bluuebunny/crossref_metadata_2025 huggingface dataset:
New Antiepileptic Drugs: From Serendipity to Rational Discovery
Authors: Porter Roger J. , Rogawski Michael A.
Published: November 2007

Summary: Antiepileptic drug discovery has made enormous progress from the serendipity and screening processes of earlier days to the rational drug development of today. The modern era of research began with the recognition that enhancement of inhibitory processes in the brain might favorably influence the propensity for seizures, γ‐aminobutyric acid (GABA) being the main inhibitory transmitter. Work in this field led to the development of vigabatrin, which inhibits the enzyme responsible for the degradation of GABA. More recently, research has focused on the therapeutic potential of blocking excitatory amino acids—in particular glutamate. Of the three receptors for glutamate, the N‐methyl‐d‐aspartate (NMDA) receptor is considered the one of most interest in epilepsy, and research on a series of competitive NMDA receptor antagonists—especially those that are orally active—is in the forefront of antiepileptic drug development today. A further alternative for diminishing neuronal excitability is to modulate sodium, potassium, or calcium channels. The latter are especially implicated in absence seizures.

Antiepileptic drug discovery has evolved from serendipity through random screening to a scientific era where drugs are designed rationally according to modern principals of neuroscience and the art of medicinal chemistry. Of the research directions currently being pursued, the following appear to be particularly promising: enhancement of inhibition, reduction in excitation, and modulation of the ionic channels that are the fundamental mediators of neuronal excitability. The application of modern approaches to drug discovery provides some optimism that effective new compounds will be marketed in the coming decade, with the promise of diminished suffering by persons with uncontrolled epilepsy.
Risks of Pregnancy in Women with Epilepsy
Authors: Yerby Mark S.
Published: November 2007

Summary: Pregnant women with epilepsy are at increased risk of seizures and complications. An increase in seizure frequency is seen in 25–30% of pregnant women with epilepsy; the offspring of mothers who experienced seizures during pregnancy are at a 2.5 times higher risk for seizures later in life. One of the main reasons for the increase in seizures during pregnancy is a decline in plasma concentrations of antiepileptic drug (AED) that occurs as pregnancy progresses, largely as a result of marked alterations in plasma protein binding. It is well known that epilepsy represents a risk for a variety of adverse pregnancy outcomes or malformations, especially in polytherapy. The adverse outcomes range from dysmorphic features to hemorrhagic disorders resulting from a deficiency of vitamin K‐dependent clotting factors or to spina bifida. Folic acid supplements appear to reduce the risk of spina bifida. A strong genetic link seems to exist for many of the malformations that occur, and more research is required in this field. In the meantime, there are interventions that clinicians can already make to reduce the risk of adverse outcomes, such as seizure control without toxicity, monotherapy, and preconceptual use of vitamins with folate.
Total Patient Care in Epilepsy
Authors: Tettenborn Barbara , Krämer Günter
Published: November 2007

Summary: The aim of total care in epilepsy is to ensure the best possible management for each individual patient. Although pharmacotherapy for reduction or suppression of seizures is the basis of treatment in epilepsy, social and environmental problems are as likely to distress patients as continuing seizures. One often neglected aspect of management is the provision of adequate information for patients and relatives with regard to the various aspects of the seizure disorder. Better education of society regarding epilepsy is necessary to remove the many preconceptions and prejudices that still prevail. It is important to encourage self‐confidence in the patient and to avoid overprotection. Restrictions on lifestyle, including driving and employment, should be decided on a case‐by‐case basis, and only imposed if really necessary. Patients with epilepsy refractory to treatment should have access to specialized referral centers and institutions. One of the major goals of total patient care should be to help the patient with a seizure disorder lead a normal life, insofar as this is not prevented by additional mental retardation or cognitive dysfunctions.
The Lennox‐Gastaut Syndrome
Authors: Dulac O. , N'Guyen T.
Published: November 2007

Summary: One of the most challenging areas in nosology is in the field of severe generalized epilepsy of early childhood. This is certainly true in the case of Lennox‐Gastaut syndrome (LGS), an age‐related epileptogenic encephalopathy which comprises several types of generalized seizures including tonic seizures, atypical absence seizures and frequent status epilepticus. EEG shows generalized slow spike waves, and as the disease progresses, cognitive functions deteriorate. LGS is listed in the 1989 classification of the International League Against Epilepsy alongside epilepsy with myoclonic astatic seizures and West's syndrome. A number of variants or atypical forms have been proposed. As a result, differential diagnosis presents a major challenge and includes specific generalized epilepsies, i.e., metabolic or inflammatory; secondarily generalized epilepsies, i.e., those arising from the frontal lobe; and severe forms of idiopathic generalized epilepsy, i.e., Doose syndrome. Antiepileptic drug (AED) treatment of LGS has been disappointing. Results obtained from anterior callosotomy have been promising, but only a small number of patients have been evaluated. Although the syndrome is rare, the severe nature and intractability of LGS emphasizes the need for the development of specific AEDs which would completely modify the quality of life for these patients.
Nonconvulsive Status Epilepticus in Adults and Children
Authors: Cascino Gregory D.
Published: November 2007

Summary: Nonconvulsive status epilepticus (SE) accounts for approximately one‐quarter of all cases of SE. The actual proportion may be higher because patients with nonconvulsive SE may go unidentified. This disorder may be divided into generalized (absence) or partial (complex partial) forms. Nonconvulsive SE may occur de novo or in patients with epilepsy. Absence SE is considered more frequent and is characterized by a continuous neurocognitive alteration. Complex partial SE may be associated with recurrent seizure activity and a cycling of the clinical states. Treatment includes antiepileptic drug(s) (AEDs) and avoidance of seizure precipitants. Electrophysiological studies are necessary to confirm the diagnosis of nonconvulsive SE and to monitor the response to AED therapy. Prompt recognition and treatment may be necessary to avoid neurological morbidity in select patients. Epilepsy with continuous spikes and waves during slow sleep (ESES) and the Landau‐Kleffner syndrome are two rare childhood disorders that are difficult to classify but may be appropriate to include in a discussion of nonconvulsive SE.
Systemic Effects of Generalized Convulsive Status Epilepticus
Authors: Walton Nancy Y.
Published: November 2007

Summary: Generalized convulsive status‐ epilepticus (GCSE) is accompanied by a marked increase in plasma catecholamines. This produces a number of changes in general systemic physiology including hypertension, tachycardia, cardiac arrhythmias, hyperglycemia, acidosis, and hyperpyrexia. If SE is stopped quickly, these changes are self‐correcting and do not produce an increased risk of neuropathology. However, if seizures continue, many of the early physiologic changes reverse, and late status epilepticus is marked by hypotension, hypoglycemia, pulmonary edema and a continued acidosis and elevation of body temperature. Prevention of serious hypoglycemia, maintenance of adequate systemic blood pressure to provide adequate cerebral perfusion, and normalizing the body temperature will minimize or prevent neuropathologic sequelae to SE of extended duration.
Procedure for Developing a Quality‐of‐Life Measure for Epilepsy Surgery Patients
Authors: Vickrey Barbara G.
Published: November 2007

Summary: In 1990, the NIH Consensus Conference Panel on epilepsy surgery called for the development and use of reliable and valid health‐related quality‐of‐life (HRQOL) measures in epilepsy surgery studies. A HRQOL measure for epilepsy surgery patients has been developed and evaluated. The procedure, which could also be used to develop HRQOL measures for other neurological diseases, entails the following steps: (a) specify desired characteristics of the measure; (b) identify relevant HRQOL areas by reviewing the literature; (c) assemble generic core items and disease‐specific supplementary items; (d) pilot test and revise the measure; (e) administer revised measure items to a large sample of epilepsy surgery patients; (f) perform item analysis to evaluate hypothesized item placement within scales; and (g) assess the reliability and validity of the scales. The product of this process, the Epilepsy Surgery Inventory (ESI)‐55, is a self‐report measure of 11 dimensions of HRQOL. It is brief, comprehensive, and reliable; preliminary evidence supports its validity.
New Quality‐of‐Life Inventory for Epilepsy Patients: Interim Results
Authors: Perrine Kenneth R.
Published: November 2007

Summary: The process for developing and evaluating a comprehensive, self‐report measure of quality of life in epilepsy (QOLIE) is described, and interim results for 64 patients are reported. A test battery of 98 quality‐of‐life items was constructed with use of the RAND 36‐Item Health Survey as a generic core and adding other quality‐of‐life items, the latter derived from a literature review and expert opinion on areas of importance to people with mild to moderate epilepsy. Seventeen scales tapping unique quality‐of‐life dimensions were identified from this QOLIE test battery. The battery was administered to 64 adults with mild to moderate epilepsy and their proxies (relative or close friend) on two separate visits 2–3 weeks apart. Patients also completed a neuropsychological test battery on the first visit. Interim analysis of these data demonstrated that 16 of 17 scales on the QOLIE test battery are sufficiently reliable for group comparison: Cronbach's alpha for the 16 scales ranged from 0.73 to 0.88; test‐retest reliability ranged from 0.56 to 0.88. Preliminary evaluation of validity confirmed hypothesized correlations between selected QOLIE scales and Profile of Mood State scales. Correlations between patient and proxy scores ranged from 0.29 to 0.69 (all statistically significant at p < 0.005). A more detailed, final analysis of data for over 300 patients currently enrolled in the study will be published later.
Clinical Uses of the Quality‐of‐Life in Epilepsy Inventory
Authors: Devinsky Orrin
Published: November 2007

Summary: The quality‐of‐life in epilepsy (QOLIE) inventory was designed to assess adult epilepsy patients. Responses to a draft 99‐question inventory administered to patients with low to moderate seizure frequency will be used to generate two or three separate instruments. The largest and most comprehensive of these will serve as a research tool for investigators and may be helpful in designing studies that compare the effects of approved or investigational antiepileptic drugs. This instrument may also be useful in documenting patient outcomes following expensive diagnostic studies, such as video‐electroencephalogram monitoring, or other therapeutic interventions, such as epilepsy surgery. An intermediate‐sized instrument may serve as a clinical tool for neurologists and epileptologists. A brief instrument may serve as a quick clinical survey for primary care physicians, neurologists, and specialists in epileptology. The abbreviated clinical inventories are intended to provide rapid assessment of quality‐of‐life issues in the office setting. Such assessments can help physicians and patients identify previously unrecognized problems and may lead to changes in care.
Mitochondrial DNA Mutations in Epilepsy and Neurological Disease
Authors: Wallace Douglas C. , Lott Marie T. , Shoffner John M. , Ballinger Scott
Published: November 2007

Summary: Recent discoveries in mitochondrial clinical genetics have revealed that a broad spectrum of clinical phenotypes are associated with mutations in mitochondrial DNA. Diseases caused by mutations in mitochondrial DNA are by nature quantitative. Myoclonic epilepsy and ragged‐red fiber disease are caused by a mutation in the transfer RNA gene lysine. Although everyone in a maternal lineage will harbor the same mutation, the nature and severity of the symptoms vary markedly among individuals. This variability correlates with the inherited percentage of mutations in the individual's mitochondrial DNA and the individual's age. Age‐related expression of mitochondrial disease has also been demonstrated for mitochondrial DNA deletions. Although deletions that retain both origins of replication result in late‐onset disease because of the progressive enrichment of the deleted mitochondrial DNA, a 10.4‐kb deletion that lacks the light‐strand replication origin and maintains a stable mutant percentage in both tissues and cultured cells has been discovered. This deletion is associated with adult‐onset diabetes and deafness, but not with ophthalmoplegia, ptosis, or mitochondrial myopathy. Biochemically, it causes a generalized defect in mitochondrial protein synthesis and oxidative phosphorylation. The age‐related decline in oxidative phosphorylation could reflect the accumulation of somatic mitochondrial DNA mutations. Inhibition of oxidative phosphorylation stimulates this accumulation. The general paradigm for mitochondrial DNA diseases may be that inherited mutations inhibit the electron transport chain. This damages the mitochondrial DNA, further reducing oxidative phosphorylation. Ultimately, oxidative phosphorylation drops below the expression threshold of cells and tissues, and clinical symptoms appear.
Basic Concepts of Molecular Biology for the Epileptologist
Authors: Lowenstein Daniel H.
Published: November 2007

Summary: Fundamental techniques used in molecular biology can be applied toward questions of relevance to epilepsy. Many of the most common techniques used for working with nucleic acids, including DNA extraction, electrophoresis, cloning in plasmid vectors, making probes, and the polymerase chain reaction are now commonly used in basic epilepsy research. Some specific approaches that can be used to address particular questions are methods for identifying a human gene (Southern analysis and screening a library), determining whether a gene is expressed in a given brain region (Northern analysis and in situ hybridization), and expressing a gene in tissue culture or a whole organism (cell transfection and transgenic animals).
Clinical Experience with Oxcarbazepine
Authors: Gram Lennart
Published: November 2007

Summary: Controlled studies of oxcarbazepine (OCBZ) and the largest of the open studies of OCBZ were reviewed. The overall results indicated that OCBZ has the same clinical effect as carbamazepine (CBZ) but causes fewer adverse effects. Studies of allergic toxicity seem to indicate that OCBZ may be tolerated in the majority of patients developing allergy towards CBZ. We concluded that OCBZ is a drug of first choice for the treatment of epilepsy.
Standard Approach to Antiepileptic Drug Treatment in the United States
Authors: Pellock John M.
Published: November 2007

Summary: Antiepileptic drugs (AEDs) are administered to patients for acute and long‐term treatment of seizures. Most patients with acute convulsions receive intravenous (i.v.) benzodiazepine (BZD), frequently followed by i.v. loading with phenytoin (PHT), especially when seizures continue. For patients with absence status epilepticus, BZD is usually followed by ethosuximide (ESM) or valproate (VPA). The decision to continue AED therapy is based on the likelihood that seizures will continue or recur. Once epilepsy is diagnosed, long‐term treatment with AEDs is recommended, beginning with monotherapy. Two studies sponsored by the U.S. Veterans Administration (VA), which compared the efficacy of carbamazepine (CBZ), PHT, phenobarbital (PB), primidone (PRM), and VPA, recommend that most adults with recurrent partial seizures receive either CBZ or PHT. The 1992 VA study suggests that VPA is equal to CBZ or PHT in efficacy when partial seizures become secondarily generalized. Primary generalized epilepsies are most frequently treated with VPA when combinations of generalized seizures exist. ESM is prescribed most often when typical childhood absence seizures exist alone. Although many authorities do not recommend long‐term treatment of childhood febrile seizures, PB is administered by some when febrile seizures have complex symptomatology. In general, AED monotherapy is currently preferred, but those with more refractory epilepsy receive polytherapy. CBZ, PHT, PB, PRM, VPA, and ESM are the primary AEDs prescribed in the United States. PHT, followed by CBZ and VPA, is the most frequently prescribed AED as both new and total prescriptions. The introduction of fel‐bamate, gabapentin, and lamotrigine may alter these patterns in the future.
Emerging Insights Into Mechanisms of Epilepsy: Implications for New Antiepileptic Drug Development
Authors: Dichter Marc A.
Published: November 2007

Summary: Most currently available antiepileptic drugs (AEDs) were developed by testing new compounds in animal models of seizures. Increased knowledge of the cellular and molecular mechanisms underlying normal CNS function and seizure phenomena is now being used to design new AEDs specifically to interfere with epileptic mechanisms. Focal epilepsy develops in areas of cortex that are damaged and in which aberrant recurrent excitatory circuits develop, producing spike discharges in the EEC Occasionally, normal membrane conductances and inhibitory synaptic currents break down and excess excitability spreads, either locally to produce a focal seizure or more widely to produce a generalized seizure. Both original synchronous activation and seizure spread appear to utilize normal synaptic pathways and mechanisms. Much new development of AEDs is targeted at modulating these excitatory and inhibitory synaptic effects, focusing directly on multiple components of gluta‐mate and GABA receptors. Intrinsic, voltage‐dependent currents are also involved in the pathophysiology of epileptic processes. Calcium currents act to amplify excess neuronal depolarization during hypersynchronous activation, are involved in neurotransmitter release, and play a role in the development of longer‐term changes in synaptic efficacy, which may be involved in some seizure phenomena. They also appear to be involved in some forms of primary generalized epilepsy, in which burst discharges due to calcium currents in deep diencephalic neurons with widely ramifying axons may act as synchronizing influences. Neuromodulatory agents, including purines, peptides, cytokines, and steroid hormones, also play important roles in regulating brain excitability. Adenosine in some experimental models acts as an endogenous antiepileptic substance, and agents that enhance the actions of adenosine are often antiepileptic in animal models. Somatostatin may modulate synaptic inhibition, and this modulation may be lost when somatostatin levels are decreased in epileptic lesions. Seizures are also influenced by hormonal changes, stress, and infections, possibly mediated via systemic factors acting on brain excitability. Each of these areas may prove fruitful in developing new AEDs in the future. Epilepsy may develop after brain injury because the axon sprouting, new synapse formation, and circuit reorganization, which occur as an attempt to repair damage and restore function, are also likely to produce epileptogenic local circuits. To address this class of epileptic syndromes, new agents must be developed to interrupt these counterproductive processes without interfering with useful restorative processes. These drugs will probably be “antiepileptic” in the truest sense of the word.
Introduction: Goals
Authors: Wieser Heinz‐Gregor
Published: November 2007

Summary: Epilepsy is characterized by recurrent seizures. Many epilepsies with focal seizures as well as convulsive generalized seizures respond satisfactorily to antiepileptic drugs (AEDs) that reduce repetitive firing (e.g., phenytoin, carbamazepine, and valproate) or that augment GABAA‐mediated inhibition (e.g., phenobarbital and benzodiazepines). A number of drugs presently under development, such as NMDA receptor antagonists, loreclezole, losigamone, meth‐ysticine, and dextromethorphan, are promising in acute animal models of otherwise drug‐resistant convulsant activity. As a result of recent studies in both experimental models and surgically resected human epileptic brain, the prospects for development of AEDs have significantly improved. Several new AEDs recently have reached the commercial market or are in experimental or clinical trials. A comparative presentation of the standing of the new AEDs with respect to their efficacy and side effects is necessary, but still very difficult. Because initial experience with new AEDs is restricted to populations with severe drug‐resistant epilepsy, the crucial question whether potential new AEDs can alter prognosis is not yet definitively answered. There is a clear need to compare the effects of standard AEDs and new AEDs in naive patients and over longer follow‐up periods. Moreover, because of the strong desire to develop antiepileptic therapy that directly treats the primary etiology of a given epileptic syndrome, or modifies the neurobiological processes that cause recurrent seizures, better experimental epilepsy models for chronic epilepsy and further clinical studies are necessary to increase the knowledge on the pathophysiology of distinct epileptic syndromes. In this respect, studies on the differences between responders and nonresponders to a given AED treatment are extremely valuable.
Strategies for the Development of Drugs for Pharmacoresistant Epilepsies
Authors: Heinemann Uwe , Draguhn Andreas , Ficker Eckardt , Stabel Jasmine , Zhang Chuan Li
Published: November 2007

Summary: Presently, most strategies for development of antiepileptic drugs (AEDs) center around seizure models that are known to respond to presently marketed AEDs. These strategies do not take into account that epilepsy can be a progressive disease. Moreover, region‐specific aspects of ep‐ileptogenesis are rarely considered when new AEDs are developed. Seizures in the temporal lobe are often difficult to treat. Animal studies on various seizure models in the hippocampus and the entorhinal cortex (EC) suggest that these structures do not a priori produce seizures that are difficult to treat. However, seizure‐like events in the EC tend to progress to a state of status epilepticus‐like activity that cannot be suppressed by presently marketed AEDs. Loss of 7‐aminobutyric acid (GABA)ergic neurotransmission and increased excitatory synaptic coupling seem to cooperate for induction of this state. Epilepsy induced alterations in the interaction between the EC and the hippocampus may lead to alterations that facilitate precipitation of seizures. Because of the recurrent interaction between the hippocampus and the EC, these seizures may reach an intensity that is no longer controllable by presently available AEDs. Ontogenetic alterations of the circuitry between the EC and the hippocampus. seizure‐induced stabilization of synaptic connections over‐expressed during ontogenesis, seizure‐induced lesions and subsequent rearrangements of internal cell properties, and synaptic arrangements and kindling‐like alterations of nerve cell and glial behavior may all be involved in the generation of a neuronal aggregate whose balance between inhibitory and excitatory processes becomes readily disturbed. Strategies for the development of AEDs treating such seizures should suppress hyperactivity and prevent progression of epilepto‐genesis. AEDs directed against seizures may be effective if they can be given in sufficient concentrations to suppress very intense local seizures.
A Comment on the Efficacy of Valproate in the Treatment of Partial Seizures
Authors: Seino Masakazu
Published: November 2007

Summary: Discrepancies in the findings of studies sponsored by the Department of Veterans Affairs (VA) in the United States and the Medical Research Council (MRC) in the United Kingdom concerning the efficacy of valproate (VPA) in controlling simple or complex partial seizures, particularly those without secondarily generalized seizures, were reviewed. It was noted that the two studies differed with respect to their subjects' pretreatment seizure frequency. The frequency of complex partial seizures before treatment was obviously greater in the VA study, where carbamazepine (CBZ) provided better seizure control than VPA. Based on other comparative and non‐comparative studies as well as the author's over 20 years of experience in the use of VPA in a tertiary epilepsy clinic, it is suggested that although VPA may be effective in controlling both the secondarily generalized seizures of symptomatic localization‐related epilepsies and the generalized tonic‐clonic seizures of idiopathic and. if not always, symptomatic generalized epilepsies, the efficacy of VPA in controlling simple or complex partial seizures is likely limited to patients with infrequent seizures.
Lamotrigine: A Review of Antiepileptic Efficacy
Authors: Yuen A. W. C.
Published: November 2007

Summary: Lamotrigine (LTG) is a chemically novel anti‐epileptic drug (AED) that blocks voltage‐sensitive sodium channels, leading to inhibition of neurotransmitter release, principally glutamate. LTG is active in a wide range of pharmacologic models of epilepsy, demonstrating a potency and duration of action generally superior to currently available AEDs. Preliminary evidence of efficacy was provided by single‐dose studies showing effects on reducing interictal spike activity and photoconvulsive response. A total of eight randomized, double‐blind, placebo‐controlled, crossover trials have established the efficacy of LTG in patients with refractory partial epilepsy. Literature reports suggest LTG also is effective in patients with idiopathic generalized epilepsy, including absence seizures, and in patients with Lennox‐Gastaut syndrome. Other reports suggest that LTG is useful in the pediatric population, and an interim report of an open monotherapy trial suggests that the efficacy of LTG was comparable to that of carbamazepine (CBZ) but the adverse experiences leading to discontinuation were less frequent.
Oxcarbazepine: Preclinical Anticonvulsant Profile and Putative Mechanisms of Action
Authors: Schmutz M. , Brugger F. , Gentsch C. , McLean M. J. , Olpe H. R.
Published: November 2007

Summary: Oxcarbazepine (OCBZ, Trileptal) and its main human monohydroxy metabolite (MHD) protected mice and rats against generalized tonic‐clonic seizures induced by electroshock with ED50 values between 13.5 and 20.5 mg/kg p.o. No tolerance toward this anticonvulsant effect was observed when rats were treated with OCBZ or MHD daily for 4 weeks. The therapeutic indices were 4 (OCBZ) and >6 (MHD) for sedation (observation test, mice and rats) and 8 (MHD) or 10 (OCBZ) for motor impairment (rotorod test, mice). Both compounds were less potent in suppressing chemically induced seizures and did not significantly influence rat kindling development. At doses of 50 mg/kg p.o. and 20 mg/kg i.m. and higher, OCBZ and, to a lesser extent, MHD protected Rhesus monkeys from aluminum‐induced chronically recurring partial seizures. In vitro, OCBZ and MHD suppressed sustained high‐frequency repetitive firing of sodium‐dependent action potentials in mouse neurons in cell culture with equal potency (medium effective concentration 5 × 10‐8M/L). This effect is probably due in part to a direct effect on sodium channels. Patch‐clamp studies on rat dorsal root ganglia cells revealed that up to a concentration of 3 × 10‐4M, MHD did not significantly interact with L‐type calcium currents, whereas OCBZ diminished them by about 30% at the concentration of 3 × 10‐4M. In biochemical investigations, no brain neurotransmitter or modulator receptor site responsible for the anticonvulsant mechanism of action of OCBZ and MHD was identified. MHD and both of its enantiomers were of equal anticonvulsant profile and potency in rodent screening tests, with ED50 values ranging from 13 to 34 and 32 to 46 mg/kg p.o. in the electroshock and pentylenetetrazol test in mice, respectively. In addition, all three compounds showed a very similar profile of unwanted side effects. In vitro, they inhibited penicillin‐induced epileptic‐like discharges in the CA3 area of rat hippocampal slices with equal potency and efficacy at concentrations of 100–500 nm. This effect was attenuated when the potassium‐channel blocker 4‐aminopyridine was added to the bath fluid, thus indicating that potassium channels may also contribute to the antiepileptic activity of OCBZ.
New Antiepileptic Drug Development
Authors: Dreifuss Fritz E.
Published: November 2007

Summary: The development of new antiepileptic drugs is poised on the cusp between empiricism and the rational scientific development of medicaments designed to perform specific neurophysiologic functions in keeping with modern ideas of epilepsy generation and spread. It takes into account the difference between seizures and their underlying disorder known as epilepsies and the fact that, although seizures can be effectively treated with pharmacologic agents, the development of epilepsy requires both a predisposition (which may be innate or preventable) and precipitating factors that determine the timing of the individual seizures. The local membrane phenomena or cellular substrates of epilepsy can be described, as can the process of epileptogenesis. New antiepileptic development can be viewed in the light of these concepts.
Effects of NMD A‐ and AMPA‐Receptor Antagonists on Different Forms of Epileptiform Activity in Rat Temporal Cortex Slices
Authors: Zhang C. L. , Gloveli T. , Heinemann U.
Published: November 2007

Summary: Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizurelike events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to. /V‐methyl‐D‐aspartate (NMDA)‐ and non‐NMDA‐receptor antagonists. As NMDA‐receptor antagonist we used dextrorphan, ket‐amine, and 2‐aminophosphonovalerate (2APV); as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA)‐receptor antagonist we employed the quinoxaline derivative glutamate 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA‐receptor antagonists. However, when dextrorphan was employed to suppress seizure‐like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 μMm. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.
Clobazam in the Treatment of Epilepsy: A Review of the Literature
Authors: Remy Claude
Published: November 2007

Summary: The literature was reviewed to define the role of clobazam (CLB) in the treatment of epilepsy. CLB is an effective antiepileptic drug (AED) in most varieties of seizures and epilepsies for both short‐term and long‐term treatment. Tolerability of CLB is satisfactory, better than for conventional benzodiazepines. CLB has no significant interaction with other drugs. Tolerance may develop, but this aspect may have been overemphasized: a long‐term benefit figure of 28% can be expected without tolerance. When CLB maintains efficacy, patients continue to benefit for years without drug dependence or unwanted side effects. CLB appears to be a useful treatment for epilepsy as intermittent or short‐term add‐on therapy; but it should also be tried as long‐term therapy in some situations, especially as add‐on therapy for patients with refractory epilepsy, as add‐on or monotherapy for patients with anxiety, or in some women in association with oral contraceptives.
Clobazam for Treatment of Intractable Epilepsy: A Critical Assessment
Authors: Schmidt Dieter
Published: November 2007

Summary: Clobazam (CLB), a 1,5‐benzodiazepine, is a remarkably effective add‐on drug for individual patients with refractory partial epilepsy. CLB has an excellent safety record. As with all benzodiazepines used for treating epilepsy, sedation and withdrawal effects, together with the development of tolerance, limit its usefulness. Recent efforts to prevent or reverse tolerance with intermittent administration of CLB or periodic injection of a benzodiazepine antagonist, flumazenil, are encouraging and justify further investigations.
Commentary: How Has Neuroimaging Improved Patient Care?
Authors: Cascino Gregory D.
Published: November 2007

Summary: Neuroimaging has significantly altered the management of patients with partial epilepsy. Magnetic resonance imaging (MRI) has been demonstrated to be a reliable and accurate indicator of the common pathologic findings underlying a partial seizure disorder. Intracranial mass lesions have been shown to be highly coherent with the localization of the epileptogenic zone. An MRI‐identified epileptogenic lesion affects the selection of patients for epilepsy surgery and alters the diagnostic evaluation and the operative strategy. The results of the MRI preoperatively have prognostic importance in patients undergoing surgical treatment for partial epilepsy. Patients with lesional epileptic syndromes are considered favorable candidates for surgical ablative treatment. Hippo‐campal volume studies may predict the neurocognitive outcome in patients undergoing temporal lobe surgery. The use of MRI has resulted in a reduction in chronic intracranial EEG monitoring at most epilepsy centers, especially in patients with lesional pathology. MRI may be a reasonable initial “screening” procedure in selected patients with intractable partial epilepsy before consideration of a presurgical evaluation. A classification of partial epilepsy is proposed, based on the results of MRI, that may be useful for patients being considered for surgical treatment. Importantly, preoperative MRI must be correlated with the electrophysiologic studies and ictal semiology before decision‐making regarding surgical therapy.
New Techniques in Magnetic Resonance and Epilepsy
Authors: Jackson Graeme D.
Published: November 2007

Summary: Developments in magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and single photon emission tomography (SPECT) have opened new opportunities for noninvasive brain investigation. Functional imaging methods involving noninvasive MRI and minimally invasive PET and SPECT are available that allow investigation of brain abnormality in intractable epilepsy patients. Noninvasive techniques enable the investigation of many aspects of the underlying neuropathologic basis of intractable seizures and of the relationship of functional abnormalities both to structural abnormalities and to the seizure focus. New MRI techniques demonstrate the structure of the brain in fine detail (especially the hippocampus), provide information about the underlying metabolism of brain regions, and demonstrate functional activity of the brain with high spatial and temporal resolution. The clinical impact of this noninvasive information cannot be overstated and these techniques provide indispensable information to neurologists specializing in epi‐leptology. The proper use and interpretation of the findings provided by these new technologies will be a major challenge to epilepsy programs in the next few years.
Operative Strategies for Patients with Cortical Dysplastic Lesions and Intractable Epilepsy
Authors: Palmini André , Gambardella Antonio , Andermann Frederick , Dubea François , da Cos Jaderson Costa , Olivi André , Tampie Donatella , Robitaill Yvon , Paglioli Eduardo , Neto Eliseu Paglioli , Coutinho Ligia , Kim Hyoung‐Ihl
Published: November 2007

Summary: Cortical dysplastic lesions (CDLs) are usually identified by magnetic resonance imaging (MRI). Clinical, electrographic and histologic findings suggest that focal CDLs (FCDLs) are highly epileptogenic, often involve the rolandic cortex, and can present variable degrees of histopathologic abnormalities. An ictal or “ictal‐like” bursting pattern of electrographic activity was recorded over dysplastic cortex in 65% of our patients. Resective surgery can eliminate or significantly reduce seizure frequency in many medically intractable patients, depending on lesion location, degree, and extent of histopathologic abnormalities. Best results are achieved when complete or major excision of both the MRI‐visible lesion and the cortical areas displaying ictal electrographic activity can be performed. This is more likely when the degree of histopathologic abnormality is mild to moderate or when the lesion is in a temporal lobe. More severe histopathologic abnormalities and central insular or multilobar lesions usually lead to less favorable results: either major excision of the visualized lesion is impractical or the lesion is microscopically more extensive than shown by MRI. Multilobar resection or hemispherectomy for patients with infantile spasms associated with CDLs and for patients with hemimegalencephaly are often associated with dramatic improvement in seizure control. Callosot‐omy can be performed in selected patients with diffuse CDLs who have intractable drop attacks.
The Relative Contributions of MRI, SPECT, and PET Imaging in Epilepsy
Authors: Spencer Susan S.
Published: November 2007

Summary: Functional and structural neuroimaging techniques are increasingly indispensable in the evaluation of epileptic patients for localization of the epileptic area as well as for understanding pathophysiology, propagation, and neurochemical correlates of chronic epilepsy. Although interictal single photon emission computed tomography (SPECT) imaging of cerebral blood flow is only moderately sensitive, ictal SPECT markedly improves yield. Positron emission tomography (PET) imaging of interictal cerebral metabolism is more sensitive than measurement of blood flow in temporal lobe epilepsy. Furthermore, PET has greater spatial resolution and versatility in that multiple tracers can image various aspects of cerebral function. Interpretation of all types of functional imaging studies is difficult and requires knowledge of time of most recent seizure activity and structural correlates. Only magnetic resonance imaging (MRI) can image the structural changes associated with the underlying epileptic process, and quantitative evidence of hippocampal volume loss has been highly correlated with seizure onset in medial temporal structures. Improved resolution and interpretation have made quantitative MRI more sensitive in temporal lobe epilepsy, as judged by pathology. When judged by electroencephalography (EEG), ictal SPECT and interictal PET have the highest sensitivity and specificity for temporal lobe epilepsy; these neuroimaging techniques have lower sensitivity and higher specificity for extratemporal EEG abnormalities. Regardless of the presence of structural abnormalities, functional imaging by PET or SPECT provides complementary information. Ideally these techniques should be used and interpreted together to improve the localization and understanding of epileptic brain.
Efficacy and Adverse Effects of Established and New Antiepileptic Drugs*
Authors: Mattson Richard H.
Published: November 2007

Summary: Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic‐clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEds. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic‐clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic‐clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second‐choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No “drug of choice” can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.
The Effect of Age on Pharmacokinetics of Antiepileptic Drugs
Authors: Willmore L. James
Published: November 2007

Summary: Management of epilepsy in the elderly requires understanding of the unique biochemical and pharmacologic characteristics of this patient population. Accurate assessment of seizures and identification of epilepsy syndromes, thorough neurologic assessment to define etiology, and comprehensive evaluation of the patient's health and living situation are necessary for informed management decisions. Challenges to treatment include concomitant diseases, polypharmacy with accompanying drug interactions, and changes in physiology, such as changes in renal clearance and hepatic function that alter drug absorption, protein binding, metabolism, and elimination. Elderly patients with declining intellectual function, motor impairment, or altered sensory function may be especially susceptible to dose‐related CNS side effects of antiepileptic drugs (AEDs). Drugs pre‐scribed for concomitant illnesses such as hypertension, cardiovascular disease, infections, behavioral problems, and gastrointestinal disturbances may alter absorption, distribution, and metabolism of AEDs, with an adverse impact on efficacy and increased occurrence of adverse effects. The AEDs may induce metabolism of other drugs, resulting in decline in target response. Addition of an AED to an elderly patient's medical regimen requires careful review of all prescribed drugs. Optimal care of elderly patients with epilepsy includes use of free drug levels to monitor AED concentrations, careful dose selection, and sensitivity to the social problems that may occur in this population.
Epilepsy Care: Image of the Future
Authors: Gram Lennart
Published: November 2007

Summary: A number of factors have contributed to improvements in the care of epilepsy during the past decade, including the International League Against Epilepsy classifications, therapeutic antiepileptic drug (AED) monitoring and the concept of monotherapy, new AEDs with novel mechanisms of action, and new insights into etiology that suggest novel therapies. Pharmacologically “clean” AEDs acting on a single known mechanism will be an important element in the future care of patients with epilepsy. Augmentation of GABAergic inhibition is being successfully exploited by AEDs, and there remains much room for further pharmacologic innovation. The potential role of AEDs acting specifically on the GAT‐1 or GAT‐4 sub‐group of γ‐aminobutyric acid transporters is a topic of current research. Specifically acting AEDs designed to have a single and known mode of action will permit true monotherapy, one AED with one target as opposed to one AED with several targets, and may open the way to rational polytherapy, i.e., designed use of one AED per mechanism in epilepsies with multifactorial causation. New research demonstrating a possible autoimmune basis for some forms of epilepsy illustrates the potential for novel nonpharmacologic approaches, and the role of prevention must also be emphasized. The image of the future is an optimistic one.
Avoiding the Pitfalls of EEG Interpretation in Childhood Epilepsy
Authors: Mizrahi Eli M.
Published: November 2007

Summary: The accurate interpretation of the electroencephalogram (EEG) of infants and children being evaluated for suspected epilepsy is based on the appreciation of normal and expected age‐dependent characteristics, an awareness of the significance of both epileptiform and non‐epileptiform activity, and the correlation of epileptiform abnormalities with clinical findings. Avoiding the pitfalls of pediatric EEG interpretation include the recognition of such normal EEG features in wakefulness as posterior slow waves of youth, mu rhythm, and lambda waves. In addition, the understanding of age‐dependent characteristics of EEG state‐changes is essential, such as: monorhythmic and paroxysmal hypnagogic hypersyn‐chrony, special features of vertex transients and sleep spindles, positive occipital sharp transients, initial arousal responses and post‐arousal hypersynchrony. The EEG response to activation procedures such as hyper‐ventilation and photic stimulation may also be a source of confusion. Patterns of uncertain diagnostic significance also may be present in children, including 14‐and 6‐Hz bursts and rhythmic temporal theta bursts of drowsiness (the so‐called psychomotor variant). Some nonepilepti‐form EEG abnormalities may also be misinterpreted as epileptiform. The determination of the clinical significance of spike foci and generalized abortive spike‐and‐wave may pose more of a problem as a potential pitfall than the identification by visual analysis of these interic‐tal discharges. Another problem posed to the electroen‐cephalographer is the determination of the EEG response to antiepileptic drug therapy including effect on spike foci, generalized spike‐and‐wave and electrical seizure activity, and effect on background activity. The recognition of the differences between the EEG of children and adults will provide the basis for more accurate interpretation and assist the electroencephalographer in avoiding the identification of normal, age‐dependent features as epileptiform.