bluuebunny/crossref_metadata_2025 huggingface dataset:
Sexual Dysfunction in Epilepsy
Authors: Morrell Martha J.
Published: November 2007

Summary: Sexual dysfunction may arise more frequently in men and women with epilepsy than with other chronic illnesses, manifesting primarily as diminished sexual desire and potency. Studies using retrospective self‐report of sexual attitude and behavior find an incidence of sexual dysfunction ranging from 14–66%. Sexual dysfunction may be more common in partial than in generalized epilepsies. Sexual dysfunction in epilepsy may result from a disturbance in social or psychological factors affecting sexual responsiveness. Alternatively, epileptiform discharges may disrupt the function of structures mediating sexual behavior, particularly the limbic cortex, or alter the release of hypothalamic or pituitary hormones. Antiepileptic drugs modulate hormone release from the hypothalamic‐pituitary‐gonadal axis and may have direct inhibitory effects on sexual behavior. Evidence both supports and refutes each of these etiologies in the sexual dysfunction seen with epilepsy. Specific evaluation and treatment protocols for patients with sexual dysfunction are available.
Drug Interactions in Epilepsy
Authors: Brodie Martin J.
Published: November 2007

Summary: The abolition of seizures using a single antiepileptic agent can be expected in more than 80% of patients, although not necessarily with the first drug tried. The remainder often receive polypharmacy, and current evidence suggests that perhaps only around 10% of these benefit significantly in terms of improved seizure control. Many more experience complicated drug interactions. Carbamazepine, phenytoin, phenobarbital, and primidone (metabolized in part to phenobarbital) all induce the synthesis of hepatic monooxygenase and conjugating enzymes. This will result in an acceleration in the metabolism of other lipid‐soluble drugs with likely attenuation of their pharmacological effects. Valproate, on the other hand, is a minor enzyme inhibitor. Pharmacokinetic interactions are almost invariable when more than one antiepileptic drug is coprescribed. The extent and direction of interactions with combinations of these drugs are varied and unpredictable. Discontinuation of an enzyme inducer or inhibitor will influence the concentrations of the remaining drug(s). Pharmacodynamic interactions also cause problems in epileptic patients. A number of commonly prescribed psychoactive drugs, such as tricyclic antidepressants and neuroleptics, can worsen seizure control by reducing the convulsion threshold. In addition, there seems little doubt that ethanol abuse and withdrawal can precipitate seizures in susceptible patients. Antiepileptic polypharmacy is more likely to impair cognitive function than the same drugs used singly. In addition, the more antiepileptic drugs received by a patient in the first trimester of pregnancy, the higher the risk of teratogenesis in the exposed infant. Drug interactions prolong and complicate the process of new drug assessment, particularly when introduced in treated patients with refractory epilepsy. The candidate antiepileptic drug may alter the concentration of concomitant therapy, or its own breakdown may be influenced by coprescribed enzyme inducers or inhibitors. Even if the new drug is excreted unchanged by the kidney, unexpected interactions can be uncovered. Pharmacodynamic interactions need not always be detrimental. Currently, there is no rational approach to the treatment of intractable epilepsy. As more new drugs with single mechanisms of action become available, the potential exists for combining these synergistically. This approach may revolutionize the pharmacological management of the epileptic patient in the 21st century.
Cognitive Function—Victim of Disease or Hostage to Treatment?
Authors: Dreifuss Fritz E.
Published: November 2007

Summary: In persons suffering from epilepsy, cognitive functioning may be compromised for various reasons, including—first and foremost—the learning and behavioral effects of the conditions causing the epilepsy. In addition, the epilepsy itself may cause changes in the nervous system through the metabolic and excitotoxic effects of the seizures and the neurotransmitter elements involved at the membrane level. The effect of the treatment modality, be it pharmacologic or surgical, may also play havoc with cognitive function. The neurobehavioral effects of antiepileptic drugs, although probably less important with the newer agents than in the past, must be considered, especially in polypharmacy, as recent reports have indicated. With increasing data, the effects of various surgical procedures on the cognitive elements of human behavior are becoming better recognized.
Felbamate in the Treatment of Refractory Partial‐Onset Seizures
Authors: Jensen Peder K.
Published: November 2007

Summary: Felbamate (FBM) is a new antiepileptic drug (AED) that has been tested in open and controlled studies in patients with therapy‐refractory partial‐onset seizures. Proof of efficacy is based on results of five controlled studies (three with polytherapy and two with monotherapy). In two of the three polytherapy studies, a classic placebo crossover design was used. The third study used a novel design evaluating the efficacy of FBM in a placebo‐controlled parallel design in patients completing an evaluation for epilepsy surgery. The primary efficacy variable in this study was the number of patients who experienced a fourth seizure before the end of the study. Forty‐six percent of patients randomized to FBM stopped treatment prematurely because of the occurrence of a fourth seizure compared with 88% randomized to placebo. Two studies investigating the efficacy in monotherapy were performed. Both studies used an identical trial design comparing FBM with a low dosage of valproate (VPA). The efficacy of FBM was found to be superior to the low‐dosage VPA for both studies. Open long‐term follow‐up studies have confirmed the long‐term efficacy of FBM for up to 12 months. Overall, FBM was well tolerated in both poly‐ and monotherapy.
Felbamate: Successful Development of a New Compound for the Treatment of Epilepsy
Authors: Schmidt Dieter
Published: November 2007

Summary: Felbamate (FBM) is an effective and safe novel antiepileptic drug (AED) for add‐on treatment in adults with refractory partial seizures as shown in three pivotal controlled trials. In addition, FBM is effective and safe in monotherapy in adults with refractory partial seizures. FBM is also effective and safe as add‐on therapy for children and adults with refractory Lennox‐Gastaut syndrome. The effective daily dosage is ˜30–45 mg/kg divided into three or four doses with resulting plasma concentrations of 50–80 mg/L. The safety profile of FBM is limited to mild gastrointestinal complaints, insomnia, and nonspecific CNS symptoms. Six pivotal controlled trials, with both classic and innovative design, showed that FBM is a useful AED.
Focal Status Epilepticus and Epilepsia Partialis Continua in Adults and Children
Authors: Schomer Donald L.
Published: November 2007

Summary: Focal status epilepticus and epilepsia partialis continua (FSE‐EPC) are most frequently seen with chronic focal progressive encephalitis of Rasmussen and Russian spring‐summer encephalitis. FSE‐EPC may be the presenting feature of nonketotic hyperglycemic diabetes mellitus but is more often noted as a late complication especially if there is a coexistent cerebral lesion such as cerebral infarction. FSE‐EPC may be related to multiple sclerosis, primary or metastatic brain tumors, the MERRF‐MELAS syndrome, benign epilepsy of childhood with rolandic spikes, and in some adults with acquired aphasia. The physiological origin of the myoclonic jerks seen in EPC is cortical and may be either spontaneous or provoked by the joint position of the affected limb. The treatment of FSE‐EPC is influenced by the underlying disorder.
Quality of Life in Epilepsy: The Clinician's View
Authors: Devinsky Orrin , Penry J. Kiffin
Published: November 2007

Summary: Quality of life in patients with epilepsy may be impaired by seizures, side effects of medication, and psychosocial problems. Doctors tend to focus their attention on managing the seizures and the side effects, but may not be meeting all of the patient's needs because of differences between their perception of these concerns and the patient's. Further, psychosocial problems often are addressed only superficially or not at all during office visits. The challenge is to integrate quality‐of‐life issues into clinical practice and to better assess the patient's perception of the disorder, the seizures, and the medications, as they impact on cognitive function, emotional well‐being, and social and economic functioning.
Advances in the Assessment of Refractory Epilepsy
Authors: Schachter Steven C.
Published: November 2007

Summary: The assessment of patients with refractory epilepsy presents both a challenge and an opportunity. The use of appropriate instruments to carefully and consistently measure a patient's seizure type and frequency, hormonal function, and medication side effects and the impact of those variables on quality of life ensures consistent, standardized assessment. A patient's epilepsy then can be classified as refractory based on any combination of factors that preclude a reasonably normal life‐style by current practice standards, given the person's capabilities. Diagnostic studies and treatment strategies should address all significant adverse findings resulting from the assessment process. Accurate diagnosis of seizure type usually requires electroencephalographic (EEG) monitoring. Postictal hormonal assays and periodic measurements of estrogen and progesterone may be useful diagnostically in a selected group of patients. Awareness of a patient's compliance history, environmental stressors, and seizure triggers may reduce seizure frequency without a change in medication. For patients with medication intolerance, the usual strategy is to modify the medication regimen or treatment schedule to minimize side effects while maximizing seizure control and compliance. For most patients, monotherapy provides a greater therapeutic window than combination therapy. Devising an effective and safe therapeutic regimen is an ongoing process and can be lengthy depending on seizure type(s), frequency, and temporal pattern; anticonvulsant pharmacokinetics; drug interactions and side effects; patient's life‐style; and other factors. Serial measurements of quality‐of‐life variables may assist in the process. Rapid strides have been recently made, and as the pace of new antiepileptic drug development quickens and surgical centers become more widely available, clinicians will need to redefine refractoriness as the expectations improve for patients with epilepsy.
Seizure Severity and the Quality of Life
Authors: Smith David , Chadwick David , Baker Gus , Davis Gary , Dewey Michael
Published: November 2007

Summary: The efficacy of an antiepileptic drug (AED) is determined at present by the drug‐elicited reduction in seizure frequency. Reduction of seizure frequency as the sole measure of efficacy does not account for treatment‐induced reductions in seizure severity and positive psychological effects experienced by the patient. A clinical trial was undertaken in which seizure frequency was the primary and seizure severity and psychological well‐being were the secondary measures of efficacy. Psychological assessment and seizure frequency were monitored in patients whose epilepsy was treated with lamotrigine (LTG) or placebo. The results indicate that LTG is an effective AED, causing reductions in seizure frequency and severity and improvements in mood and mastery. In addition, the study demonstrated that the use of seizure severity scales, especially the Ictal subscale, may enhance the sensitivity of assessment of trials of AED treatments.
Major Patterns of Human Inheritance: Relevance to the Epilepsies
Authors: Bird Thomas D.
Published: November 2007

Summary: An understanding of the basic principles of human inheritance patterns is necessary to appreciate the variety and complexity of genetic influences in the epilepsies. The various modes of human inheritance include single gene (mendelian), chromosomal, mitochondrial, and multifactorial/polygenic. Recent insights regarding imprinting, anticipation, and uniparental disomy have been made and have an impact on our understanding of human genetics. All of these phenomena are likely to be of importance in the epilepsies and form the basis for a more detailed analysis of the relevant molecular biology.
The Prevalence and Incidence of Convulsive Disorders in Children
Authors: Hauser W. Allen
Published: November 2007

Summary: Each year, about 150,000 children and adolescents in the United States will come to medical attention for evaluation of a newly occurring seizure disorder of some type. Between 2% and 4% of all children in Europe and the United States experience at least one convulsion associated with a febrile illness before the age of 5 years. The cumulative incidence of febrile convulsions among children ranges from about 1% in China to more than 8% in Japan and 14% in Guam. The peak incidence of a first febrile convulsion occurs in the second year of life. Between 0.5% and 1% of children and adolescents experience a seizure associated with other acute metabolic or neurologic insults; most of these occur in the neonatal period. The incidence of epilepsy (recurrent unprovoked seizures) in children and adolescents seems relatively consistent across all populations studied, ranging from 50 to 100/100,000. The highest incidence of epilepsy is in the first year of life. West syndrome accounts for about 2% of all childhood epilepsy, Lennox‐Gastaut syndrome for 1–2%, childhood absence epilepsy (pyknolepsy) for 10–15%, juvenile myoclonic epilepsy for 5%, and idiopathic localization‐related epilepsy for 10%. Between 0.5 and 1% of children experience a nonrecurrent, single, unprovoked convulsive episode. Following are the estimated numbers of children and adolescents with newly diagnosed convulsive disorders in the United States for the year 1990: febrile seizures, 100,000; neonatal seizures, 4,000; other provoked seizures, 6,000; single unprovoked seizures, 10,000; and epilepsy, 30,000.
Antiepileptic Drugs in Development: Prospects for the Near Future
Authors: Leppik Ilo E.
Published: November 2007

Summary: Among some 14 new antiepileptic drugs (AEDs), those most extensively tested in humans include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), vigabatrin (VGB), and zonisa‐mide (ZNS). All are currently marketed in some but not all countries. Although no large, comparative studies on efficacy have been conducted, all of these new AEDs are effective in adult localization‐related epilepsies, and some have activity in specific syndromes. Although these drugs all have some CNS side effects, especially when administered in combination with other AEDs, they also all have low toxicity profiles. The availability of AEDs with different mechanisms of action may facilitate rational polytherapy. FBM is not teratogenic in animals. Half‐life of FBM in humans is 11–28 h. Daily FBM dosages are 15–45 mg/kg in children and 2,400‐4,800 mg in adults. Side effects include insomnia and anorexia, with weight loss. FBM increases phenytoin (PHT) and valproate (VPA) concentrations, and FBM concentration may be affected by other drugs. It is available in the United States for treatment of Lennox‐Gastaut syndrome and partial seizures in adults. GBP is very water soluble. Half‐life of GBP in humans is 5–7 h and daily dosages range from 900 to 2,400 mg in adults. Few side effects have been observed. GBP is not metabolized by the liver and has no drug interactions. It is available in the United Kingdom and the United States. LTG has no teratogenicity in animal models. Half‐life of LTG in humans depends on co‐medication: with enzyme inducers it is 15–24 h, and with VPA it is approximately 60 h. LTG dosages are 100–600 mg/day in adults. LTG is available in Europe. OCBZ is rapidly metabolized to 10, 11‐dihydro‐10‐hydroxy‐carbazepine (MHD), the active compound. Animal studies have shown similar efficacy but superior toxicity to carbamazepine (CBZ) in animal models. For MHD, half‐life ranges from 10 to 15 h in patients. OGBZ dosages range from 300 to 1,800 mg/day. VGB is a potent, irreversible inhibitor of GABA transaminase which elevates GABA levels in the CNS. Daily dosages of 2,000–4,000 mg of VGB are needed in adults. Although intramyelinic edema has developed in rats and dogs, it has not yet presented in other mammals or humans. ZNS is a sulfonamide effective in animal models of epilepsy. Half‐life of ZNS is 27–36 h. ZNS daily dosage is 400–600 mg. ZNS has been effective in some cases of Baltic myoclonic epilepsy.
Vigabatrin
Authors: Mumford John P. , Cannon Deborah J.
Published: November 2007

Summary: The discovery of γ‐aminobutyric acid (GABA) as the first major inhibitory neurotransmitter and a program exploring the use of enzyme inhibition as a therapeutic tool provided the basis for the conception of vigabatrin (VGB, Sabril). This molecule, an analogue of GABA, has a highly specific activity as an enzyme‐activated irreversible inhibitor of GABA‐transaminase causing several‐fold increases in the concentration of brain GABA. In animal models for epilepsy, it was found to have a rather different spectrum of activity than conventional antiepileptic drugs (AEDs). The clinical development of VGB was delayed by the finding of focal areas of reversible microvacuolation in the white matter of the brains of rodents and dogs. An extensive human safety program has confirmed that this finding is species specific and does not occur in humans. Clinically, VGB is well tolerated and has been shown to be specially effective in the management of partial seizures that have failed to respond to other AEDs. In most controlled studies, about 50% of patients with previously uncontrolled seizures have a 50% reduction in frequency and about 4–5% become seizure‐free. In children, it also appears to be especially effective in the management of infantile spasms as well as in partial seizures. VGB offers a significant improvement in the management of epilepsy and is now under development as a first‐line agent.
Safety of Lamotrigine
Authors: Richens Alan
Published: November 2007

Summary: Clinical trials of lamotrigine (LTG) began in 1984. By November 1992 about 5,800 patient‐years' experience of adverse effects had been compiled. In general, LTG has an acceptable safety profile. Mild central nervous system adverse effects such as ataxia, dizziness, and headache occur significantly more frequently with LTG than with placebo but seldom demand discontinuation of LTG therapy. Dosage‐related allergic skin rash occurs in about 5% of patients. The rash rarely is severe enough to require hospitalization. The adverse‐reaction profile of LTG compares favorably with that of traditional antiepileptic drugs.
Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity
Authors: Trube G. , Netzer R.
Published: November 2007

Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an‐tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N‐methyl‐D‐aspartate (NMDA) receptor channels and voltage‐operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.
Gabapentin as Add‐on Therapy for Refractory Partial Epilepsy: Results of Five Placebo‐Controlled Trials
Authors: Leiderman Deborah B.
Published: November 2007

Summary: Gabapentin (GBP, Neurontin), a new antiepi‐leptic drug (AED) with a novel mechanism of action, exhibits low acute toxicity in mice, rats, and monkeys, and is not teratogenic. GBP pharmacokinetics are simple and predictable; GBP is eliminated by urinary excretion, is not protein‐bound or metabolized, does not induce or inhibit hepatic enzymes, and does not interact with other AEDs. In five placebo‐controlled, double‐blind studies of GBP as add‐on therapy, 307 patients with refractory partial seizures received placebo and 485 received GBP dosages of 600, 900, 1,200, or 1.800 mg/day for 12 weeks following a 12‐week baseline. Seizure frequency, as measured by response ratio and responder rate, was improved for patients receiving GBP compared with placebo; differences were statistically significant in two of the three large, multicenter studies. Adverse events occurred in 76% of GBP‐treated patients, compared with 57% of placebo‐treated patients. No serious adverse events were consistently attributable to GBP therapy. Changes in clinical laboratory values were not considered clinically important. GBP represents a significant addition to the armamentarium of AEDs available for treatment of patients with epilepsy.
Gabapentin: Discussion
Authors: Fromm Gerhard H. , Wieser Heinz‐Gregor
Published: November 2007

Summary: Gabapentin (GBP, Neurontin) is a novel anti‐epileptic drug (AED) that was shown to be effective against refractory partial seizures in five placebo‐controlled trials. However, a number of patients with complex partial seizures experienced an increase in seizure frequency, suggesting that patients suffering from complex partial seizures are not a homogeneous group. In fact, we found that currently available AEDs are likely to be ineffective when staring is a prominent component of complex partial seizures. The poor response of this group of patients may reflect the fact that staring spells are inhibitory seizures and that the AEDs prescribed for partial seizures appear to facilitate inhibitory mechanisms. GBP resembles phenytoin (PHT) and carbamazepine (CBZ) in depressing segmental and reticular excitatory mechanisms and facilitating segmental inhibitory mechanisms, just as it resembles PHT and CBZ in efficacy against some partial seizures and against secondarily generalized seizures. Perhaps the patients in whom GBP increased seizure frequency had complex partial seizures with staring and were therefore unlikely to benefit from drugs such as GBP, CBZ, and PHT, which enhance inhibitory mechanisms in the brain. These findings suggest that future AED trials would greatly benefit from a categorization of complex partial seizures into no‐sologically distinct groups.
Tiagabine
Authors: Mengel Helle
Published: November 2007

Summary: Tiagabine (TGB), a specific γ‐aminobutyric acid (GABA)‐uptake inhibitor, is a potential new antiepileptic drug with a novel mechanism of action. In animal models of epilepsy as well as in a placebo‐controlled trial in patients with complex partial seizures, TGB showed significant anticonvulsant effects. TGB was well tolerated by most patients.
Valproate in the Treatment of Partial Epilepsies
Authors: Chadwick David
Published: November 2007

Summary: Review of randomized controlled trials (RCTs) shows that valproate (VPA) is effective against partial seizures with or without becoming secondarily generalized. A number of RCTs show little difference in the efficacy of VPA and carbamazepine in this patient group, particularly where patients are randomized at the time of diagnosis. The length of time that it has taken to arrive at these conclusions emphasizes the importance of large active‐controlled RCTs at an early stage in drug development in informing clinical practice.
Nuclear Magnetic Resonance Spectroscopy of Seizure States
Authors: Prichard James W.
Published: November 2007

Summary: Magnetic resonance spectroscopy (MRS) can be used for noninvasive measurement of more than two dozen small metabolites in the brains of living animals and humans. In the first decade of its use for study of seizure phenomena in animals, MRS successfully detected in vivo seizure‐induced cerebral acidosis and reduction of phosphocreatine concentration, changes that had been described previously by techniques requiring destruction of tissue. Thus validated, MRS was used to reveal new aspects of epileptic pathophysiology in animals: (a) dissociation of brain lactate and pH during experimental status epilepticus of low and intermediate intensity, reflecting metabolic compartmentation; and (b) long persistence of metabolically active elevated brain lactate after brief cortical electroshock. The latter phenomenon may be an extreme form of a mechanism by which lactate production primes synaptic terminals for maximal sustained firing rates during normal brain activation. Diffusion‐weigh ted imaging of rat brain has shown that status epilepticus apparently shortens the mean path length of water diffusion, a novel finding that provides new insight concerning the physical conditions under which the seizure‐related chemical changes detected by MRS occur. MRS study of epileptic patients has been undertaken more recently as instruments large enough for observations on humans have become available. Acidosis, reduction of phosphocreatine, and elevation of lactate have all been demonstrated in the human brain during seizure discharge. Chronic reduction of N‐acetylaspar‐tate in limbic regions probably reflects neuronal loss and may correlate with mesial temporal sclerosis.
Neuropharmacology and Drug Interactions in Clinical Practice
Authors: Graves Nina M.
Published: November 2007

Summary: Absorption, distribution, and clearance are key pharmacokinetic principles. These parameters can be highly variable among patients and among compounds, and are factors that must be considered in the wide variability in response to medications. Current antiepileptic drugs (AEDs) present many challenges in their administration. However, understanding and utilizing pharmacokinetic principles can assist the clinician in the appropriate optimization of AEds.
Cognitive and Behavioral Effects of Antiepileptic Drugs
Authors: Devinsky Orrin
Published: November 2007

Summary: All antiepileptic drugs (AEDs) have the potential for adverse effects on cognition and behavior. Most of the major AEDs, administered in therapeutic doses, cause little or no cognitive or behavioral impairment in group studies. However, individual variability is considerable, and some patients do not tolerate low serum levels, whereas others tolerate high levels without subjective or objective effects. In the past, carbamazepine (CBZ) and valproate (VPA) have been reported to have the fewest adverse cognitive and behavioral effects in children and adults. However, several recent, well‐controlled studies have not found significant differences between the effects of phenytoin (PHT) and those of CBZ or VPA. Greater adverse effects have been found for phenobarbi‐tal (PB). However, we must use environmentally relevant measures of cognitive and behavioral functioning to measure effects on daily functioning. Future studies must define cognitive and behavioral toxicity in subpopulations (e.g., post‐traumatic epilepsy, mental retardation, depression) and with the new AEds.
Felbamate
Authors: Leppik Ilo E.
Published: November 2007

Summary: After the first year of clinical experience, felbamate (FBM) appears to be a valuable antiepileptic drug (AED) for the treatment of intractable epilepsy. However, many patients experience side effects that may discourage continued usage. These may be decreased by using a slower dose‐escalation schedule and/or by being more aggressive in decreasing co‐medication. The most common troublesome side effects are nausea and insomnia. With the recent observation of aplastic anemia, FBM should be considered only for persons with intractable epilepsy under the care of a physician familiar with FBM. Nevertheless, many patients have benefited significantly from FBM and have made a decision to continue receiving FBM at the presently known risk profile. A few more years of experience may be needed to more accurately determine the final place of FBM in the treatment of epilepsy.
Gabapentin
Authors: McLean Michael J.
Published: November 2007

Summary: The amino acid antiepileptic drug (AED) gabapentin (GBP) is indicated for adjunctive use in the treatment of partial seizures with or without becoming secondarily generalized in individuals older than 12 years. GBP was about as potent as phenytoin in the maximal electroshock test, but had a different profile of efficacy than standard antiepileptics in a range of animal models. Possible mechanisms of action include biochemical effects enhancing the ratio of γ‐aminobutyric acid (GABA) to glutamate, ion‐channel actions (direct or indirect), and/ or enhancement of nonsynaptic GABA release. The anticonvulsant effect appears to depend on concentration of gabapentin in neurons, presumably by the L‐system amino acid transporter that has been implicated in absorption from the gut. Data from studies for U.S. Food and Drug Administration (FDA) approval suggested a direct relationship of clinical response to dose and efficacy did not plateau at the doses used. The maximally effective dose, relationship of efficacy to blood level, and maximum tolerable dose are not yet known conclusively. Lack of significant binding to plasma proteins and lack of liver metabolism contribute to the absence of known limiting drug‐drug interactions, particularly with other AEds. Excretion intact in the urine affords dose adjustment on the basis of creatinine clearance. A half‐life of approximately 7 h necessitates multiple doses daily for many individuals. The medication is well tolerated, in general. Side effects tend to be mild to moderate in intensity, most frequently affect the central nervous system, and resolve with time in many individuals. GBP has been prescribed for approximately 70,000 individuals worldwide without untoward incidence of severe systemic toxicity to date. Safety data continue to accumulate. GBP has been labeled category C on the basis of effects on rodent fetuses. Experience with use in pregnant women is limited and human teratogenic effects have not been reported. Data from ongoing monotherapy trials will help to clarify the range of clinical utility of gabapentin.
Lamotrigine
Authors: Messenheimer John A.
Published: November 2007

Summary:Lamotrigine (LTG) is a novel antiepileptic drug (AED) with a spectrum of activity in animal models of epilepsy similar to that of phenytoin and carbam‐azepine. In some models it appears to have a broader spectrum and better tolerability than these agents, however. One mechanism of action of LTG is the marked inhibition of release of the excitatory neurotransmitters glutamate and aspartate under conditions of sustained repetitive firing. LTG appears to do this by blocking voltage‐sensitive sodium channels and has no direct effect on JV‐methyl‐D‐aspartate (NMDA) receptors. In clinical trials as add‐on therapy in medically refractory partial seizure patients, LTG has consistently produced a 50% reduction in seizure frequency in 25–34% of subjects. LTG is well tolerated, even in the add‐on situation. In part, this appears to be related to positive behavioral effects. Desirable pharmacologic properties of LTG include low protein binding (55%), an absence of enzyme induction, and linear pharmacokinetics. The most significant adverse effect is rash, leading to a withdrawal rate of 2% of patient exposures in clinical trials.
Tiagabine: The Safety Landscape
Authors: Leppik Ilo E.
Published: November 2007

Summary: Tiagabine (TGB) hydrochloride is a potential new antiepileptic drug (AED) undergoing clinical development. Experience in humans amounts to 1,810 patient‐years of exposure. TGB was found to be tolerated in an integrated safety analysis of five double‐blind, add‐on therapy trials involving approximately 1,000 patients with epilepsy with difficult‐to‐control seizures with existing AEDs. Discontinuation resulting from adverse events were infrequent, occurring in 15% of patients receiving TGB compared to 5% receiving placebo. The most frequently reported adverse event was dizziness, which was usually transient and did not require medical intervention. Adverse events that were statistically significantly more common with TGB than placebo were dizziness, asthenia, nervousness, tremor, diarrhea, and depression (not major depression). Adverse events were usually mild to moderate in severity and transient, and most were associated with dose titration. The incidence, type, and severity of adverse events in long‐term studies were comparable with those in short‐term studies. Serious adverse events were uncommon and no idiosyncratic events were reported.
International Experience with Tiagabine Add‐On Therapy
Authors: Ben‐Menachem Elinor
Published: November 2007

Summary: Tiagabine (TGB) hydrochloride is a novel antiepileptic drug (AED) that is a potent and specific inhibitor of γ‐aminobutyric acid (GABA) uptake into glial and neuronal elements. In accordance with medical and regulatory standards, the clinical development program for TGB as an AED has assessed the value of TGB in add‐on treatment, focusing mainly on partial seizures, including secondarily generalized seizures. Five add‐on, placebo‐controlled trials and six non‐comparative, open‐label, long‐term multicenter trials have been or are being conducted in Australia, Europe, and the U.S.A. The results of these trials, involving 2,261 patients, indicate that TGB has efficacy as add‐on therapy in patients with epilepsy difficult to control with existing AEDs. Efficacy of TGB is also sustained with long‐term treatment. A clear dose‐response has been demonstrated, and the minimal effective dose level is 30 mg. TGB is also tolerated, and with long‐term therapy no new or more severe types of adverse events develop. These studies have included a wide age range of patients, including adolescents and the elderly.
Developmental Aspects of Epileptogenesis
Authors: Johnston Michael V.
Published: November 2007

Summary: Several factors may contribute to the propensity for the developing brain to have seizures and develop epilepsy. Hypersynchrony of neuronal circuits contributes to the seizure potential and several neurobiological features of the immature brain may support synchronized neuronal firing. The immature cerebral cortex and hippocampus have an increased density of synapses compared to adults and also a higher density of gap junctions and of excitatory amino acid receptors. Enhanced regenerative responses to injury in the developing brain may also contribute to the formation of abnormal hippocampal connections that support epilepsy. Molecular mechanisms that contribute to enhanced synaptic plasticity in the child's brain can also contribute to epileptogenesis in certain circumstances. The phenomenon of kindling, where repeated electrical stimulation of neuronal circuits leads to the development of epileptic seizures, is easily elicited in young animals. Longterm potentiation (LTP), where repeated synpatic stimulation leads to a reduced threshold for activation of that pathway and enhanced postsynaptic potentials, is much more robust in the immature cerebral cortex and may contribute to kindling and epileptogenesis. Age related enhancement of N‐methyl d‐asparatetype glutatmate receptors, which are important for the activity dependent plasticity in the developing brain, appears to participate in LTP. This information suggests that normal developmental features of synaptic development make the immature brain more excitable than the adult brain and may contribute to epileptogenesis.
Pediatric Epilepsy Syndromes: An Update and Critical Review
Authors: Duchowny Michael , Harvey A. Simon
Published: November 2007

Summary: Epilepsy syndromes occupy an important position in the current nosology of the epilepsies, describing and classifying seizure disorders with shared clinical and EEG features. Increasingly, this schema is being refined as new information becomes available and our understanding of etiology and presentation of each syndrome widens. Advances in neuroimaging and neurogenetics have been particularly important and are likely to fundamentally change our concepts of syndrome classification. At present, the International League Against Epilepsy classification of epilepsy syndromes according to presumed localization (partial, generalized, undetermined) and etiology (idiopathic, cryptogenic, symptomatic). In clinical practice, it is often useful to conceptualize epilepsy syndromes according to their usual age at presentation, which greatly facilitates syndrome identification in new patients and recognizes the age‐related expression of many childhood epilepsies. Definitional problems exist for many pediatric epilepsy syndromes, particularly the epileptic encephalopathies of early infancy, the benign epilepsies of infancy and childhood, the myoclonic epilepsies of infancy and early childhood, and the idiopathic generalized epilepsies of childhood and adolescence. It is likely that further input from the fields of molecular genetics and neuroimaging will enable the classification of epilepsies to become more etiologically oriented and disease specific.
Antiepileptic Drug Therapy: When Is Epilepsy Truly Intractable?
Authors: Camfield Peter R. , Camfield Carol S.
Published: November 2007

Summary: We define intractable in the first 5 years of epilepsy treatment as an average of at least one seizure every 2 months. For the longer term, we define intractable as at least one seizure per year. Population studies from Chicago, IL, U.S.A., Finland, and Nova Scotia, Canada indicate that with long follow‐up, many children with intractable epilepsy eventually have remission of their seizure disorder. Epilepsy is no longer intractable when the seizures stop completely. How often does a new antiepileptic drug (AED) render a child seizure‐free when one or more AEDs have failed? Literature on adults with epilepsy suggests that few with chronic epilepsy who have not achieved seizure control with several AEDs will achieve complete seizure control with additional AEDs. The Nova Scotia study suggests that if a child's seizure fails to be controlled with a first AED, there is an increased risk of intractable epilepsy. Nonetheless, the chance of eventual, complete remission of epilepsy (seizure‐free without AED treatment) is approximately 40%. We conclude that intractability should not be considered until there has been failure of at least three first‐line AEDs. Intractable epilepsy is rare. Careful definition of the characteristics of children with intractable epilepsy who do respond completely to new AEDs will likely provide the only rational approach to treatment of children with three drug failures. Collaboration by multiple epilepsy centers will be required to gain this information.
Safety of Topiramate: Adverse Events and Relationships to Dosing
Authors: Shorvon Simon D.
Published: November 2007

Summary:To date, 1,809 individuals have been exposed to topiramate (TPM), primarily adults with partial‐onset seizures. Of this total, 665 patients have been treated for more than 1 year, 177 for more than 3 years, and 67 for more than 5 years. The profile of treatment‐emergent adverse reactions (TEAEs) observed with TPM at various dosages is based primarily on data from five double‐blind, placebo‐controlled trials in which 360 patients received TPM at target doses of 200–1,000 mg/day. Long‐term safety is assessed on the basis of 1,001 patients treated with TPM in controlled and open trials for up to 5.3 years. Most of the commonly reported TEAEs were related to the central nervous system and were observed with greater frequency at dosages above the 200–600‐mg/day range found to be optimal in dose ranging trials. Nephro‐lithiasis not requiring surgery was seen in 1.5% of patients, and mild, dose‐related weight loss was associated with TPM therapy. No clinically significant treatment‐related abnormalities were observed in clinical laboratory parameters or in neurologic, electrocardiographic, oph‐thalmologic, or audiologic tests.
Clinical Efficacy of New Antiepileptic Drugs in Refractory Partial Epilepsy: Experience in the United States With Three Novel Drugs
Authors: French Jacqueline A.
Published: November 2007

Summary: A number of new antiepileptic drugs (AEDs), including topiramate (TPM), felbamate (FBM), and gabapentin (GBP), are approved or believed to be close to approval for marketing in the United States. Key efficacy findings for these AEDs in refractory partial epilepsy were reviewed. Large and significant drug‐placebo differences were observed with TPM in two large dose‐finding trials conducted in the United States. The minimal effective dose of TPM in the population studied was determined to be approximately 200 mg/day, and doses above 600 mg/day produced good efficacy but little incremental benefit versus the lower dosages for the overall study population. FBM is active in partial epilepsy, although seizure reduction is less marked and drug interactions complicate the findings. GBP is also active in this population, but only the 1,800 mg/day dosage was significantly better than placebo with respect to percent re‐sponders. It may be useful to explore higher dosage ranges for both FBM and GBP if they can be well tolerated.
Pharmacokinetics of New Antiepileptic Drugs
Authors: Gram Lennart
Published: November 2007

Summary: This article surveys the pharmacokinetic parameters for the new antiepileptic drugs (AEDs): felba‐mate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and vigabatrin. Compared to the pharmaco kinetics of standard AEDs, these new AEDs have progressed in terms of (a) longer half‐lives, permitting once‐or twice‐daily dosing, (b) greatly reduced potential for drug interactions, thus increasing ease of treatment, and (c) general lack of hepatic enzyme induction, which facilitates polytherapy as well as other aspects of treatment.
Management of Epilepsy in the Elderly
Authors: Willmore L. James
Published: November 2007

Summary: Epilepsy in elderly patients is a growing worldwide challenge; as the population ages, the preva lence of epilepsy increases. Management of epilepsy in elderly patients requires an understanding of their unique medical and pharmacologic characteristics. Accurate as sessment of seizures, thorough neurologic assessment to define etiology, and evaluation of concomitant illnesses and living situations are necessary for comprehensive treatment planning and informed management. Expect el derly patients to present challenges to treatment that in clude concomitant diseases, obligatory polypharmacy with accompanying drug interactions, and age‐related changes in renal and hepatic physiology that alter drug metabolism and elimination. Elderly patients have declin ing intellectual function, motor impairment, or altered special sensory function that make them susceptible to dose‐related CNS side effects of antiepileptic drugs (AEDs). When AEDs are added to the medical regimen of an elderly patient, the physician must review all pre scribed drugs. Drugs prescribed for concomitant illnesses such as behavioral problems, cardiovascular disease, hy pertension, and infection may alter the distribution and metabolism of AEDs, with an impact on efficacy and oc currence of adverse effects. AEDs tend to induce metab olism of other drugs, leading to a decline in target re sponse. Optimal care of elderly patients with epilepsy includes use of free levels to monitor AED concentra tions, careful dose selection, and physician sensitivity to patients' social problems.
The Role of the Old and the New Antiepileptic Drugs in Special Populations: Mental and Multiple Handicaps
Authors: Mattson Richard H.
Published: November 2007

Summary: Epilepsy is common in individuals who are mentally retarded and/or otherwise multiply handi capped. These patients often display several seizure types. Seizure control may be difficult and drug interac tions common because of polytherapy. Cognitive, behav ioral, affective, and motor problems in these patients of ten confound accurate diagnosis and effective manage ment. Treatment often requires not only antiepileptic drugs (AEDs) but also psychoactive drugs and/or envi ronmental and personal support. To minimize unwanted drug effects, therapeutic strategies should focus on the administration of the fewest possible drugs at the lowest effective dose. The new AEDs may be of special value at times in these populations because they offer potential for improved efficacy, but especially because many of them provide better safety profiles and fewer pharmacokinetic interactions with other drugs.
Pharmacokinetics and Interaction Profile of Topiramate: Review and Comparison with Other Newer Antiepileptic Drugs
Authors: Johannessen S. I.
Published: November 2007

Summary: Standard antiepileptic drugs (AEDs) have a number of pharmacokinetic shortcomings, and AEDs with more favorable profiles would be preferred. The pharmacokinetics and interaction profile of the recently developed AED topiramate (TPM), is reviewed and compared with those of other newer AEDs including lamotrigine (LTG), gabapentin (GBP), vigabatrin (VGB), and oxcarbazepine (OCBZ). Although none of these agents meets all of the criteria of the “ideal” AED from the pharmacokinetic standpoint, a number of these drugs, including TPM, have desirable properties that distinguish them from the older AEDs and should contribute to their clinical utility.
Efficacy of Topiramate as Adjunctive Therapy in Refractory Partial Seizures: United States Trial Experience
Authors: Faught Edward
Published: November 2007

Summary: In companion double‐blind, placebo‐controlled, dose‐ranging trials performed in the United States, topiramate (TPM) daily target dosages of 200‐1,000 mg/day were evaluated as add‐on therapy in adults with refractory partial seizures with or without becoming secondarily generalized. Net reductions in median monthly seizure frequency (active drug minus placebo) with the most efficacious dosages of TPM were 35% in the low‐dose trial and 40% in the high‐dose trial. Substantial reductions in secondarily generalized seizures were also observed with TPM. TPM appears to be an efficacious new antiepileptic drug in the management of partial epilepsy.
Clinical Efficacy of Topiramate as Add‐On Therapy in Refractory Partial Epilepsy: The European Experience
Authors: Ben‐Menachem Elinor
Published: November 2007

Summary: In three randomized, double‐blind, placebo‐controlled add‐on European trials, target daily topiramate (TPM) dosages of 400, 600, and 800 mg/day (200, 300, and 400 mg bid) were evaluated in adults with refractory partial seizures with or without becoming secondarily generalized. Median reductions from baseline in monthly seizure rate were 41% with TPM 400 mg/day vs. 1% with placebo (n= 0.065), 46% with TPM 600 mg/day compared to ‐12% (a 12% increase) with placebo (p≤ 0.005), and 36% with TPM 800 mg/day versus –18% (an 18% increase) with placebo (p≤ 0.001). Differences between TPM and placebo with respect to percent responders (percent of patients demonstrating a 50% or greater reduction in seizures) significantly favored TPM (p≤ 0.05) at all three target dosages. Significant reductions in secondarily generalized tonic‐clonic seizures compared to placebo were also observed with 400 mg/day (p= 0.002) and 800 mg/day (p < 0.05) of TPM. TPM appears to be a promising new antiepileptic drug for use as adjunctive therapy in adults with refractory partial epilepsy.