摘要:

Summary:Development of clonic‐tonic flurothyl‐induced seizures was examined in both normal and genetically epilepsy‐prone rats (GEPRs). At each age, from 10 to 30 days, clonus occurred at significantly shorter latencies in GEPRs than in normal rats. The latency to onset of clonic seizures did not change with age, however, in either GEPRs or normal rats. A different pattern of response was observed in the progression to tonic seizures. As normal animals matured, the latency to tonic seizures became longer and, by day 30, the duration of flurothyl exposure necessary to induce tonus was almost 70% greater in normal rats than in the GEPRs. In contrast, in GEPRs, tonic extension occurred immediately following the onset of clonus throughout development. A subset of GEPRs failed to have audiogenic seizures in a 40‐day posttest. These animals had a flurothyl response identical to their audiogenic‐susceptible litter mates. These data suggest that (a) a protective mechanism which develops against tonic seizures in normal rats fails to mature in the GEPR, and (b) seizure inducing gene‐linked neural abnormalities occur in the GEPR independent of pathologies underlying audiogenic seizures.RÉSUMÉLa survenue de crises tonico‐cloniques induites par le flurothyl a étéétudiée chez le rat normal et chez le rat génétiquement prédispose à l'épilepsie (RGPE). Pour chaque âge (de 10 à 30 jours), la crise clonique est survenue avec une latence significa‐tivement moindre chez le RGPE que chez le rat normal. La latence d'apparition des crises cloniques n'a cependant pas changé avec l'âge, chez le RGPE comme chez le rat normal. Un type différent de réponse a été observé dans la progression vers les crises toniques. Au für et à mesure de la maturation chez le rat normal, la latence d'apparition des crises toniques croissait, et, à J30, la durée d'exposition au flurothyl nécessaire à obtenir la crise tonique était de 70% supérieure chez le rat normal que chez le RGPE. A l'inverse, chez le RGPE, les crises toniques sont toujours survenues immédiatement après le début de la crise clonique tout au long de la maturation. Un test ulteriéur à J40 a montré qu'un sous‐groupe de RGPE ne présentaient pas de crises audiogéniques. Ces animaux avaient cependant une réponse au flurothyl identique à celle de leurs congénères susceptibles aux crises audiogéniques. Ces résultats suggèrent que 1o) un mécanisme protecteur vis‐à‐vis des crises toniques se produisant pendant la maturation chez les rats normaux ne se développe pas chez les RGPE, et que 2o) les anomalies neuronales liées au gène inducteur des crises surviennent chez le RGPE indépendamment des facteurs pathologiques sous‐tendant les crises audiogéniques.RESUMENEl desarrollo de ataques clónico‐tónicos inducidos por el flurotil ha sido examinado en ratas normales y en ratas genéticamente predispuestas a epilepsia (GEPR). En cada edad, de 10 a 30 dias, los movimientos clónicos ocurrieron con latencias sig‐nificativamente más cortas en las ratas GEPR que en las normales. La latencia del comienzo de los ataques clónicos no mostró cambios con la edad en ninguno de los dos grupos dratas. Se obsrvó un partón diferente de respuesta en la progresidn los ataques tónicos. A medida que los animates normales madu‐raban la latencia de los ataques tónicos se prolongo y, al alcanzar el dia 30, la duración de la necesaria exposición al fluortil para producir tono fue casi el 70% mayor en las ratas normales que en las GEPR. Por el contrario, en las GEPRs, la extensión tónica ocurrió inmediatamente después del comienzo del clonus. El grupo de las ratas GEPR no mostró ataques audiogénicos en un test realizado 40 días más tarde. Estos animales mostraron una respuesta al fluortil idéntica a la de las restantes ratas de la misma camada que eran audiogénicamente susceptibles. Estos datos sugieren que (a) el mecanismo protector contra ataques tónicos que se desarrolla en las ratas normales no se produce durante la maduración de las GEPR y (b) el gene que induce ataques y que está asociado a anomalias neuronales ocurre en las ratas GEPR, independientemente de los mecanismos patológicos que subyacen a los ataques patogénicos.ZusammefassungBei normalen und genetisch zur Epilepsie neigenden Ratten (GEPR) wurde die Entwicklung von klonisch‐tonischen durch Flurothyl induzierten Anfällen untersucht. Bei den GEPR‐Ratten traten Kloni mit einer deutlich kürzeren Latenz in jedem Alter zwischen 10 und 30 Tagen auf als bei den Kontrolltieren. Die Latenz zum Anfallsbeginn änderte sich weder bei den GEPR‐Tieren noch bei den normalen Tieren mit dem Alter, es wurde ein unterschiedliches Antwortmuster mit Fortschreiten zu tonischen Anfällen hin beobachtet. Mit der Reifung wurden die Latenzen zu tonischen Anfällen bei Normaltieren länger und am 30. Tag war die Dauer der benötigten Flurothyl‐Exposition, um einen tonischen Anfall zu erzielen, 70% größer als bei den GEPR‐Tieren. Diese zeigten eine tonische Extension unmittel‐bar nach dem Auftrétén von Kloni während der ganzen Entwicklung. Eine Untergruppe der GEPR‐Tiere zeigte in einem 40‐Tage‐Nachtest keine audiogenen Anfälle. Diese Tiere hatten je‐doch eine zu ihren für audiogene Anfälle empfindlichen Geschwistertieren identische Flurothyl‐Antwort. Die Ergenb‐nisse legen nahe, daß a. bei den GEPR‐Tieren ein protektiver Mechanismus gegen tonische Anfälle nicht reift wie bei normalen Tieren und daß b. bei den GEPR‐Tieren Gen‐

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05273.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:Over the last 15 years, neurobiologists have begun to unravel the cellular mechanisms that underlie epileptiform activity. Such investigations have two main objectives: (I) to develop new methods for treating, “curing” or preventing epilepsy; and (2) to learn more about the normal functioning of the human brain at the cellular/ molecular and the neurological/psychological levels by analyzing abnormal brain functioning. The electroencephalogram (EEG) spike is a marker for the hyperexcitable cortex and arises in or near an area with a high epileptogenic potential. The depolarizing shift (DS) that underlies the interictal discharge (ID) appears to be generated by a combination of excitatory synaptic currents and intrinsic voltagedependent membrane currents. The hyperpolarization that follows the DS (post‐DS HP) limits ID duration, determines ID frequency, and prevents ID deterioration into seizures. The disappearance of the post‐DS HP in some models is related to the onset of seizures and the spread of epileptifonn activity. During the transition toseizures, the usually self‐limited ID spreads in time and anatomical space. Several processes may intervene in the pathophysioogical dysfunction. These include enhancing GABA‐mediated inhibition, dampening NMDA‐mediated excitability, interfering with specific Ca2+currents in central neurons, and perhaps stimulating “g

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05812.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:Benzodiazepines are potent and effective drugs for the management of acute seizures and status epilepticus. Lorazepam, diazepam, and clonazepam have been the most widely studied of the benzodiazepines in the treatment of status epilepticus. In 47 studies of these drugs involving 1,455 patients, lasting control of status epilepticus was achieved in 79% of the patients. None of these benzodiazepines is clearly superior to another for the effective control of status epilepticus. Differences in pharmacokinetic parameters, therefore, will influence the choice of drug. All three benzodiazepines are lipid‐soluble and enter the brain within seconds to minutes after intravenous administration. Diazepam, however, is very lipid‐soluble and highly protein‐bound and thus has a very large volume of distribution of unbound drug. As a result, the effective duration of action of diazepam in status epilepticus is only 20 to 30 min, whereas that of lorazepam, which has a much smaller volume of distribution of unbound drug, is at least several hours after a single intravenous injection. This allows the orderly administration of an antiepileptic drug for long‐term seizure control after status epilepticus has been controlled. For this reason, lorazepam is preferable for the initial management of status epilepticus. Continuous intravenous infusion of diazepam has been used successfully in the management of some patients with status epilepticus refractory to initial tr

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05824.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:Carbamazepine (CBZ) selectively suppressed kindled convulsions, whereas ethosuximide (ESM) suppressed spike‐wave activity accompanying systemic penicillin epilepsy in cats. Evoked potential data indicated that CBZ acted at the thalamic level, whereas ESM acted at cortex. Reduction of seizures and thalamic or cortical excitability occurred throughout the sleep‐wake cycle, but effects were most pronounced in seizure‐prone sleep or awakening states. These findings extend previous work showing differential antiepileptic drug (AED) effects on temporal lobe and absence seizures. The results are also consistent with recent work suggesting that thalamocortical pathways provide a final common pathway for the manifestation of sleep and awakening epilepsy and also reflect a chronic, latent pathophysiology.RÉSUMÉLa carbamazépine (CBZ) supprime de façon sélective les convulsions après embrasement, alors que l'éthosuximide (ESM) supprime l'activité‘de Pointes‐Ondes accompagnant l'épilepsie par administration systémique de pénicilline. Les potentiels évoqués ont montré que la CBZ agit au niveau thalamique, alors que l'ESM agit au niveau du cortex. La réduction des crises et de l'excitabilité’ thalamique et corticale survient tout au long du cycle veille‐sommeil, mais les effets sont maximaux péndant le someil favorisant les crises ou les périodes de réveil. Ces con‐stations complètes des travaux antérieurs qui avaient montré des effets différents des médicaments antiépileptiques sur les crise du lobe temporal et sur les absences. Ces résultats confirment également des travaux plus récents suggérant que les voies thalamocorticales constituent une voie finale commune pour la traduction du sommeil et de l'épilepsie du rgveil et reflètent également une physiopathologie chronique latente.RESUMENEn gatos, la carbamazepina (CBZ) suprime selectivamente las convulsiones condicionadas (kindled) mientras que la etosuxim‐ida (ESM) suprime la actividad punta‐onda que acompaña a la epilepsyía sistlmica inducida por la penicilina. La información de los potenciales evocados indica que la CBZ actua a nivel ta‐lamico mientras que la ESM actua en la corteza. La reducción de los ataques y la excitabilidad cortical ocurrió durante todo el ciclo de sueño‐vigilia, pero los efectos fueron más pronunciados en los estados de sueño o despertar con mayor tendencia a los ataques. Estos hallazgos ampían los trabajos previos que mos‐traban efectos diferenciales de las drogas antiepilépticas sobre los ataques de ausencia y del lóbulo temporal. Los resultados también son consistentes con trabajos recientes que sugieren que las vias tálamo‐corticales proporcionan una via común final para la manifestación de la epilepsia del sueño o del despertar y tam‐bién reflejan una latente y crónica patofisologia.ZUSAMMENFASSUNGCarbamazepin (CBZ) unterdrückte selektiv durch Kindling erzeugte Anfälle, wohingegen Ethosuximid (ESM) die spike wave Aktivität bei durch systemische Penicillin‐Gaben erzeugter Epilepsie bei Katzen unterdrückte. Untersuchungen mit evo‐zierten Potentialen zeigten, daß CBZ auf Thalamushöhe, ESM im Kortex wirksam war. Der Rückgang der Anfälle und thalam‐ischen oder kortikalen Erregbarkeit war während des ganzen Schlaf‐Wach‐Zyklus vorhanden, die deutlichste Wirkung zeigte sich jedoch bei Anfällen, die im Schlaf und während der Auf‐wachphase ausgelöst wurden. Die Ergebnisse führen frühere Ar‐beiten fort, die eine differenzierte antiepileptische Wirkung bei Temporallappen‐und Absencen‐Anfällen zeigen. Die Ergebnisse stehen auch in Übereinklang mit neueren Arbeiten, die thalamo‐kortikale Verbindungen als gemeinsame Endstrecke für die Manifes

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05274.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:The practice of epileptology at a molecular level, where gene products are identified by gene mapping, will soon be possible for a growing number of epilepsies. Juvenile myoclonic epilepsy (JME) is the first of such epilepsies to be mapped to a chromosome, namely chromosome 6p21.3. Family studies of 68 JME probands from California revealed 50% of all families reported seizures in first‐ or second‐degree relatives. Twelve percent of all family members other than the proband had epileptic seizures. Eighty percent of symptomatic siblings and 6% of asymptomatic siblings had diffuse 4‐ to 6‐Hz multi‐spike‐wave complexes. Twelve percent of asymptomatic parents had diffuse, nonspecific slow waves mixed with spikes or sharp waves. JME is tightly linked to the Bf‐HLA loci in chromosome 6. No matter what mode of inheritance is assumed, linkage to the clinical manifestations of JME and its associated EEG traits is indicated by lod scores over 3.0, as long as “EEG affected” but clinically asymptomatic family members are counted as affected during LIPED analysis. Studies are now being done to further localize the JME site. At the same time, further linkage studies should decide if JME is heterogeneous within itself and whether the same JME site in 6p21.3 underlies absence and gra

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05835.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:Clinical trials in children and adults indicate that the intermittent oral or rectal administration of diazepam is an effective and safe alternative for the acute management of recurrent paroxysmal disorders. Prompt home treatment of dangerous or upsetting relapses can prevent the morbid effects of prolonged seizures and offer the patients and their families a sense of control over the illness.

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05819.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:A study was conducted to assess the impact of single dosing and different dosing intervals of vigabatrin [gamma vinyl GABA (GVG)] in 11 patients with drug‐resistant complex partial seizures. Cerebrospinal fluid (CSF) concentrations of total GABA, free GABA, homocarnosine, homovanillic acid (HVA), GVG, and 5‐ hydroxyindolacetic acid were measured up to seven days after a single dose. GVG levels were maximal within 24 h, suggesting that GVG acts to inhibit GABA‐transami‐nase, and may also increase biogenic

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05826.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:The greatest value of the kindling model for new therapy of epilepsy almost certainly lies in elucidating the molecular basis of its development and persistence. Such an understanding may provide a foundation for therapies aimed at prevention or perhaps even cure of some forms of human epilepsy.

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05809.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:Vigabatrin (gamma vinyl GABA, GVG), an enzyme‐activated, irreversible inhibitor of GABA transaminase, was administered orally to rats, dogs, and monkeys to observe toxicologic reactions. Myelin vacuolation of the brain was observed. The vacuolation was limited to myelinated tracts and resulted from separation of the myelin sheath at the interperiod line. There was no evidence of demyelination, axonal degeneration, or damage uolation was histologically similar to that observed in association with other drugs such as triethyltin, isoniazid, or hexachlorophene. However, the distribution is limited to the brain and is reversible upon discontinuation of therapy. Two postmortem and three operative specimens from humans have revealed no evidence of vacuolation of myeli

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05827.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:The mechanisms of action of antiepileptic drugs effective against generalized absence seizures (antiabsence AEDs) remain uncertain. Antiabsence AEDs are generally effective against seizures induced in experimental animals by pentylenététrazol (PTZ) and methyl‐6,7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate (DMCM), drugs which reduce GABAergic inhibition. Thus, antiabsence AEDs have been suggested to enhance GABAergic inhibition. We studied the effects of several AEDs on GABA responses recorded from mouse spinal cord neurons grown in primary dissociated cell culture. Four antiabsence AEDs were included: ethosuximide (ESM), dimethadione (DMO), sodium valproate (VPA), and diazepam (DZP). Two experimental AEDs, CGS 9896 and ZK 91296, with anticonvulsant action against PTZ‐ or DMCM‐induced seizures were also included. Possible effects of the antiabsence and experimental AEDS on PTZ‐ and DMCM‐induced inhibition of GABA responses were also evaluated. PTZ and DMCM revers‐ibly reduced GABA responses in a concentration‐dependent manner. PTZ complétély inhibited GABA responses at 10mM(IC50of 1.1 mM), whereas DMCM‐induced inhibition of GABA responses reached a plateau level of 39% of control values at 1 p.M (IC50of 33 nM). ESM (1,200 μM), DMO (6mM),VPA (200 u.M), CGS 9896 (2μM),and ZK 98% (2 μM) did not alter GABA responses. DZP enhanced GABA responses in a concentration‐dependent manner. The inhibition of GABA responses produced by PTZ 1 mM was unaltered by ESM (600 μM), DMO (6mM),CGS 9896 (1μ M),or ZK 9896 (1μM)‐Coapplication of VPA (200 μM) and PTZ (1mM)slightly enhanced the PTZ effect. DZP (>10 nM), however, reversed the PTZ‐induced reduction of GABA responses. The DMCM (250 nM) inhibition of GABA‐responses was unaltered by ESM (600 μ.M), DMO (2 mM), or VPA (200 μM). CGS 9896 (2 μM) and ZK 91296 (2μM),however, antagonized the DMCM effect. DZP (>10 nM) significantly reversed the DMCM‐induced inhibition of GABA responses. The lack of effect of VPA, ESM, and DMO on postsynaptic GABA responses suggests that direct enhancement of postsynaptic GABA action is not a common mechanism of action of antiabsence AEDs. The AEDs DZP, CGS 98%, and ZK 912% all reversed DMCM, but not PTZ, reduction of GABA responses, suggesting that these AEDs blocked DMCM seizures by acting at benzodiazepine receptors. However, since only DZP enhanced GABA responses, it is unclear how CGS 98% and ZK 912% blocked PTZ seizures. Key Words: Anticonvulsants–GABA–Neuron culture–Cell culture–Spinal cord neurons–Convulsants.RESUMENLos mecanismos de accidn de las medicaciones antiepilépticas eficaces contra los ataques generalizados de ausencia (AEDs antiausencia) permanecen inciertos. Los AEDs antiausencia son, generalmente, eficaces contra ataques experimentales inducidos por el pentilentetrazol (PTZ) y el metil‐6,7‐dimetoxy‐4‐etil‐Pcarbolina‐3‐carboxilato (DMCM) en animates, medicaciones que reducen la inhibición GABAérgica. Hemos estudiado los efectos de varios AEDs sobre respuestas‐GABA registradas en las neuronas de la médula espinal de ratones que habian crecido en cultivos de células primarieas disociadas. Cuatro AEDs antiausencia fueron incluidos: etoxusimida (ESM), dimetadiona (DMO), valproato sódico (VPA) y diazepan (DZP). Tambtén se incluyeron dos AEDs experimentales, CGS 9896 y ZK 912%, con acción anticonvulsiva contra los ataques inducidos por PTZ o DMCM. Tambión se valoraron los posibles efectos de los AEDs antiausencia y experimentales sobre el PTZ y la inhibición de las respuestas‐GABA inducidas por el DMCM. El PTZ y el DMCM redujeron las respuestas‐GABA de modo reversible y dependiendo de sus concentraciones. El PTZ inhibió cmpleta‐mente las respuestas‐GABA a 10 mM (IC50de 1.1mM)mientras que la inhibitión de las respuestas GABA inducida por el DMCM alcanzó un nivel estable del 39% de los valores control con 1 μ.M(IC50de 33mM).La ESM (1200μ.M),la DMO (6 mM), el VPA (200 μM), el CGS 98% (2 μM)y el ZK 98% (2 μM)no alteraron las respuestas‐GABA. El DZP aumentó las respuestas GABA de una manera concentración‐dependiente. La inhibition de las respuestas‐GABA producidas por el PTZ (1mM),no se altero con las ESM (600 μM),la DMO (6mM),el CGS 98% (1 μM)o el ZK 98% (1 μ.M).La co‐aplicacion de VPA (200 μM)y el PTZ (1 mM) aument6 ligeramente los efectos del PTZ. Sin embargo el DZP (10nM)kehrte die durch DMCM‐induzierte Hemmung der GABA‐Antworten um. Das Fehlen einer Wirkung von VPA. ESM und DMD auf die postsynaptischen GABA‐Antworten legen nahe, daß eine direkte Verstärkung der postsynaptischen GABA‐Aktion kein gemeinsamer Mechanis‐mus der Antiabsencemittel darstellt. Die Antiepileptika DZP, CGS 98% und ZK 912% kehrten die DMCM‐Wirkung auf die GABA‐Antworten um, jedoch nicht die von PTZ, was ve

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05275.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY