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PubMed2003

Clinical trials for treatment of primary generalized epilepsies.

PURPOSE: To review the current state of knowledge of the treatment of primary (idiopathic) generalized epilepsy syndromes based on the efficacy results of clinical trials, to highlight obstacles in the design of these trials, and to suggest solutions for future research. METHODS: Published reports of controlled clinical trials, as well as large or significant uncontrolled trials of treatments for these syndromes, were reviewed. Trials were selected for discussion based on their importance or their illustration of design issues. RESULTS: Only a few randomized, controlled trials of therapy for these syndromes exist. Conclusions based on this Class I data include efficacy in absence epilepsies for ethosuximide, valproate, and lamotrigine, and for eight drugs for primary generalized tonic-clonic seizures. Many commonly accepted therapeutic strategies are not based on formal data. No controlled data exist for uncommon syndromes. CONCLUSIONS: More clinical trials of therapies for primary generalized epilepsies are needed. To overcome design obstacles, better funding, multicenter cooperation, inclusion of children, study designs requiring fewer patients, equivalent-control designs, use of EEG and video seizure counting, and better syndrome identification will be required.

Anticonvulsants↗
PubMed1999

Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24-q33.

We report the identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+). Six family members manifested isolated typical febrile seizures (FS), and five had typical FS associated with generalized epilepsy (FS+, generalized tonic/clonic seizures). Afebrile seizures occurred from childhood until the teenage years. The maximum two-point LOD score was 3.99 for markers D2S294 and D2S2314. Flanking markers place the GEFS+ locus between D2S141 and D2S116, with multipoint analysis favoring the 13-cM interval spanned by D2S294 and D2S364. This locus is the second GEFS+ locus to be reported, which suggests that this syndrome is genetically heterogeneous.

Chromosome Mapping↗
PubMed1997

Consistent EEG focalities detected in subjects with primary generalized epilepsies monitored for two decades.

PURPOSE: To describe the evolution of interictal findings in serial EEGs from patients with primary generalized epilepsy. METHODS: A cohort of 89 subjects with various primary generalized epilepsies were reviewed. Thirty-one did not meet a priori criteria. Of the 58 patients analyzed, 12 had only absence seizures, 28 had absence seizures followed by one or more generalized tonic-clonic seizures, 9 had generalized tonic-clonic seizures followed by absence and/or myoclonic seizures. and 9 had juvenile myoclonic epilepsy. Patients were followed for a mean of 16 years. An average of 39 EEGs were obtained on each patient. RESULTS: Thirty-two patients (56%) had focal features present in up to 65% of the EEGs in each of the patients. Accepted focalities were only those that were consistent in lateralization, location and, often, morphology across the span of the study. Focal findings were most often temporal or frontal. CONCLUSIONS: Patients with typical primary generalized epilepsies show a high incidence of focal EEG features that cannot be explained on the basis of structural lesions, coincidental factors, or to artifacts of the selection criteria. Although the data do not allow a definitive explanation, possible mechanisms include associated focal cortical pathology such as microdysgenesis, and development over time of localized, self-sustaining hyperexcitability in low-threshold cortical structures subjected to repeated generalized spike-wave activity. Either hypothesis implies the participation and interaction of genetic, ontogenic, and environmental factors.

Adolescent↗
PubMed2001

Idiopathic generalized epilepsies with pure grand mal: clinical data and genetics.

OBJECTIVE: To analyze the clinical features and family history of patients with idiopathic generalized epilepsy (IGE), with pure grand mal (GM), divided into epilepsies with GM occurring exclusively on awakening (GMA) and random GM (RGM). METHODS: We studied retrospectively 98 patients from a large epilepsy outpatient clinic. All patients had a full clinical examination and computed cerebral tomography scans (CCT) or magnetic resonance imaging (MRI) when feasible. We analyzed seizure type, seizure frequency, provocative factors, prognosis, electroencephalography (EEG) findings and family history. RESULTS: Sixty-eight patients had GMA and 30 had RGM. The mean age at seizure onset was 16.6 years (+/-6.3 S.D., range: 5-41) and 16.7 years in those with RGM (+/-7.5 S.D., range: 4-42, NSD). Patients with GMA had a longer course of active epilepsy (median 8.5 years) compared to RGM (median 2 years). Seizure-provoking factors, especially sleep deprivation, were significantly (P=0.001) more common in patients with GMA (52/68, 77%) than in the group with RGM (13/30, 43%). Of all patients, 23% (23/98) reported first degree relatives with seizures or epilepsy. Pure GM was found in 41% (12/29) of affected first degree relatives, other idiopathic generalized epilepsy syndromes were less frequently observed (4/29, 14%). The concordance rate was high within the syndrome - none of the patients with RGM had an affected relative with GMA and vice versa only two of affected relatives of GMA patients had RGM. CONCLUSION: GMA seems to be associated with a longer duration of active epilepsy, a higher relapse rate and a stronger tendency to be precipitated by seizure provoking factors. The different concordance rates between the syndromes suggest a genetically different background.

Adolescent↗
PubMed2006

Corpus callosotomy in refractory idiopathic generalized epilepsy.

RATIONALE: A small percentage of patients with idiopathic generalized epilepsy (IGE) do not respond to medical therapy. Generalized tonic-clonic (GTC) seizures are especially debilitating and can be associated with severe injuries. The benefit, safety and effect of corpus callosotomy (CC) in patients with IGE have not been studied. METHODS: We reviewed patients with presumed IGE who underwent CC between 1991 and 2000. Criteria for selection included history, examination, brain imagining, interictal and ictal EEG. All patients had refractory and debilitating tonic-clonic seizures (GTCS) and had failed four or more antiepileptic drugs. Seizure frequency was calculated per month over the last year and pre-operative baseline was compared to last follow-up using paired t-tests. IQ, executive function, language and verbal, non-verbal memory and quality of life (QOL) was compared before and after surgery. Serial EEGs after surgery were reviewed. RESULTS: There were nine patients (seven men), mean age 37.9 (range: 22-49), mean IQ 87.3 (range: 75-107). All had anterior CC. Mean follow-up time was 5.4 years (range: 0.6-10.3 years). One patient died from sudden death in epilepsy 9 months after surgery. There was a significant reduction of GTC seizures from 6.3 to 1.1 (p<0.005). Four patients had more than 80% and eight more than 50% reduction. Of five patients with absence seizures, two became seizure free and one had more than 80% reduction and two worsened slightly, and of three with myoclonic seizures one had more than 90% reduction. One patient had completion of the CC with improvement of myoclonus and absence seizures, but not of GTC seizures and suffered a disconnection syndrome. Another had right frontal focal resection without improvement after new seizures of focal onset. Cognitive testing showed a good outcome (improved or no change) in all cognitive domains. Post-surgical EEG showed new focal slowing and sharp waves. There was no change in QOL. CONCLUSION: CC can be effective in reducing GTC, absence and myoclonic seizures in patients with refractory IGE. These findings suggest that interhemispheric communication of the cerebral cortices plays an important role in the generation of seizures in IGE. Anterior CC appears safe while complete callosotomy has a risk of disconnection syndrome.

Adult↗
PubMed2005

Status epilepticus in idiopathic generalized epilepsy.

Status epilepticus (SE) can take various forms in idiopathic generalized epilepsy (IGE), some of which forms also occur in symptomatic or focal epilepsies. Although the clinical semiology of the SE episodes may be similar in these different epilepsies, the frequency, response to treatment and prognosis differ. (a) Convulsive SE is surprisingly uncommon in IGE and much less common than in the secondarily generalized or partial epilepsies. Also, when it does occur, it usually responds rapidly to treatment. (b) Typical absence SE occurs only in patients with IGE (the subcategories with typical absence seizures) and also in the syndrome of de novo absence SE of late onset. This form of nonconvulsive SE should be differentiated from atypical absence SE, which occurs in the secondarily generalized epilepsy encephalopathies, and from complex partial SE which occurs in focal epilepsy. The clinical symptoms of these three types overlap but the prognosis and response to treatment are different. The mechanisms underlying absence SE are uncertain and may include both genetic and environmental factors. The termination of absence seizures has been hypothesized to be due to persistent activation of a depolarizing current in thalamocortical neurons that inactivates T-type calcium channels. SE could thus result from dysfunction of this channel or mechanisms that hyperpolarize thalamocortical neurons-these include decreased cortical inhibition, increased reticular thalamic neuronal activity or increased thalamocortical neuron GABA(B)-receptor activation. (c) Generalized electrographic SE is encountered in IGE in the syndrome of phantom absence with GTCS. It also occurs in ESES and in the Landau-Kleffner syndrome. The seizure phenomenology overlaps with the focal SE of temporal or frontal lobe epilepsy. (d) Myoclonic SE is also uncommon in IGE but occurs in juvenile myoclonic epilepsy. It is more commonly encountered in progressive myoclonic epilepsies, myoclonic-astatic epilepsy and in the Dravet syndrome. (e) Autonomic status occurs largely in the Panayiotopoulos syndrome. It is included here under the rubric of IGE, although the epilepsy has focal as well as generalized features and its nosological position is controversial. Fifty percent of seizures in this syndrome could be classified as status epilepticus. There is no doubt that convulsive SE can result in cerebral damage. In animal models of focal SE, nonconvulsive forms can also result in cerebral damage, but cerebral damage is not observed in animal models of absence SE. Similarly, cerebral damage seems not to occur in the forms of nonconvulsive SE in human IGE.

Animals↗
PubMedDate not supplied

The sexual and reproductive health in men with generalized epilepsy: a multidisciplinary evaluation.

This study was specifically aimed to evaluate the sexual and reproductive health in a group of men with generalized epilepsy. In total, 44 men with generalized epilepsy were included in this study, their ages between 18 and 48 years (29.2+/-9.9) and duration of illness between 2 and 35 years (11.2+/-7.4); 34 patients were treated with conventional antiepileptic drugs (AEDs). Sexological and psychological interviews together with serum total testosterone, E(2), FSH, LH and prolactin were determined. Hyposexuality was diagnosed in 61.4%. Erectile dysfunction (ED) and premature ejaculation represented 70.4 and 66.7%, respectively. Variables such as hyposexuality, seizure duration and its poor control on AEDs were significantly associated with depressive symptoms. Compared to the normal control group, all patients reported elevated E(2) levels (P<0.001), 10 had FSH (n=4) and LH (n=6) levels exceeding that of the normal range for controls and two had hyperprolactinemia. Although the patients' mean value of total testosterone remained within the normal range, but it was significantly lower in hyposexual men compared to nonhyposexual (P<0.002), only two epileptic patients had markedly reduced level of total testosterone beyond normal control levels. This study strongly supports that: (1) The risk of hyposexuality and reproductive disturbances is high in epileptic patients with GTC convulsions despite the AEDs utilized. The risk for SD is further increased by poor seizure control and the frequently accompanied depressive manifestations. (2) It is possible that elevated E2 could increase the risk of SD by reducing active testosterone through negative feedback and the reduction of active testosterone could increase seizure intractability to antiepileptic medications.

Adult↗
PubMed1988

Functional microsurgical partial callosotomy in patients with secondary generalized epilepsies. II. Mesial surface electrocorticography.

Eight patients with secondary generalized epilepsy not alleviated by medical treatment underwent partial callosotomy. During the surgical procedure, they had mesial surface ECoG recordings taken from both frontal and parietal lobes, using large flat multilead platinum electrodes, and simultaneously recordings from a number of scalp positions, using needle electrodes. In all cases studied, this approach demonstrated one or, more commonly, several focal areas of epileptiform activity discharging independently over the mesial aspects of one or both hemispheres. The findings were correlated with the pre- and postoperative EEG patterns, in the light of current concepts of generalized epilepsies.

Adolescent↗
PubMed2003

Generalized epilepsy in hypothalamic hamartoma: evolution and postoperative resolution.

OBJECTIVE: To better understand the epileptogenesis of symptomatic generalized epilepsy in patients with hypothalamic hamartoma and intractable epilepsy, many of whom experience remission of generalized seizures and slow spike-wave discharges following surgery. METHODS: The authors documented the evolution of symptomatic generalized epilepsy in 12 of 20 children who underwent transcallosal microsurgical hypothalamic hamartoma resection. In seven patients they recorded intraoperative EEG from the hamartoma and simultaneously from the scalp and frontal cortex before, during, and after resection. RESULTS: Gelastic seizures began on average at 6 months of age (range birth to 3 years); tonic seizures began at 6 years (range 2 months to 9 years). Normal EEG were reported in early childhood; thereafter, abnormalities were progressive. Interictal spike-wave was recorded intraoperatively over the scalp and cortex in six patients, but not from the hypothalamic hamartoma. Hamartoma resection had no immediate effect on cortical spike-wave, but waking spike-wave was absent in seven patients on subsequent postoperative EEG. Tonic seizures ceased in 11 of 12 patients, but 6 of these had postoperative generalized seizures that resolved over 1 to 6 months. CONCLUSION: Gelastic seizures in hypothalamic hamartoma arise from the hamartoma itself; the interictal spike-wave does not. The evolution of EEG abnormalities, the development of generalized seizures years after onset of gelastic seizures, and the postoperative running down of interictal spike-wave and generalized seizures in these patients may reflect secondary epileptogenesis.

Child↗
PubMed2003

Generalized epilepsy with febrile seizures plus type 2 mutation W1204R alters voltage-dependent gating of Na(v)1.1 sodium channels.

Nine mutations that cause generalized epilepsy with febrile seizures plus have been identified in the SCN1A gene encoding the alpha subunit of the Na(v)1.1 voltage-gated sodium channel. The functional properties of two of these mutations (T875M and R1648H) have previously been described. T875M was shown to enhance slow inactivation, while R1648H dramatically accelerated recovery from inactivation. In this report, we have cloned, expressed and characterized the functional effects of a third generalized epilepsy with febrile seizures plus mutation, W1204R (Am J Hum Genet 68 (2001) 866). The mutation was cloned into the orthologous rat channel, rNa(v)1.1, and at the same time a single base pair insertion at base 120 in the original rNa(v)1.1 clone was corrected. The level of expression of the corrected wild-type rNa(v)1.1 was approximately 1000-fold higher than that of the original clone and comparable to that achieved with other neuronal sodium channels expressed in Xenopus oocytes. The properties of the W1204R mutant in the corrected rNa(v)1.1 were determined in the absence and presence of the beta1 subunit in Xenopus oocytes. The W1204R mutation resulted in approximately 11 mV hyperpolarized shifts in the voltage-dependence of activation and steady-state inactivation when expressed as an alpha subunit alone. When the channels were coexpressed with the beta1 subunit, the hyperpolarized shifts were still present but smaller, approximately 5 mV in magnitude. All other properties that we examined were comparable for the mutant and wild-type channels. The negative shift in activation would increase channel excitability, whereas the negative shift in inactivation would decrease excitability. The negative shifts in both properties also shifted the window current, which is the voltage region in which sodium channels can continue to open because some percentage of channels are activated and not all of the channels are inactivated. The shift in window current for the W1204R mutation could result in hyperexcitability because the neuron's potential is more likely to reach the more negative range. These results demonstrate that a third SCN1A mutation that causes generalized epilepsy with febrile seizures plus 2 alters the properties of the sodium channel in a different manner than the previous two mutations that were studied. The diversity in functional effects for these three mutations indicates that a similar clinical phenotype can result from very different underlying sodium channel abnormalities.

Animals↗
PubMed2005

The epsilon theory: a novel synthesis of the underlying molecular and electrophysiological mechanisms of primary generalized epilepsy and the possible mechanism of action of valproate.

Primary generalized epilepsy may be the result of maldevelopment of central nervous system and each seizure may be the consequence of a neuronal maladaptation to an unknown stimulus using the paleospinothalamical tract due to an overexpression of brain-derived neurotrophic factor and neurotrophin-3. The subsequent protein kinase C epsilon (PKC-epsilon) activation and intracellular Ca(2+) release causes a nociceptive hypersensitization and an increased cortical hyperexcitability because of increased frequency of synchronous Ca(2+) oscillations, cortical maldevelopment at the level of synapses and an attenuation of GABA(A) receptor mediated responses in reticular thalamic nucleus. Valproate may exert its antiepileptic effect as a PKC-epsilon inhibitor, and using with a PKC-epsilon activator that cannot pass blood brain barrier, its side effects may become avoidable.

Calcium↗
PubMed1999

The voltage gated potassium channel KCNQ2 and idiopathic generalized epilepsy.

Mutations in the voltage gated potassium channel gene KCNQ2 and the homologous gene KCNQ3 have been found to cause a rare monogenic subtype of idiopathic generalized epilepsy, the benign familial neonatal convulsions. Recently, the heteromeric KCNQ2/KCNQ3 channel was found to contribute to the native M-current, one of the most important regulators of neuronal excitability. By performing a systematic mutation scan of the coding region and an association study involving a frequent Thr752Asn substitution polymorphism, we, therefore, investigated whether allelic variation of the KCNQ2 gene confers susceptibility to common subtypes of idiopathic generalized epilepsy. Our results do not provide evidence that allelic variation of the KCNQ2 gene contributes a common and relevant effect to the pathogenesis of common subtypes of idiopathic generalized epilepsy.

Amino Acid Substitution↗
PubMed2005

Lack of an association between candidate gene loci and idiopathic generalized epilepsy in Kuwaiti Arab children.

Idiopathic generalized epilepsies (IGEs) are the most common types of epilepsy in childhood and adolescence. A variety of data suggest that IGEs have a predominant genetic etiology. Recently, a number of gene mutations have been found to be associated with various types of epilepsy in mainly the Caucasian populations. The objective of this study was to investigate the association of three different candidate genes with IGE in Kuwaiti Arab children. This study includes 123 Kuwaiti patients with a confirmed diagnosis of epilepsy. Most of the patients have had a diagnostic EEG with generalized spike-wave discharges (GSWs). All patients were evaluated by using a validated seizure questionnaire. The clinical type of epilepsy was determined by a trained neurologist/pediatrician. The study also include 100 controls, the control subjects were children which did not have any history of neurological disorders. Blood samples were collected from all patients and control subjects after taking informed consent. DNA was isolated and analyzed by molecular methods. A FokI polymorphism in neuronal nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4) gene was detected by PCR-RFLP method. A missense mutation (Ser248Phe) in CHRNA4 gene was analyzed by PCR-RFLP using HpaII. A C121W mutation in sodium-channel beta-1 subunit (SCN1B) gene was screened by a PCR-RFLP method using HinPI. A 2-bp deletion in Cystatin B gene was detected by PCR-RFLP using XcmI. The incidence of three FokI polymorphism genotypes in Kuwaiti IGE patients was 1,1 (85%), 1,2 (14%) and 2,2 (1%) respectively. The missense mutation Ser248Phe of CHRNA4 gene was not detected at all in Kuwaiti IGE patients. The C387G transversion resulting in C121W change in third exon of the SCN1B gene was detected in 3/123 patients (2%). The patients carrying this mutation also exhibited febrile seizures. The incidence of 2 bp deletion in the cystatin B gene was found to be 4% (5/123 IGE patients). The data obtained from molecular analysis show a lack of association between three candidate genes and clinical expression of IGE in Kuwaiti Arab children. This is completely different from the findings reported from Caucasian populations of France, Australia and USA in which case a strong association has been reported between IGE and these genes.

Arabs↗