CHD2 variants are a risk factor for photosensitivity in epilepsy.

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.

From global campaign to global commitment: The World Health Assembly's Resolution on epilepsy.

Tuesday May 26, 2015, will be remembered as an historic day in the fight against epilepsy. On that date, the World Health Assembly approved unanimously the Resolution on the "Global Burden of Epilepsy and the Need for Coordinated Action at the Country Level to Address its Health, Social and Public Knowledge Implications," which urges Member States to implement a coordinated action against epilepsy and its consequences. This event, which comes almost 20 years after the establishment of the Global Campaign against Epilepsy, is another landmark in the longstanding collaboration among the World Health Organization (WHO), the International League Against Epilepsy (ILAE), and the International Bureau for Epilepsy (IBE) in addressing the needs of people with epilepsy. It also acted as a catalyst for other professional societies, including the World Federation of Neurology (WFN), to join forces in promoting a common action against epilepsy. The Resolution did not happen by chance, but came at the end of a long journey that involved the hard and tireless work of many dedicated individuals around the globe.

Valproate in the treatment of epilepsy in girls and women of childbearing potential.

This document provides guidance on the use of valproate in girls and women of childbearing age from a joint Task Force of the Commission on European Affairs of the International League Against Epilepsy (CEA-ILAE) and the European Academy of Neurology (EAN), following strengthened warnings from the Coordination Group for Mutual Recognition and Decentralised Procedures-Human (CMDh) of the European Medicines Agency (EMA), which highlight the risk of malformations and developmental problems in infants who are exposed to valproate in the womb. To produce these recommendations, the Task Force has considered teratogenic risks associated with use of valproate and treatment alternatives, the importance of seizure control and of patient and fetal risks with seizures, and the effectiveness of valproate and treatment alternatives in the treatment of different epilepsies. The Task Force's recommendations include the following: (1) Where possible, valproate should be avoided in women of childbearing potential. (2) The choice of treatment for girls and women of childbearing potential should be based on a shared decision between clinician and patient, and where appropriate, the patient's representatives. Discussions should include a careful risk-benefit assessment of reasonable treatment options for the patient's seizure or epilepsy type. (3) For seizure (or epilepsy) types where valproate is the most effective treatment, the risks and benefits of valproate and other treatment alternatives should be discussed. (4) Valproate should not be prescribed as a first-line treatment for focal epilepsy. (5) Valproate may be offered as a first-line treatment for epilepsy syndromes where it is the most effective treatment, including idiopathic (genetic) generalized syndromes associated with tonic-clonic seizures. (6) Valproate may be offered as a first-line treatment in situations where pregnancy is highly unlikely (e.g., significant intellectual or physical disability). (7) Women and girls taking valproate require regular follow-up for ongoing consideration of the most appropriate treatment regimen.

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.

Methodology of photic stimulation revisited: updated European algorithm for visual stimulation in the EEG laboratory.

Intermittent photic stimulation (IPS) is a common procedure performed in the electroencephalography (EEG) laboratory in children and adults to detect abnormal epileptogenic sensitivity to flickering light (i.e., photosensitivity). In practice, substantial variability in outcome is anecdotally found due to the many different methods used per laboratory and country. We believe that standardization of procedure, based on scientific and clinical data, should permit reproducible identification and quantification of photosensitivity. We hope that the use of our new algorithm will help in standardizing the IPS procedure, which in turn may more clearly identify and assist monitoring of patients with epilepsy and photosensitivity. Our algorithm goes far beyond that published in 1999 (Epilepsia, 1999a, 40, 75; Neurophysiol Clin, 1999b, 29, 318): it has substantially increased content, detailing technical and logistical aspects of IPS testing and the rationale for many of the steps in the IPS procedure. Furthermore, our latest algorithm incorporates the consensus of repeated scientific meetings of European experts in this field over a period of 6 years with feedback from general neurologists and epileptologists to improve its validity and utility. Accordingly, our European group has provided herein updated algorithms for two different levels of methodology: (1) requirements for defining photosensitivity in patients and in family members of known photosensitive patients and (2) requirements for tailored studies in patients with a clear history of visually induced seizures or complaints, and in those already known to be photosensitive.

Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies.

PURPOSE: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. METHODS: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. KEY FINDINGS: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). SIGNIFICANCE: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.

Antiepileptic drug therapy: does mechanism of action matter?

This article represents a synthesis of presentations made by the authors during a scientific meeting held in London on 7 June 2010 and organized by GlaxoSmithKline. Each speaker produced a short précis of his lecture to answer a specific question, resulting in an overview of what we know about the relevance of the mechanisms of action of antiepileptic drugs in determining appropriate combination therapies for the treatment of drug-resistant epilepsy.

Absence-to-bilateral-tonic-clonic seizure: A generalized seizure type.

OBJECTIVE: To test the hypothesis that absence seizures can evolve to generalized tonic-clonic seizures, we documented electroclinical features of this novel seizure type. METHODS: In 4 large video-EEG databases, we identified recordings of seizures starting with impaired awareness that, without returning to baseline interictal state, evolved to generalized tonic-clonic seizures. We extracted the detailed semiologic and electrographic characteristics of these seizures, and we documented the clinical background, diagnoses, and therapeutic responses in these patients. RESULTS: We identified 12 seizures from 12 patients. All seizures started with a period of impaired awareness and bursts of generalized spike or polyspike and slow-wave discharges, the hallmark of absence seizures. Without returning to baseline, the nonmotor (absence) phase was followed by tonic-clonic convulsions. We called this novel generalized seizure type absence-to-bilateral-tonic-clonic seizure. Most patients had idiopathic generalized epilepsies, although with a high incidence of unusual features and poor therapeutic response. CONCLUSIONS: Absence-to-bilateral-tonic-clonic seizures are a novel generalized seizure type. Clinicians should be aware of this seizure for correctly diagnosing patients. This novel seizure type may further elucidate generalized ictogenesis.

Recommendations on the diagnosis and management of Niemann-Pick disease type C.

Niemann-Pick disease type C (NP-C) is a lysosomal storage disease in which impaired intracellular lipid trafficking leads to excess storage of cholesterol and glycosphingolipids in the brain and other tissues. It is characterized clinically by a variety of progressive, disabling neurological symptoms including clumsiness, limb and gait ataxia, dysarthria, dysphagia and cognitive deterioration (dementia). Until recently, there has been no disease-modifying therapy available for NP-C, with treatment limited to supportive measures. In most countries, NP-C is managed through specialist centers, with non-specialist support provided locally. However, effective patient support is hampered by the absence of national or international clinical management guidelines. In this paper, we seek to address this important gap in the current literature. An expert panel was convened in Paris, France in January 2009 to discuss best care practices for NP-C. This commentary reviews current literature on key aspects of the clinical management of NP-C in children, juveniles and adults, and provides recommendations based on consensus between the experts at the meeting.

Linkage and association analysis of CACNG3 in childhood absence epilepsy.

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12-p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD = 3.54, alpha = 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric linkage score was 2.87 (P < 0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium (P < or = 0.01) was found for SNPs within a approximately 35 kb region of high LD encompassing the 5'UTR, exon 1 and part of intron 1 of CACNG3. Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5'UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.

Linkage and mutational analysis of CLCN2 in childhood absence epilepsy.

In order to assess the chloride channel gene CLCN2 as a candidate susceptibility gene for childhood absence epilepsy, parametric and non-parametric linkage analysis was performed in 65 nuclear pedigrees. This provided suggestive evidence for linkage with heterogeneity: NPL score=2.3, p<0.009; HLOD=1.5, alpha=0.44. Mutational analysis of the entire genomic sequence of CLCN2 was performed in 24 unrelated patients from pedigrees consistent with linkage, identifying 45 sequence variants including the known non-synonymous polymorphism rs2228292 (G2154C, Glu718Asp) and a novel variant IVS4+12G>A. Intra-familial association analysis using the pedigrees and a further 308 parent-child trios showed suggestive evidence for transmission disequilibrium of the G2154C minor allele: AVE-PDT chi(1)2 = 5.17, p<0.03. Case-control analysis provided evidence for a protective effect of the IVS4+12G>A minor allele: chi(1)2 = 7.27, p<0.008. The 65 nuclear pedigrees were screened for three previously identified mutations shown to segregate with a variety of idiopathic generalised epilepsy phenotypes (597insG, IVS2-14del11 and G2144A) but none were found. We conclude that CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy.

Evaluation of CACNA1H in European patients with childhood absence epilepsy.

CACNA1H was evaluated in a resource of Caucasian European patients with childhood absence epilepsy by linkage analysis and typing of sequence variants previously identified in Chinese patients. Linkage analysis of 44 pedigrees provided no evidence for a locus in the CACNA1H region and none of the Chinese variants were found in 220 unrelated patients.

Clinical and genetic analysis of a family with two rare reflex epilepsies.

PURPOSE: To determine clinical phenotypes, evolution and genetic background of a large family with a combination of two unusual forms of reflex epilepsies. METHOD: Phenotyping was performed in eighteen family members (10 F, 8 M) including standardized EEG recordings with intermittent photic stimulation (IPS). Genetic analyses (linkage scans, Whole Exome Sequencing (WES) and Functional studies) were performed using photoparoxysmal EEG responses (PPRs) as affection status. RESULTS: The proband suffered from speaking induced jaw-jerks and increasing limb jerks evoked by flickering sunlight since about 50 years of age. Three of her family members had the same phenotype. Generalized PPRs were found in seven members (six above 50 years of age) with myoclonus during the PPR. Evolution was typical: Sensitivity to lights with migraine-like complaints around adolescence, followed by jerks evoked by lights and spontaneously with dropping of objects, and strong increase of light sensitivity and onset of talking induced jaw jerks around 50 years. Linkage analysis showed suggestive evidence for linkage to four genomic regions. All photosensitive family members shared a heterozygous R129C mutation in the SCNM1 gene that regulates splicing of voltage gated ion channels. Mutation screening of 134 unrelated PPR patients and 95 healthy controls, did not replicate these findings. CONCLUSION: This family presents a combination of two rare reflex epilepsies. Genetic analysis favors four genomic regions and points to a shared SCNM1 mutation that was not replicated in a general cohort of photosensitive subjects. Further genetic studies in families with similar combination of features are warranted.

Treatment of photosensitivity.

Not all visually sensitive patients need antiepileptic drug treatment, and even those who do can benefit from additional preventive measures. Visually provoked seizures, in particular, can be prevented or treated by avoiding or altering the triggering stimulus. Apart from individual preventive measures (use of specific television or video screens, colored glasses, etc.), prevention and warning on a larger scale are helpful. The choice for drug treatment will depend on the type of stimulus, the environment in which the person has to live and work, the frequency and severity of seizures, and the type of epileptic syndrome. A review is given of all treatment options with focus on the specific nonpharmacologic and pharmacologic tools used in clinical practice.

Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14.

A previous study of 34 nuclear pedigrees segregating juvenile myoclonic epilepsy (JME) gave significant evidence of linkage with heterogeneity to marker loci on chromosome 15q13-14 close to the candidate gene CHRNA7 (Hum. Mol. Genet. 6 (1997) 1329). The aim of this work was to further evaluate the putative aetiological role of CHRNA7 in JME within the 34 families originally described, and to assess the contribution of this locus to a broader phenotype of idiopathic generalised epilepsy (IGE). Multipoint linkage analysis and intrafamilial association studies were performed with microsatellite markers that encompass both CHRNA7 and its partial duplication (CHRFAM7A). A maximum HLOD of 3.45 [alpha=0.58; (Zall=2.88, P=0.0008)] was observed 8 cM distal to D15S1360, a CHRNA7 intragenic marker. Significant exclusion lod scores were obtained across the region in 12 mixed phenotype JME/IGE families. Mutation screening of the CHRNA7 gene (and consequently exons 5-10 of CHRFAM7A) and its putative promoter sequence identified a total of 13 sequence variants across 23 of 34 JME-affected families. Two variants (c.1354G>A and c.1466C>T) are predicted to result in amino acid changes and one (IVS9+5G>A) is predicted to result in aberrant transcript splicing. However, none of the variants alone appeared either necessary or sufficient to cause JME in the families in which they occurred. In conclusion, linkage analyses continue to support the existence of a locus on chromosome 15q13-14 that confers susceptibility to JME but not to a broader IGE phenotype. Causal sequence variants in the positional candidate CHRNA7 have not been identified but the presence of multiple segmental duplications in this region raises the possibility of undetected disease-causing genomic rearrangements.

Children with Rolandic spikes and ictal vomiting: Rolandic epilepsy or Panayiotopoulos syndrome?

Centrotemporal spikes are the EEG marker of Rolandic epilepsy, while ictus emeticus is one of the main seizure manifestations of Panayiotopoulos syndrome. Ictus emeticus has not been reported in Rolandic epilepsy. Out of a population of 1340 children with focal afebrile seizures we studied 24 children who had emetic manifestations in at least one seizure and centrotemporal spikes in at least one EEG. They were of normal neurological status and had a follow-up of at least two years after the last seizure. All children had sleep EEG following sleep deprivation. Two groups of patients were identified. Group A (12 patients) with EEG centrotemporal spikes only and group B (12 patients) with centrotemporal spikes and spikes in other locations. In 21 patients, ictal emetic manifestations culminated in vomiting and in three only nausea or retching occurred. The commonest presentation was ictus emeticus at onset followed by deviation of the eyes or staring, loss of contact and floppiness. In 79%, seizures occurred during sleep. Autonomic status epilepticus occurred in 37.5%. The mean age at onset was 5.3 years. Overall analysis of the clinical and EEG data points out that the vast majority of these patients primarily suffer from Panayiotopoulos syndrome. Twenty patients (83%) had ictal semiology typical of Panayiotopoulos syndrome, but five also had concurrent Rolandic symptoms and four later developed pure Rolandic seizures. The other four patients (17%) had typical Rolandic seizures with concurrent ictus emeticus. These findings suggest a link between Rolandic epilepsy and Panayiotopoulos syndrome, the two most important phenotypes of the benign childhood seizure susceptibility syndrome.

Epilepsy in children with congenital hemiplegia: correlation between clinical, EEG and neuroimaging findings.

OBJECTIVES: the aim of this retrospective, multicentre study was to investigate the relationship between epilepsy, clinical, electroencephalographic (EEG) and neuroimaging findings in children with congenital hemiplegia (CH). PATIENTS AND METHODS: two hundred and three children with CH were assessed by history, neurological and developmental examination. Electroencephalogram (EEG) and CT/MRI brain imaging were performed in 150 of them (81/150 had an MRI and 69/150 had a CT scan). Patients were re-evaluated every six months for, at least, a two-year follow-up period (range 2-14 yrs). RESULTS: the EEG was abnormal in 76% of patients; epileptic seizures developed in 38.9% of them. The frequency of epilepsy paralleled the degree of EEG abnormality, approaching 85% in patients with severe EEG abnormalities and was also closely related to the extent of neuroimaging findings (up to 79% in patients with cerebral malformations). The prevalence of epilepsy in 12/62 patients (19.4%) with mild hemiplegia was significantly lower as compared to 67/141 (47.5%) of patients with moderate or severe hemiplegia. 36.7% of the children had their first seizure between the 1st and the 5th year of life, and 26.5% during the first year of life. CONCLUSIONS: epileptic seizures developed in more than one third of patients with CH, although EEG abnormalities were evident in the majority of them. The prevalence of epilepsy is closely related to the severity of hemiparesis, the extent of neuroimaging findings and the degree of EEG abnormalities. The absence of EEG abnormalities and/or normal (or minor) neuroimaging findings was negatively related to the occurrence of epilepsy.