bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnosis of Childhood Seizure Disorders
Authors: Murphy Jerome V. , Dehkharghani Fereydoun
Published: November 2007

Summary: Convulsive epilepsies are generally unmistakable. Absence epilepsies, which are easily recognized by the provocation of an episode during hyperventilation and by the typical features of the EEG, can be overdiagnosed, especially in the child who daydreams in class and has scattered, asymptomatic, epileptogenic EEG changes. As in adults, complex partial seizures in children can be difficult to distinguish from certain behaviors. Several types of benign childhood epilepsies need to be distinguished from the more intractable and lesional childhood epilepsies. Two common examples, benign rolandic epilepsy and benign occipital epilepsy, can be recognized by their unique EEG changes and clinical features. Juvenile myoclonic epilepsy generally does not remit spontaneously but should be recognized because it appears to respond to valproate. Some recurrent nonepileptic events seen in children can be mistaken for seizures, including shuddering attacks, paroxysmal vertigo, breath‐holding spells, cardiogenic syncope, night terrors, and movement disorders, such as paroxysmal kinesigenic choreoathetosis.
Clinical Pharmacology and Pharmacokinetics of Oxcarbazepine
Authors: Lloyd P. , Flesch G. , Dieterle W.
Published: November 2007

Summary: Oxcarbazepine (OCBZ) is a new antiepileptic drug (AED) structurally related to carbamazepine (CBZ) but differing in several important aspects, notably metabolism and induction of metabolic pathways. Consequently, OXCB has fewer drug‐drug interactions compared with CBZ. Absorption of OCBZ is rapid and complete. In animals it is responsible for the pharmacological effect. In humans, however, the parent compound is rapidly and extensively metabolized to a monohydroxy derivative (MHD), which is responsible for the therapeutic effect. Exposure to the MHD increases dose proportionally, and steady state is achieved after only three or four doses in a twice‐daily regimen. When given with food, systemic exposure to MHD increases by about 17%. MHD is eliminated with a half‐life of about 8–10 h. About 27% of the dose is recovered in the urine as unchanged MHD and a further 49% as a glucuronide conjugate of MHD. Results suggest that the kinetics of OCBZ should not be affected by impaired liver function. Impaired kidney function does not affect the kinetics of MHD; the glucuronide conjugate will, however, accumulate in these patients. The conversion of OCBZ to MHD is catalyzed by reductase enzymes, which are not subject to induction. Furthermore, OCBZ itself does not appear to induce the cytochrome P‐450 family in general, although it does induce the P‐450IIIA subfamily; which is responsible for the metabolism of estrogens and the dihydropyridine calcium‐channel blockers (e.g., nifedipine, felodipine). In patients, linear and dose‐proportional kinetics with no autoinduction of metabolism simplify OCBZ dosage adjustment.
Oxcarbazepine: Pharmacokinetic Interactions and Their Clinical Relevance
Authors: Baruzzi Agostino , Albani Fiorenzo , Riva Roberto
Published: November 2007

Summary: Antiepileptic drug (AED) interactions are a common problem during epilepsy treatment. Oxcarbazepine (OCBZ) is a keto homologue of carbamazepine (CBZ) with a completely different metabolic profile. In humans, the keto group is rapidly and quantitatively reduced to form a mono‐hydroxy derivative (MHD), which is the main active agent during OCBZ therapy. MHD is eliminated by renal excretion, glucuronidation and, marginally, by hydroxylation to a diol derivative. This metabolic profile, and in particular the limited involvement of oxidative microsomal enzymes, suggests that OCBZ may have fewer drug interactions compared with traditional AEDs. This possibility has been investigated in experimental studies and, retrospectively, in data obtained from clinical trials. The capacity of OCBZ to induce microsomal enzymes of the P‐450 family has mostly been examined by use of antipyrine and CBZ kinetics as markers. The results suggest that OCBZ has little enzyme inducing capacity. In clinical trials in which OCBZ was substituted for CBZ, plasma concentrations of concomitant AEDs were increased, possibly as a consequence of total or partial de‐induction. OCBZ interference with other drugs has been evaluated for warfarin, felodipine, and oral contraceptives, three medications strongly influenced by enzyme‐inducing AEDs. OCBZ does not modify the anticoagulant effect of warfarin, whereas some reduction in felodipine concentration and a clinically significant reduction of contraceptive drug levels and efficacy were observed. Polytherapy with established AEDs does not significantly modify OCBZ disposition (MHD kinetics); however, available information is not extensive. Finally, the action on OCBZ kinetics of a group of drugs (verapamil, cimetidine, erythromycin, dextropropoxyphene, and viloxazine) known to inhibit the metabolism of some AEDs has been studied. None of the drugs caused kinetic modification^ likely to be of clinical relevance. OCBZ has a favorable metabolic profile and fewer drug interactions compared with established AEDs. These findings should be confirmed by more clinical trials and use.
Clinical Development Outlook of Oxcarbazepine
Authors: Schwabe Stefan
Published: November 2007

Summary: Oxcarbazepine (OCBZ) has been accepted for registration as a first‐line antiepileptic drug (AED) in several countries. However, because of changing regulations, further studies confirming statistically significant proof of efficacy are necessary in accordance with new standards. Therefore, Ciba has initiated a worldwide clinical development program to achieve registration. Four different types of design to demonstrate statistically significant proof of efficacy in partial seizures will be initiated. These studies are a “classical” poly‐therapy add‐on study, a monotherapy substitution trial, a high‐dose/low‐dose active‐control monotherapy study, and a study in presurgical patients.

Anticonvulsants
Practical Aspects of Oxcarbazepine Treatment
Authors: Dam Mogens
Published: November 2007

Summary: In patients with refractory seizures, substitution of oxcarbazepine (OCBZ) for carbamazepine (CBZ) may be associated with reduced seizure frequency and an improved mental state. The recommended dosage of OCBZ as monotherapy for adults with epilepsy is 600‐1,200 mg orally per day but may be higher in patients with refractory seizures and in patients requiring combination therapy. When OCBZ is substituted for ongoing CBZ therapy, it is possible to change the dosage immediately so that the patient finishes treatment with CBZ on one day and starts with a full dosage of OCBZ on the next day, even when the full dosage is 50% greater in milligrams than the corresponding CBZ dosage. Allergic skin reactions are rare, and crossreactivity is seen in about 25% of patients hypersensitive to CBZ. Hyponatremia after the use of OCBZ is usually benign, as long as the acute water intoxication is effectively treated. Because of its pharmacokinetic advantages' and efficacy, we believe OCBZ is better than CBZ. We therefore consider OCBZ as the drug of first choice for conditions in which CBZ is currently indicated.
Oxcarbazepine: Mechanisms of Action
Authors: McLean M. J. , Schmutz M. , Wamil A. W. , Olpe H.‐R. , Portet C. , Feldmann K. F.
Published: November 2007

Summary: The antiepileptic drug (AED) oxcarbazepine (OCBZ) and its rapidly formed 10‐monohydroxy metabolite (MHD) protect against electroshock‐induced tonic hindlimb extension in rodents (ED50 14–21 mg/kg p.o.). Both stereoisomers of MHD also protect. As with carbamazepine (CBZ), these findings suggest clinical efficacy against generalized tonic‐clonic and, to some extent, partial seizures. OCBZ (IC50 5 × 108M), MHD (IC50 2 × 10‐8M) and CBZ (IC50 6 × 10‐7M) limit the frequency of firing of sodium‐dependent action potentials by cultured mouse central neurons and reduce Vmix progressively in a use‐dependent manner at concentrations below therapeutic plasma concentrations in OCBZ‐treated patients. This suggests that blockade of voltagesensitive sodium channels could contribute to the antiepileptic efficacy of OCBZ. Blockade of penicillin‐induced epileptiform discharges in hippocampal slices by MHD and its stereoisomers was diminished when the potassium channel blocker 4‐aminopyridine was added to the bath fluid. This indicates that additional mechanisms of action, e.g., an effect on potassium channels, might be clinically important. In addition, both stereoisomers are equally responsible for the antiepileptic activity of the racemate, i.e., MHD, and are therefore likely to play a therapeutic role. Such actions could confer broad clinical utility on OCBZ.
Mechanisms of Action of Currently Prescribed and Newly Developed Antiepileptic Drugs
Authors: Macdonald Robert L. , Kelly Kevin M.
Published: November 2007

Summary: Clinically available antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium (Na) channels, ‐y‐aminobutyric acidA (GABAA) receptors, or calcium (Ca) channels. Benzodiazepines and barbiturates enhance GABAA‐receptor‐mediated inhibition. Phenytoin, car‐bamazepine and, possibly, valproate (VPA) decrease high‐frequency repetitive firing of action potentials by enhancing Na channel inactivation. Ethosuximide and VPA reduce a low threshold (T‐type) Ca‐channel current. The mechanisms of action of recently developed AEDs are less clear. Lamotrigine may decrease sustained high‐frequency repetitive firing of voltage‐dependent Na action potentials, and gabapentin (GBP) appears to bind to a specific binding site in the CNS with a restricted regional distribution. However, the identity of the binding site and the mechanism of action of GBP remain uncertain. The antiepileptic effect of felbamate may involve interaction at the strychnine‐insensitive glycine site of the Af‐methyl‐D‐aspartate receptor, but the mechanism of action is not yet proven.
Lamotrigine Versus Other Antiepileptic Drugs: A Star Rating System Is Born
Authors: Brodieg Martin J.
Published: November 2007

Summary: With the launching worldwide of a range of new antiepileptic drugs (AEDs), the prescriber has a much wider choice than ever before. Comparative studies between new and established AEDs are few, and those between new AEDs are rarely performed. This report considers the strengths and weaknesses of nine new and established AEDs. Scores ranging from ‐2 to +2 are given under six headings: mechanism of action, pharmacokinetics, efficacy, side effects, drug interactions, and a comfort factor. Perceived advantages and disadvantages in their clinical use are summarized and a final “star rating” produced for each. This process is illustrated by a detailed critique of lamotrigine (LTG). The star system is intended to stimulate dialogue among epileptologists in reaching a consensus in the pharmacologic management of the epileptic patient.
Felbamate in the Treatment of Lennox‐Gastaut Syndrome
Authors: Jensen Peder K.
Published: November 2007

Summary: Felbamate (FBM, Felbatol/Taloxa), a new an‐tiepileptic drug (AED), was tested in a placebo‐controlled add‐on design in 73 patients with therapy refractory Lennox‐Gastaut syndrome. Results of the efficacy analysis showed that FBM was statistically significantly more effective (p < 0.05) than placebo for four of five predefined efficacy variables. The total number of seizures, for example, decreased by 26% during treatment with FBM compared with an increase of 5% during placebo (p < 0.001). Retrospective analysis of percentage of patients with specific response rates confirmed results of the predefined efficacy variables. Approximately 50% of patients randomized to FBM obtained at least a 50% reduction in seizure frequency compared with about 15% receiving placebo. In addition, 12‐month follow‐up data in patients who completed the controlled part of the study confirmed the long‐term efficacy of FBM. In general, FBM was well tolerated, with only gastrointestinal symptoms and somnolence seen more often with FBM compared with placebo. FBM is the first compound shown to be effective in a controlled study in patients with Lennox‐Gastaut syndrome.
Felbamate in the Treatment of Partial‐Onset Seizures
Authors: Bourgeois Blaise F. D.
Published: November 2007

Summary: Felbamate (FBM, Felbatol/Taloxa) has been the object of several trials that are innovative and unique. First, FBM is the first antiepileptic drug (AED) to have been submitted to a controlled efficacy study in patients with the Len‐nox‐Gastaut syndrome (LGS) before being submitted for regulatory approval. Second, FBM was tested in patients discontinued from other AEDs for presurgical monitoring. Third, FBM was the first experimental AED to have been tested in controlled monotherapy trials. Overall, these studies succeeded in demonstrating that FBM is relatively safe and effective against both partial‐onset seizures and the generalized seizures occurring in the LGS. The results of some of these studies could not always be expressed by using the more familiar concept of percent seizure reduction because, for ethical reasons, the efficacy variable had to be defined in terms of time to the nlh seizure or in terms of escape criteria. This may make it more difficult to evaluate just how effective FBM is in comparison with other AEDs. Another reason why the efficacy of FBM cannot yet be fully assessed is that in all the studies the FBM dosage was limited to a maximum of 3,600 mg/day or 45 mg/kg/day. At this dosage, FBM produced no toxicity in the majority of patients, and its full therapeutic effect may have to be re‐evaluated in the future at higher dosages.
Tiagabine: A Novel Drug with a GABAergic Mechanism of Action
Authors: Gram Lennart
Published: November 2007

Summary: The various possibilities for manipulating the γ‐aminobutyric acid (GABA) system to augment GABAergic inhibition have been surveyed with reference to the relevant antiepileptic compounds that have been successfully or unsuccessfully investigated in relation to these different mechanisms of action. The first clinical studies of tiagabine (TGB), a novel GABA‐uptake inhibitor are now available. These studies utilized a novel design, the enrichment (Amery) design, which is put into perspective compared to classical clinical trial designs. Possible advantages and disadvantages of TGB, as seen at this stage in development, have been identified.
MRI‐Based Hippocampal Volume Measurements in Epilepsy
Authors: Jack Clifford R.
Published: November 2007

Summary: In the study of brain morphometry, it is accepted that a relationship exists between brain structure and function, both normal and abnormal. One descriptor of morphometric structure is volume. Abnormalities in hippocampal morphology, including unilateral or bilateral volume loss, are known to occur in epilepsy, Alzheimer's disease, and in certain amnestic syndromes. Precise quantitation should improve understanding of the role of any biologic system in normal function and in disease. The objectives of magnetic resonance (MR)‐based hippocampal volume measurements are precise quantitation, identification of a normal range, and identification of the association between biologic variables and aberrations in this volumetric parameter. Volumetric measures introduce a level of precision in the estimation of hippocampal size that is not available simply by visually inspecting a set of MR images, thus enabling statistically based hypothesis testing. To produce accurate hippocampal volume measurements with magnetic resonance imaging (MRI), attention must be directed to the two major components of the operation as a whole, MR image acquisition and image processing.
Magnetic Resonance Imaging in Developmental Disorders of the Cerebral Cortex
Authors: Kuzniecky Ruben I.
Published: November 2007

Summary: Developmental disorders of the neocortex are commonly associated with epilepsy. The development of magnetic resonance imaging (MRI) has advanced our understanding of these disorders by permitting accurate recognition and clinical correlation during life. These disorders have multiple etiologies and are dependent on the time of injury to the developing nervous system. MRI has permitted the classification of these malformations in three major groups: generalized disorders, unilateral hemispheric, and focal disorders. Generalized disorders include lissencephaly, pachygyria, band heterotopia, and subependymal heterotopias. Hemimegalencephaly comprised the unilateral disorder. Focal lesions include focal cortical dysplasia, polymicrogyria, schizencephaly, and focal subcortical heterotopias. The information provided by MRI, in conjunction with the clinicoelectrographic features, is extremely important in the recognition of these syndromes and for the appropriate medical and surgical management of those patients with epilepsy.
Clobazam, Oxcarbazepine, Tiagabine, Topiramate, and Other New Antiepileptic Drugs
Authors: Fisher Robert , Blum David
Published: November 2007

Summary: Clinical investigators recently have studied at least 21 new antiepileptic drugs (AEDs) in people with epilepsy. This review briefly examines 15 of these new AEDs: clobazam (CLB), dezinamide, flunarizine (FNR), loreclezole, milacemide (MLM), MK‐801, nafimidone, ORG‐6370, oxcarbazepine (OCBZ), progabide (PGB), ralitoline, stiripentol, tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS). CLB, PGB, and TGB represent agents that act on the GABA system, and MLM acts on the glycine system. MK‐801 and ZNS (in part) are excitatory amino acid antagonists, and FNR is a calcium‐channel antagonist. OCBZ is a keto analogue of carbam‐azepine, which is not metabolized to the epoxide and may have fewer side effects. The remaining agents are novel compounds with a variety of suspected mechanisms. TPM appears especially effective for intractable partial seizures but has a high incidence of cognitive side effects. None of these new AEDs is useful for all patients with inadequate seizure control or ongoing toxicity. The role of each will require further clinical study and experience.
Rational Polypharmacy
Authors: Ferrendelli James A.
Published: November 2007

Summary: The medical treatment of seizure disorders is a complex process, requiring extensive interaction and cooperation between physician and patient. The physician must have an accurate diagnosis of the patient's illness and a comprehensive understanding of seizures and seizure disorders. The physician must consider specific individual characteristics of the patient, especially those that will influence the choice of medical therapy, and the interrelationship between the patient's lifestyle and the seizure disorder must be appreciated to maintain an optimal quality of life. Finally, the physician must have a thorough understanding of the pharmacology of antiepi‐leptic drugs (AEDs) and experience with their therapeutic applications. It is important for patients to be fully involved in the treatment of their illness. Each patient should be informed about their disorder, should be involved in all therapeutic plans and strategies, and should be a responsible and active participant in treatment.
Antiepileptic Drug Mechanisms of Action
Authors: Macdonald Robert L. , Kelly Kevin M.
Published: November 2007

Summary: Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, γ‐ami‐nobutyric acid type A (GABAA) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABAA receptor‐mediated inhibition. Phenytoin (PHT), carbamazepine (CBZ), and possibly valproate (VPA) decrease high‐frequency repetitive firing of action potentials by enhancing sodium‐channel inactivation. Ethosuximide (ESM) and VPA reduce a low threshold (T‐type) calcium‐channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin (GBP) binds to a high‐affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of GBP into neurons; however, this has not been proven, and the mechanism of action of GBP remains uncertain. Lamotrigine (LTG) decreases sustained high‐frequency repetitive firing of voltage‐dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high‐frequency repetitive firing of voltage‐dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underlie the clinical efficacy of VGB.
Vigabatrin
Authors: Ben‐Menachem Elinor
Published: November 2007

Summary: γ‐Aminobutyric acid (GABA) was first proposed as a putative inhibitory neurotransmitter by Elliot and van Gelder in 1958. Since then, numerous efforts have been made to find ways to increase GABA at its receptor sites, based on the findings that decreased GABA results in convulsions in animals and that agents enhancing GABA‐mediated functions can have antiepi‐leptic effects. However, the relationship between GABA levels and seizures is not simple. Seizures can occur even in the presence of elevated GABA levels. Indeed, it is possible that regional biochemical differences in the brain can be important. The antiepileptic effects of GABA depend on the mechanism whereby GABA‐mediated inhibition is enhanced. Since the 1970s, several compounds have been developed that are designed to act in some manner on the GABA system. These compounds affect GABA‐mediated inhibition at different levels and appear to have varied effects, depending on their mechanism of action. To date, specific antiepileptic drugs (AEDs) with potential GABA‐inhibitory effects have been designed either to have GABA agonist properties, to inhibit GABA catabolism, to inhibit GABA uptake, or to facilitate GABA release or facilitate GABAA receptor activity. Vigabatrin (VGB) was designed specifically to inhibit GABA transaminase and thereby increase the availability of GABA in the brain. Study data and clinical experience over the past 14 years have demonstrated VGB to be an effective AED.
Important Pharmacokinetic Properties of Antiepileptic Drugs
Authors: Bourgeois Blaise F. D.
Published: November 2007

Summary: The choice of an antiepileptic drug (AED) is guided primarily by efficacy and safety criteria. However, the pharmacokinetic properties of an AED determine its ease of use, i.e., its ability to predictably produce and maintain optimal plasma concentrations. Desirable and clinically important pharmacokinetic properties of an AED include complete or constant bioavailability, slow enteral absorption or availability of a sustained‐release formulation, availability of a parenteral formulation for acute treatment, rapid penetration into the brain, a single‐compartment volume of distribution, low and nonsaturable protein binding, and linear elimination kinetics, with an elimination half‐life of about 24 h. The absence of autoinduction of enzymatic biotransformation, active metabolites, and pharmacokinetic drug interactions is also important. In clinical practice, the most undesirable pharmacokinetic properties are lack of a parenteral formulation, short elimination half‐life, nonlinear elimination kinetics, autoinduction of enzymatic biotransformation, and interaction with other drugs. No AED is presently marketed or under development that meets all of the desirable criteria. Some of the newer AEDs, although not “ideal” agents, have pharmacokinetic profiles that are not shared by their predecessors, including elimination exclusively by the kidney, absence of drug interactions, and dose‐related bioavailability.
Cytochrome P450 Isozymes and Antiepileptic Drug Interactions
Authors: Levy René H.
Published: November 2007

Summary: Recent findings about individual isoforms of the cytochromes P450 involved in the metabolism of phe‐nytoin (PHT) and carbamazepine (CBZ) make prediction of inhibition‐based interactions possible. PHT is eliminated principally by hydroxylation top‐HPPH, a reaction catalyzed primarily by CYP2C9 and secondarily by CYP2C19 (S‐mephenytoin hydroxylase). The principle of isoform specificity (drugs metabolized by the same iso‐form should exhibit interactions with the same inhibitors) was applied to the interactions of PHT with 17 inhibitors using two probes for CYP2C9, S‐warfarin and tolbutamide. Eleven of 17 interactions (sulfaphenazole, phenylbutazone, fluconazole, azapropazone, cotrimoxazole, propoxyphene, miconazole, amiodarone, disulfiram, metronidazole, and stiripentol) could be explained by inhibition of CYP2C9. The remaining interactions (felbamate, omeprazole, cimetidine, fluoxetine, imipramine, and diazepam) were attributed to inhibition of CYP2C19. For CBZ, studies utilizing chemical inhibitors, immunoinhibition, liver bank correlations, and expressed enzymes established that CYP3A4 is the main enzyme catalyzing formation of CBZ‐10, 11‐epoxide. This explains the pronounced interactions of CBZ with erythromycin, tro‐leandomycin, and other macrolide antibiotics (clarithromycin, josamycin, flurythromycin, and ponsinomycin). Work is in progress to explain the interactions of CBZ with other inhibitors. The literature contains no other information on isoforms involved in the metabolism of other major antiepileptic drugs.
Tiagabine Monotherapy in the Treatment of Partial Epilepsy
Authors: Schachter Steven C.
Published: November 2007

Summary: Three studies were conducted to assess tiagabine (TGB) hydrochloride monotherapy in patients with partial seizures. The first was a double‐blind, placebo‐controlled trial of 11 patients (seven TGB, four placebo) undergoing evaluation for epilepsy surgery. Baseline antiepileptic drug (AED) therapy was discontinued abruptly before monotherapy. Although 24‐h seizure rates increased during monotherapy in both groups, patients receiving TGB experienced fewer seizures than placebo patients. Subsequent studies (an open‐label, dose‐ranging study; n= 31 and a double‐blind, randomized comparison of 6 and 36 mg/day TGB; n= 102 and 96, respectively) involved discontinuation of baseline AEDs. In the dose‐ranging study, 19 of 31 patients (61%) converted to TGB monotherapy, with a mean final dose of 38.4 mg/day (range 24–54 mg/day) in those who completed the study (n= 12). In the low‐ vs. high‐dosage study, median 4‐week complex partial seizure rates decreased significantly in patients from both dose groups who completed the monotherapy period (p<0.05 compared with baseline). In the intent‐to‐treat analysis, significantly more patients in the high‐dose group experienced a reduction in seizures of at least 50% compared with the low‐dose group (p= 0.038). Overall, the types of adverse events with TGB monotherapy were similar to those observed in add‐on trials. These initial trials in difficult‐to‐treat epilepsy patients indicate that TGB monotherapy may provide a new approach to the treatment of patients with partial seizures refractory to other AEDs.
Tiagabine Pharmacology in Profile
Authors: Brodie Martin J.
Published: November 2007

Summary: Tiagabine (TGB) hydrochloride, a nipecotic acid derivative linked to a lipophilic anchor, potently and specifically inhibits uptake of the inhibitory neurotransmitter γ‐aminobu‐tyric acid (GABA) into astrocytes and neurons. With microdial‐ysis, TGB has been shown to increase extracellular overflow of GABA in the midbrain of awake rats. TGB administration prolongs neuronal depolarization induced by iontophoretically applied GABA in hippocampal slices. TGB is effective in a wide range of seizure models, including pentylenetetrazol‐induced, methyl‐6,7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐car‐boxylate (DMCM)‐induced tonic, amygdala‐kindled and picro‐toxin‐induced convulsions, and maximal electroshock seizures in rodents. In humans, TGB absorption is rapid and complete. It is metabolized in the liver, largely by isoform 3A of the cytochrome P450 family of enzymes. The process of elimination is linear, with a half‐life of 5–8 h. TGB does not induce Or inhibit metabolic processes, although it provides a target for enzyme inducers that can lower its elimination half‐life to 2–3 h. Accordingly, TGB does not alter the concentrations of other antiepileptic drugs (AEDs), with the possible exception of a small decrease in valproate levels. A controlled‐release formulation of TGB would offset any potential clinical disadvantage of the short elimination half‐life, particularly in patients receiving concurrent treatment with enzyme‐induced AEDs.
Neuroimaging in Pediatric Epilepsy
Authors: Kuzniecky Ruben I.
Published: November 2007

Summary: Neuroimaging techniques have advanced the diagnosis, management, and understanding of the patho‐physiology underlying the epilepsies. High‐resolution ultrasound is an important and useful technique in the investigation of prematures and neonates with seizures. Computed tomography (CT) scans have a diminishing role in the investigation of patients with epilepsy, but in the absence of magnetic resonance imaging (MRI), CT may detect gross structural pathology. MRI is the technique of choice for investigation of patients with seizure disorders. MRI provides excellent anatomic information and tissue. Contrast, resulting in high sensitivity. MRI studies should be customized to answer the appropriate clinical question. Functional imaging techniques including single photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance spectroscopy, and functional MRI are becoming increasingly important in the investigation and management of patients with seizures. These techniques permit noninvasive assessment of the epileptic substrate, functional status, ictal activity, blood flow changes, metabolism, and neuroreceptors. Application of these new techniques promises to advance our understanding and treatment of seizures in children.
Surgery for Catastrophic Localization‐Related Epilepsy in Infants
Authors: Wyllie Elaine
Published: November 2007

Summary: Cortical resection or hemispherectomy has been reported to result in cessation or dramatic reduction of seizures for small numbers of highly selected infants with severe, intractable epilepsy and developmental delay. However, identification of potential surgical candidates during infancy can be especially challenging because seizure semiology and EEG may sometimes give limited localizing information, e.g., in patients with infantile spasms and hypsarrythmia due to focal cortical dys‐plasia or a tumor. In infants as well as older patients, the location of a potentially resectable epileptogenic lesion must be defined by convergence of results from video EEG, anatomic and functional neuroimaging, and clinical examination. Reported outcomes after surgery in small series include 78% of 23 infants seizure‐free or with at least 90% seizure reduction (1993 University of California at Los Angeles series), and 75% of 12 infants seizure‐free or with rare seizures (1995 Cleveland Clinic series). A tendency of “catch‐up” developmental progress after surgery was observed in both series. A few reports of smaller groups of infants noted similar results. Prospective studies are in progress to better define the potential risks and benefits of early surgical intervention for infants and catastrophic localization‐related epilepsy.
Utilization of New Antiepileptic Drugs in Children
Authors: Pellock John M.
Published: November 2007

Summary: Studies of the newer antiepileptic drugs suggest that they are exciting additions with improved efficacy and a perhaps decreased toxicity in certain types of refractory childhood epilepsy. In some very rare syndromes only anecdotal reports exist and further study is needed. Issues of tolerability, long‐term safety in very young children, and effects on learning, behavior and other cognitive functions must be balanced with the possibility of improved efficacy. Additional well‐controlled studies taking into account both seizure types and epilepsy syndromes are very much needed in neonates, infants, school aged children and adolescents.
Alternative Epilepsy Therapies: The Ketogenic Diet, Immunoglobulins, and Steroids
Authors: Prasad Asuri N. , Stafstrom Carl F. , Holmes Gregory L.
Published: November 2007

Summary:Despite the continued development and release of new antiepileptic drugs (AEDs), many children have seizures that do not respond to conventional therapy or have related side effects that preclude continued use. While some of these children are surgical candidates, the majority do not qualify for surgical resection. In these children alternative therapies are often considered by desperate physicians and parents. Three of the less conventional therapies which are currently used for intractable epilepsy are: the ketogenic diet, immunoglobulins, and steroids. None of these therapies has been adequately studied and it remains unclear which patients may benefit or be harmed by these therapies. Despite the lack of scientific vigor in evaluating these therapies, the television and print media has proclaimed these therapies as miraculous, yet grossly under‐utilized by an ignorant medical community. The ketogenic diet has been demonstrated to reduce seizure frequency in some patients, but has an unclear mechanism of action, while immunoglob‐ulins have both unknown efficacy and an unknown mechanism of action. While steroids are accepted as an effective therapy for infantile spasms, their role in the treatment of the Landau‐Kleffner syndrome is far less clear. Although the ketogenic diet, immunoglobulins, and steroids may have a role in the treatment of severe childhood epilepsy, all three therapies need to be critically evaluated in regard to efficacy, mechanism of action, and safety.
Drug Interaction Profile of Topiramate
Authors: Bourgeois Blake F. D.
Published: November 2007

Summary: In separate studies, potential pharmacokinetic interactions of topiramate (TPM) with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated. TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800 mg/day, after which the baseline drug was discontinued, when possible. Addition of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ‐E). Modest increases in PHT plasma levels in six of 12 patients treated with PHT and TPM, and a small mean decrease in VPA levels noted in patients receiving VPA with TPM, were considered unlikely to require adjustments in the dosage of the concomitant AED when TPM is added or discontinued. When patients were changed from concomitant therapy with PHT or CBZ to TPM monotherapy, TPM clearance was reduced by approximately 50%, suggesting that an adjustment in TPM dose may be required when PHT or CBZ is discontinued from TPM‐treated patients. A slight increase in plasma TPM levels during monotherapy compared to concomitant therapy with VPA was considered clinically insignificant and not likely to require TPM dosage adjustment. In another study, oral clearance of digoxin was slightly increased when TPM was added, resulting in a small decrease in peak plasma levels of digoxin. In vitro studies conducted to date on a number of specific cy‐tochrome P450 isoforms show an effect of TPM only on the CYP2Cmeph isoform. The risk for clinically meaningful changes in plasma levels of traditional AEDs when TPM is added to or discontinued from concomitant regimens appears to be minimal. However, adjustments in TPM dosages are likely to be needed when potent enzyme inducers, such as PHT or CBZ, are added or discontinued. TPM has a relatively low propensity for clinically significant drug interactions, and its pharmacokinetic and drug interaction profiles represent a clear advance over those of the traditional AEDs.
Clinical Administration of New Antiepileptic Drugs: An Overview of Safety and Efficacy
Authors: Chadwick David W. , Marson Tony , Kadir Zakaria
Published: November 2007

Summary: Gabapentin, lamotrigine, tiagabine, topira‐mate, vigabatrin, and zonisamide are all administered as add‐on therapy for treatment of patients with refractory epilepsy. To date, no comparative randomized trials have been performed that could potentially allow an evidence‐based choice to be made between these antiepileptic drugs (AEDs). We report a series of meta‐analyses of placebo‐controlled, randomized add‐on trials in patients with partial epilepsy. Results of these meta‐analyses are compared, thus giving broad estimates of the comparative efficacy and tolerability of these AEDs. The efficacy out come is the odds ratio for the number of patients with a ≥50% reduction in seizure frequency. Reported side ef fects are also used as tolerability outcomes, and study withdrawal is used as a global outcome measure. Results are summarized as odds ratios with 95% confidence in tervals (CIs). When each outcome is compared among drugs, the 95% CIS overlap. Therefore, no conclusive ev idence of a difference in efficacy or tolerability between these AEDs was derived, even though the apparently most effective agent (topiramate) may be twice as effec tive as the apparently least effective agent (lamotrigine). Comparative randomized studies are needed to further evaluate these drugs.
Update on the Mechanism of Action of Antiepileptic Drugs
Authors: Meldrum Brian S.
Published: November 2007

Summary: Novel antiepileptic drugs (AEDs) are thought to act on voltage‐sensitive ion channels, on inhibitory neurotransmission or on excitatory neurotransmission. Two successful examples of rational AED design that po tentiate GABA‐mediated inhibition are vigabatrin (VGB) by irreversible inhibition of GABA‐transaminase, and ti‐agabine (TGB) by blocking GAB A uptake. Lamotrigine (LTG) prolongs inactivation of voltage‐dependent sodium channels. The anticonvulsant action of remacemide (RCM) is probably largely due to blockade of NMDA receptors and prolonged inactivation of sodium channels induced by its desglycinated metabolite. Felbamate (FBM) apparently blocks NMDA receptors, potentiates GABA‐mediated responses, blocks L‐type calcium channels, and possibly also prolongs sodium channel inactivation. Similarly, to piramate (TPM) has multiple probable sites of action, including sodium channels, GABA receptors, and glutamate (AMPA) receptors. Gabapentin (GBP) apparently has a completely novel type of action, probably involving potentiation of GABA‐mediated inhibition and possibly also inactivation of sodium channels. The therapeutic advantages of the novel AEDs are as yet only partially explained by our present understanding of their. Mechanisms of action.
Current Issues in the Management of Epilepsy: The Impact of Frequent Seizures on Cost of Illness, Quality of Life, and Mortality
Authors: Baker Gus A. , Nashef L. , van Hout Ben A.
Published: November 2007

Summary: Cost of illness, quality of life (QOL), and sudden unexpected death in epilepsy are disease‐related issues that have become increasingly prominent. Because new treatments for epilepsy are now becoming widely available, it is useful to attempt to determine the clinical factors most closely correlated with high disease management costs, excess mortality, and reduced QOL as a basis for considering whether new antiepileptic drugs (AEDs) or AED regimens may favorably influence these aspects of the chronic condition. Findings of recent studies in these diverse areas of epilepsy research indicate that a common clinical factor, seizure frequency, is closely associated with poorer outcomes with respect to cost of illness, QOL, and mortality. To the extent that newer AEDs can provide clinically significant reductions in seizure frequency among patients currently not optimally controlled with AEDs, a meaningful incremental benefit in each of these areas is a reasonable hypothesis. Prospective studies to assess the impact of better seizure control on these important outcomes are warranted.
Overview of the Safety of Newer Antiepileptic Drugs
Authors: Shorvon S. , Stefan H.
Published: November 2007

Summary: Standard antiepileptic drugs (AEDs) are associated with a wide variety of acute and chronic adverse events and with many interactions with each other and with non‐AEDs that complicate patient management. The safety and interaction profiles of the newer AEDs have also been intensively studied. Safety data are available for six of the newer AEDs, lamotrigine (LTG), vigabatrin (VGB), gabapentin (GBP), tiagabine (TGB), felbamate (FBM), and topiramate (TPM). The potential for the most recently developed AEDs for producing rare idiosyncratic reactions cannot be ascertained until additional patient exposures have been reported from careful postmarketing surveillance.
Practical Aspects of the Use of Topiramate in Patients with Epilepsy
Authors: Sander J. W. A. S.
Published: November 2007

Summary: Practical recommendations for the treatment of patients with the new antiepileptic drug (AED) topiramate (TPM) were developed on the basis of review of the results of controlled and open studies of TPM reported to date and on postmarketing clinical experience with TPM at two specialized epilepsy clinics in the United Kingdom. Recommendations considered important for optimal utilization of TPM include dosage titration guidelines, options for managing side effects occurring early in treatment, advice concerning the withdrawal of concomitant AEDs, indications for discontinuation of TPM, and recognition of the need for adequate patient counseling.
An Overview of the Efficacy and Tolerability of New Antiepileptic Drugs
Authors: Chadwick D. W.
Published: November 2007

Summary: To evaluate the efficacy and tolerability of recently developed antiepileptic drugs (AEDs), a systematic review of placebo‐controlled, randomized controlled trials (RCTs) of the AEDs as add‐on therapy in refractory partial epilepsy was conducted. Two or more RCTs meeting our inclusion criteria were found for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS). The outcome selected for estimation of efficacy was the proportion of patients experiencing a ≥50% reduction in seizure frequency from baseline. Tolerability was estimated on the basis of rates of patient withdrawal from study for any reason. Efficacy and tolerability odds ratios (ORs) and 95% confidence intervals (95% CIs) for each measure were generated for each trial included in the analysis, and overall efficacy and tolerability ORs were calculated for each AED across all trials and drug dosages evaluated. Because 95% CIs for both efficacy and tolerability overlapped for the six drugs, conclusive evidence of between‐drug differences in effectiveness or safety were not obtained from the analysis. However, the data suggest that the drug with the highest OR for efficacy (TPM) may be approximately twice as effective as the AED with the lowest OR for efficacy (GBP), and that the treatment that appears to most frequently cause withdrawal (ZNS) may be about four times more likely to do so that the AED with the lowest withdrawal rate (LTG). RCTs comparing newer AEDs with the older standard drugs and with each other are needed to further evaluate their relative utility.
Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs
Authors: White H. Steve
Published: November 2007

Summary: More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs). Fortunately, new AEDs commercialized since 1990 are improving the clinical outlook for many patients. Our growing understanding of anticonvulsant mechanisms and the relevance of preclinical animal studies to clinical antiepileptic activity have already contributed to the design of several new AEDs and should be increasingly beneficial to further efforts at drug development. Mechanisms have been identified for older AEDs [phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates, benzodiazepines (BZDs), ethosuximide (ESM)] and newer AEDs [vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP) tiagabine (TGB), felbamate (FBM), topiramate (TPM)]. Several novel anticonvulsant mechanisms have recently been discovered. FBM appears to be active at the strychnine‐insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glu‐tamate receptor and at a potentially novel site on the GABAA receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drug‐drug interactions, and reduced potential for pharmacodynamic tolerance.
Neuropsychological Evaluation in Epilepsy Surgery
Authors: Loring David W.
Published: November 2007

Summary: Neuropsychology has played a prominent role throughout the modern era of epilepsy surgery. Neuropsychology, including the Wada test, has been of benefit in documenting dysfunction associated with a lateralized temporal lobe seizure onset. In addition, neuropsychological results have some predicative power regarding seizure outcome following anterior temporal lobectomy. The current status of neuropsychology in patient evaluation and outcome prediction will be presented. Differences between the Wada test, an inactivation procedure, and functional magnetic resonance imaging, which is an activation procedure, will be discussed. This paper will a present preliminary information about the Wechsler Adult telligence Scale‐Ill, the recent revision of the most commo used test of intellectual function, and its effects on neurop chological performance results.
Comprehensive Management of Epilepsy in Persons with Mental Retardation
Authors: Coulter David L.
Published: November 2007

Summary: Epilepsy is a common occurrence in persons with mental retardation. The application of recent advances in epilepsy research to patients with mental retardation has shown that well‐accepted principles of management are as relevant for multiply handicapped people as for those with epilepsy alone. Quality enhancement is emphasized as the overarching concept that determines the quality of care provided to patients with epilepsy and mental retardation. This article reviews the comprehensive management of epilepsy, discusses what is known at present, and indicates what is not known and needs further research.
Seizures in Medically Complex Patients
Authors: Boggs Jane G.
Published: November 2007

Summary: Seizures are not an uncommon complication of medical conditions and should not be ascribed simply to “multifactorial” causes. Although many interacting factors may contribute to a lowered threshold for seizures, a careful systems‐oriented search usually yields specific factors that are of primary importance. Not all medically complex patients with seizures have persistent or irreversible processes that lead to recurrent seizures or a need for maintenance antiepileptic drugs (AEDs). Because AEDs contribute to the potential for drug interactions, side effects, and toxicities in situations already encumbered with significant polypharmacy, the decision not to initiate such therapy can be even more important than selecting the best agent, best route of administration, and best dose from a growing list of AEDs.
Clinical Challenges in Invasive Monitoring in Epilepsy Surgery
Authors: Sperling Michael R.
Published: November 2007

Summary: Invasive monitoring aids in selecting patients for epilepsy surgery. This article reviews the methods employed to obtain intracranial EEG, data interpretation, and problems that arise during intracranial investigations. The relative merits of depth, subdural, epidural, and foramen ovale electrodes are reviewed, and a strategy for their use is suggested. Characteristic interictal and ictal EEG findings are summarized, and the problems encountered in interpreting data are discussed.