bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐Term Experience with Topiramate as Adjunctive Therapy and as Monotherapy in Patients with Partial Onset Seizures: Retrospective Survey of Open‐Label Treatment
Authors: Rosenfeld W. E. , Sachdeo R. C. , Faught R‐ E. , Privitera M.
Published: November 2007

Summary: Because initial studies of new antiepileptic drugs (AEDs) are add‐on trials in refractory patient populations, their effectiveness as monotherapy is usually not apparent until relatively later in their development programs. The novel AED topiramate (TPM) has been found efficacious as adjunctive therapy in controlled, randomized trials in adults with partial onset seizures. We report a retrospective analysis of TPM as AED monotherapy in 214 patients from five centers who received TPM in investigational trials. Of this total, 136 (64%) were still receiving TPM at the time of the analysis, with a mean treatment duration of 2.5 years. One‐third of the patients have been successfully converted to TPM monotherapy, and 62% of those converted have been seizure‐free for at least 3 months. The results of this analysis suggest that TPM may prove to be a valuable new AED for both monotherapy and add‐on therapy in partial onset epilepsy.
Preliminary Observations on Topiramate in Pediatric Epilepsies
Authors: Glauser Tracy A.
Published: November 2007

Summary: Preliminary results of studies of topiramate (TPM) in children are now available. In a pharmacokinetic study among 18 male and female children, target daily dosages of up to 9 mg/kg/day were evaluated. TPM pharmacokinetics in children were linear. Mean TPM oral clearance (CL/F) was 44–54% higher in children [depending on concomitant antiepileptic drugs (AEDs)] compared with historical data from adults, and steady‐state plasma TPM concentrations for the same mg/kg dose were 33% lower in children compared with historical adult data. In a long‐term, open‐label pilot study of adjunctive TPM therapy in 18 patients with Lennox‐Gastaut syndrome, six of the eight patients (75%) still receiving TPM report a greater than 50% reduction in total seizures, with the best results observed in tonic‐atonic, atypical absence, and generalized tonic‐clonic seizures. Subsequent large double‐blind, placebo‐controlled trials of adjunctive TPM therapy in Lennox‐Gastaut syndrome and refractory partial‐onset pediatric epilepsy are ongoing, with high percentages of enrolled patients in both studies completing double‐blind treatment and entering long‐term TPM open extension trials. A small TPM monotherapy substitution trial in children with well controlled partial onset seizures showed that TPM monotherapeutic substitution can be achieved successfully with an acceptable amount of adverse experiences with a weekly increase of 1 mg/kg/day to a maximal dose of 3 mg/kg/day. These preliminary results suggest that TPM may be a useful new AED in pediatric patients with a variety of seizure disorders.
Women with Epilepsy: Must Contraception and Pregnan Add to the Burden of Epilepsy?
Authors: Ben‐Menachem Elinor
Published: November 2007

Summary: In addition to seizure control, women with epilepsy face particular complications associated with menstruation, fertility, contraception, pregnancy, and breastfeeding. With traditional long‐term antiepileptic drug (AED) therapy there is a risk of menstrual irregularities, contraceptive failure, and adverse pregnancy outcome. Many women intentionally discontinue AED therapy during pregnancy because of concerns about the risk of fetal malformation and effects on fetal growth and development. However, trauma resulting from seizures is the leading cause of maternal and fetal death in women with epilepsy. In addition, mothers are concerned about the presence of AEDs in breast milk and therefore tend to choose bottle feeding. Clearly, a balance must be achieved between seizure control for the mother and exposure of the fetus or infant to AEDs. Tiagabine (TGB) is a new AED which acts by inhibiting uptake of the neurotransmitter γ‐aminobutyric acid into glial cells. Animal studies show that TGB has no toxic effects either on reproductive function or on the developing fetus, although there is still insufficient evidence to permit conclusions from human studies. TGB does not induce hepatic metabolism, and a study in healthy volunteers indicates no interaction with oral contraceptives. It is hoped that the availability of new AEDs such as TGB, with the promise of a better safety profile and a lower propensity for drug interactions, will alleviate the burden for women with epilepsy.
Elderly Patients with Epilepsy: Specific Requirements
Authors: Pedersen Birthe
Published: November 2007

Summary: Epilepsy is the third most common neurologic disorder in the elderly and, combined with the progressive aging of the population, this high incidence will lead to an increasing number of elderly patients who require epilepsy care. Treatment of epilepsy in elderly patients is often complicated by the physiologic changes that occur in old age, e.g., reduced absorption, slower metabolism, and deterioration of liver and renal function. Another consideration is that elderly patients are most likely to be suffering from other diseases, necessitating multiple therapies. The potential for drug interactions is therefore high. Because of these factors, traditional antiepileptic drug (AED) therapies are associated with a higher incidence of adverse effects in elderly patients than in younger patients. Tiagabine (TGB) is one of a family of new AEDs recently developed. The newer AEDs tend to have a comparable antiepileptic efficacy and a lower potential for toxicity compared with the traditional AEDs. Clinical studies have shown that age appears to have no effect on the pharmacokinetics of TGB and that there is little difference in the incidence of adverse events between elderly and young patients. Although clinical experience with TGB in the elderly is still limited, TGB shows promise for treatment of epilepsy in the elderly population.
Tiagabine in the Management of Epilepsy
Authors: Brodie Martin J.
Published: November 2007

Summary: Tiagabine (TGB) is a new antiepileptic drug (AED) that uniquely reduces the uptake of the inhibitory neurotransmitter ‐γ‐aminobutyric acid into presynaptic neuronal and glial cells. It is metabolized in the liver with an elimination half‐life of approximately 7 to 9 h. Although TGB does not induce or inhibit hepatic metabolic processes, it does provide a target for other enzyme‐inducing AEDs. TGB has proved effective as add‐on treatment for partial seizures, with or without becoming secondarily generalized, as demonstrated in five placebo‐controlled trials and six long‐term open studies. Preliminary results with TGB in children with refractory epilepsy and as monotherapy are promising. Few patients withdrew from these trials because of adverse events. The most common side effects with TGB involved the central nervous system, i.e., dizziness, asthenia, somnolence, nervousness, headache, and tremor. Most adverse events occurred during dosage titration, were often transient, and were usually of mild to moderate severity. The recommended maintenance dose for TGB, when combined with enzyme‐inducing drugs as add‐on therapy, is 30 to 50 mg/day. Trials are under way in patients with primarily generalized seizures and in newly diagnosed epilepsy. TGB is a well‐tolerated and effective novel AED that will find an enduring place in the management of epilepsy.
Magnetoencephalography/Magnetic Source Imaging in the Assessment of Patients with Epilepsy
Authors: Ebersole John S.
Published: November 2007

Summary: Magnetoencephalographic (MEG) dipole source localization is a particularly promising new tool for noninvasive presurgical evaluation of epileptogenic foci. It is potentially more accurate than EEG localization techniques because magnetic fields are not attenuated or distorted by the skull and scalp, which allows cerebral sources to be modeled more simply. MEG spike and seizure sources are routinely co‐registered with the patient's brain MRI for clinical interpretation. This has been called magnetic source imaging. Numerous studies have shown that MEG localization of foci agreed with lesion position, depth electrode and ECoG data, PET and MRI findings, and surgical success. The recent development of whole head sensor arrays has greatly enhanced the ease with which epileptiform magnetic fields can be recorded and analyzed.
Clinical Applications of Magnetic Resonance Spectroscopy
Authors: Laxer Kenneth D.
Published: November 2007

Summary: Magnetic resonance spectroscopy (MRS) is a new tool for evaluation of patients with epilepsy, demonstrating abnormalities of energy and lipid metabolism ictally and, more recently, interictally. These metabolic abnormalities include increased inorganic phosphate, pH, and decreased phosphomono‐esters as determined by 31P MRS, as well as decreased N‐acetylaspartate determined by 1H MRS. Furthermore, increased lactic acid has been detected postictally. These metabolic changes appear to be confined to the region of seizure origination and can be detected interictally. Therefore, they can be used for lateralization of the epileptogenic focus. Ongoing research suggests that these abnormalities may also be useful in localization of the focus, demonstrating metabolic alterations in temporal lobe epilepsy (TLE) similar to those in neocortical epilepsy. However, further technical development will be required before the goal of using these techniques for localization of the epileptogenic focus can be realized. For TLE lobe epilepsy at least, the clinical utility of 'H MRS to lateralize the seizure focus has clearly been demonstrated by several centers. The consistent findings in TLE suggest that 'H MRS is ready to become part of the evaluation process of patients with medically refractory epilepsy being evaluated for seizure surgery.
Maximizing the Health of Women with Epilepsy: Science and Ethics in New Drug Development
Authors: Morrell Martha J.
Published: November 2007

Summary: Issues of unique concern to women with epilepsy largely arise from gender‐based physiological differences. Female sex steroid hormones may alter the expression of epilepsy and the efficacy of antiepileptic drugs (AEDs). Seizures and AEDs in turn affect the hypothalamic‐pituitary axis and can adversely impact reproductive function and bone health. Maternal seizures and exposure to AEDs may compromise fetal development. At this time, women with epilepsy and their medical caretakers do not have access to all the information necessary to formulate a treatment plan that will have the least impact on reproductive and general health. In part, this is because reproductive aged women are excluded from the earliest phases of drug testing and pregnant and lactating women are excluded from all aspects of new drug development. Therefore, as new AEDs enter the marketplace, women with epilepsy must decide whether a new AED is appropriate for therapy based on very limited information. Postmarketing surveillance of gender‐specific adverse effects, as with all adverse effects, depends on voluntary reporting. Only a small percentage of significant adverse events are believed to be captured by the present system. Consumers, ethicists, and some physician groups are now arguing that women should be included in all aspects of the development of drugs they will ultimately use–even pregnant and lactating women. Some of the issues of concern for women with epilepsy regarding epilepsy treatment, reproductive function and general health will be reviewed, followed by a discussion of the drug development process and how it does, and could better, address the concerns of women.
Don't Test, Do Sell: Legal Implications of Inclusion and Exclusion of Women in Clinical Drug Trials
Authors: Herz Susan E.
Published: November 2007

Summary: This article explores the historic underpinnings of the exclusion of women from clinical drug trials, identifies recent developments, and examines legal implications for women with epilepsy and for others. Distinguishing stakeholders and their interests may lead to policies that better serve all. Past and present statutory, regulatory, and judicial frameworks were reviewed, as well as legal, medical, and historical commentary. Traditionally, researchers and manufacturers have not tested particular drugs on women. Physicians and pharmacists routinely prescribe and sell these same medications regardless of gender. Only since 1993 have females been more likely to be included in clinical drug trial subject pools. The impact of past and future practices on health care provision and legal liability remains unknown. A policy of “Don't test, do sell” will not protect women with epilepsy or would‐be defendants. At this time the most effective shields will involve procurement of informed consent as well as testing of both women and men. In the long run, tort, health care, and regulatory reform will best serve all interested persons. Inclusion of women in clinical drug trials has become a how question, not an if one.
Antiepileptic Drug Monotherapy Designs in Clinical Trials
Authors: Gram Lennart
Published: November 2007

Evaluation of new antiepileptic drugs (AEDs) in monotherapy used to be performed by comparative trials between new AEDs and classical AEDs. However, the majority of these studies showed no difference in outcome, which could result in conflicting interpretations. Therefore, novel designs that avoid this problem have been developed to evaluate new AEDs. Three approaches have been proposed, each with advantages and disadvantages. The attenuated active control design compares new AEDs to suboptimal doses of a control AED. However, this situation brings about ethical concerns and strict entry criteria must be applied. The presurgical design compares new AEDs to placebo treatment. Rapid dose escalation to the therapeutic level of the new AED must be undertaken to avoid seizures resulting from extended suboptimal doses of the AED, and ethical concerns about the use of placebo also apply. The concentration controlled design is based on the assumption that a stronger correlation exists between drug blood level and therapeutic response in comparison to correlation between dose and effect. In this design, patients are randomized to be treated with different blood concentrations of a new AED, and efficacy data at these different concentrations are compared. All of these designs allow a definitive demonstration of efficacy early in the development of a new AED.
Antiepileptic Drug Monotherapy Versus Poly therapy: A Historical Perspective
Authors: Genton P. , Roger J.
Published: November 2007

Monotherapy (administration of a single drug) for the treatment of epilepsy has been the gold standard for almost two decades, although exceptions to this rule are still accepted in selected forms of epilepsy. Before this contemporary approach, other attitudes prevailed. The first effective antiepileptic drugs (AEDs), e.g., bromides and, much later, phcnobarbital (PB), were administered in association with central nervous system stimulants to counterbalance sedative effects. Phenytoin was the first effective nonsedative AED and was often administered together with phenobarbitai at moderate dosages to avoid the toxicity associated with a higher dosage of a single AED. PB was also co‐administered with ethosuximide in the treatment of absence epilepsy, to prevent the occurrence of both absence seizures and generalized tonic‐clonic seizures. Although the practice of monotherapy has become increasingly prevalent, the recent availability of new AEDs has created new problems. In fact, because of the introduction of these AEDs as effective add‐on therapy, the use of “rational polypharmacy” was reinvented. From a historical perspective, however, the trend toward simple, cost‐effective management of seizures with a single AED is still a goal.
Basic Mechanisms of Epilepsy: Targets for Therapeutic Intervention
Authors: Dichter Marc A.
Published: November 2007

Summary: Although a wide variety of drugs are available for treatment of epilepsy, many patients with epilepsy still experience uncontrolled seizures. In addition, there is a need for new drugs that can halt epileptogenesis after brain injury. Mechanisms that underlie seizure processes constitute potential target areas for the development of new antiepileptic drugs (AEDs). An understanding of the underlying mechanisms of interictal spike discharge and seizure spread is critical for the development of AEDs for treatment of partial seizures. Suppression of specific forms of voltage‐dependent calcium currents and inhibition of GABAB receptor‐mediated inhibition are two key target areas for new AEDs to treat primary generalized seizures. As researchers gain more understanding of the cellular, molecular, and genetic mechanisms underlying seizure propagation, we should be better able to develop therapeutic agents designed to suppress seizure‐provoking mechanisms and to enhance the brain's natural protective mechanisms.
The Mortality Associated with Epilepsy, with Particular Reference to Sudden Unexpected Death: A Review
Authors: O'Donoghue M. F. , Sander J. W. A. S.
Published: November 2007

Summary: Recent studies indicate that the overall mortality rate for persons with epilepsy is elevated two‐ or threefold compared with the general population. The standardized mortality ratio (SMR) is greatest in the first few years after diagnosis and in symptomatic epilepsies. Idiopathic epilepsies also have a small increase in SMR. The sudden unexpected death rate in those with epilepsy (SUDEP) depends on the population examined. In the general population of persons with epilepsy, the risk is between 1:500 and 1:1,000 person‐years. For those with severe epilepsy or other neurologic impairments, the risk appears to be 1:200 person‐years. The risk in children remains uncertain. Estimates of mortality should be borne in mind when patients are counseled about the risks and benefits of various treatment strategies.
Sudden Unexpected Death in Patients with Epilepsy: Issues for Further Study
Authors: Hauser W. A.
Published: November 2007

Summary: Understanding of mechanisms and the development of interventions to prevent sudden unexpected death in epilepsy (SUDEP) can be enhanced only through multicenter studies. Although current definitions are useful and congruent, there is insufficient guidance to allow others to duplicate studies. A working algorithm should be developed, preferably through review of current series, along with alternative definitions to allow external comparison with cardiovascular studies.
Epileptic Sudden Death: Animal Models
Authors: Simon R. P.
Published: November 2007

Summary: The pathologic hallmark of sudden unexpected death in epilepsy (SUDEP) in humans is pulmonary edema. In an animal model of seizures, pulmonary vascular pressure, but not systemic pressure, increases in proportion to seizure duration. The induced pulmonary vascular hypertension drives fluid out of the vascular compartment into the lung parenchyma. Blocking intraictal pulmonary vascular pressure elevations prevents changes in the observed doubling of the pulmonary transcapillary fluid flux. In this animal model, the main difference between surviving animals and those that die during the seizure is apnea, with a precipitous fall in the partial pressure of oxygen (p02) and a parallel elevation in the partial pressure of carbon dioxide (pC02) recorded in nonsurvivors. Pulmonary artery and left atrial pressures in animals that die are double those of surviving animals, with a resultant increase in extra‐vascular lung water at postmortem examination. The pulmonary edema is due to the combined effects of seizure‐ and hypoxia‐induced pulmonary vascular hypertension. This animal model reproduces both death during epilepsy and pulmonary edema at postmortem examination. The etiology of the pulmonary edema appears to be that of pulmonary vascular hypertension, and the etiology of sudden death appears to be that of centrally induced apnea.
Sudden Death in Epilepsy: Can Any Lessons be Learned From Convulsive Therapy?
Authors: Betts T.
Published: November 2007

Summary: Convulsive therapy (chemically or electrically induced) has been used since the mid‐1930s. Initially it had a high mortality rate, but this has been falling slowly in response to refinements in technique (introduction of muscle paralysis during the seizure, brief intravenous general anesthesia and, more recently, the acceptance that adequate ventilation and oxygenation are necessary during the procedure). Mortality during convulsive therapy has been ascribed to both cardiac and respiratory causes (particularly acute arrhythmias and pulmonary edema). There is some evidence that supporting respiration during and after the convulsion has reduced mortality significantly, such that electrical convulsive therapy is now a very low‐risk procedure, even in the very elderly. This gives tenuous support for the view that death in epileptic seizures may be of respiratory origin.
Arrhythmogenic Seizures
Authors: Jallon P.
Published: November 2007

Summary: Arrhythmogenic seizures may represent one of the mechanisms implicated in sudden unexpected death in epilepsy. Various cardiac changes can be observed during epileptic seizures. However, reports of well‐documented, life‐threatening cardiac arrhythmias in the literature are scarce. The pathogenesis of these arrhythmias and speculations about the cortical localization of cardioarrhythmogenic triggers are reviewed.
An Economic Appraisal of Carbamazepine, Lamotrigine, Phenytoin and Valproate as Initial Treatment in Adults with Newly Diagnosed Epilepsy
Authors: Heaney Dominic C. , Shorvon Simon D. , Sander Josemir W. A. S.
Published: November 2007

Summary: We undertook an economic appraisal of four drugs used in monotherapy during the first 2 years of treatment for newly diagnosed patients with epilepsy: carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), and valproate (VPA). We adopted the cost‐minimization model because, although no single trial compares all four drugs directly, the clinical trials comparing two or more of these drugs in newly diagnosed cases show no significant difference in efficacy between the drugs in terms of seizure frequency: Considered in the cost analyses were frequency of side effects, retention rates, medical consultations, inpatient and accident and emergency costs, laboratory investigations, and drug changes. A Delphi panel provided the treatment pathways, including frequency of clinical consultations, second‐line monotherapy, and side‐effects management. A sensitivity analysis was performed, varying the assumptions on which the calculations were based. Analysis was completed for a prospective, intention‐to‐treat perspective and also for those patients continuing the initial drug. The direct medical costs of 2‐years therapy (intention‐to‐treat analysis) calculated for each trial were £795–829 for CBZ, £1,525‐2,076 for LTG, £736–768 for PHT, and £868–884 for VPA. A sensitivity analysis provided similar relative estimates. We found that LTG for newly diagnosed patients is significantly more expensive in direct health service costs incurred. This analysis incorporated seizure control, side effects, and tolerability. We recommend that a similar type of analysis be considered as part of all clinical trials of antiepileptic drugs in which efficacy of outcome is similar as a guide to assess optimal cost effectiveness.
Benign Epilepsy of Childhood With Centrotemporal Spikes
Authors: Wirrell Elaine C.
Published: November 2007

Summary: Benign epilepsy of childhood with centrotemporal spikes (BECT) is the most common partial epilepsy syndrome in the pediatric age group, with an onset between age 3 and 13 years. The typical presentation is a partial seizure with paresthesias and tonic or clonic activity of the lower face associated with drooling and dysarthria. Seizures commonly occur at night and may become secondarily generalized. They are usually infrequent and may not require antiepileptic drugs but, if treated, they tend to be easily controlled. Children with BECT are neurologically and cognitively normal. The EEG shows characteristic high‐voltage sharp waves in the centrotemporal regions, which are activated with drowsiness and sleep. In this typical form, BECT is easily recognized. However, atypical cases are common and the definition of BECT can become blurred. Although further investigations are not required in cases with typical clinical and EEG findings and normal neurologic examinations, neuroimaging studies may be required in atypical cases to rule out other pathology. The long‐term medical and psychosocial prognosis of BECT is excellent, with essentially all children entering long‐term remission by mid‐adolescence.
Motor and Sensory Mapping of the Frontal and Occipital Lobes
Authors: Lesser Ronald P. , Arroyo Santiago , Crone Nathan , Gordon Barry
Published: November 2007

Summary: In patients with intractable epilepsy, surgical resections are performed with the primary goal of improving seizure control. The risk is that the resections may also remove tissues crucial for normal activities. The goal of surgical planning is therefore to determine as accurately as possible the regions of seizure onset and the regions controlling important functions, so that one can determine what to remove and what to leave in place. Clinical functional localization has been performed using cortical stimulation for over half a century, using both intraoperative and extraoperative methods. Signal averaging also has been widely used. More recently, techniques based on analysis of EEG in the frequency domain have shown promise. The methods appear to accurately indicate the function of the region assessed but do not necessarily predict functional consequences of resection. We review these methods, their indications, and the results obtained by their use.
Multiple Subpial Transection in Patients with Extratemporal Epilepsy
Authors: Smith Michael C.
Published: November 2007

Summary: Multiple subpial transection (MST) was developed to permit the treatment of partial epilepsies that reside in or encroach on eloquent cortex (language and sensorimotor cortex). It was conceived after the discoveries of the columnar organization of neocortex and that expression and spread of seizures utilize the transverse fiber network. Although the technique is simple in principle, it takes a skilled and practiced hand to avoid damage to the neocortical columns and vascular supply. The efficacy in controlling seizures with MST in extra‐temporal epilepsy is similar to that of resective surgery. Activities of daily living are not adversely impacted by MST. MST is a viable alternative to resection in extratemporal epilepsy.
Epileptic Seizures and Pseudoseizures from the Viewpoint of the Hierarchy of Consciousness
Authors: Oana Yasunori
Published: November 2007

Summary: Epileptic seizures and pseudoseizures in temporal lobe epilepsies were studied from the viewpoint of the hierarchy of consciousness. Twenty‐two patients with temporal lobe epilepsies (TLE) who showed true amnesia or impairment of consciousness developing from the dreamy state, even though their actions and movement continued, were selected among 160 patients with TLE. nine patients with manifested pseudo‐seizures, pseudoseizure status, and complex partial seizure status (CPSE) were investigated. Twelve, patients in whom impairment of consciousness followed the dreamy state recognized their own existence and maintained some self‐directed consciousness. The other 10 patients with amnesia were aware of their goals. Furthermore, pseudostatus ranged from epileptic seizures during pseudoseizure status to pseudoseizures during status epilepticus (SE). In some cases of CPS, awareness and self‐directed consciousness were only partially pseudoseizures, disorders of self‐directed consciousness are assumed to influence awareness and arousal.
West Syndrome and its Related Epileptic Syndromes
Authors: Ohtsuka Yoko
Published: November 2007

Summary: The purpose of this project was to study the relationship between West syndrome (WS) and its related epileptic syndromes, and reconsider the nosological limits of WS. The electroclinical features of 45 patients who experienced spasms in series were investigated, as well as some features not common in patients with WS. All patients were mentally retarded. The patients were divided into three groups: Group 1 consisted of 12 patients with refractory epilepsies with onset in early infancy, group 2 consisted of 5 patients with symptomatic localization‐related epilepsies associated with spasms in series, and group 3 consisted of 28 patients with generalized epilepsies who had spasms in series after age 2 years. Partial seizures were the dominant symptom throughout the clinical course and spasms in series associated with atypical hypsarrhythmia appeared transiently during infancy in a significant number of the patients in group 1. In group 2, complex partial seizures (CPS) were the main seizure type and hypsarrhythmia was not observed during the clinical course. The EEGs in group 3 patients showed diffuse slow spike‐waves or multifocal epileptic discharges in all but 1 patient. The EEG of the remaining patient still showed hypsarrhythmia at age 8 years. Therefore, group 1 patients should be classified as having WS although cortical mechanisms play a critical role in the occurrence of their seizures. Group 2 patients should be considered as having a type of localization‐related epilepsy even though they share a similar pathophysiological mechanism with group 1. In group 3, 1 patient whose EEG still showed hypsarrhythmia was classified as having WS. The other patients should be classified as having generalized epilepsies other than WS.
Antiepileptic Drug Treatment of West Syndrome
Authors: Ito Masatoshi
Published: November 2007

Summary: We sent questionnaires about current therapy for West syndrome (WS) to 208 institutions at which the pediatric members of the Japan Epilepsy Society were in residence. One hundred twenty‐nine institutions (62%) responded. Thirty‐eight institutions (29.5%) treated symptomatic and cryptogenic WS differently. Vitamin B6 was the most preferred first‐line drug, followed by the combination of vitamin B6 and valproate (VPA) or monotherapy with VPA. ACTH was the third choice among drugs. The combination therapy of vitamin B6 and VPA was effective in 58.3% of the patients with symptomatic WS.
Consequences of Cortical Dysplasia During Development in Rats
Authors: Holmes Gregory L. , Sarkisian Matthew , Ben‐Ari Yehezkel , Liu Zhao , Chevassus‐Au‐Louis Nicolas
Published: November 2007

Summary: Purpose:To determine whether focal cortical dysplasia alters excitability in regions distant to the region of the dysplasia.

Methods; We studied the physiological consequences of cortical dysplasia induced by either m e or three freeze lesions at birth. Seizure susceptibility was assessed at age 35 days by unygdala kindling. C‐fos immunoataining was performed after kainic acid‐induced seizures at 10. 20, or 30 days to evaluate the patterns of neuronal activation.

Results: Freeze lesions consistently produced uniform regions of dysplasia. No significant differences in seizure susceptibility, as measured by afterdischarge threshold and kindling rate. were seen between controls and rats receiving either one or three freeze lesions. C‐fos activation after kainic acid injection was not observed in the region of the dysplasia. However, rats with freeze lesions at age 30 days dcinonstrated asymmetric c‐fos staining with greater staining in CAI ipsilateral. than contralateral, to the lesion.

Conclusions: Focal cortical dysplasia resuIts in enhnncemen of c‐fos activation in regions outside the borders of the dysplasia. However, as indicated by kindling rate. the functional con sequences of these alterations do not appear to be robust.
New Antiepileptic Drugs: Comparison of Key Clinical Trials
Authors: Cramer Joyce A. , Fisher Robert , Ben‐Menachem Elinor , French Jacqueline , Mattson Richard H.
Published: November 2007

Summary: Purpose: Data accrued from clinical trials of five new antiepileptic drugs (AEDs) are compared for efficacy in reducing seizures and self‐reported adverse events as a basis of selection among new AEDs. Drawbacks to use of these data also are demonstrated.

Methods: A review of double‐blind, placebo‐controlled clinical trials of a new AED or placebo added to a standard AED provided data on reduction of complex partial seizures (CPSs). Success is 50% fewer CPSs with a new AED or placebo; Overall Improvement is the success rate with drug minus the success rate with placebo. Adverse events were tabulated from product‐labeling lists of COSTART items (incidence, 5%). The Summary Complaint score is the total number of reports of individual events for each AED.

Results: Efficacy data demonstrate differences in Overall Improvement rates among five new AEDs and placebos (p =0.001). However, rates of response to placebo also differed significantly among trials (p = 0.01). Adverse events predominantly affect central nervous system, psychiatric, and general body systems. However, patients in the placebo control groups did not consistently report adverse effects. Summary Complaint scores differ among the five new AEDs, but variability in use of COSTART terms nullifies comparisons.

Conclusions: Comparisons of data for five new AEDs provide information for selection among treatments when a second drug is needed to improve control of CPSs. However, significant differences among the control groups and other problems make comparisons between trials problematic. The final choice should be based on the need of the individual patient for superior seizure control versus minimal adverse effects.
Idiopathic Rolandic Epilepsy with “Interictal” Facial Myoclonia and Oromotor Deficit: A Longitudinal EEG and PET Study
Authors: de Saint‐Martin A. , Petiau C. , Massa R. , Maquet P. , Marescaux C. , Hirsch E. , Metz‐Lutz M‐N.
Published: November 2007

Summary: Purpose: The prognosis of benign epilepsy with centrotemporal spikes (BECTS) is always favorable as far as the epilepsy is concerned. However, some data suggest that affected children may be at risk for minor cognitive impairment. We report here the longitudinal study of a young girl demonstrating that BECTS also may be associated with severe motor disturbances.

Methods: BECTS (rare left oromotor seizures, right rolandic spike‐waves activated during sleep) started at the age of 3 years 6 months in a gir! with normal initial psychomotor development. Her clinical, neuropsychological, and EEG status was assessed every 3–6 months. Regional cerebral glucose metabolism was measured by using the [18F]fluorodeoxyglucose‐positron emission tomography (FDG‐PET) method.

Results: Between the age of 5 and 6 years, the girl had (a) increased seizure frequency; (b) brief perioral and palpebral myoclonic jerks, concomitant with the spike component of interictal spike‐waves, and (c) persistent but fluctuating oromotor deficits (drooling, dysarthria, dysphagia). The EEG showed a marked increase in abundance and amplitude of wake and sleep interictal abnormalities, which became bilateral. Awake FDG‐PET revealed a bilateral increase of glucose metabolism in opercular regions. A complete and definitive EEG and clinical remission occurred at age 5 years 11 months and has persisted since (present age, 7 years 9 months).

Conclusions: This case confirms that during BECTS, epileptiform dysfunctions within rolandic areas may induce “interictal” positive or negative oromotor symptoms, independent of classic seizures.
Partial Seizure with Aphasic Speech Arrest Caused by Watching a Popular Animated TV Program
Authors: Kobayashi Masahito , Takayama Hideichi , Mihara Ban , Sugishita Morihiro
Published: November 2007

Summary: On the evening of December 16, 1997, about 700 children across Japan were hospitalized because of convulsive seizures or vomiting experienced while watching a popular animated TV program that included blue and red stimuli that alternated at 12 flashes per second. In one case, an 11‐year‐old girl developed a hallucination in the right visual field and a subsequent cramp on the right side of her face, with aphasic speech arrest. She had no history of seizures. Her electroencephalogram (EEG) showed normal background activity and no epileptiform discharges. Intermittent photic stimulation provoked a photoparoxysmal response. Her main clinical manifestation was a TV‐induced left occipital lobe seizure spreading toward the left inferior frontal lobe. This suggested a functional link from the occipital lobe to the frontal operculum.
Nitric Oxide Synthase Expression in the Cerebral Cortex of Patients with Epilepsy
Authors: González‐Hernández Tomás , García‐Marín Victor , Perez‐Delgado María del Mar , González‐González María Ligia , Rancel‐Torres Nélida , González‐Feria Luis
Published: November 2007

Purpose: Nitric oxide (NO), a short‐lived radical synthesized from L‐arginine by activation of the enzyme nitric oxide synthase (NOS), has been implicated in the pathophysiology of epilepsy by some investigators. However, the current data about NO and NOS in epilepsy are controversial and are derived only from animal models of epilepsy. In this study we investigated possible changes in NOS expression in the cerebral cortex of patients with epilepsy.

Methods: Qualitative and quantitative parameters of the im‐munolabeling pattern of the neuronal, endothelial, and inducible isoforms of NOS were analyzed in biopsy material obtained from patients with short and long seizure history and from patients without epilepsy.

Results: The comparative study showed that in the cerebral cortex of patients with epilepsy, particularly in those with a long seizure history, the number and labeling intensity of NOS‐positive neurons increased, and that a subpopulation of nonpy‐ramidal GABAergic neurons (type H NOS neurons) was responsible for this phenomenon.

Conclusions: The fact that NOS upregulation is more evident in patients with a long seizure history suggests that this is a consequence of seizures, acting probably as an adaptative response to the sustained release of excitatory amino acids.
Cost Minimization Analysis of Antiepileptic Drugs in Newly Diagnosed Epilepsy in 12 European Countries
Authors: Heaney D. C. , Shorvon S. D. , Sander J. W. A. S. , Boon P. , Komarek V. , Marusic P. , Dravet C. , Perucca E. , Majkowski J. , Lima J. Lopes , Arroyo S. , Tomson T. , Ried S. , van Donselaar C. , Eskazan E. , Peeters P. , Carita P. , Tjong‐a‐Hung I. , Myon E. , Taieb C.
Published: November 2007

Summary A recent United Kingdom cost minimization analysis (CMA) of four antiepileptic drugs (AEDs) used to treat newly diagnosed adult epilepsy demonstrated that a new drug, lamotrigine (LTG), incurred higher costs than carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA), whose costs were similar. This analysis took account of each drug's side‐effect and tolerability profile. The present analysis investigated the costs of treatment with LTG, CBZ, PHT, and VPA in 12 European countries. Data were derived from published sources and from a panel of locally based experts. When no published data were available, estimates were obtained using expert opinion by a consensus method. These data were incorporated into a treatment pathway model, which considered the treatment of patients during the first 12 months after diagnosis. The primary outcome considered was seizure freedom. Randomized controlled trials demonstrate that the drugs considered are equally effective in terms of their ability to achieve seizure freedom, and thus the most appropriate form of economic evaluation is a CMA. These trials provided data on the incidence of side effects, dosages, and retention rates. The economic perspective taken was that of society as a whole and the analysis was calculated on an “intent‐to‐treat” basis. Only direct medical costs were considered. In each country considered, LTG was twofold to threefold more expensive than the other drugs considered. A sensitivity analysis demonstrated that varying each of the assumptions (range defined by expert panels) did not significantly alter the results obtained.
Agenesis of the corpus callosum and cerebral anomalies in inborn errors of metabolism
Authors: Prasad Asuri N. , Bunzeluk Kelly , Prasad Chitra , Chodirker Bernard N. , Magnus Kenneth G. , Greenberg Cheryl R.
Published: November 2007

ABSTRACT Dysgenesis of the corpus callosum has been recognized as a marker for aberrant development of the central nervous system. It has been suggested that developmental defects of the corpus callosum may be more frequently encountered in patients with inborn errors of metabolism. The objectives of the present study were to determine the prevalence of developmental defects of the corpus callosum in patients attending a genetics‐metabolic disorders clinic, to describe the spectrum of abnormalities in brain development in patients with confirmed inborn errors of metabolism and abnormalities of the corpus callosum as ascertained by neuroimaging and/or postmortem studies. Nineteen patients (10 males, 9 females) with confirmed metabolic diagnoses were identified by systematic search of the genetics clinic database. All 19 (100%) expressed variable degrees of hypoplasia, complete or partial agenesis (ACC). Abnormalities of head size were noted in 17/19 (89.5%). The majority 12/17 (70.5%) were associated with microcephaly, while macrocrania was noted in 5/17 (29.5%). Associated central nervous system (CNS) anomalies included abnormalities in ventricular morphology in 18/19 (94.7%), ventriculomegaly in 11/19 (63.1%), increased extraxial cerebrospinal fluid space in 11/19 (57.9%), changes in the gray matter (neuronal migration defects, porencephaly) in 9/19 (47.3%), white matter changes in 12/19 (63.1%) and abnormalities of the posterior fossa and hindbrain in 12/19 (63.1%). In patients with inborn errors of metabolism, dysgenesis of the corpus callosum serves as a marker for other developmental defects within the nervous system. We discuss here potential mechanisms by which metabolic defects affect diverse biochemical pathways, altering key neurobiological processes (e.g. defective cell membrane formation, cellular bioenergetics and cell‐to‐cell signaling), that eventually lead to structural abnormalities in the developing nervous system.
Evaluation of reproductive and developmental toxicity of the rubber accelerator N,N‐dicyclohexyl‐2‐benzothiazolesulfenamide in rats
Authors: Ema Makoto , Fujii Sakiko , Yabe Kaoru , Matsumoto Mariko , Hirata‐Koizumi Mutsuko
Published: November 2007

ABSTRACT  Male and female Crl:CD(SD) rats were fed a diet containing the rubber accelerator N,N‐dicyclohexyl‐2‐benzothiazolesulfenamide (DCBS) at 0, 1500, 3000, 6000 or 10 000 p.p.m. (0, 83, 172, 343 or 551 mg/kg bw/day in males and 0, 126, 264, 476 or 707 mg/kg bw/day in females) for a total of 57 days beginning 16 days before mating in males, and a total of 61–65 days from 16 days before mating to day 21 of lactation in females. Body weight gains and food consumption were reduced in males at 6000 p.p.m. and higher and in females at 3000 p.p.m. and higher. The weights of the spleen at 6000 and 10 000 p.p.m. and of the thymus at 10 000 p.p.m. were decreased in females. No changes in estrous cyclicity, copulation index, fertility index, gestation index, delivery index, precoital interval or gestation length were observed at any dose of DCBS. Numbers of implantations at 6000 and 10 000 p.p.m. and pups delivered at 10 000 p.p.m. were reduced. There were no changes in the sex ratio or viability of pups. The body weights of male and female pups were lowered at 6000 p.p.m. and higher. Decreased weight of the spleen in weanlings was also observed in males at 1500 p.p.m. and higher and in females at 3000 p.p.m. and higher. The data indicate that DCBS possesses adverse effects on reproduction and development in rats.
Unruptured term pregnancy with a live fetus with placenta percreta in a non‐communicating rudimentary horn
Authors: Patra Sharda , Puri Manju , Trivedi Shuba Sagar , Yadav Reena , Bali Jyoti
Published: November 2007

ABSTRACT  Pregnancy in a non‐communicating rudimentary horn is rare and such a pregnancy culminating in the delivery of a live fetus is even rarer. Despite advances in ultrasonography, the accuracy of ultrasound in diagnosing rudimentary horn pregnancy at advanced gestation remains elusive. Confirmatory diagnosis is made only at laparotomy. We report a multigravidae who presented at 37 weeks with transverse lie oligoamnios and decreased perception of fetal movement since quickening. Laparotomy for placenta accreta suspected on ultrasound revealed non‐communicating unruptured rudimentary horn pregnancy with a live fetus and placenta percreta. Successful extraction of a term live fetus weighing 2.7 kg with excision of the rudimentary horn was carried out.
Hyperhomocysteinemia in women with advanced breast cancer
Authors: GATT A. , MAKRIS A. , CLADD H. , BURCOMBE R. J. , SMITH J. M. , COOPER P. , THOMPSON D. , MAKRIS M.
Published: November 2007

Patients with malignancy have an increased risk of venous thromboembolic disease but the pathophysiology of this association has not been precisely defined. Hyperhomocysteinemia has become established as one of the commonest conditions associated with venous and arterial thrombosis. We examined the prevalence of hyperhomocysteinemia in women with early (group A, n = 31), metastatic breast cancer (group B, n = 41) and in a group of healthy females (group C, n = 29). Blood samples were collected at diagnosis or prior to treatment. We measured both total plasma homocysteine (tHcy) and red cell folate (RCF). The Mean (SD) tHcy were group A – 9.43 μmol/l (5.6), group B – 11.34 μmol/l (5.1) and group C – 7.9 μmol/l (1.5). A total of 39% of patients with metastatic and 22.6% with early breast cancer had tHcy concentrations above the upper limit of normal. Women with metastatic disease had significantly higher tHcy compared with controls (P < 0.01) but not when compared with women with early breast cancer. Also, no difference was observed when women with early disease were compared with controls. We found no correlation between age and tHcy. Lower RCF levels were identified in group B compared with group A, but this does not fully explain the increased tHcy levels seen within the same group. We conclude that hyperhomocysteinemia is common in women with advanced breast cancer. This observation could explain the high rate of venous thrombosis in women with metastatic breast malignancy.
Annular Extrudate Swell of Newtonian Fluids: Effects of Compressibility and Slip at the Wall
Authors: Mitsoulis Evan
Published: November 2007

Numerical simulations have been undertaken for the benchmark problem of annular extrudate swell present in pipe extrusion and parison formation in blow molding. The effects of weak compressibility and slip at the wall are studied through simple linear laws. The finite element method is used to provide numerical results for different inner/outer diameter ratios κ under steady-state conditions for Newtonian fluids. The present results provide the shape of the extrudate, and, in particular, the thickness and diameter swells, as a function of the dimensionless compressibility and slip coefficients, B and Bsl, respectively. The pressures from the simulations have been used to compute the excess pressure losses in the flow field (exit correction). Weak compressibility slightly affects the thickness swell (about 1% in the range of simulations 0⩽B⩽0.02) mainly by a swell reduction, while slip drastically reduces the swelling to 1–2% for obvious slip (Bsl≈1) and to 0 for perfect slip (Bsl>10). The exit correction increases with increasing compressibility levels and is highest for the tube (κ=0) and lowest for the slit (κ=1). It decreases monotonically to 0 as the dimensionless slip coefficient reaches its asymptotic limit of perfect slip. All results are ordered with the diameter ratio κ, between the limits of tube (κ=0) and slit (κ=1).