Epilepsia

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Online ISSN: 0013-9580
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Article
SGB-017 (ADCI) is a novel anticonvulsant that blocks both voltage-activated sodium channels and N-methyl-D-aspartate (NMDA)-receptor-gated channels. Results by Rogawski et al. suggested that SGB-017 produces its anticonvulsant action primarily by inhibition of NMDA-receptor channels. However, SGB-017 is effective in several animal models of epilepsy that are unresponsive to NMDA antagonists. These results indicate that block of NMDA-receptor channels is not the only mechanism contributing to its anticonvulsant activity. Thus the effects of SGB-017 on neuronal sodium channels were investigated. Whole cell voltage-clamp techniques were used to record sodium currents in freshly dissociated rat superior cervical ganglion (SCG) and hippocampal neurons and cultured human NT2 neurons. The effects of SGB-017 on the amplitude of sodium currents, elicited by a depolarizing pulse to 0 mV from different holding potentials, were measured and compared with those of carbamazepine (CBZ). SGB-017 inhibited sodium currents in rat SCG and hippocampal neurons with a similar potency to CBZ. Like CBZ, the inhibition of sodium channels by SGB-017 was voltage dependent. Its median inhibitory concentration (IC50) for inhibition of sodium channels at depolarized holding potentials is similar to that for its inhibition of NMDA receptor channels. In human hNT2 neurons, SGB-017 was more potent than CBZ at inhibiting sodium currents. SGB-017 produces its anticonvulsant activity by blocking both sodium- and NMDA-receptor channels in a voltage- and use-dependent manner. The combination of these two mechanisms of action makes SGB-017 an effective AED in several different animal models of epilepsy.
 
Article
Purpose: There is strong evidence of an association between the presence of the human leukocyte antigen (HLA)-B*15:02 and two severe adverse drug reactions-Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)-in patients taking carbamazepine (CBZ), a common treatment for patients with epilepsy and neuropathic pain. As a result, there are calls for all patients that are due to undergo CBZ therapy to be screened for this genetic marker before commencing their therapy. This study aims to determine the value for money of HLA-B*15:02 screening compared to the following: (1) administering CBZ therapy without conducting patient screening, and (2) not prescribing CBZ but alternative drugs that are less likely to result in severe reactions, but that come at a higher cost. Method: An economic evaluation was carried out by using a decision tree and Markov models to examine the cost-utility of providing HLA-B*15:02 screening for all patients with either newly diagnosed epilepsy or neuropathic pain in the Thai setting. All transitional probabilities were derived from the national and international literature. The majority of the data on direct medical care costs were collected from 10 community, provincial, and regional hospitals throughout Thailand. Direct non-medical cost and health-related quality of life (HRQoL) data were obtained from interviews that were conducted with 33 patients, some of whom had experienced severe drug reactions. Key findings: The incremental cost-effectiveness ratio (ICER) of adopting a universal HLA-B*15:02 screening policy was estimated at 222,000 Thai baht, THB/quality-adjusted life year (QALY) gained for epilepsy patients and 130,000 THB/QALY gained for patients with neuropathic pain. Furthermore, we found that 343 patients need to be tested for HLA-B*15:02 allele to prevent one case of SJS/TEN. Significance: Universal HLA-B*15:02 screening represents good value for the money in terms of preventing SJS/TEN in CBZ-treated patients with neuropathic pain at the Thai ceiling ratio of 120,000 THB/QALY gained. However, the prevalence of CBZ-induced SJS/TEN in the Thai population and the positive predictive value (PPV) are major factors that influence the cost-effectiveness of HLA-B*15:02 screening. Therefore, an active surveillance system to make a more accurate assessment of the prevalence CBZ-induced SJS/TEN in the Thai population would enhance the generalizability of the results.
 
Article
Newly designed antiepileptic drugs (AEDs) are being evaluated for their efficacy in preventing seizures and for their toxic profiles. We investigated and compared the toxic effects of two dibenz[b,f]azepine derivatives with anticonvulsant activity, 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide (BIA2-024) and (S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f] azepine-5-carboxamide (BIA2-093), with the structurally related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), both in current use for the treatment of epilepsy. Primary rat hippocampal neurons were used to evaluate neuronal morphology and biochemical changes induced by the AEDs used in this study. Immunocytochemical staining against MAP-2 was used to evaluate neuronal morphology. Reactive oxygen species (ROS) and changes in mitochondrial membrane potential (Psim) were measured by fluorescence techniques. Intracellular adenosine triphosphate (ATP) levels were quantified by high-performance liquid chromatography (HPLC). Hippocampal neurons treated for 24 h with CBZ or OXC (300 microM) showed degeneration and swelling of neurites, but this effect was not observed in neurons treated with BIA 2-024 or BIA 2-093 (300 microM). ROS production also was increased in neurons treated with OXC, but not in neurons treated with the other AEDs. ATP levels were significantly decreased only in neurons treated with OXC, although the energy charge was not altered. Furthermore, OXC led to a decrease of Psim. In all parameters assayed, OXC was more toxic than the other AEDs used. Because the new putative AEDs have previously been shown to have an efficacy in preventing seizures similar to that of CBZ and OXC, and are less toxic to neuronal cells, they may be considered as alternatives to the current available therapies for the treatment of epilepsy.
 
Article
W-554 (ADD 03055, 2-phenyl-1,3-propanediol dicarbamate) has broad-spectrum antiepileptic activity in animal models of epilepsy. We evaluated its pharmacokinetics and toxicity as an adjunctive medication in eight adult male patients with uncontrolled seizures, treated with phenytoin (n = 4) or carbamazepine (n = 4). After a single 200-mg dose, peak W-554 serum levels of 2.65-4.10 mg/L were achieved in 1-4 h. Half-lives were 11.2-16.1 h and clearance varied from 34.2-64.6 ml/h X kg. The apparent volume of distribution was 0.726-1.046 L/kg. Chronic dosing at 400, 800, 1,200, and 1,600 mg/day resulted in median steady-state trough levels of 5.1, 10.2, 14.6, and 20.3 mg/L. A second kinetic study at the end of chronic dosing indicated no change in volume of distribution, decreased clearance, and increased half-life, compared with single dose data. Urinary excretion of unchanged drug was 13.8-28.6% of the dose. Only one subject had toxicity (mild blurred vision and tremor) possibly attributable to W-554. Seizure control was improved in six of eight subjects, and seizures were less severe in three, while on W-554. Addition of W-554 resulted in increases in serum phenytoin levels, and small decreases in serum carbamazepine levels.
 
Article
BIA 2-093 [(S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide] is endowed with an anticonvulsant potency similar to that of carbamazepine (CBZ), but produces less cognitive and motor impairment. This study evaluated whether voltage-gated sodium channels (VGSCs) are a primary locus for the action of BIA 2-093. We used the whole-cell voltage-clamp technique in the mouse neuroblastoma cell line N1E-115 to investigate the effects of BIA 2-093 and CBZ on VGSCs, displacement of [3H]-batrachotoxinin A 20-alpha-benzoate ([3H]-BTX), and [3H]-saxitoxin to define their relative potency to bind to rat brain sodium channels, and inhibition of uptake of 22Na by rat brain cortical synaptosomes stimulated by veratridine as a measure of sodium entry. The inhibitory potencies of BIA 2-093 and CBZ increased as the holding potential was made less negative (-100, -90, -80, and -70 mV) with median inhibitory concentration (IC50) values (in microM) of, respectively, 4,337, 618, 238, and 139 for BIA 2-093, and 1,506, 594, 194, and 101 for CBZ. BIA 2-093 displayed a similar potency in displacing [3H]-BTX (IC50 values, 222 vs. 361 microM; p > 0.05) and inhibiting the uptake of 22Na (IC50 values, 36 vs. 138 microM; p > 0.05). Both drugs failed to displace [3H]-saxitoxin in concentrations up to 300 microM. BIA 2-093, like CBZ, inhibits sodium currents in a voltage-dependent way by an interaction predominantly with the inactivated state of the channel and interacts with neurotoxin receptor site 2, but not with receptor site 1. BIA 2-093 displayed a potency blocking VGSCs similar to that of CBZ.
 
Article
With the development of intensive care, the survival of extremely low-birthweight (ELBW) infants (<1,000 g) has greatly improved. The aim of our study was to report the incidence of epilepsy after a follow-up of >7 years in a population of ELBW children, born in central and southern Sardinia between 1991 and 2000. We analyzed data of 104 children. All infants had had serial cranial ultrasound echography (CUE) in the neonatal period and some also had magnetic resonance imaging (MRI). At last follow-up we evaluated the occurrence of epilepsy through a review of clinical charts and a structured telephone interview. In 11 (10.6%) of 104 of children we observed febrile seizures (FS). Epilepsy occurred in 9 (8.6%) of 104 ELBW children, and in these patients a frequent positive family history for epilepsy and/or FS was present. In four epilepsy patients CUE was highly pathologic, showing intraventricular hemorrhage (IVH) of grade IV and in two mildly abnormal (IVH of grade I-II). In three additional children with normal neonatal ultrasound scan, a later magnetic resonance imaging (MRI) study revealed lesions related to neonatal insult. In our ELBW population, epilepsy had an incidence clearly superior to that expected in infancy (8.6% vs. 0.6-0.8%). A frequent positive familiar history for epilepsy and/or FS suggests that a genetic predisposition may also play a role. Subjects with highly abnormal CUE are a subgroup with high risk for seizures; however, epilepsy can occur even with normal CUE.
 
Article
The present prospective study undertaken in a specialized neurological center of a developing country deals with 1,000 epileptic patients classified in accordance with the International Classification. Eighty-one percent of the patients could be classified, with a lower incidence in the younger age group. Partial epilepsy was found to be far more common than generalized epilepsy (80% versus 20%). Primary generalized epilepsy was seen in 15% and secondary generalized in 5%. Partial epilepsy with elementary symptomatology was seen in 58% and complex symptomatology in 7%. Secondarily generalized seizures were seen in the remaining 15%. Primary generalized epilepsy and partial epilepsy with complex symptomatology were more common in adults. Secondary generalized epilepsy and partial epilepsy with secondarily generalized seizures were more common in children. Partial epilepsy with elementary symptomatology, however, did not vary significantly with age. The higher incidence of partial epilepsy in our patients, compared to the West, could be due to greater frequency of CNS infections and birth injuries, which are common childhood hazards in the developing countries.
 
Article
A new anticonvulsant compound, zonisamide (1,2 benzisoxazole-methanesulfonamide), was studied in 10 adults with medically refractory partial seizures. Following a single oral dose of 400 mg, peak plasma levels occurred an average of 2.8 h after dosing, and the mean clearance from plasma was 2.34 L/h. Whole blood concentrations were higher than plasma concentrations because of red blood cell binding. Steady-state plasma concentrations were higher than predicted from a linear kinetic model. In most patients, seizure frequency was reduced after zonisamide was substituted for a standard antiepileptic drug. Dose-related reversible side effects in the central nervous and gastrointestinal systems were observed. Most patients tolerated doses between 5.2 and 12.5 mg/kg/day.
 
Article
The relationships between plasma concentrations of diphenylhydantoin (DPH), phenobarbital (PB), carbamazepine (CBZ), and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant and neurotoxic effects were studied in various species of animals. Anticonvulsant activities of test drugs were examined by the maximal electroshock seizure (MES) test. Neurotoxicities were determined by the rotorod performance test in mice and rats and by behavioral observations in rabbits, dogs, and monkeys. It was demonstrated that both the anticonvulsant effects and the neurotoxic effects of the drugs tested were more closely correlated with their plasma concentrations than with the dosages administered. There was a critical plasma concentration for each drug to show an anticonvulsant effect or to cause a neurotoxic effect in an individual animal. The critical plasma concentrations for anticonvulsant and neurotoxic effects of each drug were relatively constant among different species, with the exception of DPH in rabbits, which had twice the value in other species. The therapeutic ranges of plasma concentrations of DPH, PB, and CBZ determined in various species of animals coincided well with those recommended clinically. AD-810 was found to be effective against MES without signs of neurological toxicity in the ranges of plasma concentrations of 9.8 to 74.0, 10.8 to 95.0, 9.6 to 117.0, and 12.6 to 96.2 microgram/ml in mice, rats, rabbits, and dogs, respectively. These results seem to suggest that AD-810 may be effective clinically at plasma concentrations above 10 microgram/ml, with a therapeutic range up to 70 microgram/ml, which is much wider than the therapeutic ranges of DPH (10--20 microgram/ml), PB (10--30 microgram/ml), and CBZ (4--10 microgram/ml).
 
Article
Acetone, one of the principal ketone bodies elevated during treatment with the ketogenic diet, exhibits anticonvulsant properties that may contribute to the seizure protection conferred by the diet. The anticonvulsant mechanism of acetone is unknown, but it is metabolized to several bioactive substances that could play a role. Acetone and its major metabolites-acetol, 1,2-propanediol, methylglyoxal, and pyruvic acid-were assessed for anticonvulsant activity in two mouse seizure models. Various doses of the substances administered intraperitoneally were characterized for their ability to elevate the threshold for clonic seizures induced by intravenous infusion of pentylenetetrazol (PTZ) and for protection against tonic seizures induced by subcutaneous bolus administration of 4-aminopyridine (4-AP). The inverted-screen test was used to assess acute neurological toxicity. Acetone (1-32 mmol/kg, i.p.), in a dose-dependent fashion, elevated the PTZ threshold and conferred protection against 4-AP seizures (ED(50), 26.3 mmol/kg). Effective doses of acetone (10-32 mmol/kg) did not cause motor impairment in the inverted-screen test (TD(50), 45.7 mmol/kg). In doses 10-fold greater than the minimally effective dose of acetone (3.2 mmol/kg), the metabolites acetol, 1,2-propanediol, and pyruvic acid were inactive in the PTZ model. At higher doses that produced motor impairment, acetol and 1,2-propanediol (but not pyruvic acid) did elevate the PTZ threshold. Methylglyoxal had both proconvulsant and anticonvulsant actions, and had substantial toxicity, producing respiratory distress, motor impairment, and death. None of the acetone metabolites protected against 4-AP seizures. This study confirms the broad-spectrum anticonvulsant properties of acetone and indicates that the seizure protection conferred is unlikely to result from its major metabolic products.
 
Article
ADD 17014[1-(4-chlorophenyl)-5-(4-pyridyl) delta 2-1,2,3-triazoline], is a representative member of a hitherto unknown, structurally novel family of anticonvulsant agents. The anticonvulsant profile of ADD 17014 following intraperitoneal (i.p.) and oral administration in mice and rats was evaluated using a battery of well-standardized anticonvulsant tests and compared with phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), and valproate (VPA). The results indicate that ADD 17014 is effective in nontoxic i.p. doses in mice by the maximal electroshock seizure (MES), Metrazol (subcutaneous, s.c. Met), bicuculline (s.c. Bic) and picrotoxin (s.c. Pic) tests, but ineffective against strychnine-induced seizures; it is also effective after nontoxic oral doses in both mice and rats by the MES and s.c. Met tests. Protective indices (PI = TD50/ED50), calculated from i.p. data in mice, were highest for ADD 17014 by the s.c. Met (26.02) and s.c. Bic (93.93) tests; the PIs, after oral administration in mice and rats, were equal to or higher than those of the prototype agents. In vitro receptor binding studies of ADD 17014 and potential metabolites indicated no significant inhibitory activity except for the beta-amino alcohol, which displaced almost 93% of [3H]glutamate from the glutamate receptors, suggesting that ADD 17014 may be functioning as a prodrug and an excitatory amino acid antagonist. The overall results indicate that ADD 17014 is a relatively nontoxic agent that more closely resembles PB and VPA, with a broad and unique spectrum of anticonvulsant activity.
 
Article
Felbamate (FBM) pharmacokinetic parameters, safety and tolerability in the dose range of 1,200-6,000 mg/day were assessed in two open-label studies with similar designs. In study A, newly diagnosed subjects with epilepsy receiving FBM monotherapy at a starting dose of 1,200 mg/day (400 mg/three times daily, t.i.d.) and increased 1,200 mg/day, if tolerated, at 14-day intervals to 3,600 mg/day were investigated. In study B, epilepsy subjects with prior FBM monotherapy exposure received ascending FBM doses in five consecutive 14-day periods with a starting dose of 3,600 mg/day (1,200 mg t.i.d.) FBM. In each successive period, if FBM was well tolerated, the dose was increased by 600 mg/day to a maximum of 6,000 mg/day (2,000 mg t.i.d.). The pharmacokinetic parameter estimates maximum observed concentration (Cmax), area under the concentration-time curve (AUCtau) Ctrough, and Cav showed a linear dependence to dose above the 1,200-6,000 mg/day FBM dose range (F-tests; p < 0.0001) with apparent clearance (Cl/kg) and Tmax (time to Cmax) independent of dose. When AUCtau, Cmax and Ctrough were adjusted for dose, there were no significant differences between the dosing periods. The data establish that plasma concentrations of FBM are linear with respect to dose to 6,000 mg/day. In addition, FBM was safely administered at these doses for periods as long as 14 days to epileptic subjects with prior exposure to FBM. FBM-naive subjects appeared to report more adverse experiences (generally of mild to moderate severity) than did subjects with prior FBM exposure.
 
Article
The 1981 International Classification of Epileptic Seizures (ICES) was used to study the distribution of seizure types in 1,250 patients attending an Epilepsy Clinic in Sri Lanka. Based on seizure symptomatology 94.6% of the cases could be classified, and by adding the routine interictal EEG findings the percentage of classifiable seizures increased to 97%. Partial seizures (73.8% cases) were three times as common as generalized seizures (23.3% cases). Of the partial seizures, simple partial seizures (SPS) accounted for only 0.4% cases, and complex partial seizures (CPS) for 8.8%, whereas partial seizures secondarily generalized (PSGS) accounted for 64.6%. PSGS had simple onset in 12.5% and complex onset in 34.8% of cases. Myoclonic seizures were the commonest of the generalized seizures, accounting for 14.6% of all cases. Tonic-clonic seizures accounted for 7.4% of cases; absence seizures accounted for only 1.3%. The study showed the 1981 ICES to be relevant and applicable in a clinical setting with limited investigatory facilities. Difficulties encountered with regard to certain subcategories could be overcome with minor modifications which made the classification operative. Routine EEG confirmed the diagnosis in a significant number of cases but changed the diagnosis in only a few, confirming that a good standardized questionnaire is the key instrument for classifying epileptic seizures.
 
Article
The 1,4-benzodiazepines have a recognised place in the treatment of epilepsy. Thus, diazepam, clonazepam, and, more recently, lorazepam are used intravenously for status epilepticus. Oral clonazepam has proved useful as adjunctive therapy in generalised absence seizures, myoclonic seizures, and partial seizures. Oral nitrazepam is well known for its use in the treatment of infantile spasms with hypsarrhythmia and in the myoclonic epilepsies of childhood. Clobazam, a 1,5-benzodiazepine, has been shown in controlled studies to be superior to placebo, and in open studies it has produced an overall reduction in seizure frequency of 65%. The main indication for its use is as oral adjunctive therapy in refractory epilepsy. It has a rapid onset of action, is well tolerated, and many studies indicate it has a psychotropic action and produces minimal or no cognitive impairment. The most common side-effect reported was sedation, while the overall incidence of side-effects in the open studies was 38%. In all studies reviewed, 4% of patients had to be withdrawn because of adverse reactions. In general, there are no significant interactions with other anticonvulsants, although changes in a few have been described. Withdrawal seizures can occur and require gradual termination of clobazam. The main disadvantage of clobazam is the development of tolerance, which develops in approximately 36% of patients, and there is no way of predicting in which patients or when the phenomenon is likely to occur. A dose of 20 to 30 mg at night is recommended, possibly commencing at 10 mg.
 
Article
We will present data from the comparison between four tests in mice of 10 1,4-benzodiazepines and one 1,5-benzodiazepine (clobazam). The tests used were: the "4 plates test" of anxiolytic activity; the electroshock test to determine the anticonvulsive effects; actimetry to predict the sedative effect on motricity; and traction test to predict the myorelaxant effect. The latter two tests have been suggested to be predictive of side-effects that damage psychomotor efficiency in human patients. A comparison of ED50s determined from the predictive tests of the therapeutic effect and those of the side-effects led to the calculation of ratios considered to be predictive of the safety margin. A classification according to this margin shows the advantages of the 1,5-benzodiazepine compared with the 1,4-benzodiazepines. Despite the caution needed in the extrapolation of the results from animals to humans, this work stresses the interesting place that the 1,5-benzodiazepine seem to hold as anticonvulsant in clinical practice.
 
Article
Fructose-1,6-diphosphate (FDP), an intracellular metabolite of glucose, has anticonvulsant activity in several models of acute seizures in laboratory animals. The anticonvulsant effect of FDP is most likely due to a direct effect since intraperitoneal and oral administration results in significant increases in brain levels. A number of mechanisms have been proposed for this action of FDP. One possibility is that peripheral administration of FDP results in changes in brain metabolism that are anticonvulsant. Glucose can be metabolized through the glycolytic or pentose phosphate pathway. There is evidence that the pentose phosphate pathway is more active in the brain than in other tissues, and that, in the presence of elevated levels of FDP, the majority of glucose is metabolized by the pentose phosphate pathway. The pentose phosphate pathway generates NADPH, which is used to reduce glutathione. The reduced form of endogenous glutathione has been shown to have anticonvulsant activity. Taken together, the data suggest a hypothesis that exogenously administered FDP gets into the brain and astrocytes where it increases the flux of glucose through the pentose phosphate pathway, generating additional NADPH for the reduction of glutathione.
 
Article
We evaluated prospectively the occurrence of seizures within 15 days of a first stroke or transient ischemic episode in 1,640 patients to study relation between seizures and type of stroke. Seizures occurred in 90 patients (5.4%), including 36 (4.4%) of 814 with infarct owing to atheroma, 21 (16.6%) of 126 with infarct owing to cardiogenic embolus, 3 (1%) of 273 owing to lacunar infarct, 5 (1.9%) of 259 owing to transient ischemic attack (TIA), 21 (16.2%) of 129 owing to supratentorial hematoma, and 4 (16.6%) of 24 owing to subarachnoid hemorrhage. Thirteen (14.6%) of 89 subcortical infarcts were associated with seizures. Seizures were the initial sign of stroke in 80 (89%) of 90 cases and were usually single and partial. Seizure symptoms were most often motor, sensory, or visual.
 
Article
This study utilizes ciinicai and anamnestic data concerning epileptic subjects (males and females) of ages ranging between 1 month and 21 years. These patients were treated in the Neurology Department of the University of Turin, during the following periods: 1948–1958, 1960–1964, 1970–1974. All possible etiologies of epilepsy were included in the study except those of genetic and tumoral origin. The clinic data, including 68,222 EEG recordings, were considered. An initial sample of 4,947 subjects, aged from 1 month to 21 years, suffering from epileptic seizures was selected, and a final sample of 1,785 cases, with complete clinical and anamnestic data, was analyzed. The results identify an etiological factor in 44% of the cases. The remaining 56% do not show any probable etiology. The distribution of etiologic factors is as follows: (1) birth injuries including neonatal hemorrhagic and hypoxic encephalopathies, prematurity, and kernicterus, 40.66%; (2) postimmuniza-tion and postinfectious encephalitides, 10.49%; (3) encephalitides and meningoencephalitides of various etiology, 16.75%; (4) craniocerebral trauma, 27.88%; (5) CNS malformations and congenital metabolic encephalopathies, 4.22%. The most interesting finding was the failure to identify any probable etiology in 70% of the subjects with partial epilepsy with complex symptomatology, and in 44% of subjects with generalized seizures (excluding petit mal). These findings can provide a preliminary data base for programs of prevention and for further investigations of the etiology of epilepsy. Cette étude utilise les données cliniques et anamnes-tiques issues d'une eatude de sujets éapileptiques, des deux sexes compris entre l'âge de un mois à 21 ans. Les patients ont été traites dans le Departmement de Neurologie de l'Université de Turin, péndant les periodes suivantes de: 1948 à 1958, de 1960 à 1964, de 1970 à 1974. Tous les facteurs ètiologiques possibles ont été inclus à l'exception des facteurs génétiques et tumoraux. On a considéré les données cliniques y compris les 68,222 tracés EEG. Un premier échantil-lon 4,947 patients avec eapilepsie, âgés entre un mois et 21 ans, a éte sélectionne et on a analysé un dernier échantillon de 1,785 cas avec les données cliniques est anamnestiques complètes. Les résultats indiquent la preasence de facteurs étiologiques dans 44% des cas, les restants 56% n'ayant pas d'étiologie evidente. La distribution des facteurs etiologiques est la suivante: (1) trauma a la naissance, comprenant des enceaphalopathies hémorragiques néonatales, et hypoxiques, prématurite et dysmaturitea, et ictere: 40.66%; (2) encéphalites post-vaccinales et post-infectieuses: 10.49%; (3) encéphalites et meningoencephalites de differentes etiologies: 16.75%; (4) trauma cranio-cérébral: 27.88%; (5) malformation du SNC et encéphalopathies meataboliques: 4.22%. La donnée la plus intéressante àété l'impossibilite de retrouver une etiologie probable dans 70% des sujets avec une epilepsie partielle a symptomatologie complexe, et chez 56% des sujets avec crises gen6ralis6es (a l'exclusion du petit mal). Ces donnees peuvent constituer une etape preliminare pour des programmes de prévention et des investigations ultérieures sur L'eatiologie de L'eapilepsie. Este estudio utiliza la información clinica referente a epilépticos (varones y hembras) de edades comprendidas desde 1 mes y 21 anos. Estos enfermos han sido tratados en el Departamento de Neurologia de la Universidad de Turin en los aňos 1948–1958, 1960–1964, 1970–1974. Se incluyeron todas las etiologias de epilepsia excepto las geaneticas o tumor-ales. La información clinica, incluyendo 68,222 EEGs fue considerada. Se seleccionaron una muestra inicial de 4,947 epilépticos de edades comprendidas entre 1 mes y 21 aňos y otra muestra final de 1,785 casos con imformación clinica completa. En el 44% de los casos se supuso un factor etiológico y en el restante 56% no se identificó etiología alguna. La distribución de los factores etiológicos es: (1) Un 40.66% de lesiones de parto incluyendo hemorragia neonatal, encefalopatl'a hipóxica, prematuridad y kernicterus; (2) un 10.49% de encefalopatías post-immunización y post-infecciosas; (3) un 16.75% de encefalitis y meningoencefalitis de varias etiologias; (4) un 27.88% de trauma craneo-cerebral; y (5) un 4.22% de malformaciones del SNC y encefalopatias metabolicas congdnitas. El hallazgo más interesante consistió en la imposibilidad de encontraruna probable etiologia en un 70% en los enfermos con epilepsia parcial con sintomatologia compleja y en un 56% de las convulsiones generalizadas (excluyendo petit mal). Esta informaci6n puede servir de base preliminar para programas de prevencibn e investigacibnes futuras de las etiologias de la epilepsia. Diese Arbeit beniitzt klinische und anamnestische Daten die Epileptiker (männlich und weiblich) im Alter von einem Monat bis zu 21 Jahren betrachten. Diese Patienten wurden in der neurologischen Abtei-Iung der Universitat Turin wahrend der folgenden Perioden behandelt 1948–1958, 1960–1964, 1970–1974. Alle möglichen Etiologien der Epilepsie wurden, ausser jener mit genetischen und tumorischen Ursprung, in die Arbeit eingeschlossen. Die klinischen Daten von 68,222 EEG Registrationen wurden in Betracht gezogen. Es wurde eine Gruppe von 4,947 Epileptikern im Alter von einem Monat bis zu 21 Jahren herausgenommen. Davon wurde eine andere Gruppe von 1,785 Fälle, deren klinische und anamnestische Daten vollständig waren, isoliert. Das Resultat zeigt einen etiologischen Faktor in 44% der Fälle auf. Die restlichen 56% zeigen keine Etiologie. Die Vertei-lung von der etiologischen Faktoren ist folgende: (1) Geburtschaden einschliesslich, Geburtsblutung und hypoxische Enzephalopatie, Früh-und Spätgeburt und Kernicterus: 40.66%; (2) Enzephalopatien nach Impfung und nach Infection: 10.49%; (3) Enzephalopatien und Meningoenzephalopatien von verschie-dener Etiologie: 16.75%; (4) Gehirntrauma: 27.88%; (5) ZNS Missbildungen und angeborene metabolische Enzephalopatien: 4.22%. Die interessanteste Beob-achtung war keine Etiologie in 70% der Fälle mit partialer Epilepsie mit komplexer Symptomatologie und für in der 44% der Fälle mit generalisierten Krisen (einschliesslich Petit Mal), zu finden. Diese Beobachtung kann einen Anfang für ein Vorbeugungs-programm und für weitere Forschlungen der epilep-tischen Etiologie bilden.
 
Article
Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI) are associated with sodium channel α-subunit type-1 gene (SCN1A) mutations. Febrile seizures and partial seizures occur in both GEFS+ and SMEI; sporadic onset and seizure aggravation by antiepileptic drugs (AEDs) are features of SMEI. We thus searched gene mutations in isolated cases of partial epilepsy with antecedent FS (PEFS+) that showed seizure aggravations by AEDs. Genomic DNA from four patients was screened for mutations in SCN1A, SCN2A, SCN1B, and GABRG2 using denaturing high-performance liquid chromatography (dHPLC) and sequencing. Whole-cell patch clamp analysis was used to characterize biophysical properties of two newly defined mutants of Na(v) 1.1 in tsA201 cells. Two heterozygous de novo mutations of SCN1A (R946H and F1765L) were detected, which were proven to cause loss of function of Na(v) 1.1. When the functional defects of mutants reported previously are compared, it is found that all mutants from PEFS+ have features of loss of function, whereas GEFS+ shows mild dysfunction excluding loss of function, coincident with mild clinical manifestations. PEFS+ is similar to SMEI clinically with possible AED-induced seizure aggravation and biophysiologically with features of loss of function, and different from SMEI by missense mutation without changes in hydrophobicity or polarity of the residues. Isolated milder PEFS+ may associate with SCN1A mutations and loss of function of Na(v) 1.1, which may be the basis of seizure aggravation by sodium channel-blocking AEDs. This study characterized phenotypes biologically, which may be helpful in understanding the pathophysiologic basis, and further in management of the disease.
 
Article
Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) differ in their clinical severity and prognosis even though mutations of the Na(v) 1.1 sodium channel are responsible for both disorders. We compared the electrophysiologic properties of two mutant Na(v) 1.1 channels characterized by distinct amino acid substitutions at the same residue position: GEFS+ (A1685V) and SMEI (A1685D). Both the mutants showed complete loss of function when expressed alone. However, the function of A1685V can be partly rescued by the β(1) subunit, consistently with a folding defect, whereas that of A1685D was not rescued. These electrophysiologic differences are consistent with the divergence in clinical severity between GEFS+ and SMEI.
 
Article
The transient and the persistent Na(+) current play a distinct role in neuronal excitability. Several antiepileptic drugs (AEDs) modulate the transient Na(+) current and block the persistent Na(+) current; both effects contribute to their antiepileptic properties. The interactions of the AEDs carbamazepine (CBZ) and topiramate (TPM) with the persistent and transient Na(+) current were investigated. HEK293 cells stably expressing the alpha-subunit of the Na(+) channel Na(V)1.3 were used to record Na(+) currents under voltage-clamp by using the patch-clamp technique in whole-cell configuration and to investigate the effects of CBZ and TPM. The persistent Na(+) current was present in all cells and constituted 10.3 +/- 3.8% of the total current. CBZ partially blocked the persistent Na(+) current in a concentration-dependent manner [median effective concentration (EC(50)), 16 +/- 4 microM]. CBZ also shifted the steady-state inactivation of the transient Na(+) current to negative potentials (EC(50), 14 +/- 11 microM). TPM partially blocked the persistent Na(+) current with a much higher affinity (EC(50), 61 +/- 37 nM) than it affected the steady-state inactivation of the transient Na(+) current (EC(50), 3.2 +/- 1.8 microM). For the latter effect, TPM was at most half as effective as CBZ. The persistent Na(+) current flowing through the alpha-subunit of the Na(V)1.3 channel is partially blocked by CBZ at about the same therapeutic concentrations at which it modulates the transient Na(+) current, adding a distinct aspect to its anticonvulsant profile. The TPM-induced partial block of the persistent Na(+) current, already effective at low concentrations, could be the dominant action of this drug on the Na(+) current.
 
Article
Hippocampal volumetry using magnetic resonance imaging (MRI) is a common clinical study in epilepsy patients. Most clinical MR scans operate at 1.5 tesla (T); however, there is increasing use of scanners of a higher field strength. We analyzed whether control data of hippocampal volumes can be used across different field-strength scanners. We studied eight adult healthy controls twice at both 1.5 and 3 T. Bilateral hippocampal volumes were measured by manual outlining. Measurement error was analyzed based on the variability between two measurements at the same field strength, and intrascanner variability was analyzed based on the difference between measurements obtained at 1.5 and at 3 T. The measurement error was 4.0% (+/-3.1) at 1.5 T, and 3.4% (+/-2.5) at 3 T. The intrascanner variability between measurements at 1.5 and at 3 T was 6% (+/-3.9). The intrascanner variability was not different from the measurement error. Control hippocampal volume measurements obtained at 1.5 and at 3 T were not different.
 
Article
To examine the utility of fluid-attenuated inversion recovery (FLAIR) imaging and three-dimensional short tau inversion recovery (3DSTIR) imaging using a 3-Tesla (3-T) magnetic resonance (MR) imager in the preoperative evaluation of hippocampal sclerosis (HS). Thirteen patients with intractable medial temporal lobe epilepsy who underwent anterior temporal lobectomy with amygdalohippocampectomy were studied. MR images were obtained twice, once with a 1.5-T imager and once with a 3-T imager. The extent of hippocampal resection was determined according to the findings on intraoperative hippocampal electroencephalography. We compared the diagnostic utility of FLAIR for HS between 1.5-T and 3-T MR imaging. In addition, the relationship between the existence of hypointense areas in the hippocampus (HIAs) on 3DSTIR and the severity of HS pathology (as evaluated using Watson's grading) was examined. The relationship between postoperative seizure outcome and postoperatively remaining HIAs was also evaluated. There was no difference between FLAIR images from 1.5-T and 3-T imaging in the detection of HS. With 3DSTIR, an HIA in unilateral hippocampus was observed in all of the nine cases exhibiting severe pathologic HS (Watson's grade III-V). In seven cases with HIA, the extent of hippocampal resection was smaller than the HIAs. Every case showed good seizure outcome (Engel's class I and II). In the diagnosis of HS, no substantial difference was noted between 1.5-T and 3-T MR imaging. However, 3DSTIR using 3-T MR imaging is useful for evaluating the extent of HS, although postoperative HS remnants are not correlated with surgical outcomes.
 
Article
Carbamazepine-10,11-epoxide (CBZ-OX) was determined in physiological solutions by means of EMIT carbamazepine reagent. It was recognized as 12 to 20% of the total amount, the cross-reaction being higher at lower CBZ-OX concentrations. A correction for CBZ-OX is necessary when one wants to correlate EMIT carbamazepine values with gas-liquid chromatography values. However, this correction is relevant only for body fluids other than plasma, since the unbound fraction of CBZ-OX would greatly influence the ultrafiltrate serum ratios.
 
Article
Total and free serum concentrations of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) at steady state were determined in 10 infants (ages 4-13 months), 10 preschool children (ages 3-5 years), and 11 school children (ages 7-11 years) receiving equivalent doses of CBZ alone. Free and total CBZ levels tended to increase with increasing age, while CBZ-E levels did not show any significant age dependency. As a result, CBZ-E/CBZ ratios were higher in infants and preschool children than in the older age group. The degree of plasma protein binding of CBZ and CBZ-E did not show any important differences among the various groups. These data provide evidence that, within a pediatric population, CBZ shows age-related dispositional changes which may be clinically important.
 
Article
The mechanism responsible for the valproate (VPA)-induced elevation of serum carbamazepine-10,11-epoxide (CBZ-E) levels was investigated in 6 normal subjects who received single oral doses of CBZ-E (100 mg) in a control session and during concurrent treatment with sodium VPA [500 mg twice daily (b.i.d)]. VPA caused a significant prolongation of CBZ-E terminal half-life (t 1/2 from 6.3 ± 1.2 to 9.0 ± 2.0 h, mean values ± SD) and decreased CBZ-E clearance (from 90.6 ± 18.8 to 63.2 ± 16.1 ml h-1 kg-1, mean values ± SD) without affecting CBZ-E apparent volume of distribution (from 0.82 ± 0.19 to 0.81 ± 0.24 l kg-1, mean values ± SD). These findings indicate that VPA impairs the elimination of CBZ-E, presumably by inhibiting its metabolism.
 
Article
Hourly salivary concentrations of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (EP) were studied during 2 consecutive days in a group of epileptic children receiving twice daily CBZ monotherapy either as the tablet or syrup formulation. Relatively large fluctuations were observed for both CBZ (mean, 57%; range, 32-100%) and EP (mean, 97%; range, 19-189%) during a dosage interval. However, concentrations of EP were generally much lower, approximately 34% of corresponding CBZ levels, and in absolute terms the concentration-time curves for EP appeared much less variable. Further evidence supporting extensive CBZ concentration fluctuations during the day was provided by an additional group of 30 epileptic children receiving CBZ monotherapy whose time of dosage was manipulated to achieve peak and trough concentrations during assessment with a psychomotor test battery. Changes in salivary CBZ concentrations within subjects ranged from 4 to 272% (median, 65%), excluding two atypical cases who showed greater than 10-fold increases in the expected high concentration. These results suggest that in children there is a substantial risk of error in the interpretation of CBZ concentrations from a single sample without consideration of the time of last dose. The implications of these findings for clinical treatment with regard to the appearance of side effects and changes in psychomotor function are discussed.
 
Relation between the oral dosages of oxcarbazepine (OXC; 600 to 2,400 mg/day) and the plasma concentrations of 10-OHCBZ and DiOH-CBZ in pharmacoresistant epilepsy patients. In nine adult pharmacoresistant patients (1–9; mean age, 38.8 ± 6 years; see Table 1), OXC was metabolized in plasma to the active metabolite 10-OHCBZ (solid squares) and to the inactive metabolite DiOH-CBZ (open dots). Therapeutic plasma Css (∼15 to 35 μg/ml) were measured in eight of nine adult patients. The relatively low blood concentration of the inactive metabolite Di-OHCBZ confirms that oxidation is a minor route of 10-OHCBZ elimination. A positive linear correlation was found between the doses of OXC and the plasma levels of its main metabolites (solid line; y = 3,17 + 0.08x; r2= 0.741; p < 0.01) and DiOH-CBZ (dotted line; y =–0,766 + 0.018x; r2= 0.545; p < 0.05) by using least-square linear regression analysis. Plasma Css of 10-OHCBZ were associated with highly variable 10-OHCBZ brain concentrations, and no correlation was found between these parameters (y = 15.37 – 0.35x; r2= 0.05; p = 0.6; see Table 1). Data relative to the two pediatric patients are reported in Table 1.
Clinical and experimental data of patients.
Article
Purpose: We measured the brain-to-plasma partition of 10,11-dihydro-10-hydroxy-5H-dibenzo(b,f)azepine-5-carboxamide (10-OHCBZ) in epilepsy patients undergoing surgery to alleviate drug-resistant seizures and administered with different oral doses of oxcarbazepine (OXC). We addressed the possible contribution of the multidrug transporter P-glycoprotein (P-gp or MDR1) in determining 10-OHCBZ brain levels by measuring whether this active metabolite is a substrate of P-gp and the relation between the level of expression of MDR1 and the drug concentration in the same brain tissue specimens. Methods: Steady-state plasma and brain concentrations (C(ss)) of 10-OHCBZ were determined intraoperatively in 11 patients by high-performance liquid chromatography (HPLC) with UV detection. The level of expression of MDR1 mRNA was measured in surgically resected brain tissue by reverse transcriptase polymerase chain reaction (RT-PCR). The ability of 10-OHCBZ to act as substate of P-gp was evaluated by measuring its uptake in cell lines expressing different levels of P-gp, in the presence or absence of a selective P-gp inhibitor. Results: OXC was converted to 10-OHCBZ and to Di-OHCBZ, the two main metabolites measured in plasma. The brain concentrations of the active metabolite 10-OHCBZ did not reflect plasma C(ss). A significant inverse linear correlation was found between 10-OHCBZ brain-to-plasma concentration ratio and the level of brain expression of MDR1 mRNA. In vitro uptake studies demonstrated lower intracellular 10-OHCBZ levels in cells with higher P-gp expression. Intracellular drug concentration was increased by XR9576, a specific P-gp blocker. Conclusions: Pharmacologic failure of OXC in pharmacoresistant epilepsy is unlikely to be due to alterations in drug metabolism. 10-OHCBZ does not appear to cross the blood-brain barrier by simple diffusion, and it acts as a substrate of P-gp. The level of expression of MDR1 is inversely correlated with 10-OHCBZ concentration in the epileptic tissue. P-gp may play a role in the pharmacoresistance to OXC by determining the attainment of insufficient concentrations of its active metabolite at neuronal targets.
 
Article
The anticonvulsant profiles of two potent and orally active gamma-aminobutyric acid (GABA) uptake inhibitors, 1-(4,4-diphenyl-3-butenyl)-3-piperidine-carboxylic acid hydrochloride (SK&F 89976-A) and 1-(4,4-diphenyl-3-butenyl)-1,2,5,6-tetrahydro-3-pyridine-carboxylic acid hydrochloride (SK&F 100330-A), were determined with a battery of well-standardized tests in mice and rats and compared with the profiles of phenytoin (PHT), carbamazepine (CBZ), valproate (VPA) and clonazepam (CZP) when subjected to the same tests. ED50 values were calculated and compared with TD50 values for minimal motor impairment to provide protective indexes (PI = TD50/ED50). The anticonvulsant profiles of SK&F 89976-A and SK&F 100330-A were similar and suggest that these compounds raise the threshold for seizure initiation rather than inhibit seizure spread. Like intraperitoneal (i.p.) PHT, CBZ, VPA, and CZP, SK&F 89976-A and SK&F 100330-A inhibited seizures in corneally kindled rats. The profiles of SK&F 89976-A and SK&F 100330-A were most similar to that of CZP and virtually opposite to that of PHT. Intraperitoneal SK&F 100330-A provided complete protection against pentylenetetrazol-induced seizures [subcutaneous (s.c.) PTZ] in mice but was ineffective against seizures induced by maximal electroshock (MES) at doses slightly greater than its TD50. SK&F 100330-A provided complete protection against picrotoxin-induced seizures (s.c. Pic) and against both clonus and forelimb tonic extension induced by NMDA N-methyl-D-aspartate [intracerebral ventricular (i.c.v.)-NMDA] in mice; however, SK&F 100330-A was ineffective against seizures induced by bicuculline (s.c. Bic) and strychnine (s.c. Strych) at doses slightly greater than its TD50. SK&F 89976-A was similar but provided partial protection against NMDA-induced clonus.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Article
To redefine benign myoclonus of early infancy (BMEI) through analysis of clinical and neurophysiologic features in 102 patients with the aim to widen the spectrum of the syndrome, including a number of different clinical expressions of transient nonepileptic paroxysmal movements occurring in normal infants. We recruited patients from one center in Argentina and two in Italy, including infants with normal neurologic and psychomotor development presenting with brief paroxysmal abnormal movements. Children with motor phenomena occurring only during sleep were excluded. Patients with abnormal interictal or ictal electroencephalography (EEG) findings were also excluded. The follow-up ranged from 2-40 years. One hundred and two infants (60 male) met the inclusion criteria. Age at onset ranged from 1-12 months, with a median age of 6.2 months. The following nonepileptic paroxysmal motor phenomena were recognized: (1) myoclonus, (2) spasms and brief tonic contractions, (3) shuddering, (4) atonia or negative myoclonus, (5) more than one type of motor phenomenon. In the majority of cases the episodes occurred only while awake and repeated several times a day. In 45 (44.1%) of the 102 cases contractions appeared in clusters. Based on the analysis of clinical and EMG features in this large series of infants, we postulate that the spectrum of the syndrome is wider than initially suspected, and that the different transient motor manifestations and their correlation with different EMG patterns will allow recognition of this definitely benign condition comprising a variety of episodic motor phenomena in normal babies.
 
Article
Refractory status epilepticus (SE) has a mortality rate of up to 35%. Current treatment protocols for the treatment of SE begin with benzodiazepines and then proceed to conventional anticonvulsants. If seizures continue, SE is considered refractory (RSE) and treatment with anesthetic agents in undertaken. Twenty-four h to 48 h after initiation of anesthesia with midazolam, pentobarbital or thiopental, or propofol, an attempt is made to wean the anesthetic. If this fails and seizures recur, SE is considered highly refractory (HRSE) and repeated attempts are undertaken. No randomized trial data are available to guide the choice of anesthetic agent in either RSE or HRSE status. Medication resistance in established SE is thought to result, in part, from internalization of synaptic γ-aminobutyric acid (GABA) receptors, making them unavailable for modulation. Neurosteroids act on both synaptic and extrasynaptic GABAA receptors, which are not internalized, and are therefore hypothesized to have a role in the treatment of RSE. SGE-102 is a neurosteroid metabolite of progesterone with demonstrated anticonvulsant properties in animal seizure models. A randomized double-blind placebo-controlled adjunctive trial of SGE will include subjects randomized at the time that initial treatment with anesthesia is initiated. Subjects will receive midazolam and either SGE-102 or placebo. Midazolam will be tapered and discontinued between hours 24 and 48. SGE-102 or placebo will be continued through hour 120. The primary end point will be the difference in proportion of subjects from each arm who remain seizure free through hour 120. Secondary end points will include the proportion of subjects who are seizure free at hour 168, 2 days after discontinuation of the experimental agent. The study will be powered to have a 90% chance of detecting a clinically meaningful reduction in seizure recurrence at 120 h. Comprehensive safety and pharmacokinetic data will also be obtained during the course of the trial.
 
Article
Presentation of epilepsy suffered by Byzantine Emperor Michael IV, Paphlagon (who reigned from 1034 to 1041 A.D.) and the attitude of his contemporary society to his disorder. Research into the accounts of Byzantine historians and chroniclers referring to the case of the emperor and Byzantine medical texts revealing the opinion of official medicine about the disorder. Byzantine historians and chroniclers provide detailed clinical descriptions of the seizures of Emperor Michael IV. Nearly all, expressing popular opinion, considered his disease to be demonic possession that constituted a form of divine punishment for the emperor's adultery and act of murder; his royal entourage continually attempted euphemistically to present this condition as a psychic disease. On the contrary, research into Byzantine medical texts reveals that the physicians, already from the 4th century, following Hippocratic tradition, believed that epilepsy was primarily a brain-related disorder and based their treatment on this etiological principle. From the study of the Byzantine histories and chronicles, it can be deduced that Emperor Michael IV, Paphlagon, suffered from generalized tonic-clonic epileptic seizures. Despite the concept then held by well-educated Byzantine doctors, who considered epilepsy a brain disorder, information indicates the deep prejudices of his social environment.
 
Article
In 2002, we reported our preliminary experience using the ketogenic diet (KD) for predominantly intractable infantile spasms (IS) in 23 infants. Since that time, we have increased our use of the KD for this condition including those with new-onset IS. Infants were referred and prospectively started on the traditional KD from 1996 to 2009 at our institution. Included subjects had documented clinical IS, hypsarrhythmia on electroencephalography (EEG), and parental consent to start the KD. Efficacy was assessed through phone communication, clinic visits, and EEG every 3 months. Results:  One hundred four infants, mean age 1.2 years, were started on the KD for IS, of which 74 (71%) had a symptomatic etiology. Previous therapy for this patients included a mean of 3.6 anticonvulsants; 71% including corticosteroids or vigabatrin. Using an intent-to-treat analysis, > 50% spasm improvement occurred in 64% at 6 months and 77% after 1-2 years. Thirty-eight (37%) became spasm-free for at least a 6-month period within a median 2.4 months of starting the KD. In addition, 62% reported improvement in development, 35% had EEG improvement, and 29% were able to reduce concurrent anticonvulsants. Adverse effects were noted in 33%, of which 6% had diminished linear growth. Older age at onset of IS and fewer prior anticonvulsants were more likely to be associated with > 90% spasm improvement at 6 months. The KD is an efficacious therapy for IS in approximately two-thirds of patients treated, and it should be considered strongly after failure of corticosteroids and vigabatrin.
 
Article
The effects and side-effects of treatment with Zarondan in 105 patients with epilepsy are described. In 3 of these patients, five psychotic attacks occurred in close relation to Zarondan treatment. The case histories of, the 3 patients are reported, with special reference to the type of psychosis involved. It is emphasised that the five psychotic episodes were confined to adults, all of whom had previously shown signs of a brittle psychic constitution, but who had not previously manifested psychotic phases. Les effets désirables et indesirables du traitement par le Zarondan ont été appréciés chez 105 sujets épileptiques. Chez trois de ces sujets, 5 épisodes psychotiques sont survenus en relation étroite avec le traitement. L'histoire de ces 3 patients est rappelée en détail, notamment en ce qui concerne le type de psychose qu'ils ont présenté: il est remarquable que les 3 sujets en cause étaient tous adultes et avaient préalablement présenté des signes d'une constitution psychique fragile mais sans épisodes psychiques caractérisés.
 
Article
The nucleus of the solitary tract (NTS) is a primary site at which vagal afferents terminate. Because afferent vagal nerve stimulation has been demonstrated to have anticonvulsant effects, it is likely that changes in synaptic transmission in the NTS can regulate seizure susceptibility. We tested this hypothesis by examining the influence of gamma-aminobutyric acid (GABA) ergic and glutamatergic transmission in the NTS on seizures evoked by systemic and focal bicuculline and systemic pentylenetetrazol (PTZ) in rats. Muscimol (256 pmol), a GABA(A)-receptor agonist, bicuculline methiodide (177 pmol), a GABA(A)-receptor antagonist, kynurenate (634 pmol), a glutamate-receptor antagonist, or lidocaine (100 nl; 5%), a local anesthetic, was microinjected into the mediocaudal (m)NTS. Ten minutes later, seizure activity was induced by either a focal microinfusion of bicuculline methiodide (177 pmol) into the rostral piriform cortex, systemic PTZ (50 mg/kg, i.p.), or systemic bicuculline (0.35 mg/kg, i.v.). Muscimol in mNTS (but not in adjacent regions of NTS) attenuated seizures in all seizure models tested, whereas bicuculline methiodide into mNTS did not alter seizure responses. Kynurenate infusions into mNTS significantly reduced the severity of seizures evoked both systemically and focally. Anticonvulsant effects also were obtained with lidocaine application into the same region of mNTS. Unilateral injections were sufficient to afford seizure protection. Our results demonstrate that an increase in GABA transmission or a decrease in glutamate transmission in the rat mNTS reduces susceptibility to limbic motor seizures. This suggests that inhibition of mNTS outputs enhances seizure resistance in the forebrain and provides a potential mechanism for the seizure protection obtained with vagal stimulation.
 
Study schematic. Epilepsia © ILAE
Plot depicting response to IPS and plasma concentrations of ICA-105665 for a single subject dosed at 400 mg. Filled bars represent SPR on day 1 (placebo) and hatched bars represent SPR on days 2 and 3 (ICA-105665). An exception is the black bar plotted at the 24 h time point. For comparative purposes this SPR value is from predose on day 2 and is therefore represented twice on the plot (predose as a hatched bar and 24 h as a filled bar). SPR is on the left y-axis. Filled circles and connecting lines represent ICA-105665 plasma concentration (right y-axis). For ease of viewing, the x-axis is broken into two segments. The left represents predose to 12 h and the right represents 24–28 h postdose.
ICA-105665 plasma concentration by time for each dose group in study ICA-105665-04. Note that only one subject in the 600-mg dose group received ICA-105665.
Comparison of Cmax and AUC24 by presence (Yes) or absence (No) of dizziness as a reported AE (adverse event). Filled circles represent individual subjects that did not report dizziness. Filled squares represent subjects that did report dizziness. Lines represent mean values for each group.
Article
Purpose: To assess the effects of ICA-105665, an agonist of neuronal Kv7 potassium channels, on epileptiform EEG discharges, evoked by intermittent photic stimulation (IPS), the so-called photoparoxysmal responses (PPRs) in patients with epilepsy. Methods: Male and female patients aged 18-60 years with reproducible PPRs were eligible for enrollment. The study was conducted as a single-blind, single-dose, multiple-cohort study. Four patients were enrolled in each of the first three cohorts. Six patients were enrolled in the fourth cohort and one patient was enrolled in the fifth cohort. PPR responses to 14 IPS frequencies (steps) were used to determine the standard photosensitivity range (SPR) following placebo on day 1 and ICA-105665 on day 2. The SPR was quantified for three eye conditions (eyes closing, eyes closed, and eyes open), and the most sensitive condition was used for assessment of efficacy. A partial response was defined as a reduction in the SPR of at least three units at three separate time points following ICA-105665 compared to the same time points following placebo with no time points with more than three units of increase. Complete suppression was defined by no PPRs in any eye condition at one or more time points. Key findings: Six individual patients participated in the first three cohorts (100, 200, and 400 mg). Six patients participated in the fourth cohort (500 mg), and one patient participated in the fifth cohort (600 mg). Decreases in SPR occurred in one patient at 100 mg, two patients receiving 400 mg ICA-105665 (complete abolishment of SPR occurred in one patient at 400 mg), and in four of six patients receiving 500 mg. The most common adverse events (AEs) were those related to the nervous system, and dizziness appeared to be the first emerging AE. The single patient in the 600 mg cohort developed a brief generalized seizure within 1 h of dosing, leading to the discontinuation of additional patients at this dose, per the predefined protocol stopping rules. Significance: ICA-105665 reduced the SPR in patients at single doses of 100 (one of four), 400 (two of four), and 500 mg (four of six). This is the first assessment of the effects of activation of Kv7 potassium channels in the photosensitivity proof of concept model. The reduction of SPR in this patient population provides evidence of central nervous system (CNS) penetration by ICA-105665, and preliminary evidence that engagement with neuronal Kv7 potassium channels has antiseizure effects.
 
Article
To describe and report initial findings of a system for prospective identification and follow-up of patients with newly diagnosed single unprovoked seizures and epilepsy in Stockholm, Sweden, the Stockholm Incidence Registry of Epilepsy (SIRE). From September 2001 through August 2004, a surveillance system has been in use to identify incident cases of first unprovoked seizures (neonatal seizures excluded) and epilepsy among residents of Northern Stockholm, an urban area with approximately 998,500 inhabitants. Potential cases are identified through multiple mechanisms: Network of health care professionals, medical record screening in specific hospital units, including outpatient clinics, emergency room services, and review of requests for electroencephalography (EEG) examination. Potential cases are classified 6 months after the index seizure based on review of medical records. After screening approximately 10,500 EEG requests and 3,300 medical records, 1,015 persons met the criteria for newly diagnosed unprovoked seizures (430 single seizures; 585 epilepsy). The crude incidence for first unprovoked seizures and epilepsy was 33.9/100,000 person years, (the same adjusted to the European Standard Million), highest the first year of life (77.1/100,000) and in the elderly. No cause could be identified in 62.4%. We have established a sustainable system for prospective identification of new onset epilepsy cases in Stockholm. Despite a possible under-ascertainment, the registry provides a useful starting point for follow-up studies.
 
Article
The symptomatology, electroencephalographic and other correlates, development, and genetics of a new mutant in mice for spontaneous seizures are described. This recessive mutant is designated 'spontaneous seizures' and is assigned the gene symbol sps. Just at or after puberty, 25% of the sps/sps homozygotes show behavioral arrest and spontaneous generalized convulsions. The behavioral arrest is associated with 1-2/s high-voltage spikes in the neocortex and the generalized convulsions are associated with paroxysmal activity in the neocortex. The effects of this mutant are compared with those of others for reflex or spontaneous seizures in mice.
 
Article
To describe the phenotypic expression of a new family with familial lateral temporal lobe epilepsy with aphasic seizures, and to compare the findings with the clinical features of previously reported families linked to chromosome 10q22-q24. Medical records were collected from 12 living affected members. The patients underwent a personal interview and a clinical neurologic examination. Results from interictal scalp EEGs and neuroimaging examinations were obtained. The cardinal ictal symptom was a brief sensory aphasia in eight of the patients. In four, this was accompanied by auditory symptoms, usually in the form of monotonous unformed sounds. Simple partial seizures with psychic or somatosensory seizures also were present. Visual ictal symptoms and complex partial seizures were absent. All patients had generalized tonic-clonic seizures. Magnetic resonance imaging (MRI) or computed tomography (CT) did not reveal morphologic correlates. Improvement with age seemed to occur in many patients. Significant linkage to chromosome 10q22-q24 was established by testing 17 polymorphic microsatellite markers. The epilepsy of this family appears to represent a variety of autosomal dominant lateral temporal lobe epilepsy. Aphasic seizures and a peculiar seizure-precipitating effect of the activation of speech (initiation or perception) may serve as markers for identifying further families with this phenotype.
 
Article
Autosomal dominant partial epilepsy with auditory features (ADPEAF) is a rare form of nonprogressive lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances. The gene predisposing to this syndrome was localized to a 10-cM region on chromosome 10q24. We assessed clinical features and linkage evidence in four newly ascertained families with ADPEAF, to refine the clinical phenotype and confirm the genetic localization. We genotyped 41 individuals at seven microsatellite markers spanning the previously defined 10-cM minimal genetic region. We conducted two-point linkage analysis with the ANALYZE computer package, and multipoint parametric and nonparametric linkage analyses as implemented in GENEHUNTER2. In the four families, the number of individuals with idiopathic epilepsy ranged from three to nine. Epilepsy was focal in all of those with idiopathic epilepsy who could be classified. The proportion with auditory symptoms ranged from 67 to 100%. Other ictal symptoms also were reported; of these, sensory symptoms were most common. Linkage analysis showed a maximum 2-point LOD score of 1.86 at (theta=0.0 for marker D10S603, and a maximum multipoint LOD score of 2.93. These findings provide strong confirmation of linkage of a gene causing ADPEAF to chromosome 10q24. The results suggest that the susceptibility gene has a differential effect on the lateral temporal lobe, thereby producing the characteristic clinical features described here. Molecular studies aimed at the identification of the causative gene are underway.
 
Article
The purpose of the present investigation was to quantify alterations in GABA(A) receptor density in vivo in rats subjected to amygdala kindling. The GABA(A) receptor density was quantified by conducting a [(11)C]flumazenil (FMZ) positron emission tomography (PET) study according to the full saturation method, in which each animal received a single injection of FMZ to fully saturate the GABA(A) receptors. Subsequently, the concentration-time curves of FMZ in blood [using high-pressure liquid chromatography with UV detector (HPLC-UV) or high-performance liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS)] and brain (with PET-scanning) were analyzed by population modeling using a pharmacokinetic model, containing expressions to describe the time course of FMZ in blood and brain. The GABA(A) receptor density (B(max)) in kindled rats was decreased by 36% compared with controls. This is consistent with a reduction of 28% in electroencephalography (EEG) effect of midazolam in the same animal model, suggesting that a reduced number of GABA(A) receptors underlies the decreased efficacy of midazolam. Furthermore, receptor affinity (K(D)) was not changed, but the total volume of distribution in the brain (V(Br)), is increased to 178% of control after kindling, which might indicate an alteration in the transport of FMZ across the blood-brain barrier. Both the GABA(A) receptor density (B(max)), and possibly also the blood-brain barrier transport of FMZ (V(Br)) are altered after kindling. Furthermore, this study indicates the feasibility of conducting PET studies for quantifying moderate changes in GABA(A) receptor density in a rat model of epilepsy in vivo.
 
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Eleven months after the completion of primary site amygdaloid (AM) kindling, three cats experienced kindling of the secondary site AM. At the secondary site, animals developed kindled seizure with a mean of eight stimulations, which was significantly fewer than the 29 required at the primary site, indicating a presence of a positive transfer effect. However, the ictal architecture of the secondary site-kindled seizure was significantly different from that of the primary site: in the former, there was a marked delay in secondary generalization, with individual kindled seizure having a significantly prolonged seizure duration. Both the transhemispheric positive and negative transfer effects observed with the secondary site AM kindling reflect the lasting nature of the neural remodeling induced by the primary site AM kindling. This finding may have clinical relevance.
 
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ADCI (5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine), a low-affinity uncompetitive N-methyl-D-aspartate (NMDA) antagonist, is a broad-spectrum anticonvulsant with a favorable side-effect profile. In the present study, we sought to determine if tolerance develops to the anticonvulsant activity of ADCI, using the maximal electroshock (MES) test to assess seizure protection. Mice were treated with three daily injections of a 2 x ED50 dose for MES protection (18 mg/kg, intraperitoneally, i.p.) or vehicle for 7 or 14 days. On the day after the chronic treatment protocol, all animals received a challenge dose of ADCI (18 mg/kg) and 15 min later were evaluated in the MES test. In control animals, 83-94% of animals were protected and the ADCI plasma levels immediately after the MES test were 5.5-9.7 micrograms/ml. In treated animals, 29 and 0% of animals were protected at 7 and 14 days, respectively, and the ADCI plasma levels were 77 and 52% of the control values. [3H]Dizocilpine binding to brain NMDA receptors was unaltered by the chronic drug treatment. In subsequent experiments, we determined that 14-day chronically treated animals could be completely protected by increased doses of ADCI (ED50 28.9 mg/kg). In both naive and chronically treated animals receiving a challenge dose of ADCI, plasma drug levels decreased in two phases, the first with a time constant of approximately 55 min and the second with a much slower rate. The estimated plasma concentrations of ADCI reflecting threshold (3-5 micrograms/ml) and 50% protection (5-7.5 micrograms/mg) were similar in naive and chronic animals.(ABSTRACT TRUNCATED AT 250 WORDS)
 
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Changes in the metabolism of polyunsaturated fatty acids (PUFA), both in children on the high fat ketogenic diet (KD) for seizure control and in rats on a KD enriched in PUFA, raise the possibility that increased brain arachidonic acid (ARA) and/or docosahexaenoic acid (DHA) may contribute to better seizure control. Our studies with PUFA and several other reports raise the question of whether persistent ketonemia or elevated brain uptake of ketones are strictly necessary for the clinical effectiveness of the KD in intractable epilepsy. To address this question, we have developed the synthesis of carbon-11 labeled acetoacetate ((11)C-AcAc) for PET studies to investigate brain ketone uptake directly in humans and animals. In rats on the KD for 10 days, (11)C-AcAc uptake by the brain increased 7- to 8-fold, an increase similar to that induced by 48 h fasting. In rats and humans, paired PET scans ((11)C-AcAc followed immediately by(18)fluorodeoxyglucose) will be conducted to assess the uptake of AcAc and glucose by the brain while on the KD and in neurological disorders associated with aging.
 
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We surveyed the treatment of 1104 patients admitted to 27 out of the 46 departments of neurology (64.5%), neurosurgery (23.0%), and child neurology (12.5%) of Lombardy, the largest Italian Region (population, 9,000,000). Our main aim was to assess the penetration of correct diagnostic and clinicopharmacological information into routine practice. A detailed analysis and discussion are given of data concerning reasons for hospital admission (therapeutic adjustment accounting for 27.3%; diagnostic ascertainment, 53.8%); characteristics of the disease, in terms of duration, clinical manifestations, and pattern of seizures; associated disorders; prevalence and criteria for the use of instrumental diagnostic procedures (EEG, brain scan, computed tomography, etc.); pattern of prescriptions of anticonvulsant drugs at admission and at discharge, with particular emphasis on specific drug choices by specialty; prevalence of single-drug therapy (41% at admission and 47.0% at discharge) versus polytherapy; degree of correspondence between recommended and observed dosage regimens (undertreatment being a more common problem than excessive dosing); and reporting of side effects. Although some of the findings of some recent studies are confirmed, this report documents the feasibility of a regular audit program of the performance of an entire health care system in the treatment of epilepsy.
 
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Distribution of the enzyme monoamine oxidase B (MAO-B) and the peripheral benzodiazepine binding site (omega-3 site) was studied by quantitative autoradiography using [H-3]L-deprenyl and [H-3]PK 11195, two tentative glial markers, as ligands. Sclerotic hippocampus from seven patients who had had anterotemporal lobe resection because of intractable complex partial epilepsy were investigated and compared with postmortem hippocampus from three nonepileptic controls. A significantly higher degree Of L-deprenyl and PK 11195 binding was observed in the epileptic cases. The increased binding of both ligands correlated to extent of neuronal loss, but only PK 11195 showed correlation to degree of gliosis. We conclude that both ligands could provide useful markers for quantitating the degree of gliosis in pathologic states such as epilepsy. They may be applicable in future in vivo studies with positron emission tomography (PET).
 
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A retrospective study of 113 patients treated with a sustained-release form of valproate (SRF-VPA), known as the "chrono" formulation in most European countries, led to the following conclusions: Patients treated with the old VPA formulation could immediately receive the same daily dosage of SRF-VPA without loss of seizure control when administered as a single evening dose. The tolerability of SRF-VPA was good and twice or single daily dosing was preferred by all our patients. Whether or not SRF-VPA should be used as first or second-line treatment in partial seizures that do or do not secondarily generalize is unclear. Our study demonstrates that the efficacy of SRF-VPA is comparable with that of other major antiepileptic drugs such as carbamazepine (CBZ). In refractory seizures, the combination of SRF-VPA and CBZ seemed to be the most satisfactory treatment. Based on these results SRF-VPA is a promising drug for all types of seizures even in low daily dosage, but further clinical work is required to confirm our observations.
 
Top-cited authors
Christian E Elger
  • University of Bonn
Emilio Perucca
  • University of Pavia
Ley Sander
  • UCL Queen Square Institute of Neurology
Orrin Devinsky
  • NYU Langone Medical Center
Frederick Andermann
  • McGill University