bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sudden Unexplained Death in Epilepsy: Observations from a Large Clinical Development Program
Authors: Leestma Jan E. , Annegers John F. , Brodie Martin J. , Brown Stephen , Schraeder Paul , Siscovick David , Wannamaker Braxton B. , Tennis Patricia S. , Cierpial Mark A. , Earl Nancy L. 
Published: August 2005

Summary: Purpose: The present study was conducted to determine the rate of sudden unexplained death in epilepsy (SUDEP) in a well‐defined cohort of patients included in the lamotrigine (LTG) clinical development database. Methods: A panel of scientists experienced in the area of SUDEP was assembled and provided with case summaries on all deaths (n = 45) reported during the initial clinical development of LTG. The panel developed a set of criteria for classifying cases as SUDEP (definite or highly probable), possible SUDEP, or non‐SUDEP. This classification algorithm was then applied to the LTG cases, and SUDEP rates were calculated using patient‐years of exposure as the denominator. Results: At the time of the study, 4,700 patients (5,747 patient‐years of exposure) were included in the worldwide LTG clinical trials database. In this cohort, 45 deaths were reported. Eighteen were judged by the panel to be SUDEP, 6 were defined as possible SUDEP, 20 were judged to be due to other causes (non‐SUDEP), and 1 lacked sufficient data from which to make a classification. The overall SUDEP rate (definite/highly probable SUDEP and possible SUDEP combined) was calculated to be 3.5 in 1,000 patient‐years of exposure to LTG. Conclusions: The rate of SUDEP in this cohort of patients was comparable to the rate that would be expected in young adults with severe epilepsy (the subgroup of patients believed to be at highest risk of SUDEP). The data suggest that the rate of SUDEP in the LTG clinical development program is a function of the clinical trial population and is unrelated to drug treatment.
Functional Anatomy of Spontaneous Seizures in a Rat Model of Limbic Epilepsy
Authors: Bertram Edward H. 
Published: August 2005

Summary: Purpose: The substrate of seizure initiation in partial epilepsy is not well understood. Although many studies imply a focus that is will localized to a single structure, some information suggests that seizures arise regionally with simultaneous or near‐simultaneous onset at several separate sites. To determine the physiological pattern of seizure onset, recordings were made of spontaneous seizures from multiple limbic structures in a rat model of limbic epilepsy. Methods: Seventeen rats with chronic spontaneous limbic seizures that occurred after an episode of electrical hippocampal stimulation‐induced status epilepticus (SE) underwent chronic recording of seizures with a minimum of four electrodes placed bilaterally in the midventral hippocampus and either the amygdala or piriform cortex. As many as 15 of the first recorded spontaneous seizures (mean of 12 seizures, range 2–15) was evaluated for each animal with regard to pattern of seizure onset (focal hippocampal, focal nonhippocampal, or diffuse). The results were evaluated for number of seizure patterns displayed by each animal and the potential change in the pattern of onset with successive seizures (from the first to the fifteenth). Results: In all, 210 seizures were evaluated, beginning 1 week after SE and with monitoring lasting ≥18 weeks (mean recording duration 6 weeks) to record a maximum of 15 seizures for each animal. Overall, 54% of the seizures were of diffuse onset, 25% were of nonhippocampal onset, and 21% were of hippocampal onset. Eight of the 17 (47%) animals had seizures with all three patterns of onset. Evaluation of the evolution of the pattern of onset from the first to the fifteenth seizure recorded for the animals showed a clear tendency for the later seizures to have diffuse onsets (regression analysis r = 0.737, p < 0.002). Qualitative histologic analysis demonstrated neuronal loss in the recorded regions. Conclusions: These findings indicate that the epileptogenic zone is broad in this model of limbic “focal” epilepsy and suggest that the substrate for seizure generation is distributed over several structures.
Intravenous Carbamazepine: Comparison of Different Parenteral Formulations in a Mouse Model of Convulsive Status Epilepticus
Authors: Löscher Wolfgang , Hönack Dagmar 
Published: August 2005

Summary: Purpose: A drawback of carbamazepine (CBZ), a major antiepileptic drug (AED) with clinical efficacy against partial and generalized convulsive seizures, is its isolubility in aqueous vehicles, which is generally considered a contraindication to parenteral administration in epileptic patients. However, CBZ can be dissolved in glycofurol, a solvent used clinically as a vehicle for parenteral preparations of drugs such as diazepam (DZP) and phenytoin (PHT). Furthermore, aqueous CBZ solutions can be prepared by complexing CBZ with 2–hy‐droxypropyl‐β‐cyclodextrin (HPPCD), an inert β‐cyclodextrin derivative believed to have acceptable tolerability for human use. Such solutions of CBZ have been proposed to be suitable for intravenous administration in treatment of convulsive (grand mal) status epilepticus (CSE). Methods: A series of five generalized tonic‐clonic seizures (GTCS) in 30 min was induced by repeated transauricular electrical stimulation in mice. In this model of convulsive (grand mal) SE, the anticonvulsant potency of intravenous CBZ dissolved in aqueous dilutions of either HPβCD or glycofurol was evaluated. Results: In both solutions, CBZ rapidly suppressed seizures after intravenous bolus injection. Potent anticonvulsant activity was obtained as early as 30 s after injection, and peak effects were observed at ∼3 min. ED50 for blockade of GTCS throughout the 30–min period of repeated electrical stimulation was ∼7 mg/kg, similar to the potency of DZP in this model. Whereas the HPβCD/CBZ solutions were tolerated by the animals, with no pronounced behavioral or motor adverse effects, the glycofurol/CBZ solutions induced marked sedation and motor impairment, indicating interactions between drug and solvent. Determination of CBZ in plasma and brain demonstrated that the rapid onset of anticonvulsant action after intravenous bolus injection was related to rapid drug penetration into brain tissue. Conclusions: An intravenous formulation of CBZ achieved through complexing with HPβCD might be suitable for parenteral use in acute clinical conditions such as SE, particularly because CBZ has the advantage of being almost free of respiratory or cardiovascular adverse effects.
Ictal Laughter Associated with Paroxysmal Hypothalamopituitary Dysfunction
Authors: Arroyo Santiago , Santamaría Joan , Sanmartí Francesc , Lomeña Francisco , Catafau Ana , Casamitjana Roser , Setoain Javier , Tolosa Eduardo 
Published: August 2005

Summary: Purpose: Seizures with ictal laughter (also termed gelastic seizures) have been associated with hypothalamic hamartomas and precocious puberty. It is not known, however, where in the brain such seizures originate. We describe a child with gelastic seizures and a hypothalamic lesion (probably a hamartoma) in whom two dysfunctional phenomena were observed. Results: First, there was a hyperperfusion in the hypothalamopituitary areas shown by ictal [99m]Tc hexamethyl‐propyleneamine oxime (HM‐PAO) single photon‐emission computed tomography (SPECT). Second, there was an ictal pulse of gonadotropins, 17β‐estradiol, and growth hormone well above the normal limits in one of the seizures. Conclusion: These findings suggest that gelastic seizures associated with hypothalamic hamartomas are generated in the hypothalamus or in its neighboring regions and that these seizures may cause paroxysmal dysfunction of the hypothalamo‐pitutary axis.
Cysticercosis and Epilepsy: A Critical Review
Authors: Carpio Arturo , Escobar Alfonso , Hauser W. Allen 
Published: August 2005

Summary: Neurocysticercosis (NC) remains a major public health problem in developing and some developed countries. Currently, the best procedures for diagnosing NC are neuroimaging studies. Immunoserologic assays, such as enzyme‐linked immunoelectrotransfer blot assay (EITB) or enzyme‐linked immunosorbent assay (ELISA), detect antibodies against Taenia solium, or cysticercus. Consequently, they are useful in identifying a population at risk of contact with the parasite but do not necessarily indicate a systemic active infection. Most seropositive individuals are asymptomatic. No data from prospective studies concern the proportion of these individuals that will develop seizures or other neurologic symptoms. There is a discrepancy between the results of serologic assays and neuroimaging studies: >50% of those individuals with NC diagnosed by computed tomography (CT) scan test EITB negative.Pathophysiologic classification of NC into active, transitional, and inactive forms permits a good correlation between clinical manifestations and neuroimaging procedures and facilitates medical and surgical management and research. The most frequent clinical manifestations of NC are seizures. We assume that NC is the main cause of symptomatic epilepsy in developing countries; however, no case‐control or cohort studies demonstrate this association. Most patients with NC with seizures have a good prognosis; nevertheless, further studies analyzing factors related to recurrence of seizures and possibilities of discontinuation of antiepileptic medications (AEDs) are needed.Regarding treatment of NC with antihelminthic drugs, no controlled clinical trials exist that establish specific indications, definitive doses, and duration of treatment. The most effective approach to taeniasis/cysticercosis infection is prevention. This should be a primary public health focus for developing countries.We critically review the available information regarding the epidemiology and diagnosis of human cysticercosis, the physiopathology and imaging correlation of the parasite in the central nervous system (CNS) of the host, the relation between seizures or epilepsy and NC, and the issues surrounding the treatment and prognosis of NC, including the use of antihelminthic therapy.
Glucose Utilization During Interictal Intervals in an Epilepsy Model Induced by Pilocarpine: A Qualitative Study
Authors: Scorza F. A. , Sanabria E. R. G. , Calderazzo L. , Cavalheiro E. A. 
Published: August 2005

Summary: Purpose: Interictal intervals in pilocarpineinduced chronic epilepsy are characterized by apparent normal electrographic activity and longer sleep periods or drowsiness or both. Sparse information exists concerning the neural network activity during these seizure‐free intervals. In our research, a [14C]2‐deoxy‐D‐glucose (2DG) autoradiographic technique was used to investigate interictal changes in the metabolism of the epileptic rat brain. Methods: Epileptic rats were monitored by video‐EEG for ‐120 days, with [14C]2DG injected after a seizure‐free interval of ≥24 h. Results: Autoradiographic analysis revealed an increase in glucose utilization by several brain regions; the most consistent increase was found in the lateral posterior thalamic nucleus and pretectal region. Conclusions: These findings suggest that the lateral posterior thalamic nucleus and the pretectal region may be involved in cerebral circuits inhibiting epileptic activity during interictal intervals.
Does Short‐Term Antiepileptic Drug Treatment in Children Result in Cognitive or Behavioral Changes?
Authors: Williams Jane , Bates Stephen , Griebel May L. , Lange Bernadette , Mancias Pedro , Pihoker Catherine M. , Dykman Roscoe 
Published: August 2005

Summary: Purpose: To determine possible cognitive and behavioral effects of antiepileptic drug (AED) therapy by assessing children with newly diagnosed epilepsy before and after initiation of treatment. A comparison group of children with diabetes mellitus (DM) was included to control for the effects of practice, maturation, and chronic illness. Methods: Baseline neuropsychological assessments were completed for children with epilepsy (n = 37) and children with DM (n = 26) recruited through outpatient clinics at a regional children's hospital. Children were reevaluated 6 months from baseline testing. At follow‐up, children with epilepsy had therapeutic AED levels and controlled seizures. Statistical analysis included a between‐group repeated measures ANCOVA with pretest scores serving as the covariate. Results: Significant differences between groups were not found for any cognitive or behavioral factors, including attention (p < 0.24), immediate memory (p < 0.24), delayed memory (p < 0.10), complex motor speed (p < 0.19), or behavior problems (p < 0.89). Conclusions: Changes in performance on cognitive and behavioral measures were not different for children treated with AEDs and controls. Although adverse effects may be associated with prolonged treatment, results would not suggest adverse effects from AED monotherapy during the first 6 months of therapy.
Antiepileptic Drug‐Related Cognitive Complaints in Seizure‐Free Children with Epilepsy Before and After Drug Discontinuation
Authors: Aldenkamp A. P. , Alpherts W. C. J. , Sandstedt P. , Blennow G. , Elmqvist D. , Heijbel J. , Nilsson H. L. , Tonnby B. , Wåhlander L. , Wosse¶ E. 
Published: August 2005

Summary: The cognitive complaints reported by children and their parents, as subjectively associated with antiepileptic drug (AED) treatment, were evaluated in seizure‐free children before and after drug discontinuation. The aim of the design was to isolate the cognitive side effects of AEDs from other factors, such as the effect of seizures. Our inventory explored the following areas: “alertness,”“concentration,”“activation/ tiredness,”“memory,”“drowsiness,”“depression,”“aggressiveness,” and “hyperactivity,” using a 5‐point Likert scaling procedure. One hundred two eligible patients were selected, each matched with a healthy control and assessed when still on antiepileptic medication. All children were seizure free for at least 1 year. The medication was then discontinued gradually over a 3‐month period. Four months after the children were completely medication free, a second assessment was carried out, but only in the 83 children who remained seizure free and in their matched controls.The results of the reports made by the children themselves did not show differences with the matched controls, and only showed improvement after drug discontinuation for complaints about “tiredness.” Parents of the children with epilepsy reported significant improvement in all areas related to “alertness and activation” after discontinuation of the drugs.The finding that only a limited number of children have cognitive complaints, both when still on AEDs and after discontinuation, may be in line with the reports that the major factor contributing to quality of life is whether patients are seizure free or still have seizures. All patients in this study were seizure free for a period >1 year, which may have caused the favorable pattern of response in our patient group.
Neuropsychological Outcomes in Randomized Controlled Trials of Antiepileptic Drugs: A Systematic Review of Methodology and Reporting Standards
Authors: Cochrane Haydee C. , Marson Anthony G. , Baker Gus A. , Chadwick David W. 
Published: August 2005

Summary: Purpose: To systematically review the methodology and use of neuropsychological tests in randomized controlled trials (RCTs) of antiepileptic drugs (AEDs) in patients with epilepsy. Methods: Trial reports were found by searching Medline 1966–1996 and searching through journals by hand. Inclusion and exclusion criteria were applied, and methodological and neuropsychological test data was extracted by using a pro‐forma. Results: 43 reports met our inclusion criteria, representing 40 RCTs, as three RCTs had generated two reports. Twenty‐two were actively controlled, and 18 were placebo‐controlled studies. Reporting of basic methods such as randomization method was poor. There has been no uniform approach to the use of neuropsychological tests, and a total of 87 has been used. The Stroop Colour Word Test and the Finger Tapping Test were most commonly used, at 13 times each, but were not used or reported in a uniform manner. Conclusions: Poor reporting of methods and the use of a plethora of neuropsychological tests create great difficulties for anyone wishing to make sense of currently available data. If we are better to understand the neuropsychological effects of AEDs, a more rational approach is needed, for which recommendations are made.
Bicuculline‐Induced Rhythmic EEG Episodes: Gender Differences and the Effects of Ethosuximide and Baclofen Treatment
Authors: Matějovská Iveta , Velis̃ková Jana , Velis̃ek Libor 
Published: August 2005

Summary: Purpose: There are gender differences in the expression of seizures. We tested rhythmic EEG episodes induced by low doses of bicuculline in rats for gender differences. To verify the validity of these discharges as a model of absence seizures in both male and female rats, we tested the antiabsence drug ethosuximide (ESM) and a γ‐aminobutyric acid (GABAB)‐receptor agonist, baclofen, which may exacerbate absence seizures. Methods: Adult rats of both sexes were used. Under general anesthesia, EEG electrodes were implanted over frontal and occipital cortex, and some females were ovariectomized. After recovery, male, intact female rats, and female rats ovariectomized and ovariectomized rats with estradiol replacement were compared for occurrence of rhythmic EEG episodes (∼6 cycles/ s) induced by 2.5 mgkg of bicucullin?, s.c. Because of gender differences in sensitivity to bicuculline, further pharmacologic effects of ESM (125 and 250 mgkg, i.p.) and baclofen (2 mgkg, i.p.) were tested separately in male (3.0 mgkg of bicuculline), and female (2.5 mgkg of bicuculline) rats. Results: After the identical dose of bicuculline, s.c., male and female rats differed in the incidence of rhythmic episodes and in the latency to onset of the first as well as the generalized episode. Female rats with natural or exogenous estrogens (but not ovariectomized rats) developed EEG episodes more often than did males, and this effect could be attributed to the presence of estrogens. ESM pretreatment suppressed the episodes, whereas baclofen enhanced their occurrence, as well as the total duration of episodes without gender‐specific differences. Conclusions: The study demonstrates gender differences (related probably to the presence of circulating estrogens) in the susceptibility of rats to develop rhythmic EEG episodes induced by threshold doses of bicuculline. This activity has some features of an acute absence seizure model.
Comparison of Combined Versus Subdural or Intracerebral Electrodes Alone in Presurgical Focus Localization
Authors: Brekelmans G. J. F. , van Emde Boas W. , Velis D. N. , Lopes da Silva F. H. , van Rijen P. C. , van Veelen C. W. M. 
Published: August 2005

Summary: purpose: The yield of subdural versus intracerebra1 electrodes for ictal localization remains a point of controversy. We assessed the relative sensitivity of these two types of electrodes per case. Methods: Eighty‐three intracranial recordings obtained from 82 patients were retrospectively reviewed to establish which type of electrode performed best in which patients and which seizure types. Results: Sixty (73%) of 82 patients had temporal lobe seizure onsets, eight frontal, nine widespread or multifoca/multilobar or both, whereas in five, seizure onset was not localized. Exclusive use of intracerebral electrodes would have been sufficient for accurate localization of the seizure—‐onset zone in all 35 patients with strictly mesial temporal seizure onsets. In only 20 (57%) of these 35 patients, the same decision would have been reached with exclusive use of subdural electrodes. In wide‐spread neocortical and mesial temporal seizures (n = 25). yield of both electrode types was at about the same level, but neither was sufficient to identify the zone of ictal onset on its own. In frontal or multilobar seizures (n = 22), yield of subdural electrodes was slightly better then that of the intracerebral electrodes, but was not sufficient in all cases. Conclusions: This study indicates that, depending on the characteristics of the seizure disorder, exclusive use of either intracerebral or subdural electrodes may easily result in erroneous diagnosis because of insufficient sampling of the brain. These findings are in contrast with other studies emphasizing the high yield of reliable EEG findings in evaluations with a single type of electrode and corroborate the results of one of our previous studies.
The Effects of Genetic Polymorphisms of CYP2C9 and CYP2C 19 on Phenytoin Metabolism in Japanese Adult Patients with Epilepsy: Studies in Stereoselective Hydroxylation and Population Pharmacokinetics
Authors: Mamiya Kohsuke , Ieiri Ichiro , Shimamoto Junta , Yukawa Eiji , Imai Jun , Ninomiya Hideaki , Yamada Hiroaki , Otsubo Kenji , Higuchi Shun , Tashiro Nobutada 
Published: August 2005

Summary: Purpose: The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed. Methods: The genotype of CYP2C9 (Arg144/Cys, Ile359/Leu) and CYP2C19 (*1, *2 or *3) in 134 Japanese adult patients with epilepsy treated with PHT were determined, and their serum concentrations of 5‐(4‐hydroxyphenyl)‐5‐phenylhydantoin (p‐HPPH) enantiomers, being major metabolites of PHT, were measured. A population pharmacokinetic analysis (NONMEM analysis) was performed to evaluate whether genetic polymorphism of CYP2C9/19 affects the clinical use of PHT by using the 336 dose‐serum concentration data. Results: The mean maximal elimination rate (Vmax) was 42% lower in the heterozygote for Leu359 allele in CYP2C9, and the mean Michaelis‐Menten constants (K,) in the heterozygous extensive metabolizers and the poor metabolizers of CYP2C19 were 22 and 54%, respectively, higher than those without the mutations in CYP2C9/19 genes. (R)‐ and (5′)‐p‐HPPHPHT ratios were lower in patients with mutations in CYP2C9 or CYP2C19 gene than those in patients without mutations. Conclusions: Although the hydroxylation capacity of PHT was impaired with mutations of CYP2C9/19, the impairment was greater for CYP2C9. In view of the clinical use of PHT, two important conclusions were derived from this population study. First, the serum PHT concentration in patients with the Leu359 allele in CYP2C9 would increase dramatically even at lower daily doses. Second, the patients with CYP2C19 mutations should be treated carefully at higher daily doses of PHT.