摘要:

Summary:To investigate the role of the substantia nigra (SN) in kindling, electrical stimulation of the SN was delivered at various times before or after stimulation of the amygdala (AM) or pyriform cortex during or after kindling in rats. The results were as follows: (a) Ipsilateral SN stimulation delivered prior to each AM kindling stimulation for 14 days significantly retarded the appearance of Stage 4 and 5 seizures and shortened the afterdischarge (AD) duration, (b) Bilateral SN prestimulation blocked seizure generalization in some AM‐ or pyriform cortex‐kindled animals, prolonged the latency to bilateral forelimb clonus in others, and shortened the AD duration of the kindled seizure in a current intensity‐dependent fashion, (c) These effects were only partially antagonized by haloperidol, but were completely abolished by picrotoxin. The picrotoxin alone significantly reduced the latency, (d) Almost no effect was found when the SN stimulation was delivered after the onset of bilateral fore‐limb clonus. We conclude that the SN might be an important mediator of the early aspects of seizure generalization from limbic epileptic foci. The relative involvements of GABAergic 7‐aminobutyric acid and dopaminergic systems of the SN in this inhibitory function are discussed.RESUMENPara investigar la función de la substancia nigra (SN) en el condicionamiento (kindling), se procedió a estimular la SN durante varias ocasiones antes o despues de la estimulación de la amígdala (AM) o de la corteza piriforme durante o después del condicionamiento en ratas. Los resultados fueron: (1) La estimulación ipsilateral de la SN llevada a cabo antes de cada estimulacion para condicionar la AM durante 14 días retrasó de modo significativo la aparición de los ataques de los estadíos 4 y 5 acortó la duración de las 2 descargas (AD). (2) La preestimula‐cion bilateral de la SN bloqueó la generalización de los ataques en algunos animales en los que se había condicionado la AM o la corteza piriforme, prolongó la latencia del clonus bilateral de las extremidades anteriores en otros animales y acorto la duracion de las AD de los ataques producidos por condicionamiento de un modo dependiente de la intensidad de la corriente. (3) Estos fueron sólo parcialmente inhibidos por el haloperidol pero fueron completamente abolidos por la picrotoxina. La picro‐toxina, por si sola, redujo significativamente la latencia. (4) No se encontró prácticamente efecto alguno cuando la estimulación de la SN se llevó a cabo después del comienzo de los movie‐mientos clónicos bilaterales de las extremidades anteriores. Concluimos que la SN puede ser un mediador importante en los aspectos precoces de la generalización de los ataques desde focos límbicos epilépticos. La relativa participación de los sis‐temas GABAergico y dopaminergico de la SN en esta función inhibitoria han sido discutidos.ZUSAMMENFASSUNGUrn die Rolle der Substantia nigra (SN) beim Kindling zu un‐tersuchen, wurde die Elektrostimulation der SN mehrfach vor und nach Stimulation der Amygdala oder des Cortex pyriformis wahrend oder nach Kindling der Ratte durchgefuhrt. Ergeb‐nisse: 1. Ipsilaterale SN‐Stimulation, die vor jeder AM‐Kin‐dling‐Stimulation für 14 Tage durchgeführt wurde, verzögerte signifikant das Auftreten von Stadium 4 und 5–Anfällen und verkiirzt die Nachentladungsdauer. 2. Bilaterale SN‐Praestim‐ulation blockierte die Anfallsgeneralisierung bei einigen Amygdala‐ oder Cortex pyriformisstimulierten Tieren, verlängerte bei anderen die Latenz des ‘Forelimb‐Klonus' und verkiirzte die Nachentladungsdauer des “Kindled‐Anfalls' in einer laufenden. intensitats‐abhangigen Weise. 3. Diese Effekte waren nur teil‐weise durch Haloperidol antagonisiert, aber vollständig aufge‐hoben durch Picrotoxin. Picrotoxin alleine verminderte die Latenz. 4. Fast gar kein Effekt der SN‐Stimulation war erkennbar, wenn sie nach dem ’Forelimb‐Klonus' erfolgte. Wir schließen daraus auf eine wichtige Mediator‐Funktion der SN im Rahmen früher Anfallsgeneralisierung limbischer, epileptogener Foci. Die relativ

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1987.tb03613.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Summary:Epidemiological studies indicate that the incidence of seizures is highest early in life. This report discusses the experimental data derived from studies of focal epileptogenesis of the immature brain in tandem with ongoing maturational changes. During development, neurons have characteristic neurophysiological properties. Local interictal discharges are long in duration, lack a stereotypic morphology, and have limited fields. Yet the immature brain is very susceptible to the development of bilateral, although asynchronous, seizures and status epilepticus induced by amygdala kindling or by convul‐sant drugs. This increased seizure susceptibility may be due to a functional immaturity of a substantia nigra, GABA‐sensitive output system. The morbidity of convulsions occurring early in life may not be as grave as previously thought in terms of subsequent acquisition of “normal” developmental milestones. The propensity to develop recurrent convulsions in adulthood is not related to the severity of a single seizure in infancy. Although multiple severe seizures may predispose animals to the development of seizures later in life, this is not a unique feature of the immature brain, since it also occurs in the adult brain. Finally, there is evidence that the immature brain may respond to anticonvulsant drugs differently from its mature counterpart; these findings emphasize the need to develop new antiepileptic therapies that take into account the maturational state of th

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1987.tb05753.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Summary:Sodium valproate enteric‐coated tablets were administered as monotherapy to 118 patients (median age, 19 years) with primary generalized epilepsies. More than half (56%) of these patients were transferred from prior drug therapy, most of them because of inadequate seizure control, and some because of adverse effects. Seventy‐one percent of the patients experienced tonic‐clonic seizures, either alone or in combination with other types of seizures, principally absences. Mean duration of follow‐up was 18 months (median, 17 months; range, 1–68 months). At a mean daily dosage of<20 mg/kg, 83% of the patients became seizure‐free. Therapy was equally effective against tonic‐clonic seizures, absences, and myoclonic seizures. Tonic‐clonic seizures were suppressed in 85% of cases (89% when patient had only one seizure type), absences in 82% (95% when patient had only one seizure type), and myoclonic seizures in 82%. Paroxysmal activity was present in 88% of the electroencephalogram (EEG) records before valproate monotherapy, and in 32.4% at the study's end. These results were achieved with generally mild and mostly transient side effects; side effects were reported by 16% of patients during the first month, and 2% at the last follow‐up. No hematologic or hepatic toxicity was observed. The lag time between attaining steady‐state serum concentrations and achieving maximal clinical improvement suggests that sodium valproate monotherapy should be given an adequate trial to ensure that patients derive the greatest possible benefit before adding or switch

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1987.tb05769.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Summary:Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic‐clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizure

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1987.tb05784.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Summary:In previous studies of experimental and human epilepsy, defects have been shown in the 7‐amino‐butyric acid (GABA) receptors. We further investigated the role of the GABA/benzodiazepine/picrotoxinin receptor complex in the epileptic focus and also in other regions of the rat brain. The focus was induced by cobalt implantation to the right motor cortex, and the brains were dissected 16–19 days after the operation. Benzodiazepine (using [3H]flunitrazepam as a ligand; FLU), GABA [3H]muscimol; MUS), and picrotoxinin ([35SJt‐bu‐tylbicyclophosphorothionate; TBPS) receptor bindings were measured in different brain areas and the values were compared with glass‐implanted controls. In the focal area, the specific receptor binding decreased in the order TBPS; FLU; MUS. In the perifocal area only TBPS binding decreased, and Scatchard analysis showed a decrease in the number of binding sites (p<0.05) without any effect on binding affinity. No change was seen in the binding characteristics of the other areas studied. According to our results, in cobalt‐induced epilepsy the GABA/benzodiazepine/picrotoxinin receptor complex is modulated in the focal area; this may lead to a defect in chloride conductance, which in turn induces disturbed control of neuronal activity in the epileptic focus.RÉSUMÉUn déficit des récepteurs du GABA a été démontre én épilep‐tologie humaine et expérimental. Nous avons poursuivi ľétude du complexe récepteur GABA/benzodiazépine/picrotoxinine au niveau du foyer épileptique et au niveau ďon;autres zones du cer‐veau de rat. Le foyer a été induit par 1'implantation de Cobalt dans le cortex moteur droit, et les cerveaux analyses 16 a 19 jours après ľintervention. La liaison au récepteur des benzodiazepines a étéétudiée avec comme ligand le H3‐flunitrazépam (FLU), celle du GABA avec le H3‐muscimol (MUS), celle de la picrotoxinine avec le S35‐t‐butylbicyclophosphorothionate (TBPS) au niveau de differentes zones cérébrales, et les valeurs constatees ont été comparées à celles observées chez les ani‐maux contrôles implantés avec du verre. Au niveau du foyer, la liaison spécifique au récepteur a été diminuée, dans ľordre sui‐vant: TBPS; FLU; MUS. Dans la région périfocale, seule la liaison du TBPS a été diminuée, et ľanalyse selon le Scatchard a montré une diminution du nombre de sites de liaison (p<0.05) sans effet sur ľaffinité de la liaison. Nous n'avons pas constaté de modification des caractéristiques de liaison au niveau des autres régions étudiées. Ďon;après nos résultats, dans ľépilepsie au cobalt, le complexe récepteur GABA/benzodiazépine/picro‐toxinine est modulé au niveau du foyer; ceci peut avoir comme conséquence une modification de la conductance du chlore,

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1987.tb03614.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Summary:For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1987.tb05766.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Summary:Several different types of chemical compounds are useful as antiepileptic drugs. Their mechanisms of action, as well as their physical structures, differ. Compounds such as carbamazepine, phenytoin, and probably valproate act by modifying ionic conductances, particularly sodium and calcium, in excitable membranes, thus limiting sustained high‐frequency neuronal discharges. In contrast, barbiturates and benzodiazepines tend to affect 7‐aminobutyric acid (GABA) mediation of the chloride channel opening. Knowledge of drug mechanisms is important for choosing the proper drug for various seizure types. In addition, an understanding of antiepileptic drug pharamcokinetics, nonther‐apeutic effects, and interactions is essential for optimal therapy. The lack of uniform pharmacokinetics among patients and among different formulations of a drug can make it difficult to arrive at uniform criteria for both seizure control and determinations of toxicity. Both pharmacokinetic and pharmacodynamic interactions can occur between antiepileptic medications and other drugs. Three major types of side effects with anticonvulsants can be identified: dose‐related alterations of neurologic function, idiosyncratic reactions, and nonidiosyncratic direct actions on other organ systems. These effects often compromise tr

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1987.tb05772.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Summary:We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non‐febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examine

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1987.tb05750.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Summary:For a study of the effects of ACTH on established seizures, 16‐day‐old rats that had been previously kindled in the amygdala were given a high daily dosage of ACTH gel for 15 days and then underwent transfer kindling in the contralateral amygdala. There were no significant differences in the rate of transfer kindling between the controls and ACTH‐treated rats. This study indicates that in the immature animal ACTH does not alter the kindled state.RÉSUMÉRESUMENPara estudiar los efectos del ACTH en ataques establecidos, se han administrado diariamente dosis altas de gel de ACTH durante 15 dfas a ratas de 16 días de edad que habían sido pre‐viamente condicionadas (kindled) en la amígdala. Posterior‐mente el condicionamiento fue transferido a la amígdala contralateral. No se encontraron diferencias significativas en la pro‐porción del condicionamiento transferido entre los animates control y las ratas tratadas con ACTH. Este estudio indica que en el animal inmaduro el ACTH no altera el estado de condicionamiento.ZUSAMMENFASSUNGUm die Wirkung von ACTH auf bestehende Anfälle zu untersuchen wurden 16‐Tage‐alte Ratten nach vorherigem Kindling der Amygdala täglich mit einer hohen Dosis ACTH‐Gel für 15 Tage behandelt. Danach erfolgte Transfer‐Kindling der kontrala‐teralen Amygdala. Es konnten keine signifikanten Unterschiede in der Häufigkeit des Transfer‐Kindlings zwischen ACTH‐be‐handelten und Kontroll‐Tieren gefunden werden. Die Studie zeigt, daß beim unreifen Tier ACTH die Kindling‐Reaktion nicht verändert.Afin ď;étudier ľeffet de ľACTH sur les crises établies, des rats de 16 jours, qui avaient subi un embrasement au niveau de ľamygdale, ont reçu une dose élevée de gel ď;ACTH pendant 15 jours avant de subir un transfert ď;embrasement au niveau de ľamygdale controlatérale. II n'a pas été constaté de différence significative dans le taux de transfert ď;embrasement entre les rats traités par ľACTH et les rats témoins. Cette étude indique que, chez ľanimal im

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1987.tb03615.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY

摘要:

Summary:Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug‐related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are “tolerable” for epileptic pat

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1987.tb05767.x

出版商:Blackwell Publishing Ltd    

年代:1987

数据来源: WILEY