for epilepsy.
Altered White-Matter Functional Network in Children with Idiopathic Generalized Epilepsy
2024, Academic Radiology
The white matter (WM) functional network changes offers insights into the potential pathological mechanisms of certain diseases, the alterations of WM functional network in idiopathic generalized epilepsy (IGE) remain unclear. We aimed to explore the topological characteristics changes of WM functional network in childhood IGE using resting-state functional Magnetic resonance imaging (MRI) and T₁-weighted images.
A total of 84 children (42 IGE and 42 matched healthy controls) were included in this study. Functional and structural MRI data were acquired to construct a WM functional network. Group differences in the global and regional topological characteristics were assessed by graph theory and the correlations with clinical and neuropsychological scores were analyzed. A support vector machine algorithm model was employed to classify individuals with IGE using WM functional connectivity as features, and the model's accuracy was evaluated using leave-one-out cross-validation.
In IGE group, at the network level, the WM functional network exhibited increased assortativity; at the nodal level, 17 nodes presented nodal disturbances in WM functional network, and nodal disturbances of 11 nodes were correlated with cognitive performance scores, disease duration and age of onset. The classification model achieved the 72.6% accuracy, 0.746 area under the curve, 69.1% sensitivity, 76.2% specificity.
Our study demonstrated that the WM functional network topological properties changes in childhood IGE, which were associated with cognitive function, and WM functional network may help clinical classification for childhood IGE. These findings provide novel information for understanding the pathogenesis of IGE and suggest that the WM function network might be qualified as potential biomarkers.
Effects of the coronavirus disease outbreak on the development of neurological disorders in children: A comparison of the incidence of febrile seizure and epilepsy using an interrupted time-series approach
2024, Journal of Infection and Public Health
With the outbreak of COVID-19, school closures and quarantines following social distancing have brought significant changes to children's lifestyles. Therefore, we aimed to compare the population-adjusted incidence of febrile seizures(FS) and epilepsy before and after the COVID-19 outbreak in Korea and to assess the effects of the COVID-19 outbreak on the incidence by region and age group.
A retrospective cohort study was conducted using nationwide claims data and covid data from January 2019 to December 2020. The incidence of diseases and difference in incidence before (Jan 20 to Dec 30, 2019) and after (Jan 20 to Dec 30, 2020) the COVID-19 outbreak was measured using rate ratio. An Interrupted time series analysis was used to identify the effect of COVID-19 on trends of FS and epilepsy. Subgroup analysis by age, sex, insurance, and risk of coronavirus by area were conducted.
Following the onset of the pandemic, the number of newly diagnosed FS cases decreased sharply by 69 % (24,182 to 7238), whereas the incidence of epilepsy, increased to 1.02 times (30,286−29,312), when adjusted in proportion to the population. Notably, a greater decrease in the incidence of FS were found in the regions with high-risk of coronavirus. A result of segmented regression analysis proved the decrease was significant and made immediately after the pandemic started(p < 0.001). In contrast to the incidence of FS, that of epilepsy did not exhibit a significant month-to-month change during the baseline period, immediately after the pandemic started, and during the pandemic.
The COVID-19 outbreak and resulting social distancing measures reduced the incidence of febrile seizure immediately rather than gradually. Unlike in the case of acute febrile seizure, the COVID-19 pandemic had no effect on the incidence of chronic epilepsy.
Disturbed white matter integrity on diffusion tensor imaging in young children with epilepsy
2024, Clinical Radiology
To evaluate whether abnormalities in white matter (WM) integrity are present in young children with epilepsy.
Twelve children (3–6 years old) with epilepsy and six matched healthy controls were recruited for brain diffusion tensor imaging (DTI). Track-based spatial statistics (TBSS) was used to analyse and compare DTI indices of mean diffusivity (MD), fractional anisotropy (FA), axial and radial diffusivity (AD/RD) between patients and controls, and correlations between clinical variables and DTI parameters were analysed.
Compared with controls, patients showed increased FA in the left superior corona radiata and increased AD in the bilateral superior corona radiata. In children with generalised epilepsy, FA was increased in the left external capsule, while AD was decreased in the body of the corpus callosum, the left external capsule and the left superior longitudinal fasciculus. In those with focal epilepsy, FA was increased in the genu and body of the corpus callosum, and RD was decreased in the genu of the corpus callosum and left external capsule. Compared with partial epilepsy, generalised epilepsy was associated with increased FA in the right anterior corona radiata and decreased RD in the right anterior corona radiata and the genu and body of the corpus callosum. No significant correlations were observed between clinical variables and DTI parameters.
The results of this study indicate that the microstructure of the white matter is disturbed by epileptic discharges and a compensatory response occurs during early brain development.
Development and Validation of Physiologically Based Pharmacokinetic Model of Levetiracetam to Predict Exposure and Dose Optimization in Pediatrics
2023, Journal of Pharmaceutical Sciences
Levetiracetam (Lev) is an antiepileptic drug that has been increasingly used in the epilepsy pediatric population in recent years, but its pharmacokinetic behavior in pediatric population needs to be characterized clearly. Clinical trials for the pediatric drug remain difficult to conduct due to ethical and practical factors. The purpose of this study was to use the physiologically based pharmacokinetic (PBPK) model to predict changes in plasma exposure of Lev in pediatric patients and to provide recommendations for dose adjustment. A PBPK model of Lev in adults was developed using PK-Sim® software and extrapolated to the entire age range of the pediatric population. The model was evaluated using clinical pharmacokinetic data. The results showed the good fit between predictions and observations of the adult and pediatric models. The recommended doses for neonates, infants and children are 0.78, 1.67 and 1.22 times that of adults, respectively. Moreover, at the same dose, plasma exposure in adolescents was similar to that of adults. The PBPK models of Lev for adults and pediatrics were successfully developed and validated to provide a reference for the rational administration of drugs in the pediatric population.
Adult epilepsy
2023, The Lancet
Epilepsy is a common medical condition that affects people of all ages, races, social classes, and geographical regions. Diagnosis of epilepsy remains clinical, and ancillary investigations (electroencephalography, imaging, etc) are of aid to determine the type, cause, and prognosis. Antiseizure medications represent the mainstay of epilepsy treatment: they aim to suppress seizures without adverse events, but they do not affect the underlying predisposition to generate seizures. Currently available antiseizure medications are effective in around two-thirds of patients with epilepsy. Neurosurgical resection is an effective strategy to reach seizure control in selected individuals with drug-resistant focal epilepsy. Non-pharmacological treatments such as palliative surgery (eg, corpus callosotomy), neuromodulation techniques (eg, vagus nerve stimulation), and dietary interventions represent therapeutic options for patients with drug-resistant epilepsy who are not suitable for resective brain surgery.

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SeminarEpilepsy in children

Summary

Section snippets

Definitions and terminology

Epidemiology

Natural history

General aspects of prognosis

Cause and pathophysiology

Diagnosis

Differential diagnosis

Structural neuroimaging

Classification and response to treatment of the different epilepsy types

Idiopathic focal epilepsies

Idiopathic generalised epilepsies

Epilepsy with seizures precipitated by light stimulation

The epileptic encephalopathies

Febrile seizures

Progressive myoclonus epilepsies

Status epilepticus and seizure-induced brain damage

Molecular targets and clinical efficacy of antiepileptic drugs

Search strategy and selection criteria

Trends Mol Med

Am J Hum Genet

Brain Dev

Neuron

Pediatr Neurol

Seizure

Am J Hum Genet

Epilepsy Res

Lancet

Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology

Epilepsia

Proposal for revised clinical and electroencephalographic classification of epileptic seizures

Epilepsia

International League Against Epilepsy (ILAE). A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology

Epilepsia

Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE)

Epilepsia

Proposal for revised classification of epilepsy and epileptic syndromes

Epilepsia

Incidence and prevalence

Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984

Epilepsia

Prevalence and incidence of epilepsy in Tokyo

Epilepsia

The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: an extended follow-up

Pediatrics

Epilepsy after a first unprovoked seizure in childhood

Neurology

Risk of seizure recurrence following a first unprovoked seizure in childhood: a prospective study

Pediatrics

Long-term outcome of epilepsy

Epileptic Disord

A practical guide to when (and how) to withdraw antiepileptic drugs in seizure-free patients

Drugs

Antiepileptic drug withdrawal in childhood epilepsies: preliminary results of a prospective study

Some aspects of prognosis of the epilepsies: a review

Epilepsia

Early identification of refractory epilepsy

N Engl J Med

Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel b1 subunit gene SCN1B

Nat Genet

Genetics of the epilepsies

Epilepsia

Concordance of clinical forms of epilepsy in families with several affected members

Epilepsia

The risks of seizure disorders among relatives of patients with childhood onset epilepsy

Neurology

Epilepsies in twins: genetics of the major epilepsy syndromes

Ann Neurol

Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies

Nat Genet

Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy

Nat Genet

Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures

Nat Genet

A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions

Arch Neurol

On the cellular and network bases of epileptic seizures

Annu Rev Physiol

Seminar
Epilepsy in children

Febrile seizures and generalized epilepsy associated with a mutation in the Na⁺-channel b1 subunit gene SCN1B