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PubMed1998

A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.

Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.

Amino Acid Sequence↗
PubMed2006

Inherited cortical HCN1 channel loss amplifies dendritic calcium electrogenesis and burst firing in a rat absence epilepsy model.

While idiopathic generalized epilepsies are thought to evolve from temporal highly synchronized oscillations between thalamic and cortical networks, their cellular basis remains poorly understood. Here we show in a genetic rat model of absence epilepsy (WAG/Rij) that a rapid decline in expression of hyperpolarization-activated cyclic-nucleotide gated (HCN1) channels (I(h)) precedes the onset of seizures, suggesting that the loss of HCN1 channel expression is inherited rather than acquired. Loss of HCN1 occurs primarily in the apical dendrites of layer 5 pyramidal neurons in the cortex, leading to a spatially uniform 2-fold reduction in dendritic HCN current throughout the entire somato-dendritic axis. Dual whole-cell recordings from the soma and apical dendrites demonstrate that loss of HCN1 increases somato-dendritic coupling and significantly reduces the frequency threshold for generation of dendritic Ca2+ spikes by backpropagating action potentials. As a result of increased dendritic Ca2+ electrogenesis a large population of WAG/Rij layer 5 neurons showed intrinsic high-frequency burst firing. Using morphologically realistic models of layer 5 pyramidal neurons from control Wistar and WAG/Rij animals we show that the experimentally observed loss of dendritic I(h) recruits dendritic Ca2+ channels to amplify action potential-triggered dendritic Ca2+ spikes and increase burst firing. Thus, loss of function of dendritic HCN1 channels in layer 5 pyramidal neurons provides a somato-dendritic mechanism for increasing the synchronization of cortical output, and is therefore likely to play an important role in the generation of absence seizures.

Action Potentials↗
PubMed2006

Coexisting muscular dystrophies and epilepsy in children.

Muscular dystrophies are composed of a variety of genetic muscle disorders linked to different chromosomes and loci and associated with different gene mutations that lead to progressive muscle atrophy and weakness. Fukuyama congenital muscular dystrophy is frequently associated with partial and generalized epilepsy and congenital brain anomalies, including cobblestone complex and other neuronal migration defects. We report generalized convulsive epilepsy in a boy with normal brain magnetic resonance imaging and Duchenne muscular dystrophy with deletion of dystrophin gene, and we report absence epilepsy with normal brain magnetic resonance imaging in another boy with limb girdle muscular dystrophy with partial calpain deficiency. We, therefore, review coexisting muscular dystrophies and epilepsy in children. In addition to Fukuyama congenital muscular dystrophy, partial or generalized epilepsy has also been reported in the following types of muscular dystrophies, including Duchenne/Becker dystrophy, facioscapulohumeral dystrophy, congenital muscular dystrophy with partial and complete deficiency of laminin alpha2 (merosin) chain, and limb girdle muscular dystrophy with partial calpain deficiency.

Brain↗
PubMed2002

Genetics of epilepsy: current status and perspectives.

Epilepsy affects more than 0.5% of the world's population and has a large genetic component. The most common human genetic epilepsies display a complex pattern of inheritance and the susceptibility genes are largely unknown. However, major advances have recently been made in our understanding of the genetic basis of monogenic inherited epilepsies. Progress has been particularly evident in familial idiopathic epilepsies and in many inherited symptomatic epilepsies, with the discovery that mutations in ion channel subunits are implicated, and direct molecular diagnosis of some phenotypes of epilepsy is now possible. This article reviews recent progress made in molecular genetics of epilepsy, focusing mostly on idiopathic epilepsy, and some types of myoclonus epilepsies. Mutations in the neuronal nicotinic acetylcholine receptor alpha4 and beta2 subunit genes have been detected in families with autosomal dominant nocturnal frontal lobe epilepsy, and those of two K(+) channel genes were identified to be responsible for underlying genetic abnormalities of benign familial neonatal convulsions. The voltage-gated Na(+) -channel (alpha1,2 and beta1 subunit), and GABA receptor (gamma2 subunit) may be involved in the pathogenesis of generalized epilepsy with febrile seizure plus and severe myoclonic epilepsy in infancy. Mutations of Ca(2+)-channel can cause some forms of juvenile myoclonic epilepsy and idiopathic generalized epilepsy. Based upon these findings, pathogenesis of epilepsy as a channelopathy and perspectives of molecular study of epilepsy are discussed.

Chromosomes↗
PubMed1998

Long-term follow-up of childhood epilepsy associated with tuberous sclerosis.

PURPOSE: To study the clinical and electroencephalographic (EEG) characteristics of patients whose epilepsy is associated with tuberous sclerosis, with special reference to their clinical course. METHODS: We investigated the electroclinical and radiologic features of 38 patients with epilepsy associated with tuberous sclerosis. RESULTS: Eleven patients showed only generalized epilepsy, and 10 showed only localization-related epilepsy throughout their clinical course. Among the other 17 cases, the nature of the epilepsy changed between generalized and localization-related epilepsies during the clinical course. A shift from generalized to localization-related epilepsies was more common than the reverse. Seventeen had West syndrome (WS), three had Lennox-Gastaut syndrome (LGS), and eight had epilepsies that evolved from WS to LGS. Tonic spasms, mostly in series, were seen in all 28 patients with generalized epilepsy. Eleven of the 28 patients had partial seizures and tonic spasms in the same period. Six of them showed "simultaneous seizures," consisting of tonic spasms in series and a partial seizure. Partial seizures were the main seizure type in 27 patients with localization-related epilepsy, but three of them also showed tonic spasms that included "simultaneous seizures." Ictal EEGs revealed multiple active foci in the same period that could shift during the clinical course. Neither the location nor number of tubers was related to the clinical course. As for seizure outcome, 12 (32%) of 38 patients were free from seizures at follow-up. CONCLUSIONS: In epilepsies associated with tuberous sclerosis, there may be an interrelation between generalized and localization-related epilepsies, as well as one between generalized and partial seizures.

Child↗
PubMed1998

Role of vigabatrin and lamotrigine in treatment of childhood epileptic syndromes.

PURPOSE: Vigabatrin (VGB) and lamotrigine (LTG) are two new antiepileptic drugs (AEDs) with different mechanisms of action for treatment of refractory epilepsies. Previous reports have indicated efficacy of both drugs in a number of epileptic syndromes. METHODS: We compared these new AEDs drugs to determine their respective efficacy against different types of epileptic syndrome and to develop a rational approach to their use. We reviewed the charts of 105 children, with partial and generalized epilepsies. RESULTS: VGB was to be significantly more effective in children with partial epilepsies, and LTG was more effective in those with generalized epilepsies. CONCLUSIONS: VGB and LTG have different therapeutic profiles. Combination treatment with the two drugs may represent rational polytherapy for patients with epilepsy resistant to treatment with either drug alone or as add-on to other AED treatment.

Adolescent↗
PubMed1991

Antiepileptic drugs as 'tracers' of disease. A calculation of the prevalence of epilepsy through an analysis of drug consumption. The Group for the Study of Epilepsy in General Practice.

Antiepileptic drug (AED) consumption, expressed according to a standardized measurement of the average daily doses of each active principle (the defined daily dose, DDD), was assessed as a source of morbidity data to calculate the prevalence of AED takers. In a population of 51,220 from three areas in Italy (Arcisate, Treviglio, S. Giovanni Rotondo) all the patients treated with AEDs, traced by the local general practitioners, were examined by a neurologist. The diagnosis of epilepsy was confirmed in 199 of 223 AED takers, giving an overall prevalence rate of 3.94 per 1,000 (Arcisate 3.96; Treviglio 4.04; S. Giovanni Rotondo 3.89). There was a significant overlap between the observed and expected number of AED takers (the latter obtained from regional sales and expressed in DDD). Prevalence rates calculated from drug sales were 5.58 in Arcisate and 6.11 in Treviglio. The ratio of patients with epilepsy to AED takers in the two areas was 0.7 and corresponded to the mean proportion of AEDs prescribed for epilepsy in the years 1983-1988 by a sample of Italian physicians. Although the prevalence rate calculated from AED sales tends to approximate that of treated epilepsy, AEDs can be reasonably used as 'tracers' of disease for the easy access to drug sales in Italy, the appropriateness of the DDD as a standard measure of the daily doses of AED, the steady pattern of consumption, the comparability of data covering different areas and periods, and the stable proportion of drugs delivered for epilepsy.

Adolescent↗
PubMed1990

Selection of drugs for the treatment of epilepsy.

Antiepileptic drug selection is based on efficacy for specific seizure types and epileptic syndromes. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the drug of choice is valproate. Secondary generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single drug or combination of drugs. The drugs of choice for absence seizures are ethosuximide and valproate. For control of tonic-clonic seizures, any of the other major antiepileptic drugs can be effective. If valproate cannot be used, carbamazepine, phenobarbital, phenytoin, or primidone is effective, but ethosuximide or a benzodiazepine needs to be added to control associated absence or myoclonic seizures. The drugs of first choice for partial epilepsies with partial and secondarily tonic-clonic seizures are carbamazepine and phenytoin. Increasing evidence suggests that valproate may be a third alternative. Phenobarbital and primidone are second choice selections because of side effects. A combination of two of these five major antiepileptic drugs may be necessary for inadequately controlled patients. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, and alcoholic epilepsy require specific drug treatment. For all these seizure types and epilepsy syndromes, treatment ultimately must be selected to provide maximal efficacy and minimal adverse effect for each individual patient.

Anticonvulsants↗
PubMed1988

Ictus emeticus induced by photic stimulation.

It has been recently established that ictus emeticus originates from mesial temporal lobe structures. We herein report a patient with generalized epilepsy who exhibited ictus emeticus reflexly triggered by intermittent photic stimulation accompanied by generalized photoparoxysmal responses on the electroencephalogram. All seizures and EEG abnormalities ceased after treatment with valproic acid. The occurrence of ictus emeticus in generalized epilepsy is an apparent paradox, better explained by the theory of "secondary temporalization" implying the selective engagement of temporal lobe structures during generalized seizures.

Electroencephalography↗
PubMed2004

Effects of zonisamide on the electroencephalogram of a patient with juvenile myoclonic epilepsy.

Zonisamide, a newer antiepileptic drug (AED) with multiple mechanisms of action, has been increasingly used in patients with generalized epilepsies. This case study focuses on the effects of zonisamide on the EEG of a patient with juvenile myoclonic epilepsy. The patient had complete resolution of myoclonic jerks and absence and generalized seizures on introduction and titration of therapy with zonisamide; his EEG showed almost complete resolution of generalized spike and wave discharges and electrographic absence seizures. This case report suggests that zonisamide may be effective in the treatment of medication-resistant idiopathic generalized epilepsy and that it may lead to a significant improvement of the EEG.

Adult↗
PubMedDate not supplied

[Anticonvulsant action of pargyropyranone in various models of experimental epilepsy in the cat].

The new anticonvulsant drug pargypiranone was studied in different models of experimental epilepsy in cat (penicillin and Premarin cortical focus, cobalt cortical focus, penicillin generalized epilepsy). The drug proved to possess a strong anticonvulsant effect upon focal electroclinical phenomena and a poor effect on penicillin generalized epilepsy. It seems probably that pargypyranone has a valid effect on partial epileptic seizures.

Animals↗
PubMed1999

Distribution of epilepsy syndromes in a cohort of children prospectively monitored from the time of their first unprovoked seizure.

PURPOSE: To assess the distribution of epilepsy syndromes and their stability in children. METHODS: A cohort of 407 children with a first unprovoked seizure was prospectively recruited and followed up for a mean of 9.4 years. Etiology and epilepsy syndromes were classified by using the International League Against Epilepsy (ILAE) guidelines in the 182 children with two or more seizures. Classification was done both at time of second seizure and at last follow-up. Two-year terminal remission also was analyzed by etiology and epilepsy syndrome. RESULTS: Etiology of epilepsy syndromes was idiopathic in 45 (25%), cryptogenic in 89 (49%), and remote symptomatic in 48 (26%). In the initial classification, 114 (63%) children had a localization-based epilepsy syndrome including idiopathic in 26, cryptogenic in 34, and symptomatic based on localization or etiology in 54. Twenty-one (12%) children had a generalized epilepsy syndrome, including 19 with primary generalized epilepsy. Forty-seven (26%) cases were in the category of undetermined if focal or generalized. At last follow-up, there was a change in either etiology (n = 16) or the final epilepsy syndrome classification (n = 33) or both (n = 15) in 34 (19%) cases. At time of last follow-up, 144 (79%) of the children with epilepsy were in 2-year terminal remission, and 108 (59%) were in 2-year terminal remission without medications. Factors associated with a favorable prognosis included an idiopathic or cryptogenic etiology and having a localization-based idiopathic epilepsy syndrome. CONCLUSIONS: After two seizures, childhood-onset epilepsy can be classified by etiology and epilepsy syndrome. Prognosis is favorable in the majority of cases. However, the apparent syndrome may change with longer follow-up. The ability to classify these cases early in the clinical course is important if they are to be used for prognostic purposes.

Adolescent↗
PubMed1984

Comparison of the psychosocial effects of epilepsy and narcolepsy/cataplexy: a controlled study.

A questionnaire survey compared the psychosocial effects of epilepsy in 60 patients without major organic pathology (selected cases with temporal lobe epilepsy or primary generalized epilepsy) with those of matched (duration of illness, sex) patients with narcolepsy/cataplexy and with those of age- and sex-matched controls. Comparing epileptic patients with controls, we confirmed the well-documented marked deleterious effects of epilepsy upon work, education, occupational and household accidents, recreation, personality, interpersonal relations, and other parameters. Comparisons of epileptic and narcoleptic patients, however, showed that, in general, persons with narcolepsy are even more psychosocially impaired. The narcoleptic patients showed greater frequencies of disease-attributed reduced performance at work, poorer driving records, higher accident rates from smoking, greater problems in planning recreation, and other significant differences. Rather dissimilar profiles of psychosocial impairment were found to characterize the two conditions, and these were largely understandable as a function of their symptoms. The only areas in which epileptic patients showed greater problems than those with narcolepsy were in educational achievement and in ability to maintain a driving license. Most of the intergroup differences remained significant even for smaller groups matched also for age. The somewhat greater psychosocial impact of narcolepsy appears to be due to the continuous excessive daytime sleepiness that persists between the diagnostic attacks, whereas persons with epilepsy are relatively alert between seizures.

Accidents↗
PubMed1988

[Epilepsies in puberty and adolescence. Follow-up and drug therapy].

1. Puberty and adolescence mainly can have a bad effect on idiopathic generalized epilepsies. This can show up in the first onset of seizures in adolescence, e.g. as a form of idiopathic grand mal on awakening, juvenile absence epilepsy or juvenile myoclonic epilepsy (impulsive petit mal). Also, already diagnosed absence epilepsy can become worse, e.g. by recurring absence seizures or grand mal seizures or the new onset of grand mal on awakening. 2. Exogenous factors, like changing the time of sleeping and waking, lack of sleep and the abuse of alcohol, play an important role in these types of epilepsy. Cutting out these factors is just as important as the consequent drug treatment on a longterm basis. 3. Drug treatment of idiopathic generalized epilepsy will be done with valproate, barbiturates and ethosuximide. Regarding fatal complications of liver function, which are more frequent than previously thought of, valproate can be recommended as a drug of first choice, especially in early childhood and when a combination of drugs is used. 4. A very good effect of adolescence is seen in children with benign idiopathic focal epilepsy with a centro-temporal spike focus. Antiepileptic treatment with carbamazepine as an agent of first choice can be done less vigorously. 5. Menstruation usually only modifies but does not worsen the natural course of epilepsy. There is still no real therapeutical plan for this rare form of epilepsy. 6. It cannot be a general rule, not to change current medical treatment before or during puberty in order to avoid any worsening of seizures. A decision always has to be made regarding the form of epilepsy and the individual situation, which has to be discussed with the patient and perhaps his family.

Adolescent↗
PubMed2006

Effects of non-competitive AMPA receptor antagonists injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy.

CFM-2 [1-(4-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one] and THIQ-10c [N-acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline], are two non-competitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) receptor antagonists, which demonstrated to antagonize generalized tonic-clonic seizures in different animal models. We have evaluated the effects of such compounds in a genetic animal model of absence epilepsy, the WAG/Rij rat. Animals were focally microinjected into specific brain areas of the cortico-thalamic circuit in order to evaluate the effects of these compounds on the number and duration of epileptic spike-wave discharges (SWDs) and better characterize the role of AMPA neurotransmission in this animal model. The focal microinjection of the two AMPA antagonists into some thalamic nuclei (ventralis posteromedialis (VPM), reticularis (NRT), ventralis posterolateralis (VPL) and the primary somatosensory forelimb region (S1FL)) was, generally, not able to significantly modify the occurrence of SWDs. Whereas, both compounds were able to reduce the number and duration of SWDs dose-dependently when microinjected into the peri-oral region of the primary somatosensory cortex (S1po). These findings suggest that AMPA receptor antagonists might play a role in absence epilepsies and that it might depend on the involvement of specific neuronal areas.

Animals↗
PubMed1986

Effect of sleep on the electrographic manifestations of epilepsy.

Alterations in the level of arousal have profound predictable effects on the electrographic manifestations of epileptogenic abnormalities. The changes produced by sleep are dramatic in patients with generalized epilepsy as compared to patients with partial epilepsy. The epileptiform complexes associated with the generalized epilepsies show changes in spatial distribution, voltage, temporal sequencing, and waveform morphology. The changes are qualitatively similar in the different types of generalized seizure disorders but vary in the degree to which they are expressed in proportion to the "severity" of the seizure disorder. The presence of a generalized epileptogenic abnormality may result in alteration of K-complex waveform morphology. Multifocal spikes occurring in conjunction with bilateral synchronous discharges are frequently represented by a spatial field distribution consistent with a "horizontal dipole," during sleep especially in children.

Adult↗
PubMedDate not supplied

[Epilepsy in advanced age].

A study was performed on 174 epileptic patients aged of 65 years and over. This semeiology of seizures of 156 patients can be categorized according to the international Classification of the epilepsies. Correlations were made between epilepsy form and scan. We had found that majority (74%) of the patients manifested parital seizures either with elementary or a complex symptomatology. The generalized tonico-clonic seizures of the aged were less frequent: 9% consisted of partial seizures secondarily generalized, 1% of Grand Mal primary generalized epilepsies and 16% of secondary generalized epilepsies due to a cerebral involution which can be only detectable with CT-scan. By means of CT-scan we were able to define the true etiology in 63% of our patients.

Age Factors↗