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ObjectivesDepending on patient age at onset, absence epilepsy is subdivided into childhood and juvenile forms. Absence seizures can occur several times per day (pyknoleptic course) or less frequently than daily (non-pyknoleptic course). Seizures typically terminate before adulthood, but a quarter of patients need ongoing treatment beyond adolescence. Little is known about their long-term seizure and psychosocial outcome.MethodsFiles of 135 outpatients with absence epilepsy (76 females; 123 had additional generalised tonic–clonic seizures) were retrospectively analysed after a median follow-up of 45.4 years (IQR: 31.9–56.2). Eighty-two subjects completed an additional interview. Patients were dichotomised according to age at epilepsy onset (childhood: n=82; juvenile: n=53) and course of absence seizures (pyknoleptic: n=80; non-pyknoleptic: n=55).ResultsAmong all patients, 53% achieved 5-year terminal seizure remission, 16% without antiepileptic medication. Median age at last seizure was lower in patients with childhood onset of absence epilepsy (37.7 years) versus juvenile onset (44.4 years; P≤0.01). However, rates and duration of terminal seizure remission were similar. Pyknoleptic versus non-pyknoleptic course of absence seizures made no difference for long-term seizure outcome. Multivariate analysis identified only higher age at investigation to be associated with terminal 5-year seizure remission. Regarding aspects of psychosocial outcome, there were no significant differences between the respective subgroups.ConclusionsThese data indicate that if absence epilepsy persists beyond adolescence, long-term seizure and psychosocial outcome do not differ between childhood and juvenile onset or between pyknoleptic and non-pyknoleptic course of absence epilepsy. However, higher patient age increases the chance of terminal seizure remission.

SummaryObjective Until now, it has been unclear if the three subsyndromes of adolescent-onset generalized genetic epilepsy (GGE) differ in long-term prognosis. Therefore, this study aimed to compare long-term seizure outcome in juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic–clonic seizures alone (EGTCS). Methods This retrospective study is based on the archive of an institutional tertiary care outpatient clinic for adult patients with epilepsy. Charts of 870 epilepsy outpatients were reviewed among whom 176 had adolescent-onset GGE (53 JAE, 66 JME, 57 EGTCS). Median patient age at investigation was 60 years; median follow-up time was 42.5 years. If possible, GGE patients were additionally interviewed on psychosocial and clinical variables. Results Age at first seizure was significantly higher in EGTCS patients (median 18 years) than in patients with JAE or JME (14 years each; p ≤ 0.001). Long-term seizure outcome hardly differed between the three subsyndromes. At the end of follow-up, 60% of all patients were in 5-year terminal seizure remission, and in 14%, epilepsy even had resolved (>10 years without seizures, >5 years without pharmacotherapy). Twenty percent of patients had persistent seizures during the last year of follow-up. Across all patients, 23% reported a psychiatric comorbidity, 87% had married, and 57% had achieved university entrance qualification. Significance Long-term outcome was shown to be highly similar across all subsyndromes of adolescent-onset GGE. Even in a selection of difficult-to-treat epilepsy patients still attending an adult epilepsy clinic, most become seizure-free. To confirm these findings, prospective studies are needed.

Epilepsy with grand mal on awakening (EGMA) is a well-defined subtype of idiopathic generalized epilepsy. Patients with follow-up of at least 20 years were assessed retrospectively regarding 5-year terminal seizure remission. Forty-two patients were included (mean age = 60 ± 13 years). After follow-up of 40 ± 13 years, 26 patients (62%) were in remission, 5 without antiepileptic drugs. Age at investigation (odds ratio = 0.939, 95% confidence interval = 0.887–0.994, p = 0.029) independently predicted lacking remission. Nineteen patients (45.2%) had withdrawn from antiepileptic drugs at least once; 12 of those (63.2%) had seizure relapse. EGMA has a favorable long-term prognosis. With increasing age and treatment duration, antiepileptic drug withdrawal may be justified. Ann Neurol 2014;75:298–302

Objective: Prospective memory (PM) describes the ability to fulfill previously planned intentions and is highly dependent on executive functions. Previous studies have shown deficits in executive functions in patients with juvenile myoclonic epilepsy (JME) and in their unaffected siblings. JME has a strong genetic predisposition and it is hypothesized that cognitive deficits are also genetically determined. The present study aimed at investigating potential differences in PM between patients with JME, their siblings, and healthy controls. Methods: Nineteen patients with JME, 21 siblings, and 21 healthy controls were examined with a complex PM paradigm allowing us to evaluate the different phases of PM (i.e., intention formation, intention retention, intention initiation, intention execution). Results: Patients with JME and siblings showed specific deficits during intention formation and intention execution of PM. Patients with JME were more impaired than both siblings and healthy controls. Correlation analysis revealed an influence of planning on prospective memory abilities in patients with JME. Conclusion: The results of this study support the hypothesis of frontal dysfunctions being part of the epileptic syndrome and therefore genetically determined. As in this study patients with JME are more severely cognitively impaired than their siblings, additional influencing factors, such as side effects of anticonvulsants or cognitive effects of subclinical epileptic discharges, might contribute to patients9 performance.

SUMMARY In contrast to the pathology of the so-called temporal or psychomotor epilepsy which has been thoroughly investigated in recent times, there has been, until now, no corresponding research into the so-called petit mal or centrencephalic epilepsy. We are therefore making a detailed examination of the clinico-anatomical connections between a case of idiopathic epilepsy with impulsive petit mal (also called myoclonic petit mal with multi-spikes-waves) and grand mal on awakening. The case in question concerns a 28-year old woman who ever since the age of 16 had suffered from convulsions of varying severity, occurring either singly or several at a time, in her shoulders, neck and arms, without however losing consciousness, frequently following lack of sleep and consumption of alcohol, and mainly after waking in the morning. During the whole course of the disease only 7 grand mal occurred which appeared mainly after waking and were characterized by opisthotonus during the seizure and extreme cyanosis. The cause of death was probably suicide. With reference to our pathological examination the following remarks can be made: 1. No evidence was discovered which could be diagnosed as responsible for causing the disease. 2. In view of the clinically benign course of the disease, the extent of the ictal damage was surprisingly great. We interpreted this as a consequence of the especially serious impulsive grand mal which took the form of paroxysmal herniations. 3. The sequence of ictal damage usually expected in idiopathic epilepsies according to Scholz varied somewhat in our case, in that the Ammon's horn was affected least of all. On the other hand, the most serious changes took place in the cerebellar cortex, the nucleus dentatus and, strangely enough, in the nucleus ruber. The predilection towards ictal damage in mesencephalic and cerebellar structures is completely consistent with the functional structures of the rubro-neuronal system, which for clinical reasons have been diagnosed already as responsible for this type of petit mal. 4. The discovery of inhibited migration in the cerebellar cortex seemed significant to us in explaining the age dependency of impulsive petit mal, as well as a series of anomalies of constitution and growth characteristic of this manifestation of the disease. The question is raised as to how far disturbances of the development of this kind, which are too minor to be decisive for the aetiology, are an aid to lending profile to the characteristic features of the special clinical picture. RESUME Au contraire de ce qui a ete fait pour la pathologie de l'epilepsie dite temporale ou psycho-motrice, qui a ete etudiee a fond ces derniers temps, on n'a pas effectue jusqu'a present de recherches analogues concernant ce qu'on appelle le petit mal ou epilepsie centrencephalique. Pour cette raison, nous faisons un examen detaille des rapports clinico-anatomiques entre un cas d'epilepsie idiopathique avec petit mal impulsif (aussi appele petit mal myoclonique avec polypointes-ondes) et le grand mal au reveil. Le cas en question concerne une femme de 28 ans qui, depuis l'age de 16 ans a souffert de convulsions de gravite variable, se manifestant seules ou plusieures a la fois, dans les epaules, le cou et les bras, sans pourtant qu'elle perde connaissance, et generalement a la suite d'un manque de sommeil et de consommation d'alcool, et presque toujours le matin, apres le reveil. Durant tout le cours de la maladie, il n'y a eu que 7 crises de grand mal, generalement au reveil, avec opisthotonos au cours de la crise et une cyanose extrěme. La cause de la mort est probablement le suicide. Nous referant a notre etude pathologique, nous pouvons faire les remarques suivantes: 1. On n'a pu decouvrir aucune preuve qui puisse ětre consideree comme responsable d'avoir provoque la maladie. 2. Si l'on considere le cours, cliniquement benin, de la maladie, la lesion causee par les crises est extrěmement etendue. Nous avons interprete ceci comme la consequence des crises de grand mal impulsif particulierement graves, qui ont pris l'aspect de formations de hernies paroxysmiques. 3. La succession des dommages causes par ictus que, selon Scholz, on rencontre generalement dans les cas d'epilepsie idiopathique, a ete legerement differente dans le cas que nous avons etudie; en effet, c'est la corne d'Ammon qui a ete le moins affectee. D'autre part, les modifications les plus graves ont ete constatees dans le cortex cerebelleux, le corps rhomboidal et, chose curieuse, dans le noyau rouge de Stilling. La predominance de dommages dans les structures mesencephaliques et cerebelleuses s'explique par le fait que, pour des raisons cliniques, les structures fonctionnelles du systeme des neurones du noyau rouge ont deja ete diagnostiquees comme responsables de ce type de petit mal. 4. La decouverte d'une migration inhibee dans le cortex cerebelleux nous semble significative pour expliquer la dependance du petit mal impulsif de l'ǎge du malade, ainsi qu'une serie d'anomalies de constitution et de croissance qui characterisent cette manifestation de la maladie. La question qui se pose est celle de savoir jusqu'a quel point de telles perturbations du developpement, qui sont trop peu importantes pour ětre decisives pour l'etiologie, pourraient former le profile de l'image clinique speciale.

INTRODUCTION: We tested the hypothesis that genetic variants within the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster on chromosome 15q11-q13 confer genetic susceptibility to common subtypes of idiopathic generalized epilepsy (IGE). MATERIAL AND METHODS: Ninety-four families were selected from IGE patients with either juvenile myoclonic epilepsy (JME), juvenile (JAE) or childhood absence epilepsy (CAE). Cosegregation was tested between dinucleotide polymorphisms associated with the human GABA(A) alpha5, beta3 and gamma3 subunit gene cluster and three different IGE trait models. RESULTS: Evidence against linkage to the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster was found in the entire family set and subsets selected from either CAE or JAE. In 61 families of JME patients, a maximum lod score (Zmax=1.40 at Theta(max)=0.00) was obtained for a broad IGE spectrum ("idiopathic" generalized seizure or generalized spike and wave discharges in the electroencephalogram) assuming genetic heterogeneity (alpha=0.37; P=0.06) and an autosomal recessive mode of inheritance. CONCLUSION: The possible hint of linkage in families of JME patients emphasizes the need for further studies to determine whether a recessively inherited gene variant within the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster contributes to the pathogenesis of "idiopathic" generalized seizures and associated EEG abnormalities in a proportion of families.

Die Deutsche Sektion der Internationalen Liga gegen Epilepsie (ILAE) begeht in diesem Jahr ihr funfzigjahriges Jubilaum, die Internationale Liga wird 2009 100 Jahre alt. Dieser Bericht gibt einen historischen Abriss der wechselvollen Geschichte und mahnt die Herausforderungen von Gegenwart und Zukunft an.

Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder affecting about 0.4% of the world's population. Mutations in ten genes causing distinct forms of idiopathic epilepsy have been identified so far, but the genetic basis of many IGE subtypes is still unknown. Here we report a gene associated with the four most common IGE subtypes: childhood and juvenile absence epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal seizures on awakening (EGMA; ref. 8). We identified three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations result in (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations that provide distinct explanations for their pathogenic phenotypes. M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition. G715E alters voltage-dependent gating, which may cause membrane depolarization and hyperexcitability.

Summary Purpose Juvenile myoclonic epilepsy (JME) is a well-defined subsyndrome of idiopathic generalized/genetic epilepsy. It is allegedly related to specific personality characteristics and has been associated with unfavorable social outcome. We aimed to analyze psychosocial outcome in patients with JME. To delineate consequences of the chronic seizure disorder from possible neurobiologic contributions being inherent to the condition itself, we compared social outcome in JME subjects with that of age- and sex-matched control patients with absence epilepsy (AE). Methods Patients with an epilepsy course of at least 20 years were included. All JME and AE patients (n = 41 in each group) answered a structured questionnaire asking about seizures, treatment, and psychosocial variables. In addition, patients with JME were assessed with the Quality of Life in Epilepsy Inventory 31 (QOLIE-31). Results In JME, 46.3 years (20–69) after onset of epilepsy, the overall psychosocial long-term outcome was favorable (80.5% of patients had never been unemployed for more than 1 year, 90.2% were well integrated into social context). Quality of life in all inquired subdomains revealed high scores. Compared with AE controls, JME patients did not perform worse regarding psychosocial outcome; rate of university access and degrees in JME patients was even higher (70% vs. 34%, p = 0.001). JME patients showed a high level of quality of life, and current or previous psychiatric comorbidity was associated significantly with lower overall quality of life scores (p = 0.02). Significance Our long-term study on JME patients demonstrated favorable psychosocial outcome that contrasted previous findings. This is the first study to compare social outcome in JME with another genetically determined form of epilepsy. Similar outcomes in JME and AE patients argue against specific neurobiologic alterations in JME that may predispose to social deficits. In JME, reduced quality of life seems to be associated with psychiatric comorbidity.

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Summary: Purpose: To evaluate the efficacy and tolerability of levetiracetam (LEV, Keppra) as add-on therapy in patients with refractory partial seizures. Methods: In this European multicenter, double-blind, randomized, placebo-controlled trial, LEV (500 or 1,000 mg twice daily) was compared with placebo as add-on therapy in 324 patients with uncontrolled simple or complex partial seizures, or both, with or without secondary generalization. After enrollment, three parallel groups were assessed during a baseline period of 8 or 12 weeks, followed by a 4-week titration interval and a 12-week evaluation period. Results: LEV significantly decreased partial seizure frequency compared with placebo. A reduction in seizure frequency of 50% occurred in 22.8% of patients in the 1,000-mg group and 31.6% of patients in the 2,000-mg group, compared with 10.4% of patients in the placebo group. Administration of LEV did not affect plasma concentrations of concomitant an-tiepileptic drugs or alter vital signs or laboratory parameters. No significant difference in the incidence of adverse events was observed between treatment groups (70.8% for the 1,000-mg group and 75.5% for the 2,000-mg group), or between the LEV and placebo groups (73.2% for placebo group). The most commonly reported adverse effects in the LEV group were asthenia, headache, and somnolence. Conclusions: The antiepileptic efficacy and tolerability of LEV (1,000 mg/d and 2,000 mg/d, administered in two divided doses) as add-on therapy was established in patients with refractory partial seizures in this clinical study.

The alpha4 subunit gene of the neuronal nicotinic acetylcholine receptor (CHRNA4) has recently been identified as the first gene underlying an idiopathic partial epilepsy syndrome in human, autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). CHRNA4 is located in the candidate region for benign familial neonatal convulsions and low-voltage EEG on chromosome 20q. In the present study, we examined the possible role of CHRNA4 in common subtypes of idiopathic generalized epilepsy (IGE), comprising childhood and juvenile absence epilepsy and juvenile myoclonic epilepsy (JME), by systematically screening the coding region of the gene for sequence variants. We present here a population-based association study testing the hypothesis that variants of the CHRNA4 gene confer genetic susceptibility to common subtypes of IGE. The missense mutation (Ser248Phe), associated with ADNFLE, and four silent polymorphisms in the CHRNA4 gene were genotyped in 103 IGE patients and 92 controls by polymerase chain reaction and subsequent restriction analysis. Without correction for multiple testing, the frequency of the T-allele of the silent CfoI bp595 polymorphism was increased in the entire group of IGE patients (f(T) = 0.085) compared to that in the controls (f(T) = 0.027). The allelic association was not restricted to any subgroup of IGE with either JME or idiopathic absence epilepsies. This result suggests that variation of the CHRNA4 gene, or so-far-undetected sequence variants near the CHRNA4 locus, confer susceptibility to the common IGE syndromes.

Objectives: Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized epilepsy subsyndrome, contributing to approximately 3% to 11% of adolescent and adult cases of epilepsy. However, little is known about the long-term medical evolution of this clinical entity. The aim of this study was to analyze long-term outcome in a clinically well-defined series of patients with JME for seizure evolution and predictors of seizure outcome. Methods: In this retrospective cohort study, we analyzed seizure outcome in 66 patients who had JME, were treated at the Department of Neurology, Charite–Universitatsmedizin Berlin, and were initially diagnosed by a single senior epileptologist. Results: After a mean follow-up time of 44.6 years (20–69 years), 59.1% of patients remained free of seizures for at least 5 years before the last contact. Among the seizure-free patients, 28 (71.8%) were still taking antiepileptic drugs and 11 (28.2%) were off medication for at least the last 5 years. We identified manifestation of additional absence seizures at onset of JME as an independent predictor of an unfavorable outcome regarding seizure freedom. Conclusions: A significant proportion of patients with JME were seizure-free and off antiepileptic drug therapy in the later course of their disorder. Patients with JME and additional absence seizures might represent a different JME subtype with a worse outcome.

Epilepsy with grand mal on awakening (EGMA) is a well-defined subtype of idiopathic generalized epilepsy. Patients with follow-up of at least 20 years were assessed retrospectively regarding 5-year terminal seizure remission. Forty-two patients were included (mean age=60 ± 13 years). After follow-up of 40 ± 13 years, 26 patients (62%) were in remission, 5 without antiepileptic drugs. Age at investigation (odds ratio=0.939, 95% confidence interval=0.887-0.994, p=0.029) independently predicted lacking remission. Nineteen patients (45.2%) had withdrawn from antiepileptic drugs at least once; 12 of those (63.2%) had seizure relapse. EGMA has a favorable long-term prognosis. With increasing age and treatment duration, antiepileptic drug withdrawal may be justified.

Summary The treatment of status epilepticus has changed over the past five decades since the first colloquium on status epilepticus, held in Marseille in 1962. New intravenous drugs, such as valproate, levetiracetam, lacosomide or ketamine and new routes of administration, such as intranasal or bucal, as well as high-class randomized clinical trials in the prehospital setting and early stages of status have changed the field. However it is remarkable, how the basic principles and difficulties of treatment of status epilepticus have remained the same. This article is as a translation of a narrative review authored by Dieter Janz at the Marseille Colloquium 1962, published in 1967. The medical practice and all available treatment at that time have been reviewed critically in the article. The translation of the original French article has been kept as close as possible to the original, to give a detailed account on the treatment of status at that time.

An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME ("Janz syndrome"), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME. The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6-25years). For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy. Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs). Results of an inventory of the different clinical management strategies are given. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The frequent neuropathological occurrence of microdysgeneses in the brain of IGE patients implies that genes regulating neural migration and cell adhesion might be involved epileptogenesis of age-related generalized seizures. Our present linkage study tested the hypothesis that DNA sequence variants associated with the gene encoding the neural cell adhesion molecule (NCAM) confer genetic susceptibility to IGE traits in 57 families ascertained through patients with either juvenile myoclinic epilepsy, juvenile or childhood absence epilepsy. Our consistently negative results provide evidence against a common major effect of NCAM gene variants to the expression of IGEs with age-related onset from childhood to adolescence.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The pivotal function of ionotropic gamma-aminobutyric acid type A receptors (GABRs) in inhibitory neurotransmission in the mammalian central nervous system suggests that they may be involved in epileptogenesis and genetic predisposition to IGEs. Dinucleotide repeat polymorphisms associated with the human GABAA receptor alpha 1 (GABRA1) and gamma 2 subunit (GABRG2) gene cluster on chromosome 5q32-q35 offer the opportunity to test whether these candidate genes confer susceptibility to IGEs. Our linkage analyses in 63 families ascertained through IGE patients with either juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy do not support the hypothesis that variants within the GABRA1 and GABRG2 gene cluster contribute a frequent major gene effect to the expression of the common familial IGEs.

Juvenile myoclonic epilepsy is the most frequent idiopathic generalized epilepsy syndrome. It is characterized by predominant myoclonic jerks of upper limbs, often provoked by cognitive activities, and typically responsive to treatment with sodium valproate. Neurophysiological, neuropsychological and imaging studies in juvenile myoclonic epilepsy have consistently pointed towards subtle abnormalities in the medial frontal lobes. Using functional magnetic resonance imaging with an executive frontal lobe paradigm, we investigated cortical activation patterns and interaction between cortical regions in 30 patients with juvenile myoclonic epilepsy and 26 healthy controls. With increasing cognitive demand, patients showed increasing coactivation of the primary motor cortex and supplementary motor area. This effect was stronger in patients still suffering from seizures, and was not seen in healthy controls. Patients with juvenile myoclonic epilepsy showed increased functional connectivity between the motor system and frontoparietal cognitive networks. Furthermore, we found impaired deactivation of the default mode network during cognitive tasks with persistent activation in medial frontal and central regions in patients. Coactivation in the motor cortex and supplementary motor area with increasing cognitive load and increased functional coupling between the motor system and cognitive networks provide an explanation how cognitive effort can cause myoclonic jerks in juvenile myoclonic epilepsy. The supplementary motor area represents the anatomical link between these two functional systems, and our findings may be the functional correlate of previously described structural abnormalities in the medial frontal lobe in juvenile myoclonic epilepsy. © 2011 The Author. Wellcome Trust (Project Grant No 079474); The Big Lottery Fund, Wolfson Trust and the Epilepsy Society (ES MRI scanner). Part of this work was undertaken at University College London Hospitals who received a proportion of funding from the NIHR, Biomedical Research Centres funding scheme.

Professor J.A.N. Corsellis, whose life and work is recalled here, gained great insight into the meaning of morphological cerebral aberrations found in neuropsychiatric disease through exact neuropathological investigations of tissue specimens obtained from patients with distinct syndromes. He was a leading authority in the field. We have searched and compiled resources relating to J.A.N. Corsellis' life and work, including personal memories from colleagues and data from scientific publications. J.A.N. Corsellis made seminal contributions to the understanding of neuropsychiatric disease; his works substantially added to the understanding of the dementias, schizophrenia and the psychoses, and morphological sequelae of boxing. In seizure disorders, his name is linked to the first description of focal cortical dysplasia and limbic encephalitis, the pathology of status epilepticus and Ammon's horn sclerosis, and the systematic investigation of epilepsy surgery specimens in general. Both his life and work are closely linked to Runwell Hospital, Wickford, Essex and the Maudsley Hospital. During his professional life he established a large brain bank, now known as the Corsellis Collection. J.A.N. Corsellis had significant impact on neuroscience; many of his observations were groundbreaking and are still valid.

The GABAA receptor is the major inhibitory neurotransmitter receptor in the mammalian brain. To date, 14 genes that encode subunits of this receptor have been identified; these appear to be scattered throughout the human genome and are under investigation as candidate loci for a number of neurological and psychiatric disorders. We report here a highly polymorphic (dC-dA)n repeat within the human alpha 1-subunit gene (GABRA1). Typing of this marker in the Centre d'Etude du Polymorphisme Humain (CEPH) panel of families confirms the previous assignment of the GABRA1 locus to the distal portion of chromosome 5q by demonstrating linkage to the markers CRI-L45 (D5S61) (Zmax = 11.00, theta max = 0.15), CRI-V1022 (D5S54) (Zmax = 7.25, theta max = 0.20), and CRI-P148 (D5S72) (Zmax = 5.71, theta max = 0.24).

A recent genome-wide scan showed strong evidence for a major locus for common syndromes of idiopathic generalized epilepsy (IGE) at the marker D18S474 on chromosome 18q21.1 (LOD score 4.5/5.2 multipoint/two-point). The present replication study tested the presence of an IGE locus in the chromosomal region 18q21.1. Our linkage study included 130 multiplex families of probands with common IGE syndromes. Eleven microsatellite polymorphisms encompassing a candidate region of 30 cM on either side of the marker D18S474 were genotyped. The two-point homogeneity LOD score for D18S474 showed strong evidence against linkage at the original linkage peak (Z = -18.86 at theta(m = f) = 0.05), assuming a recessive mode of inheritance with 50% penetrance. Multipoint parametric heterogeneity LOD scores-2 were obtained along the candidate region when proportions of linked families greater than 35% were assumed under recessive inheritance. Furthermore, non-parametric multipoint linkage analyses showed no hint of linkage throughout the candidate region (P0.19). Accordingly, we failed to support evidence for a major IGE locus in the chromosomal region 18p11-18q23. If there is a susceptibility locus for IGE in this region then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.

Awakening epilepsy (AE) is an age related syndrome of idiopathic generalized epilepsy (IGE) characterized by generalized tonic clonic seizures (GTCS) occurring predominantly on awakening (independent of the time of day) or at leisure time (almost at evening). The GTCS can be the only symptom or they can be combined with the other subsyndromes of IGE in childhood or adolescence. The EEG shows the characteristics of IGE (generalized spike wave frequent, foca1 abnormalities rare, photosensitivity increased). The common denominator of external seizures precipitating influences is lack of sleep. The sleep habits of patients with AE who could roughly be characterized as late sleepers and late risers may dispose them to a chronic sleep deficit. Polygraphic studies indicated that their sleep is more unstable and subject to external influences. Microstructural sleep analysis confirms the presence of a disturbance of sleep stability in patients with IGE. Furthermore, it clearly shows that in the prototype of AE, the juvenile myoclonic epilepsy, the epileptiform activity during non-REM sleep is correlated with the arousal phase of the so called cyclic alternating pattern indicating that even in the smallest sleep-waking oscillations awakening is the most sensitive part.

Pharmacological and autoradiological studies suggest that mu-opioid receptor (OPRM) mediated neurotransmission is involved in the generation of absence seizures. Mutation screening of the human OPRM gene identified a common amino acid substitution polymorphism (Asn40Asp) that differentially modulates the binding affinity of beta-endorphin and signal transduction of the receptor. The present association study tested the candidate gene hypothesis that the Asn40Asp substitution polymorphism in the N-terminal OPRM domain confers genetic susceptibility to idiopathic absence epilepsy (IAE). The genotypes of the Asn40Asp polymorphism were assessed by allele-specific polymerase chain reaction in 72 German IAE patients and in 340 ethnically matched control subjects. The frequency of the Asp40 allele was significantly increased in the IAE patients [f(Asp40) = 0.139] compared to the controls [f(Asp40) = 0.078; chi2 = 5.467, df = 1, P = 0.019; OR = 2.03; 95%-CI: 1.12-3.68]. This allelic association suggests that the functional Asp40 variant of OPRM modulates neuronal excitability underlying the epileptogenesis of IAE.

Genetic factors play a major role in the aetiology of idiopathic generalised epilepsies (IGEs). The present genome scan was designed to identify susceptibility loci that predispose to a spectrum of common IGE syndromes. Our collaborative study included 130 IGE-multiplex families ascertained through a proband with either an idiopathic absence epilepsy or juvenile myoclonic epilepsy, and one or more siblings affected by an IGE trait. In total, 413 microsatellite polymorphisms were genotyped in 617 family members. Non-parametric multipoint linkage analysis, using the GeneHunter program, provided significant evidence for a novel IGE susceptibility locus on chromosome 3q26 (Z(NPL) = 4.19 at D3S3725; P = 0.000017) and suggestive evidence for two IGE loci on chromosome 14q23 (Z(NPL) = 3.28 at D14S63; P = 0.000566), and chromosome 2q36 (Z(NPL) = 2.98 at D2S1371; P = 0.000535). The present linkage findings provide suggestive evidence that at least three genetic factors confer susceptibility to generalised seizures in a broad spectrum of IGE syndromes. The chromosomal segments identified harbour several genes involved in the regulation of neuronal ion influx which are plausible candidates for mutation screening.

The PAX-6 gene is a member of the paired-box-containing ( PAX ) gene family, encoding a transcriptional activator, that plays an important role in the development of the central nervous system. The present association study tested the hypothesis that length variation of a novel regulatory dinucleotide repeat polymorphism in the promoter region of the PAX-6 gene ( PAX-6 gene-linked polymorphic region, PAX-6 LPR) confers susceptibility to the epileptogenesis of common subtypes of idiopathic generalized epilepsy (IGE). The repeat length of the regulatory dinucleotide repeat polymorphism was assessed in 354 German control subjects and 125 German IGE patients, comprising 70 patients with juvenile myoclonic epilepsy (JME) and 55 patients with an idiopathic absence epilepsy (IAE). The allelic distribution of the PAX-6 LPR did not deviate significantly between the controls and the IGE patients (Wilcoxon Rank-Sum test: P >0.76), or both subgroups of either JME patients ( P >0.78) or IAE patients ( P >0.87). Our results do not provide evidence that length variation of the polymorphic dinucleotide sequence in the PAX-6 LPR contributes a frequent and relevant effect to the pathogenesis of common subtypes of IGE.

Juvenile myoclonic epilepsy (JME) is a genetically determined common subtype of idiopathic generalized epilepsy (IGE). Significant evidence for linkage has been reported for a susceptibility locus for JME in the chromosomal region 15q14 that harbors the gene encoding the alpha7 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA7). The present study was designed to test the earlier linkage finding and to explore whether this susceptibility locus is involved in the epileptogenesis of a broader spectrum of IGE syndromes. Multipoint parametric and nonparametric linkage analyses with seven microsatellite polymorphisms encompassing the region of the CHRNA7 gene were performed using two diagnostic schemes of JME-related traits in two groups of multiplex families ascertained through probands with either JME (n = 27) or idiopathic absence epilepsy (n = 30). The present linkage study failed to replicate evidence for a major susceptibility locus for JME in the region encompassing the CHRNA7 gene. In addition, we found no hint in favor of linkage to 15q14 under the broad diagnostic scheme in any of the sets of families. If genetic variation in this region confers susceptibility to JME, then its effect size might be too small or its occurrence too rare to be detected in the investigated families.

The present association study tested whether length variations of two adjacent polymorphic CAG repeats in the coding sequence of a small-conductance, calcium-activated potassium channel (hKCa3) confer susceptibility to common subtypes of idiopathic generalized epilepsy (IGE). We found no significant difference in the allelic length distribution of the CAG repeats between 290 healthy German controls and the entire sample of 126 German IGE patients (Wilcoxon rank-sum test, P = 0.44) or two subgroups, comprising either 78 patients with juvenile myoclonic epilepsy (Wilcoxon rank-sum test, P = 0.74) or 59 patients with idiopathic absence epilepsies (Wilcoxon rank-sum test, P = 0.44). Moreover, the allelic distribution in parents-child trios of 46 IGE offspring did not differ significantly between the transmitted and non-transmitted parental alleles (Wilcoxon rank-sum test, P = 0.48). Therefore, our association study provides no evidence that length variations of polyglutamine arrays in the N-terminus of the hKCa3 channel exert a frequent and relevant effect in the epileptogenesis of common subtypes of IGE.

Publisher Summary This chapter discusses various aspects of juvenile myoclonic epilepsy (JME). The cardinal symptoms of JME are very brief bilateral arrhythmic jerks, affecting mainly shoulders and arms. The jerks may occur singly or in clusters at irregular intervals, and they may vary in frequency and intensity. The generalized tonic-clonic seizures in patients with JME have some distinctive features initiated by more or less frequent jerks. With a prevalence of 7% to 9% in an unselected patient population comprising children, juveniles, and adults, JME is one of the most common types of epilepsy and, with 20% to 25%, certainly a very common form of idiopathic generalized epilepsy. The jerks, and correspondingly, the major seizures manifest themselves predominantly on waking and usually after a lack of sleep. The characteristic electroencephalogram of jerks in JME is bilaterally symmetrical, frontocentrally accentuated polyspike-waves. A burst of spikes suddenly occurs simultaneously with the jerks and is followed by slow waves of varying frequency and amplitude. It is suggested that a susceptibility gene in the region of the human leukocyte antigen locus on the short arm of chromosome 6 contributes to the expression of JME and associated idiopathic generalized epilepsy phenotypes.

Mutations in the gene encoding the alpha1A-calcium channel subunit play a causative role in the epileptogenesis of absence seizures in tottering mutant mice. The present family-based association and non-parametric linkage study tested the hypothesis that allelic variants of the homologous human gene (CACN1A4) confer susceptibility to common subtypes of idiopathic generalized epilepsy (IGE). An expressed polymorphic CAG trinucleotide repeat in the 3' end of the CACN1A4 gene was assessed in 70 families ascertained through members with either childhood (CAE) and juvenile absence epilepsy (JAE), or juvenile myoclonic epilepsy (JME). Our association analysis using the haplotype-based haplotype relative risk statistic provided no evidence for an allelic association of the CAG repeat polymorphism with either IGE, or CAE and JAE, or JME. We found no relation between the CAG repeat length and susceptibility neither to IGE, nor to CAE and JAE, nor to JME. Non-parametric linkage analysis revealed no evidence for linkage of IGE traits with the CACN1A4 locus in 42 families of patients with either CAE or JAE. A weak trend towards an excess of allele sharing (identity by descent) among family members affected by an IGE was obtained in 26 families of JME patients (Z[NPL] = 1.25 at theta = 0.000, p = 0.057). Taken together, we found no statistically significant evidence that genetic variants of the CACN1A4 gene play a causative role in the pathogenesis of common subtypes of IGE in humans.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs).The pivotal function of glutamate receptors (GluRs) in excitatory neurotransmission implicates their involvement in epileptogenesis and genetic susceptibility to IGEs. A trinucleotide repeat polymorphism detected in the 3 prime untranslated region of the kainate-selective GluR6 receptor gene (GRIK2) on chromosome 6 makes it possible to perform linkage and association studies with this high-ranking candidate gene. The present study tested the hypothesis that allelic variants of GRIK2 contribute to the genetic susceptibility to the common IGEs. Linkage and association analyses were conducted in 63 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, or childhood absence epilepsy. Our linkage and association results suggest that allelic variants of GRIK2 are not involved in the expression of the common familial IGEs, and radiation hybrid mapping assigns GRIK2 to the chromosomal region 6q16.3-q21. This localization excludes GRIK2 as a candidate for the putative IGE susceptibility locus ``EJM199 on the short arm of chromosome 6. NEUROLOGY 1995;45: 1713-1720

Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder affecting about 0.4% of the world's population. Mutations in ten genes causing distinct forms of idiopathic epilepsy have been identified so far, but the genetic basis of many IGE subtypes is still unknown. Here we report a gene associated with the four most common IGE subtypes: childhood and juvenile absence epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal seizures on awakening (EGMA; ref. 8). We identified three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations result in (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations that provide distinct explanations for their pathogenic phenotypes. M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition. G715E alters voltage-dependent gating, which may cause membrane depolarization and hyperexcitability.

Nachuntersuchungen an 16 Patienten, die vor 12–27 Jahren eine Triarylphosphat(ATP)-Vergiftung durchgemacht hatten, liesen im Ruckblick erkennen, das alle Falle einen Symptomwandel von schlaffen Lahmungen zu spastischen Symptomen durchgemacht hatten. TAP fuhrt also generell zu einem „toxischen Systemschaden“ (Vogel, 1947) am ersten und zweiten motorischen Neuron. Diese Entwicklung lies sich bei den geheilten Fallen klinisch wahrscheinlich machen und bei den Fallen mit Restparesen elektromyographisch durch den Nachweis einer von den schlaffen Lahmungen verdeckten Spastik belegen. Das die Nervenfasern nach Masgabe ihrer Langenausdehnung dem Gift ausgesetzt waren, bestatigte sich auch in der Ruckbildung der Symptome. Die Restitution, die in den Armen einen gunstigeren Verlauf nahm als in den Beinen, ging an den oberen wie an den unteren Extremitaten von proximal nach distal vor sich. Nach der Art der Symptome bildeten sich die schlaffen Lahmungen besser zuruck als die spastischen Symptome. Die geringste Ruckbildungsneigung zeigten die vegetativ-vasomotorischen Storungen. Nur in 3 Fallen kam es zu weitgehender Symptomfreiheit. In 10 Fallen bestanden noch deutliche, in 3 Fallen noch erhebliche Restlahmungen.