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Historical aspects of idiopathic generalized epilepsies.

Early in these proceedings, the origin of the three terms in the title, "idiopathic generalized epilepsy," is discussed with respect to their significance over time, and typical misunderstandings. In the mid-20th century, a rather chaotic use of a multitude of often loosely defined terms had developed, which increasingly became an obstacle to a meaningful international discussion. The International League against Epilepsy (ILAE) took the initiative to develop an internationally accepted terminology with a classification system consisting of a classification of seizures (1981) and a classification of syndromes (1989). The Idiopathic Generalized Epilepsies are one of its four major groups emerging from a double dichotomy of generalized versus localization-related and idiopathic versus symptomatic. The inclusion of biologic aspects such as syndrome-specific ages of onset ("age-related syndromes") or syndrome-specific relations of seizure occurrence to the sleep-wake cycle ("Epilepsy with Grand Mal on Awaking") meant that the syndrome classification merged the more biological views of the German school with the more neurophysiological ones of the French. Apart from establishing a common international language concerning epilepsy, the International Classification of Epilepsies and Epileptic Syndromes became an important stimulator of research, especially concerning the idiopathic epilepsies. In particular, genetic and functional imaging investigations aim at a better understanding of these conditions. It is now understood that most idiopathic syndromes have a--sometimes complex--genetic background, but we are also becoming aware of the inappropriateness of the time-honored term "generalized" and part of our dichotomies. Both localization-related and "generalized" idiopathic epilepsies seem to share a principle of ictogenesis based on functional anatomic pathogenic networks, and we seem to move toward understanding them as functional system disorders of the brain.

Electroencephalography↗

Levetiracetam reduces frequency and duration of epileptic activity in patients with refractory primary generalized epilepsy.

PURPOSE: Levetiracetam (LEV) is a new antiepileptic drug highly effective as add-on treatment in refractory partial epilepsies. In animal models, LEV is effective against absence seizures. A limited number of case reports and series indicate that LEV reduces seizure frequency in patients with generalized epilepsies. METHOD: We evaluated with continuous EEG eight adult patients with idiopathic generalized epilepsy (IGE). All patients were refractory to the conventional therapy for IGE. Four patients received LEV as add-on therapy, and in four, a conversion to LEV monotherapy was undergone. Epileptic activity was analyzed in order to determine spike-wave density as well as median and maximal duration of spike-wave discharges. Each patient underwent a 24h EEG baseline monitoring before starting LEV therapy. A second 24h EEG examination was performed after a mean follow-up period of 136 days. RESULTS: Spike-wave density (spikes/h) was reduced by 78% after LEV administration. Median spike-wave duration decreased by 72% (p < 0.05). Maximal spike-wave duration was 6s before, and 1.5s after LEV with a percentage change of 81% (p < 0.05). The four patients on LEV monotherapy evidenced also a considerably improvement after conversion. CONCLUSIONS: This study showed that LEV produces a consistent long-term reduction of interictal epileptic activity in patients with refractory IGE. The reduction in the spike-wave activity additionally correlated with a clinically relevant antiepileptic effect. Our results support the concept that LEV could be an alternative therapy in primary generalized epilepsies.

Adolescent↗

Vagus nerve stimulation for symptomatic generalized epilepsy: a pilot study.

PURPOSE: Patients with symptomatic generalized epilepsy (SGE) may have antiepileptic drug (AED)-resistant mixed generalized seizures. Vagus nerve stimulation (VNS) reduces partial seizures and may help SGE. METHODS: We added VNS to stable AED therapy in five SGE patients. Nine-month postoperative VNS treatment seizure rates were compared to a 1-month preoperative baseline. RESULTS: All patients had mixed generalized seizures, EEG generalized slow spike-and-wave and behavioral abnormalities. Median number of previous AEDs taken was 6 (range 5-12). Median baseline seizure rate was 75/month (range 29-110). VNS produced a median seizure rate production of -41% (range -40% - -85%). Adverse events reported in one patient each were: incisional infection, choking sensation and voice change; and coughing (noted by two patients). One patient discontinued VNS due to coughing. CONCLUSIONS: We conclude that VNS may be useful add-on therapy for SGE. A larger, controlled, and blinded trial may be warranted.

Adult↗

Regional effects of lamotrigine on cerebral glucose metabolism in idiopathic generalized epilepsy.

BACKGROUND: Antiepileptic drugs have been reported to affect cerebral metabolism. We performed (18)F-fluorodeoxyglucose positron emission tomography (PET) before and after lamotrigine administration to investigate its effects on cerebral glucose metabolism in patients with drug-naïve idiopathic generalized epilepsy. DESIGN: We included patients who were newly diagnosed as having idiopathic generalized epilepsy or who had not taken an antiepileptic drug after the diagnosis was made. Antiepileptic drug (18)F-fluorodeoxyglucose PETs were obtained before and after lamotrigine administration in 21 subjects (male-female ratio, 10:11; mean +/- SD age, 24.3 +/- 2.8 years). The mean lamotrigine dosage was 211.9 mg/d (range, 175.0-275.0 mg/d). For statistical parametric mapping analysis, all PET images were spatially normalized to the standard PET template and then smoothed using a 14-mm full width at half-maximum gaussian kernel. The paired t test was used to compare premedication and postmedication (18)F-fluorodeoxyglucoae PET images. RESULTS: After lamotrigine administration, cerebral metabolism was decreased in bilateral thalami, bilateral caudate nuclei, the left side of the putamen, the left entorhinal area, bilateral parahippocampal gyri, the right inferior temporal gyrus, the left rectosubcallosal gyrus, bilateral superior frontal gyri, the left middle frontal gyrus, the right precentral gyrus, left pericentral gyri, the right superior parietal lobule, and bilateral substantia nigra at P<.05 corrected for multiple comparisons using the false discovery rate approach. No brain region showed increased metabolism after lamotrigine administration. CONCLUSION: This study revealed that lamotrigine treatment reduces glucose metabolism in the thalamus, basal ganglia, and multiple regions of the cerebral cortex in drug-naïve patients with idiopathic generalized epilepsy.

Adolescent↗

Refractory calculation-induced idiopathic generalized epilepsy: a case report and review of the literature.

We report a case with calculation-induced idiopathic generalized epilepsy (IGE) that, unlike most patients with IGE, was refractory to medications. This patient had a family history of (1) a similar condition in a relative of hers who, however, did not have identical manifestations, and (2) a mother who had migraine. Our observations illustrate that the occurrence of IGE in families usually follows rather complex patterns of inheritance and that some of them can be refractory to therapy.

Adolescent↗

Seizure anticipation by patients with focal and generalized epilepsy: a multicentre assessment of premonitory symptoms.

PURPOSE: To assess subjective seizure anticipation in patients with focal and generalized epilepsy. METHODS: Five hundred consecutively recruited out-patients (251 male, 249 female, mean age 38.1 year) from three German tertiary epilepsy referral centres filled out questionnaires regarding subjective anticipation of seizures by at least 30 min and to timing and semiologic characteristics of their premonitory symptoms versus those of ictal phenomena. Patients were not regarded as having prodromi if the semiology of symptoms reported long before a seizure was identical to auras. RESULTS: 6.2% of patients reported that they were able to anticipate seizures. Premonitory symptoms were classified as stereotyped in all but one patient. An intraindividual semiologic analysis showed that the majority of these patients had symptoms, which were distinct from ictal experiences during auras. Seizure anticipation was reported both by patients with focal and idiopathic generalized epilepsy. The median estimated time interval between occurrence of premonitory symptoms and seizure onset was 90 min. CONCLUSIONS: This study gives evidence that both patients with focal and idiopathic generalized epilepsy may subjectively anticipate the occurrence of epileptic seizures. Premonitory symptoms are distinct from auras in terms of semiology and time of occurrence. The lower percentage of patients regarded as having premonitory symptoms as compared to some earlier reports may be related to stricter criteria and to the exclusion of auras, which could directly evolve into seizures, and other ictal events. Premonitory symptoms occur at similar periods prior to seizures as anticipatory EEG-changes have been reported using methods from time series analysis.

Adult↗

Auras are frequent in idiopathic generalized epilepsy.

The occurrence of an aura is often considered evidence of a partial rather than an idiopathic generalized epilepsy syndrome. The authors examined this hypothesis by prospectively recording reports of auras by patients being admitted for video-EEG monitoring. Auras were equally common (70%) among patients with idiopathic generalized epilepsy as they were among those with localization-related epilepsy. Presence of an aura is not a reliable indicator of localization-related epilepsy.

Adult↗

Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2.

Two mutations that cause generalized epilepsy with febrile seizures plus (GEFS+) have been identified previously in the SCN1A gene encoding the alpha subunit of the Na(v)1.1 voltage-gated sodium channel (Escayg et al., 2000). Both mutations change conserved residues in putative voltage-sensing S4 segments, T875M in domain II and R1648H in domain IV. Each mutation was cloned into the orthologous rat channel rNa(v)1.1, and the properties of the mutant channels were determined in the absence and presence of the beta1 subunit in Xenopus oocytes. Neither mutation significantly altered the voltage dependence of either activation or inactivation in the presence of the beta1 subunit. The most prominent effect of the T875M mutation was to enhance slow inactivation in the presence of beta1, with small effects on the kinetics of recovery from inactivation and use-dependent activity of the channel in both the presence and absence of the beta1 subunit. The most prominent effects of the R1648H mutation were to accelerate recovery from inactivation and decrease the use dependence of channel activity with and without the beta1 subunit. The DIV mutation would cause a phenotype of sodium channel hyperexcitability, whereas the DII mutation would cause a phenotype of sodium channel hypoexcitability, suggesting that either an increase or decrease in sodium channel activity can result in seizures.

Amino Acid Substitution↗

[Mexidol in treatment of children with generalized epilepsy and febrile seizures].

The aim of our study was to estimate the role of Mexidol in ceasing of epileptic fits and improving electroencephalographic (EEG) pathological patterns in children. 120 patients with generalized epilepsy (from 4 to 16 years old) were investigated. All patients were treated by Depakin chrono 30 mg/kg. Children were divided into 2 groups: 1st--study group consisted of 60 children with combined treatment with Depakin and Mexidol (5 mg/kg). In the control group (60 children) treatment was performed only by Depakin. 100 children with the first episode of febrile seizures (from 6 months to 4 years old) were investigated. 50 children composed the study group with monotheraphy by Mexidol and 50 patients--the control group, without any treatment. The EEG examination was done by computer EEG Topography "Brain Surveyor Saico". Using Depakin in combination with Mexidol in the study group of patients with generalized epilepsy, improvement of clinical picture of disease and normalization of EEG patterns in 93% of cases has been observed. In the study group of patients with febrile seizures, normalization of EEG pathological patterns was observed in 82% cases and in 18% its improvement was seen. The relapse of seizures at high temperature was observed in 3 patients. In control group EEG patterns were improved only in 20%, in 48% no positive effect was observed and in 41% the worsening of EEG findings was seen. The relapse of febrile seizures was observed in 26 cases. Mexidol titrated to the target doze of 5mg/kg may be effective in combination with Depakin for treatment of patients with generalized epilepsy and as monotherapy in patients with first episode of febrile seizures.

Adolescent↗

[Side effects of anticonvulsants in the treatment of idiopathic generalized epilepsy].

This investigation was ainced on detection of frequency and main features of side effects of anticonvulsants in therapy of idiopathic generalized epilepsy. There were observed 190 patients aged 5-29 years suffering from different forms of idiopathic generalized epilepsy. Side effects were revealed in 48.4% of patients as a result of the investigation. Almost half of patients (49.0%) who were administered valproic acid developed side effects. Neuroendocrine dysfunctions and digestive disturbances were the most frequent. Side effects were revealed within the first two months after administration of valproats. Only in 13.2% of cases the treatment and to be stopped at the expense of severeness of side effects. Barbiturates caused side effects in 39.6% of cases. Toxic damage of CNS was the most significant. Hyperkinetic syndrome with lack of attention was observed 37.9% of cases. Succinimides caused side effects in 37.9% of cases. Toxic damage of CNS was the most frequent--in 22.4% of cases, digestive disturbances was in 15.5% of cases. There are no really effective means for correction of above mentioned side effects.

Adolescent↗

Ictal patterns in generalized epilepsy.

Ictal EEG may be of great benefit in facilitating accurate classification of the underlying seizure disorder in some patients and thus guiding further investigation and management. Ictal recordings in patients with generalized epilepsies are protean in their manifestations and yet may have considerable overlap. Classification is only possible through careful synthesis of all available clinical and electrophysiological data. Although the underlying pathophysiological mechanisms of the generalized epilepsies remain uncertain, evidence from EEG recordings tends to support Gloor's concept of corticoreticular epilepsy.

Cerebral Cortex↗

Increase in enkephalin-like immunoreactivity in hippocampi of adults with generalized epilepsy.

The changes of opioid peptide reactivity in seizure activity have been well studied in animals. Increased enkephalin and dynorphin immunoreactivity in the hippocampi of animals are interpreted as the result of seizure induced mossy fibre sprouting. We studied the hippocampi of six patients with a history of long-standing grand mal seizures and six age-matched control patients with no history of epilepsy or neurologic disease, using frozen sections which were immunostained with antibodies against Leu-enkephalin and Met-enkephalin. The staining intensity in the CA3, CA4 and internal molecular layer of the dentate fascia in each case was quantified using optical densitometry image analysis. The CA3 and CA4 of the epileptic hippocampi showed highly significant increase in Leu-enkephalin-like immunoreactivity compared to the controls (P < 0.005) while the inner molecular layer showed only significant increase (P < 0.05). Met-Enkephalin-like immunoreactivity was only significantly increased in CA4 of the epileptic hippocampi (P < 0.05).

Adult↗

A family of generalized epilepsy with febrile seizures plus type 2-a new missense mutation of SCN1A found in the pedigree of several patients with complex febrile seizures.

We report a family with complex febrile seizures (FS). The proband is a 15-year-old boy with seizures that persisted beyond 6 years of age. His father, aunt, and cousin also have the histories of FS until 8, 9, and 8 years old, respectively. A base substitution 5569G-->T of voltage-gated sodium channel alpha-1 subunit gene was found in DNA derived from the affected members of this family.

DNA Mutational Analysis↗

Mutations linked to generalized epilepsy in humans reduce GABA(A) receptor current.

The first mutations of the GABA(A) receptor channel linked to familial epilepsy in humans were reported in the gamma2L subunit. When expressed in Xenopus oocytes, the gamma2 subunit R43Q mutation abolished current enhancement by the benzodiazepine, diazepam, and the gamma2 subunit K289M mutation decreased current amplitudes. In this study, single channel recording and concentration jump techniques were used to evaluate the effects of these mutations on GABA(A) receptor currents from receptors expressed in human embryonic kidney cells. When co-expressed with alpha1 and beta3 subunits, the mutated gamma2 subunits did not alter current activation rates or rates or extent of desensitization during prolonged (400 ms) GABA application (1 mM). Deactivation following brief (5 ms) or prolonged (400 ms) GABA application was accelerated for the K289M, but not the R43Q mutation. Single channel analysis showed shorter mean open duration, suggesting that the faster deactivation was likely caused by altered gating efficacy. Interestingly, the R43Q mutation did not alter diazepam potentiation. However, significantly smaller current amplitudes were observed that were not explained by decreased single channel conductance or open time, suggesting this mutation resulted in reduced surface expression of functional receptors. These two gamma mutations likely produce disinhibition and familial epilepsy by distinct mechanisms, suggesting that maintenance of normal neuronal inhibition depends on both the peak amplitude of IPSCs and their time course.

Amino Acids, Basic↗