bluuebunny/crossref_metadata_2025 huggingface dataset:
Biotin‐Responsive Infantile Encephalopathy: EEG‐Polygraphic Study of a Case
Authors: Colamaria Vito , Burlina Alberto B. , Gaburro Dino , Pajno‐Ferrara Franco , Saudubray Jean Marie , Merino Rosal Grimau , Bemardina Bernardo Dalla
Published: November 2007

Summary: A case of an infant suffering from progressive lethargy, sparse scalp hair, autistic‐like behavior, myoclonias, and drug‐resistant generalized seizures is reported. Laboratory investigations revealed, in the absence of metabolic acidosis, an increased urinary excretion of 2‐ketoglutaric acid and a small peak of 3‐hydroxyisovaleric acid. The serum biotinidase activity was 0.15 nmol min‐1 ml“(normal range 5.2 ± 0.9) in the propositus and 0.310 and 0.420 in her father and mother, respectively. The interictal EEG showed multifocal abnormalities; numerous seizures were recorded, with the pattern of true tonic‐clonic fits, exceptional in infancy. Also myoclonias, auditory myoclonus, and repetitive startles were documented. Because of dramatic improvement of ail symptoms and signs after starting biotin (5 mg twice daily), the authors suggest a therapeutical trial in all drug‐resistant infantile seizures.

Les auteurs rapportent un cas d'un nourrisson présentant une léthargie progressive, une chevelure clairsemée, un comporte‐ ment d'allure autistique, des myoclonies et des crises généralisées résistant aux traitements. Les examens de laboratoire ont mis en évidence, en l'absence d'acidose métabolique, une excrétion urinaire augmentée d'acide de céto‐glutarique, et un petit pic d'acide 3 hydroxy‐hydro‐valérique. l'activité biotinidase du sérum a étéévaluée à 0.15 nmol/mn/ml (valeurs normales (5.2 ± 0.9) chez la patiente, les chiffres étant respectivement de 0.31 et de 0.42 chez le père et la mère. l'EEG intercritique a montré des anomalies multi‐focales; de nombreuses crises ont été enregis‐trées, d'aspect lonico‐clonique vrai, ce qui est exceptionnel chez le nourrisson. Les auteurs ont aussi enregistré des myoclonies, un myoclonus réflexe aux stimulations auditives, et des sursauts répétitifs. Tous les sympôdmes ont été amétioris de façon im‐portante après mise en route d'un traitement par biotine (5 mg, 2 fois par jour); les auteurs suggèrent que ce type de traitement doit être essayé dans toutes les crises infantiles rebelles aux traitements.
Familial Occurrence of Benign Myoclonus of Early Infancy
Authors: Galletti F. , Brinciotti M. , Emanuelli O.
Published: November 2007

Summary: Three cases of benign myoclonus of early infancy (BMEI) were observed in the same family. Previously, only sporadic cases have been reported. Electroencephalogram (EEG) recordings were consistently normal, and the affected girls had normal neurological development. Therapy was not administered and the episodes spontaneously disappeared within the first months of life. While etiological mechanisms of BMEI are still unknown, a hereditary mechanism is now hypothesized on the basis of these cases.

On a observé trois cas de “benign myoclonus of early infancy” an sein d'une famille; jusqu‘à present seulement des cas sporadiques ont été rapportés. Les tracés EEG étaient tou‐jours normaux et les filles avaient un développement neu‐rologique normal. On n'a administré aucun traitment. Les épisodes de crises ont disparus spontanéinent dans les premiers mois de vie. On ne connait pas encore le mécanisme étiologique de ces spasmes bénins de la première enfance. Pour la première fois on peut hypotiser un mécanisme héréditaire sur la base de cette etude.

Se han observado tres casos de mioclonias benignas de la pri‐mera infancia en la misma familia. Previamente, solamente se han publicado casos esporádicos. Los registros de EEG fueron consisténtemente normales y las niñas afectas mostraron un de‐sarrollo neurológico normal. Los episodios desaparecieron es‐pontáneamente durante el primer mes de vida sin medicación alguna. Aunque los mecanismos etiológicos de las mioclonias benignas de la primera infancia permanecen desconocidos, se postula un mecanismo hereditario de acuerdo con lo observado en estos tres casos.

In einer Fainilie wurden 3 Fälle von benignem frühkindlichem Myoklonus beobachtet. Bisher wurde nur über sporadische Fälle berichtet. Die EEG‐Ableitung fiel konstant normal aus, die erkrankten Mädchen boten eine normale neurologische Entwick‐lung. Eine Therapie wurde nicht eingeleitet–die Zustände verschwanden innerhalb des ersten Lebensmonats. Während bisher die Aetiologie des benignen Myoklonus unbekannt ist, kann nun ein hereditärer Faktor aufgrund der dargestellten Fälle angenommen werden.
Cellular Mechanisms of Epilepsy and Potential New Treatment Strategies
Authors: Dichter Marc A.
Published: November 2007

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 to seizures, 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 “gating” pathways.
Designing Molecules: Specific Peptides for Specific Receptors
Authors: Hruby Victor J.
Published: November 2007

Summary:Peptides are the largest class of mediators of intercellular communication in the central nervous system. These molecules pose special problems in design for potential medical applications because of the high degree of flexibility, lack of high receptor selectivity, and ready biodegra‐dation or clearance. The global and local use of conformational constraints has overcome these difficulties. Structure‐biological activity relationships, molecular modeling, conformational analysis, conformational calculations, and molecular dynamics simulations can all be used to derive suitable lead structures and conformational models. Often, a single, constrained peptide analogue can be designed, which will have many of the desired biological and biophysical properties, and will serve as a template. Peptide analogues with high potency, exquisite receptor selectivity, and biological stability can be obtained. The approach is illustrated by the design of cyclic enkephalin‐ago‐nist analogues with exceptional δ‐opioid‐receptor selectivity, and of constrained somatostatin analogues that have become opioid peptides and possess potent opioid antagonist activities and exceptional selectivity for μ‐opioid receptors.
Hazards of Inference: The Active Control Investigation
Authors: Leber Paul D.
Published: November 2007

Summary: A finding of no significant difference in seizure incidence and/or severity among groups of epileptic patients prospectively randomized to treatment with either a standard or experimental antiepileptic drug is often advanced as compelling proof of the latter's anticonvulsant efficacy. Regrettably, the finding of no difference does not, on its own at least, support such a conclusion. A finding of no difference between treatments has numerous explanations that have nothing whatsoever to do with the pharmacological actions of the experimental drug. To be clear, it is possible to argue that a pharmacological effect is the most plausible explanation for a finding of no difference in an active control study, but this argument is only supportable if it is based on additional information gathered from sources external to the study. In most circumstances, the essential external evidence is not available, and the interpretation of the null difference as a positive result turns entirely upon the truth or falsity of the sanguine assumptions made. There is a risk in inferring efficacy from the seemingly consistent results of a series of active control studies that fail to find differences. Despite the long‐recognized deficiencies in the active control study design, it remains popular.
Juvenile Myoclonic Epilepsy: Long‐Term Response to Therapy
Authors: Penry J. Kiffin , Dean J. Christine , Riela Anthony R.
Published: November 2007

Summary: Data from 50 patients with juvenile myoclonic epilepsy (JME) were analyzed retrospectively to assess the response to drug therapy–long‐term seizure control, relapse rates, and confounding factors in seizure recurrence. Valproate is the only available antiepileptic drug that has been shown to be effective in controlling the generalized seizure components of JME–myoclonic, tonoclonic, and absence seizures–without significant side effects. Data were collected using the EpiMonitor software and represented case follow‐up from 2 months to 9 years. Forty‐three patients (86%) were seizure free for at least 1 year; 25 patients (50%) relapsed at some point during follow‐up. Relapses were precipitated most frequently by fatigue, noncompliance, stress, sleep deprivation, and alcohol consumption. With accurate diagnosis and appropriate therapy, seizures in JME can be adequately controlled, although JME is a chronic disorder that may require lifelong therapy. To minimize relapse, patient management must also focus on patient lifestyle to eliminate or control lifestyle‐associated precipitants of seizure relapse.
Antiepileptic Drugs, Cognitive Function, and Behavior in Children: Evidence from Recent Studies
Authors: Trimble M. R.
Published: November 2007

Summary: The effects of antiepileptic drugs (AEDs) on cognitive function and behavior in children are reviewed on the basis of published studies. Individual AEDs have been shown to differ–the deleterious effects of phenytoin generally contrasting with the relatively minimal effects of valproate and carbamazepine. Some of the differences between results may be attributed to the psychological tests used and to age differences. However, there appears to be a dissociation between AEDs that affect higher cognitive function, e.g., phenytoin, and those mainly affecting motor function, e.g., carbamazepine, which appears to increase speed of performance. AEDs should be prescribed with care in children with epilepsy, taking account of their differing effects on cognitive function and behavior.
Computerized Neuropsychological Assessment of Cognitive Functioning in Children with Epilepsy
Authors: Alpherts W. C. J. , Aldenkamp A. P.
Published: November 2007

Summary: The value of a range of computer‐aided tests in the neuropsychological assessment was investigated in 94–177 children with epilepsy, aged 8–18 years, compared with 68–161 controls in the same age group. Children from the age of 8 years could cope with rather complex tests in a wide range of functions: reaction time measurements, motor speed, information processing, and memory. The speed of performance tended to increase with age in both groups, with differences in information processing becoming apparent from the age of 12 years. The precise control of stimulus and response required to define the mainly minor differences between the epilepsy and control groups can only be fulfilled by computerized testing, which should undergo further refinement including voice and language recognition, followed by artificial intelligence.
Effects of Dextromethorphan, a Nonopioid Antitussive, on Development and Expression of Amygdaloid Kindled Seizures
Authors: Takazawa Akira , Anderson Paul , Abraham Wickliffe C.
Published: November 2007

Summary: The effects of dextromethorphan (DM), a nonopioid antitussive and a functional N‐methyl‐ D‐aspartate (NMDA) antagonist, on expression and development of amygdaloid kindled seizures were examined. The maximum anticonvulsant effect of DM (30 mg/kg) on fully kindled seizures appeared within 30 min of administration and lasted for at least 2 h. DM decreased, in a dose‐dependent manner [10–70 mg/kg, intraperitoneally (i.p.)], the severity of kindled seizures 30 min after injection, but the estimated ED50 was 3 times higher than the previously reported value for maximal electroshock convulsions. Furthermore, the high dose (70 mg/kg), while suppressing kindled seizures, produced myoclonus which coincided with EEG spike activity in the amygdala and the cortex. When tested on the development of kindling, 30 mg/kg DM retarded the growth of afterdischarge in the amygdala and the cortex, but had no effect on the development of behavioral seizures. DM 60 mg/kg accelerated development of kindling and produced spontaneous seizures. These results indicate that DM, unlike other NMDA antagonists, has a narrow therapeutic window as an anticonvulsant on kindled seizures and that higher doses may potentiate the kindling process.

Se nan examinado los efectos del dextrometorfano (DM), un antitusigeno no‐opiaceo y un antagonista functional del M‐ metil‐D‐aspartato (NMDA), sobre la expresión y desarrollo de los ataques condicionados (kindled) de la amigdala. El mayor efecto antoconvulsivo del DM (30 mg/kg) sobre los ataques plenamente condicionados (kindled) apareció durante los 30 min. después de la administración y duró, al menos, dos horas. El DM redujo, de una manera dosis‐dependiente, (10 a 70 mg/kg. i.p.) la severidad de los ataques condicionados 30 min después de la inyección pero la ED50 estimada fue de tres veces más elevada que los valores publiocados previamente para las convulsiones producidas por electroshock máximo. Además la dosis alta (70 mg/kg), aunque suprimía los ataques condicionados, produjo mioclinias que coincidieron con una actividad de puntas en el EEG, en la amígdala y en la corteza. Cuando se estudio su acción con respecto al desarrollo del condicionamiento (kindling), se observó que 30 mg/kg de DM retrasaron el incremento de la post‐ descarga en la amígdala y en la corteza pero no produjo efecto sobre el desarrollo de los ataques de comportamiento. También se observó que 60 mg/kg de DM aceleraron el desarrollo del condicionamiento y produjeron ataques espontáneos. Estos resultados indican que el DM, contrariamente a otros anatagonistas del NMDA, tiene una ventana terapéutica estrecha como anticonvulsivante sobre los ataques condicionados y que dosis más elevadas pueden potenciar el proceso de condicionamiento (kindling).
Status Epilepticus Characterized by Repetitive Asymmetrical Atonia: Two Cases Accompanied by Partial Seizures
Authors: Kanazawa O. , Kawai I.
Published: November 2007

Summary: Two cases of discontinuous status epilepticus (SE) characterized by repetitive asymmetrical atonic episodes associated with diffuse but asymmetrical spike waves are reported. Both patients also had partial seizures and interictal rolandic discharges. Dynamic EEG topography was performed to investigate the location or propagation of each ictal discharge overlying the scalp during status and showed immediate bilateral spread of discharges originating from a primary epileptogenic focus from a rolandic area.

Deux cas d'états de mal épileptiques discontinus caractéiisés par des épisodes atoniques asymétriques répéitifs associés avec des pointes‐ondes diffuses mais asymétriques sont rapportés par les auteurs. Les deux patients présentment également des crises partielles et des décharges rolandiques intercritiques. Une étude topographique dynamique de l'EEG a été réalisée afin de Préiser la localisation et la propagation de chaque décharge critique s'étendant sur le scalp pendant l'état de mal. Les auteurs ont mis en évidence une extension bilatérale immédiate des décharges prenant leur origine au niveau d'un foyer épileptique primaire de la région rolandique.

Se presentan dos casos de “status epilepticus” discontinuo caracterizados por episodios atónicos asimétricos y repetitivos asociados a puntas difusas pero asimétricas. Ambos pacientes tambtén tenfan ataques parciales y descargas rolándicas interictales. La topograffa del EEG dinámico, realizada para investigar la localización o propagacibn de cada descarga ictal sobre el cuero cabelludo durante el status, mostró una propagacidn bilateral inmediata de las descargas originadas de un foco epileptogénico primario en el área rolándica.

Es wird über 2 Fälle mit diskontinuieriichem Status epilepticus berichtet, die durch repetitive asymmetrische atonische Episoden charakterisiert sind und mit asymmetrischen Spike‐Wave einhergehen. Beide Patienten zeigten zusätzlich Partialanfälle sowie interiktale Rolando‐Entladungen. Es wurde eine dynamische EEG‐Topographie abgeleitet, urn die Lokalisation oder Fortpflanzung der jeweiligen iktalen Entladungen über der Schädeloberfläche während des Status zu untersuchen. Dies zeigte eine unmittelbare bilaterale Ausbreitung der Entladungen, die von dem primären epileptogenen Fokus über der Rolando'schen Gegend ihren Ausgang nahm.
Paroxysmal Kinesigenic Choreoathetosis with Abnormal Electroencephalogram During Attacks
Authors: Hirata Koichi , Katayama Soichi , Saito Tomoji , Ichihashi Kinya , Mukai Tadao , Katayama Mari , Otaka Takashi
Published: November 2007

Summary: An 18‐year‐old man with paroxysmal kinesigenic choreoathetosis (PKC) showed rhythmic electroen‐cephalographic (EEG) discharges of 5‐Hz spikes over the entire scalp during episodes. The EEG findings in this case suggest that PKC may have an epileptogenic basis.

Chez un jeune homme de 18 ans présentant une choréoathélose paroxystique kinésigénique (CPK), ľélectroencéphalogramme a mis en évidence des décharges rythmiques de pointes à 5 Hz couvrant toute ľétendue du scalp pendant les épisodes. Des constatations EEG recueillies dans ce cas suggèrent que la CPK pourrait étre ďorigine épileptique.

Un varón de 18 años de edad con coreoatetosis quinesigénica paroxística (PKC), mostró descargas electroencefalográficas clínicas de puntas de 5 Hz. en todo el cuero cabelludo durante los episodios. Los hallazgos del EEG en este caso sugieren que la PKC puede tener bases epileptogénicas.

Ein 18 jähriger Mann mit paroxysmaler kinesiogener Choreoathetose (PKC) zeigte rhythmische 5 Hz Spike Entladung wahrend einer Episode über dem gesamten Kopf. Dieser EEG‐Befund läßt vermuten, daß PKC möglicherweise eine epileptogene Grundlage haben.
Study of the Prevalence of Epilepsy Among Schoolchildren in Valladolid, Spain
Authors: Sangrador Carlos Ochoa , Luaces Rafael Palencia
Published: November 2007

Summary: A population study was performed to estimate the prevalence of epilepsy in the juvenile population of Valladolid, Spain. Using a mixed questionnaire (postal‐domiciliary), we studied a sample of 5,100 primary school pupils (aged between 6 and 14 years) and 48 pupils receiving state‐run special education. We also identified all the students receiving private special education and from specific special education centers belonging to the same age group (90 and 145, respectively). The prevalence of epilepsy in the school age population on December 1, 1987 was estimated at 5.72/1,000 inhabitants. Our results are comparable to those of other studies in Western countries.

Une étude de population a été effectuee afin d'évaluer la prévalence de éepilepsie dans la population juvénile de Valladolid, en Espagne. Les auteurs ont utilisé un questionnaire mixte (postal et domicileé) pour éludier un échantillon de 5,100 éleves d'école primaire, âgés de àà 14 ans, et 48 Aleves éenéficiant d'une éducation spécialisée publique. Les auteurs ont également identifyé tous les élèves recevant une éducation spécialisée privée ou fai‐sant partie de centres d'éducation spécialisée spécifiques et ap‐partenant au meme groupe d'age (n = 90 et 145 respectivement). La prevalence de I'epilepsie dans la population d'âge scolaire au ler décembre 1987 a été estimée à 5.72 pour mille. Ces résultats sont comparables à ceux d'autres éludes effectuées dans des pays occidentaux.

Realizamos un estudio de población para estimar la prevalencia de la epilepsia en la población infantil de Valladolid, España. Estudiamos mediante una encuesta mixta (correo‐domiciliaria) una muestra de 5,100 alumnos de Enseñanza General Básica (con edades entra 6 y 14 años) y 48 alumnos de Unidades de Educatión Especial (EE) públicas. Asimismo revisamos la totalidad de los alumnos de Unidades de EE privadas y Centros específicos de EE que pertenecían al mismo grupo de edad (90 y 145 respectivamente). La prevalencía de epilepsia en la poblacion en edad escolar con fecha de 1 de Diciembre de 1987 se estimó en 5,72 casos por mil habitantes. Nuestros resultados son equiparables a los obtenidos por otros autores en paises occidentales.

Die Studie wurde durchgeführt, um die Häufigkeit von Epilepsie bei Kindern in Valladolid (Spanien) zu ermitteln. Wir be‐nutzten einen gemischten Fragebogen,
Carbamazepine‐Induced Antinuclear Antibodies and Systemic Lupus Erythematosus‐Like Syndrome
Authors: De Giorgio Christopher M. , Rabinowicz Adrian L. , Olivas Regina D.
Published: November 2007

SUMMARY: A 20‐year‐old woman developed a systemic lupus erythematosus (SLE)‐like syndrome and a positive antinuclear antibody (ANA) soon after initiation of carbamazepine (CBZ) therapy. Symptoms and serology became normal after CBZ was discontinued. CBZ‐induced SLE is an important but underecognized phenomenom.

Una mujer de 20 años de edad desarrolló un síndrome parecido a un Lupus Eritematoso Sistémico (SLE) y anticuerpos antinucleares (ANA) positivos tras la initiateón de un tratamiento con carbamacepina (CBZ). Los síntomas y las serologías se normalizaron después de interrumpir la CBZ. La CBZ induce un importante pero poco reconocido cuadro de SLE.

Eine 20 jährige Frau entwickelte ein Lupus‐erythematodes ähnliches Syndrom mit positiven antinukleáren Faktoren kurz nach Beginn der Carbamazepintherapie. Symptome und Serologie normalisierten sich nach Absetzen von CBZ. Der CBZ‐induzierte LE stellt ein wichtiges aber zu weniges beachtetes Phänomen dar.
Clinical Pharmacology of Lamotrigine
Authors: Peck A. W.
Published: November 2007

Summary: The pharmacokinetics and pharmacodynamics of lamotrigine (LTG), a new antiepileptic drug (AED), were studied in healthy volunteers. In an open dose‐escalating study, LTG 240 mg produced peak plasma concentrations of around 3 μg/mg with no significant adverse events. Subsequent pharmacokinetic studies revealed complete oral absorption, first‐order kinetics with a mean half‐life of approximately 1 day, and elimination mainly as a glucuronide in the urine. Early studies in patients with epilepsy revealed more rapid metabolism when given with enzyme‐inducing AEDs and delayed metabolism by valproate. A placebo‐controlled, double‐blind study compared LTG 120 and 240 mg with phenytoin (PHT) 500 and 1,000 mg, and diazepam (DZP) 10 mg. Visual analogue scales showed sedation after PHT 1,000 mg and DZP 10 mg, but not after LTG. Smooth pursuit eye movements and adaptive tracking were impaired by DZP and PHT 1,000 mg. LTG did not affect these variables. A comparison of LTG 150 and 300 mg and carbamazepine (CBZ) 200, 400, and 600 mg demonstrated impairment of smooth pursuit and saccadic eye movements by CBZ 600 and 400 mg, but not by LTG. Additionally, CBZ 600 mg impaired adaptive tracking and increased body sway and heart rate. These studies have shown LTG to have desirable and predictable pharmacokinetic properties for an AED. Pharmacodynamic effects were absent, suggesting a high therapeutic index.
Reproductive Endocrine Considerations and Hormonal Therapy for Women with Epilepsy
Authors: Herzog Andrew G.
Published: November 2007

Summary: Animal experimental and human clinical investigations show that estrogens lower and progestins raise many seizure thresholds. In women, seizure frequency varies with the serum estradiol to progesterone ratio. The fluctuation of this ratio during the menstrual cycle is a major factor in catamenial epilepsy. A decline in serum antiseizure medication levels premenstrually may be another factor. Estradiol to progesterone ratios are elevated in anovulatory or inadequate luteal phase cycles. This may explain a propensity for seizure onset at the time of menarche and the exacerbation of seizures during the months or years leading up to menopause. It may also be an important factor in the association between reproductive endocrine disorders and epilepsy. Specifically, polycystic ovarian syndrome and hypogonadotro‐pic hypogonadism are significantly overrepresented among women with epilepsy. Epilepsy may promote the development of these disorders. These disorders, in turn, are characterized by inadequate luteal phase cycles that may promote the development or occurrence of seizures. In the setting of catamenial epilepsy or reproductive endocrine disorders, progestins, such as natural progesterone and parenteral medroxyprogesterone, or antiestrogenic agents, such as clomi‐phene, constitute rational and effective adjuncts to therapy.
Antiepileptic Drug Mechanisms of Action
Authors: Macdonald Robert L. , Kelly Kevin M.
Published: November 2007

Summary: Clinically used antiepileptic drugs (AEDs) decrease membrane excitability by interacting with ion channels or neurotransmitter receptors. Currently available AEDs appear to act on sodium channels, GABAA receptors, or calcium channels. Phenytoin, carbamazepine, and possibly valproate (VPA) decrease high‐frequency repetitive firing of action potentials by enhancing sodium channel inactivation. Benzodiazepines and barbiturates enhance GABAA receptor‐mediated inhibition. Ethosuximide and possibly VPA reduce a low‐threshold calcium current. The mechanisms of action of AEDs currently under development are less clear. Lamotrigine may decrease sustained high‐frequency repetitive firing. The mechanisms of action of felbamate are unknown. Gabapentin (GBP) appears to bind to a specific binding site in the central nervous system with a restricted regional distribution, but the identity of the binding site and the mechanism of action of GBP remain uncertain.
Teratogenic Effects of Antiepileptic Drugs: Implications for the Management of Epilepsy in Women of Childbearing Age
Authors: Lindhout Dick , Omtzigt Juliette G. C.
Published: November 2007

Summary:Exposure to antiepileptic drug (AED) treatment in utero occurs in 1 of every 250 newborns. The absolute risk of major malformations in these infants is about 7–10%, ˜3–5% higher than in the general population. Specific risk factors include high maternal daily dosage or serum concentrations of AED, low folate levels, polytherapy, and generalized seizures during pregnancy. Adverse pregnancy outcomes, including congenital heart malformations, facial clefts, spina bifida aperta, hypospadias, growth retardation, and psychomotor and mental retardation, are associated with, although not necessarily caused by, AED exposure. Specific cognitive defects, hypertelorism, and nail hypoplasia can be causally related to specific AED exposures. To prevent teratogenic side effects, the prospective mother should be treated with AEDs only when absolutely necessary. Monotherapy with the AED that is most effective in the lowest possible daily dose (divided into at least two or three administrations) should be prescribed. High‐dose folate supplementation (4–5 mg/day) reduces the risk of a neural tube defect in a child whose sibling had such a defect, but its impact on the specific teratogenic risks of AEDs is unknown. A substantial proportion of fetal malformations may be secondarily prevented by prenatal diagnosis, consisting of a fetal structural ultrasound examination at weeks 18 and 20 of gestation and, with VPA or CBZ administration, an α1‐fetoprotein analysis of amniotic fluid at week 16. Determination of a specific defect prevention strategy depends largely on parental attitudes toward prenatal diagnosis and termination of pregnancy, which should be discussed before conception. The availability of many new AEDs, many of which will be used in polytherapy, will make prospective evaluation of large numbers of pregnancy outcome on a population basis even more important in the future.
Standard Approach to Antiepileptic Drug Treatment in the United Kingdom
Authors: Chadwick David
Published: November 2007

Summary: In the United Kingdom, the question of whether to commence antiepileptic drug (AED) treatment remains controversial. Surveys indicate that 15% of patients are treated after a first seizure. Pediatricians often wait for a third or fourth seizure before treating, whereas clinicians who deal with adult patients are more likely to intervene early, largely because of concerns about driving and employment. Monotherapy is becoming the rule for the majority of patients. The four primary AEDs in the United Kingdom are carbamazepine and phenytoin (˜ 30% each), valproate (VPA; ˜25%), and phenobarbital (˜ 18%). For partial epilepsies, studies show few major differences in efficacy among these four AEDs. A first‐line AED should be one, such as VPA, with a broad spectrum of activity that is easily managed by clinicians who may not have special expertise in the recognition of differing seizure types and epilepsy syndromes. Where differences in efficacy are marginal, comparative drug toxicity may be a major factor in AED selection. Most new AEDs have low toxicity profiles. With respect to discontinuation, pediatricians usually recommend a trial discontinuation period in most children who achieve a 1‐ or 2‐year remission of epilepsy. For adults, however, overall relapse rates after discontinuation are – 401‐50%; therefore, patients usually opt for long‐term AED therapy.
New Antiepileptic Drugs Already Registered
Authors: Wolf P.
Published: November 2007

Summary: Vigabatrin, lamotrigine, and oxcarbazepine are three of the many new antiepileptic drugs (AEDs) already registered in several countries that highlight some of the typical problems and prejudices of new AEDs. Both the therapeutic action and the side‐effect profiles of new AEDs are only basically known with marketing. For all three of these new AEDs, antiepileptic effects have been demonstrated beyond doubt, but they still must withstand the test of clinical usefulness in substantial patient numbers. All three have some effect on focal seizures, but their clinical spectrum probably will turn out to be by no means uniform. These three AEDs are, in general, well tolerated, but it would be premature to compare their safety with traditional AEDs as one must be prepared for rare or delayed untoward effects that may be discovered later, as occurred with some older AEDs.
Vigabatrin: Effects on Human Brain GABA Levels by Nuclear Magnetic Resonance Spectroscopy
Authors: Mattson Richard H. , Petroff Ognen , Rothman Douglas , Behar Kevin
Published: November 2007

Summary: Vigabatrin (VGB, Sabril) is a new antiepileptic drug used for treatment of partial and secondarily generalized tonic‐clonic seizures. Many controlled short‐ and long‐term trials have established efficacy as add‐on therapy. Side effects have been infrequent. VGB acts as an irreversible substrate for 7‐aminobutyric acid (GABA) transaminase that leads to elevated brain GABA levels. Although this mechanism has been confirmed in animals and in cerebrospinal fluid of humans, we report the first study of brain GABA levels using noninvasive nuclear magnetic resonance spectroscopy. GABA elevation in brain closely parallels VGB dosage and reaches concentrations 2–3 times control values at daily dosage of 3 g. This technique offers promising potential to monitor changes induced by VGB as a function of time, dose, and clinical effect.
Oxcarbazepine: Clinical Development Program
Authors: Schwabe Stefan
Published: November 2007

Summary: Oxcarbazepine (OCBZ, Trileptal) is registered in several countries and has been well received by patients and physicians. However, newer standards in many other countries require additional data before registration can be achieved. For this reason, Ciba has implemented further clinical studies. OCBZ has a chemical structure that is closely related to carbamazepine (CBZ). In humans, OCBZ is not oxidatively metabolized, therefore causing little, if any, induction of hepatic enzymes. Because of this, and because of low protein‐binding properties, OCBZ causes markedly fewer interactions with concomitant medications than most marketed antiepileptic drugs. OCBZ has been shown to have significantly fewer limiting side effects (described as side effects leading to discontinuation of treatment) than CBZ, while showing comparable efficacy. Many patients who are hypersensitive to CBZ can be treated with OCBZ. The usually administered dosage of OCBZ is approximately 50% higher than that of CBZ. However, better tolerability of OCBZ makes it possible to give higher dosages. The plasma concentration half‐life of the active metabolite (monohydroxy derivative; MHD) makes it possible to administer OCBZ twice daily. No changes in dosage are necessary in patients with impaired renal function unless creatinine clearance is below 30 ml/ min. In patients with such severely reduced creatinine clearance, the dose of OCBZ should be halved. Specific questions e.g., such as whether OCBZ causes hepatic enzyme induction at higher doses and the effect of OCBZ on intrinsic sex hormones, will be answered in future studies. In addition, the tolerability and pharmacokinetics of OCBZ in specific target populations such as the elderly, children, and hepatically impaired patients will be addressed. This will enable a more complete delineation of the clinical profile of OCBZ, thereby helping physicians to decide how best to use OCBZ in their patients with epilepsy.
A Retrospective Study of 113 Epileptic Patients Treated with Sustained‐Release Valproate
Authors: Despland P.‐A.
Published: November 2007

Summary: 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.
Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms
Authors: Kraemer Diana L. , Awad Issam A.
Published: November 2007

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.
Future Directions for Functional Mapping
Authors: Perrine Kenneth
Published: November 2007

Summary: The intracarotid amobarbital procedure and direct cortical stimulation are commonly used techniques for functional mapping in candidates for epilepsy surgery. The role of these two procedures has been challenged recently. Emerging technologies recently applied to functional mapping include optical imaging, functional positron emission tomography studies, transcranial magnetic stimulation, magnetoencephalography, and fast magnetic resonance imaging. Studies have used these new technologies and the potential for these procedures to replace the established but more invasive techniques is being considered.
Antiepileptic Drugs in Pediatric Practice
Authors: Bourgeois Blaise F. D.
Published: November 2007

Summary: Several factors characterize the current medical treatment of epilepsy during childhood. Children do not present the same types of seizures or epilepsies as adults, and certain epilepsy syndromes are seen only during childhood. Accordingly, the choice of antiepileptic drugs (AEDs) may differ in children. In addition, certain medical therapies, such as ACTH or pyridoxine, are used only in children. It is also common practice to prescribe AEDs in children for indications that are “off‐label,” such as the treatment of partial‐onset seizures with car‐bamazepine before the age of 6 years. The natural history of epilepsy and the risk for seizure recurrence may be different in the pediatric age range, and this may influence the decision to institute chronic prophylactic therapy in children. Similar considerations may apply to the decision to discontinue AED therapy. The pharmacokinetics of several AEDs are age‐dependent, and dosages are more variable among patients. The adverse effects of AEDs may be age‐dependent, and the pattern of exacerbation of certain seizures by AEDs may be different in children. In addition, several new AEDs are now available, or are about to be released, and the preferential sequence of AEDs of choice in children with epilepsy will need to be reassessed as experience grows and as the results of comparative studies become available.
Antiepileptic Drug Monitoring: A Reappraisal
Authors: Mattson Richard H.
Published: November 2007

Summary: As clinical experience with the pharmacokinetic properties and optimal dosing of the established antiepileptic drugs (AEDs) has increased, frequent monitoring of AED concentration in the blood may be less necessary than it was 15 to 25 years ago. Monitoring continues to be valuable at initiation of treatment, addition or removal of other interacting drugs, at the time of unexpected seizure breakthrough, or when symptoms suggest AED toxicity. Occasional determination to monitor compliance may also be appropriate. Blood level determinations of certain of the new, less familiar AEDs, including felbamate, lamotrigine, and oxcarbazapine, appear to be useful. However, new approaches are needed to monitor the efficacy and possible toxicity of other new AEDs for which the correlation between blood concentration of AED and clinical outcome is less clear. For administration of these AEDs, including gabapentin, ti‐agabine, and vigabatrin, other indirect measures, such as determination of γ‐aminobutyric acid (GABA) levels in the cerebrospinal fluid or by nuclear magnetic resonance spectroscopy, may prove useful. For monitoring compliance, alternate technologies, such as a medication‐dispensing vial with an electronic memory chip, may be of clinical value. In the clinical management of patients with epilepsy, blood level monitoring plays an important role, but methods of using this monitoring have evolved with increased experience and the introduction of AEDs with new mechanisms of action.
Pharmacokinetic Profile of Topiramate in Comparison with Other New Antiepileptic Drugs
Authors: Perucca Emilio
Published: November 2007

Summary: Antiepileptic drugs (AEDs) in broad use today have a number of pharmacokinetic liabilities, including a propensity for clinically meaningful drug interactions. Therefore, new AEDs with improved pharmacokinetic characteristics would be welcomed. The pharmacokinetic proftles of six newer AEDs—topiramate (TPM), gaba‐pentin (GBP), vigabatrin (VGB), lamotrigine (LTG), ox‐carbazepine (OCBZ), and felbamate—were reviewed. Some of these AEDs offer an improvement in one or more pharmacokinetic parameters compared with traditional AEDs, with TPM, GBP, VGB, and OCBZ demonstrating the most advantageous overall pharmacokinetic profiles.
Topiramate as Adjunctive Therapy in Refractory Partial Epilepsy: Pooled Analysis of Data from Five Double‐Blind, Placebo‐Controlled Trials
Authors: Reife R. A. , Pledger G. W.
Published: November 2007

Summary: A pooled analysis of data from five similarly designed double‐blind, placebo‐controlled trials of topiramate (TPM) as add‐on therapy in patients with partial epilepsy was performed. The pooled analysis allowed evaluation of efficacy end points and response to treatment for a number of study subgroups not statistically evaluable in the individual study analyses due to limited sample sizes. The five trials included 534 patients, 360 who received TPM at target dosages of 200‐1,000 mg daily and 174 who received placebo. In the intent‐to‐treat pooled analysis, TPM was significantly (p≤ 0.01) superior to placebo in reducing total seizures by ≥ 75% or by 100%. When seizure types were evaluated independently, TPM significantly (p≤ 0.001) reduced the frequency of simple partial, complex partial, and secondarily generalized seizures. TPM was significantly (p≤ 0.001) better than placebo regardless of gender, patient age, baseline seizure rate, and concomitant AEDs. The efficacy of TPM in partial epilepsy is consistent across efficacy end points and across strata defined by study population characteristics.
Preliminary Open‐Label Experience with Topiramate in Primary Generalized Seizures
Authors: Biton Victor
Published: November 2007

Summary: Preliminary data concerning the effectiveness of topiramate (TPM) in the management of resistant primary generalized seizures were obtained from the open‐label extension of a double‐blind, placebo‐controlled trial of TPM. The controlled trial enrolled patients experiencing three or more primary generalized tonic‐clonic seizures (PGTCS) during an 8‐week baseline period. Twelve of 13 patients who completed double‐blind treatment elected to receive extended open therapy with TPM and were followed for periods ranging from 2 to 11 months. Of the 12 patients, 11 (92%) experienced a 50% or greater reduction in tonic‐clonic seizures during their last 2 months of open‐label TPM therapy compared to their pre‐double‐blind baseline period, and 7 (58%) were seizure‐free during the open extension. Of five patients reporting absence seizures at baseline, four (80%) demonstrated a 50% or greater reduction in seizures. In seven of the 12 patients, a concomitant antiepileptic drug (AED) was discontinued or its dosage was reduced during open TPM treatment. The most common adverse events observed in the open study extension were weight reduction (five patients), weight increase (two patients), and drowsiness (two patients). The results of controlled trials are needed to determine the efficacy of TPM in primary generalized seizures. However, these preliminary findings are encouraging.
Effect of Seizures and Epileptiform Discharges on Cognitive Function
Authors: Aldenkamp Albert P.
Published: November 2007

Summary: Several relationships have been obtained between cognitive impairment and epilepsy‐related or treatment‐related factors. One of these factors is treatment‐related: the central cognitive side effects of the antiepileptic drugs (AEDs). The second and third factors are disease‐related factors, i.e., the effect of the seizures and underlying epileptiform discharges in the brain and the localization of the epileptogenic focus in specific areas of the brain. Although most cognitive problems have a multifactorial origin and often several factors combined are responsible for the “make‐up” of a cognitive problem, we have attempted to isolate one factor: the effect of seizures and epileptiform EEG discharges on cognitive function. Several studies show the impact of ictal activity, but special attention is required for the postictal and interictal effects of epilepsy on cognitive functions. This may explain substantial cognitive impairments in children with subclinical epileptiform discharges or with infrequent subtle seizures.
Antiepileptic Drug Monotherapy Versus Poly therapy: Economic Aspects
Authors: Shorvon Simon
Published: November 2007

The costs of medical health care have increased worldwide in recent years, prompting health care authorities to examine methods to reduce health care expenditure. One method of achieving this is to examine the cost of drugs. As a result, the pharmacoeconomic aspects of monotherapy vs. poly‐therapy in epilepsy have come under close scrutiny. To assess the cost effectiveness of any intervention, both cost of treatment and effectiveness of therapy must be taken into account. The cost of polytherapy is higher than that of monotherapy, often because newer, more expensive antiepileptic drugs (AEDs) are used in combination with the traditional AEDs. Approximately 70% of patients with newly diagnosed epilepsy tolerate monotherapy well with traditional AEDs. The assessment of effectiveness of any intervention can be assessed by economic appraisal studies. Four types of analysis can be applied to epilepsy: cost minimization; cost effectiveness; cost utility; and cost benefit analyses. However, to date, the only published study that examines the addition of new AEDs to the therapy of patients with intractable partial epilepsy is a cost minimization analysis.
Monotherapy Clinical Trials of New Antiepileptie Drugs: Design, Indications, and Controversies
Authors: Chadwick David
Published: November 2007

Summary: The focus in assessing new antiepileptie drugs (AEDs) varies with the needs of the assessor. Patients and doctors seek evidence‐based clinical information, regulatory agencies look for efficacy and safety, and the health‐care industry demands data on the risk‐benefit ratio attached to a product. The pharmaceutical companies attempt to satisfy the interests of all parties involved. Most new AEDs obtain a first license based on placebo‐controlled, randomized clinical trials as add‐on therapy in patients with chronic refractory partial epilepsy, a method which, in fact, explores the efficacy of different drug combinations rather than measuring the efficacy of the new drug itself. Although that methodology satisfies the requirements of the licensing authorities, it fails to provide the clinical community with the information necessary to make rational treatment decisions, as would be derived from monotherapy studies. This article reviews controversies surrounding monotherapy studies and the design of comparative monotherapy clinical trials. A persuasive argument can be made that the goal of clinical trial design should be ethically acceptable, clinically meaningful studies in which new AEDs are compared with optimal doses of standard AEDs to inform clinical practice, meet licensing requirements, guide reasonable marketing efforts, and allow appropriate reimbursement.