bluuebunny/crossref_metadata_2025 huggingface dataset:
Hormone Profiles in Young Adults with Epilepsy Treated with Sodium Valproate or Lamotrigine Monotherapy
Authors: Stephen Linda J. , Kwan Patrick , Shapiro David , Dominiczak Marek , Brodie Martin J.
Published: March 2003

Summary:  Purpose: Treatment with sodium valproate (VPA) may be associated with polycystic ovarian syndrome (PCOS) in some women with epilepsy. By comparing hormone profiles in young adults taking VPA or lamotrigine (LTG) as monotherapy, this study aimed to explore whether a pharmacologic effect of VPA could be responsible for this observation.

Methods: Hormone profiles in men and women taking VPA (n = 40) or LTG (n = 36) monotherapy for epilepsy were compared. None of the women were receiving hormonal contraception or replacement. Patients gave details of seizure type and frequency, menstrual cycle, and medical and drug history. Body mass index was calculated, and fasting insulin, glucose, cholesterol, triglycerides (TG), high‐ and low‐density lipoproteins, testosterone, dihydroepiandosterone (DHEA), androstenedione, sex hormone–binding globulin (SHBG), free androgen index (FAI), luteinising hormone (LH), follicle‐stimulating hormone (FSH), and antiepileptic drug (AED) concentrations were measured.

Results: There were no differences between treatment groups for both sexes in age and seizure control. Only four obese VPA‐treated women were hyperinsulinaemic (p = 0.05); three with abnormal menstrual cycles; one with raised testosterone. Testosterone (p = 0.02), FAI (p = 0.03), and TG (p = 0.02) levels were higher, however, in women taking the drug. Obese patients of both sexes (p = 0.01) and VPA‐treated men (p = 0.03) had higher insulin concentrations.

Conclusions: VPA therapy may be associated with subclinical elevation in fasting insulin levels. Testosterone and TG levels were higher in VPA‐treated women compared with the levels in those taking LTG. However, only a minority of obese females exhibited biochemical characteristics suggestive of PCOS. Biochemical screening may allow women at risk of developing PCOS to avoid VPA.
Time Trends in Incidence, Mortality, and Case‐Fatality after First Episode of Status Epilepticus
Authors: Logroscino Giancarlo , Hesdorffer Dale C. , Cascino Gregory , Annegers John F. , Hauser W. Allen
Published: March 2003

Summary:  Purpose: Status epilepticus (SE) is a medical emergency associated with a high mortality. Clinical series have suggested that mortality after SE has decreased. No studies have systematically examined trends in incidence, mortality, and case fatality after SE in a well‐defined population.

Methods: All first episodes of SE receiving medical attention between January 1, 1935, and December 31, 1984, were ascertained through the Rochester Epidemiology Project Records‐Linkage System and followed up until death or study termination (February 1, 1996). We calculated incidence rates in the 50‐year period (1935–1984), while we considered mortality and case‐fatality in the last 30‐year period (1955–1984).

Results: Incidence of SE increased over time to 18.1/100,000 (1975 through 1984). The increase was related to an increased incidence in the elderly and to the advent of myoclonic SE after cardiac arrest, a condition not seen in the early decades. In the last decade, ∼16% of the incidence was due to myoclonic SE. The mortality rates increased from 3.6 per year in the decade 1955–1965 to 4.0/100,000 per year between 1975 and 1984. The 30‐day case‐fatality (CF) was unchanged, although a trend toward improvement was shown after excluding myoclonic SE.

Conclusions: Incidence and mortality rates of SE have increased in the last 30 years. Case fatality remained the same. The increased incidence and mortality are due to the occurrence in the last decade of myoclonic SE after cardiac arrest. The mortality in the elderly was twice that of the youngest age group, across all study periods. Changes in the age and cause distribution of SE over time are responsible for the stable survivorship. There is improvement in survivorship in the last decade when myoclonic SE is excluded.
Stupor from Lamotrigine Toxicity
Authors: Sbei Mouaz , Campellone Joseph V.
Published: March 2003

Summary:  Purpose: To report that acute lamotrigine poisoning may result in severe encephalopathy.

Methods: A 55‐year‐old woman became stuporous after overdose with lamotrigine (LTG) and valproic acid (VPA) tablets. Evaluation revealed elevated serum LTG levels and no other etiology for encephalopathy.

Results: LTG was withheld, and the patient experienced a complete recovery in conjunction with reduced serum levels.

Conclusions: LTG overdose may result in a severe but reversible encephalopathy, a previously undescribed phenomenon. LTG toxicity should be considered in patients taking this drug who have depressed mental status.
Cell Death and Synaptic Reorganizations Produced by Seizures
Authors: Ben‐Ari Yehezkel
Published: March 2003

Summary: The events that follow epilepsy seizures are not restricted to the immediate period. A series of long‐term alterations occurs, including synaptic rearrangements, which have an impact on the brain circuit's mode of operation. With models of temporal lobe epilepsy, seizures have been shown to generate long‐lasting changes in synaptic efficacy (epileptic long‐term potentiation) because of removal of the magnesium block, activation of N‐methyl‐d‐aspartate receptors, and an increase in intracellular calcium. This novel form of synaptic plasticity provides a link between memory effects and pathologic processes. Additionally, high‐affinity kainate autoradiography, Timm stain, intraventricular injection of kainic acid, and 3D reconstruction experiments clearly indicate that even brief seizures produce changes in synaptic efficacy, followed 2–3 weeks later by aberrant neosynapse formation. Several key steps have been identified in the cascade leading from transient hyperactivity episodes to long‐lasting, quasi‐permanent modification of the neuronal circuit organization. These include the activation of immediate‐early genes, activation of growth factor genes within hours, alterations in glutamate receptors, glial hypertrophy, and cytoskeletal protein changes. The cascade is activated by the increase in intracellular calcium and leads to axonal growth and neosynapse formation, which in turn participates in the etiology of the syndrome by reducing the threshold for further seizures. In summary, study data imply that the mature epileptic circuit has unique features in comparison with those present before a seizure episode, including new receptors, ionic channels, and other proteins. It is therefore essential to develop novel strategies based on the unique mode of operation of the mature epileptic circuit, rather than on acute models of epilepsy.
Management Strategies for Refractory Localization‐Related Seizures
Authors: Brodie Martin J.
Published: March 2003

Summary: Localization‐related epilepsy, the most common type of seizure disorder, often provides major management problems. Five new antiepileptic drugs (AEDs) with different mechanisms of action have been licensed in the United Kingdom in the 1990s for adjunctive use in the management of poorly controlled partial seizures. These were, in chronologic order, vigabatrin, lamotrigine, gabapentin, topiramate, and tiagabine. Their practical deployment is explored here. Mention also is made of clobazam and acetazolamide. Combination therapy with two or even three AEDs having complementary pharmacologic effects can provide an essential contribution to the management of partial seizures. This article discusses some of the pharmacologic strategies used in treating patients with refractory localization‐related epilepsy.
Tiagabine (Gabitril) Experience in Children
Authors: Pellock John M.
Published: March 2003

Summary: Tiagabine (TGB) is indicated as adjunctive therapy for partial seizures in adults and children aged 12 years and older. Double‐blind, placebo‐controlled studies of TGB treatment are under way in younger children with various forms of epilepsy. The results of pediatric pharmacokinetic trials indicate patterns similar to those seen in adults. An open‐label study was conducted in the United States in 31 children with refractory complex partial seizures, with doses escalated every 2 weeks by 0.25 mg/kg up to a maximal daily dose of 1 mg/kg. Twenty‐nine patients were treated with TGB for >1 year; 26 completed the study, of whom 18 were receiving monotherapy at study completion. A European dose‐escalation study evaluated TGB (0.25–1.5 mg/kg/day) as add‐on therapy in 52 children aged 2–15 years. TGB appeared to be more effective in localization‐related epilepsy syndromes, with 17 of 23 patients with localization‐related epilepsy having a 33% median reduction of seizure rate compared with baseline in the fourth month of treatment, and six patients having ≥50% seizure rate reduction. In this study, myoclonic seizures and spasms showed a poor response as opposed to encouraging findings reported by other groups with these seizure types. The adverse effect profile of TGB in children with epilepsy is similar to that in adults. In the U.S. study, most common adverse events were related to the central nervous system (CNS) and decreased over time. In the European study, mostly mild to moderate adverse events, including asthenia (19%), nervousness (19%), dizziness (17%), and somnolence (17%), were reported by 83% of TGB‐treated children (39% of children reported adverse events during the single‐blind placebo period). In summary, preliminary pediatric data with TGB suggest particular efficacy against epilepsy characterized by partial seizures or other syndromes, and further investigation is warranted.
Photosensitivity in Relation to Epileptic Syndromes: A Survey from an Epilepsy Center in Japan
Authors: Shiraishi Hideaki , Fujiwara Tateki , Inoue Yushi , Yagi Kazuichi
Published: March 2003

Summary:  Purpose: We examined the incidence and distribution of photosensitivity among the different age groups and different types of epilepsies and epileptic syndromes. Furthermore, we considered the influence of ethnic and geographic factors on the incidence of photoparoxysmal response (PPR) in epilepsy patients.

Methods: We analyzed the responses to intermittent photic stimulation (IPS) by using a Grass PS22 or PS33 photic stimulator for in 2,187 unselected patients with epilepsy who were treated in our center.

Results: The classic PPR was elicited in 37 (1.7%) patients. The mean age of these 37 patients was 17.0 years. The subpopulation of patients having PPR included 2.0% of all patients with symptomatic generalized epilepsy, 5.6% (p < 0.01) of those with idiopathic generalized epilepsy, 0.7% of those with symptomatic localization‐related epilepsy, and 2.9% of those with undetermined epilepsy. PPR accounted for 17.4 % (p < 0.01) of the patients with juvenile myoclonic epilepsy, 7.6% (p < 0.01) of those with grand mal on awakening, and 6.1% (p < 0.01) of those with symptomatic occipital lobe epilepsy. The incidence of PPR increased in patients up to age 15 years, and suddenly decreased after age 20 years.

Conclusion: The present study presents the first report from eastern Asia, analyzing the incidence of PPR with a restricted definition comparable to the other studies, and the rate of PPR was relatively low compared with the studies performed in the European countries. We could confirm the clear relation between age and positive PPR.
Loss of the Potassium Channel β‐Subunit Gene, KCNAB2, Is Associated with Epilepsy in Patients with 1p36 Deletion Syndrome
Authors: Heilstedt Heidi A. , Burgess Daniel L. , Anderson Anne E. , Chedrawi Aziza , Tharp Barry , Lee Olivia , Kashork Catherine D. , Starkey David E. , Wu Yuan‐Qing , Noebels Jeffrey L. , Shaffer Lisa G. , Shapira Stuart K.
Published: March 2003

Summary:  Purpose: Clinical features associated with chromosome 1p36 deletion include characteristic craniofacial abnormalities, mental retardation, and epilepsy. The presence and severity of specific phenotypic features are likely to be correlated with loss of a distinct complement of genes in each patient. We hypothesize that hemizygous deletion of one, or a few, critical gene(s) controlling neuronal excitability is associated with the epilepsy phenotype. Because ion channels are important determinants of seizure susceptibility and the voltage‐gated K+ channel β‐subunit gene, KCNAB2, has been localized to 1p36, we propose that deletion of this gene may be associated with the epilepsy phenotype.

Methods: Twenty‐four patients were evaluated by fluorescence in situ hybridization with a probe containing KCNAB2. Clinical details were obtained by neurologic examination and EEG.

Results: Nine patients are deleted for the KCNAB2 locus, and eight (89%) of these have epilepsy or epileptiform activity on EEG. The majority of patients have a severe seizure phenotype, including infantile spasms. In contrast, of those not deleted for KCNAB2, only 27% have chronic seizures, and none had infantile spasms.

Conclusions: Lack of the β subunit would be predicted to reduce K+ channel–mediated membrane repolarization and increase neuronal excitability, suggesting a possible relation between loss of this gene and the development of seizures. Because some patients with seizures were not deleted for KCNAB2, there may be additional genes within 1p36 that contribute to epilepsy in this syndrome. Hemizygosity of this gene in a majority of monosomy 1p36 syndrome patients with epilepsy suggests that haploinsufficiency for KCNAB2 is a significant risk factor for epilepsy.
The Effect of Vagus Nerve Stimulation on Epileptiform Activity Recorded from Hippocampal Depth Electrodes
Authors: Olejniczak Piotr W. , Fisch Bruce J. , Carey Michael , Butterbaugh Grant , Happel Lee , Tardo Carmela
Published: March 2003

Summary:  Purpose: To assess the effect of vagus nerve stimulation (VNS) on interictal epileptiform activity in the human hippocampus. Clinical studies have established the efficacy of vagus nerve stimulation in patients with epilepsy (VNS Study Group, 1995), although the electrophysiologic effects of VNS on the human hippocampus and mesial temporal lobe structures remain unknown.

Methods: We report a case study in which a patient with an implanted VNS underwent intracranial electrode recording before temporal lobectomy for intractable complex partial seizures. Epileptiform spikes and sharp waves were recorded from a depth electrode placed in the patient's left hippocampus. Spike frequencies and sharp‐wave frequencies before and during VNS were compared using both a 5‐ and a 30‐Hz stimulus. Different stimulation rates were tested on different days, and all analyses were performed using a Student's t test.

Results: We found no significant differences in spike frequency between baseline periods and stimulation at 5 and 30 Hz. In contrast, stimulation at 30 Hz produced a significant decrease in the occurrence of epileptiform sharp waves compared with the baseline, whereas stimulation at 5 Hz was associated with a significant increase in the occurrence of epileptiform sharp waves.

Conclusions: VNS produces a measurable electrophysiologic effect on epileptiform activity in the human hippocampus. Although a clinical response to VNS did not occur in our patient before surgery, 30‐Hz VNS suppressed interictal epileptiform sharp waves that were similar in appearance to those seen during the patient's actual seizures. In contrast, 5‐Hz stimulation appeared to increase the appearance of interictal sharp waves.
Infantile Spasms in Down Syndrome: Good Response to a Short Course of Vigabatrin
Authors: Nabbout R. , Melki I. , Gerbaka B. , Dulac O. , Akatcherian C.
Published: March 2003

Summary:  Purpose: To evaluate the efficacy of vigabatrin (VGB) in the treatment of infantile spasms (ISs) associated with Down syndrome (DS) and to assess the feasibility of early discontinuation to reduce the possible retinal toxicity.

Methods: Five children with ISs with DS were treated with vigabatrin as first‐line monotherapy in an open prospective study. The short‐term response was evaluated, and VGB was continued in responders. The treatment was stopped after 6 months in children who were still spasm free.

Results: Four children of five became spasm free with VGB, three of them responding within 1 week. This response was maintained during the 6 months of VGB treatment. After VGB discontinuation, and with a follow‐up ranging from 2 to 4 years, none of the responders experienced spasm recurrence or other types of seizures.

Conclusions: This study confirms the efficacy of VGB in ISs associated with DS. Moreover, it shows that the duration of VGB treatment can be reduced to 6 months without relapse of ISs. This short treatment might reduce the risk of developing visual field constriction.
MEG Predicts Epileptic Zone in Lesional Extrahippocampal Epilepsy: 12 Pediatric Surgery Cases
Authors: Otsubo Hiroshi , Ochi Ayako , Elliott Irene , Chuang Sylvester H. , Rutka James T. , Jay Venita , Aung Maung , Sobel David F. , Snead O. Carter
Published: March 2003

Summary:  Purpose: To discover whether the spatial distribution of spike sources determined by magnetoencephalography (MEG) provides reliable information for planning surgery and predicting outcomes in pediatric patients with lesional extrahippocampal epilepsy.

Methods: We retrospectively studied 12 children with extrahippocampal epilepsy secondary to cortical dysplasia (CD), tumor, or porencephalic cyst. We compared interictal MEG spike source locations and somatosensory evoked fields derived from equivalent‐current dipole modeling with intraoperative or extraoperative electrocorticography (ECoG).

Results: MEG spike sources were found in proximity to the lesion in all patients and extended from lesions in five patients with CD. Marginal spike sources were noted in three patients with tumors, one patient with a cyst, and one with CD, and extramarginal sources in three patients with tumors. Three patients with tumors underwent lesionectomy only; two had further cortical excisions. One patient with CD underwent lesionectomy only, three had lesionectomy and cortical excisions, and two had lesionectomy and multiple subpial transection. Asymmetric MEG spike sources correlated with ECoG findings in all patients. Residual epileptiform discharges on postexcisional ECoG corresponded to spike sources in three patients with tumors and one patient with a cyst. Eleven patients have been seizure free for 1–6 years (mean, 4 years). One patient had residual seizures after incomplete excision of right temporal CD.

Conclusions: MEG delineated asymmetric epileptogenicity surrounding lesions and the eloquent cortex. Complete tumor resection produced favorable outcomes despite residual postexcisional ECoG spikes and extramarginal MEG spike sources. CD characterized by clusters of MEG spike sources within and extending from lesions seen on magnetic resonance imaging (MRI) should be removed to prevent seizures.
Successful Cognitive‐Behavioral Habituation Training Toward Photophobia in Photogenic Partial Seizures
Authors: Noeker Meinolf , Haverkamp Fritz
Published: March 2003

Summary: We report on the cognitive‐behavioral treatment of a 12‐year‐old boy with photogenic partial seizures with secondary generalization who had developed phobic avoidant behavior toward all kinds of situations with potential photostimulation, leading to serious impairments of life quality. Based on a behavioral analysis of seizure and anxiety reaction, a habituation training (systematic desensitization procedure) was developed and performed, while maintaining protection against seizures with antiepileptic pharmacotherapy. The treatment was to gradually increase exposure to computer monitor and television screen photostimulation, closely adjusted to the level of subjective distress and tolerance. In addition to exercising control of photogenic input by regulating the monitor control button, rapid relaxation and imagery techniques were taught and applied as countermeasures at the onset of seizure precipitants. The treatment resulted in complete remission of phobic anxieties and responses and may also have facilitated ongoing seizure control after termination of antiepileptic medication.
The Health‐Related Quality of Life of Children with Refractory Epilepsy: A Comparison of Those With and Without Intellectual Disability
Authors: Sabaz Mark , Cairns David R. , Lawson John A. , Bleasel Andrew F. , Bye Ann M. E.
Published: March 2003

Summary:  Purpose: To determine whether refractory epilepsy affects the health‐related quality of life (HRQOL) of children with or without intellectual disability (ID), and if the presence of ID independently compromises HRQOL in children with refractory epilepsy.

Methods: Subjects were parents of children with refractory epilepsy, whose syndrome had been defined using ILAE (International League Against Epilepsy) criteria and video‐EEG monitoring. Children had the presence or absence of ID determined by formal neuropsychological or educational assessment. The relative effect of epilepsy on the two intellectual ability groups was determined using relevant clinical variables. Parents completed a valid epilepsy‐specific HRQOL questionnaire for children, the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE), and, depending on intellectual ability level, the Child Behaviour Checklist or Developmental Behaviour Checklist.

Results: Both intellectually normal children with epilepsy and children with epilepsy and ID were more likely to have psychosocial problems compared with their respective intellectual ability reference populations. The results also revealed that children with ID had reduced HRQOL compared with intellectually normal children; a result independent of epilepsy. Analysis of the relationship between epilepsy variables and HRQOL revealed that the QOLCE was the most sensitive in detecting variation in age at onset, seizure frequency, and medications taken.

Conclusions: The HRQOL of children with refractory epilepsy is greatly affected, regardless of intellectual ability level. The presence of ID in children with epilepsy independently depresses HRQOL outcomes. Compared with two generic HRQOL measures, the QOLCE was the most sensitive measure to variation in epilepsy variables.
Cryptogenic Epilepsy: An Infectious Etiology?
Authors: Stommel Elijah W. , Seguin Rosanne , Thadani Vijay M. , Schwartzman Joseph D. , Gilbert Karen , Ryan Kathleen A. , Tosteson Tor D. , Kasper Lloyd H.
Published: March 2003

Summary:  Purpose: Cryptogenic epilepsy, the group of epilepsy syndromes for which an etiology is unknown, comprises ∼20% of all epilepsy syndromes. We selected patients in this subgroup of epilepsy and tested them for evidence of Toxoplasma gondii IgG antibodies by the enzyme‐linked immunosorbent assay. T. gondii is found in up to 20% of the U.S. population forming dormant brain cysts in the latent bradyzoite form. We investigated the hypothesis that dormant T. gondii infection might be associated with cryptogenic epilepsy.

Methods: We selected patients with cryptogenic epilepsies and tested them for evidence of T. gondii IgG antibodies by the enzyme‐linked immunosorbent assay. A control group was also tested for comparison.

Results: We have found a statistically‐significant elevation of T. gondii antibodies among cryptogenic epilepsy patients as compared to controls [59% increase in optical density (OD), p = 0.013]. This association persisted after adjustment for subjects' gender and age in a multiple logistic regression model; however, it was no longer as statistically significant.

Conclusions: Our results suggest that chronic T. gondii infection with brain cysts may be a cause of cryptogenic epilepsy.
Study on Photo‐Pattern Sensitivity in Patients with Electronic Screen Game–Induced Seizures (ESGS): Effects of Spatial Resolution, Brightness, and Pattern Movement
Authors: Funatsuka Makoto , Fujita Michinari , Shirakawa Seigo , Oguni Hirokazu , Osawa Makiko
Published: March 2003

Summary:  Purpose: With the ever‐increasing popularity of computers, electronic screen game–induced seizure (ESGS) is beginning to pose a serious social problem. To elucidate the pathophysiology of ESGS, with the ultimate goal of prevention, we have been studying photo‐pattern sensitivity in detail with a pattern‐stimulation test using a CRT (cathode ray tube) display. This method is referred to as the “CRT‐pattern test.”

Methods: We studied 17 patients brought to our department for evaluation of ESGS. EEG responses were recorded during exposure to various patterns consisting of three elements: spatial resolution, brightness perception, and pattern‐movement recognition displayed on a CRT monitor. Photo‐paroxysmal response (PPR) frequencies were compiled for each stimulation.

Results: PPR was induced by the CRT‐pattern test in nine of the 17 cases. In four cases, PPR induction was obtained only after introducing CRT‐pattern tests in addition to standard intermittent photic stimulation (IPS). The rate of PPR induction differed according to the type of pattern, spatial frequency, and pattern‐reversal frequency. However, neither the clarity of the edges of a pattern nor changes in the brightness of a pattern element had any effect on the rate of PPR induction. With the exception of a few subjects, the stimulation caused by pattern movement was not effective in eliciting PPR. Six cases in whom spatial resolution was involved showed occipital dominance in PPR provocation, and three in whom brightness perception and pattern movement recognition was involved showed frontal dominance.

Conclusions: The CRT‐pattern test is useful for identifying patients with photosensitivity among patients considered to have incidental or nonphotosensitive seizures unresponsive to standard IPS. Patients with ESGS caused by photosensitivity can be divided into two groups: those with occipital dominance for PPR provocation, in whom spatial resolution is involved; and another group with frontal dominance, in whom brightness perception and pattern‐movement recognition (or possibly perception of colors) are involved.
Distribution of Valproate to Subdural Cerebrospinal Fluid, Subcutaneous Extracellular Fluid, and Plasma in Humans: A Microdialysis Study
Authors: Lindberger Martin , Tomson Torbjörn , Wallstedt Lars , Ståhle Lars
Published: March 2003

Summary: We sought to study the time course of the distribution of valproate (VPA) to subdural cerebrospinal fluid (CSF) in relation to subcutaneous extracellular fluid (ECF) and plasma after a single oral dose and to study the distribution to these three compartments under steady‐state conditions. Microdialysis was used to estimate unbound VPA concentrations in subdural CSF and subcutaneous ECF, and blood samples were drawn for estimation of total and unbound VPA plasma concentrations in four patients with drug‐resistant partial epilepsy undergoing presurgical evaluation with subdural EEG monitoring. Three patients were given a single oral dose of VPA, and one patient was receiving regular VPA treatment. VPA was analyzed by gas chromatography with flame ionization detection. The distribution of VPA to subdural CSF was rapid (Tmax, 3.5 h in two patients and 5.5 h in one patient) and subject to a minor delay in all three patients compared with that in the subcutaneous tissue ECF (Tmax, 2.5 h in all three patients), which in turn exhibited no evidence of a distribution delay compared with plasma. Subdural CSF levels of VPA were slightly lower than subcutaneous ECF levels (mean ratio, 0.78) and unbound plasma levels (mean ratio, 0.91). VPA rapidly enters the subdural CSF in unbound concentrations marginally lower than those obtained in subcutaneous ECF and plasma. These findings provide a pharmacokinetic rationale for acute administration of VPA. The good correlation between VPA concentrations in subcutaneous ECF and subdural CSF indicates that estimation of unbound VPA concentrations in subcutaneous tissue using microdialysis sampling has the potential to be useful for monitoring purposes.
A Possible Role for Gap Junctions in Generation of Very Fast EEG Oscillations Preceding the Onset of, and Perhaps Initiating, Seizures
Authors: Traub Roger D. , Whittington Miles A. , Buhl Eberhard H. , LeBeau Fiona E. N. , Bibbig Andrea , Boyd Stewart , Cross Helen , Baldeweg Torsten
Published: March 2003

Summary:  Purpose: We propose an experimentally and clinically testable hypothesis, concerning the origin of very fast (>∼70 Hz) EEG oscillations that sometimes precede the onset of focal seizures. These oscillations are important, as they may play a causal role in the initiation of seizures.

Methods: Subdural EEG recordings were obtained from children with focal cortical dysplasias and intractable seizures. Intra‐ and extracellular recordings were performed in rat hippocampal slices, with induction of population activity, as follows: (a) bath‐applied tetramethylamine (an intracellular alkalinizing agent, that opens gap junctions); (b) bath‐applied carbachol, a cholinergic agonist; and (c) focal pressure ejection of hypertonic K+ solution. Detailed network simulations were performed, the better to understand the cellular mechanisms underlying oscillations. A major feature of the simulations was inclusion of axon–axon gap junctions between principal neurons, as supported by recent experimental data.

Results: Very fast oscillations were found in children before seizure onset, but also superimposed on bursts during the seizure, and on interictal bursts. In slice experiments, very fast oscillations had previously been seen on interictal‐like bursts; we now show such oscillations before, between, and after epileptiform bursts. Very fast oscillations were also seen superimposed on gamma (30–70 Hz) oscillations induced by carbachol or hypertonic K+, and in the latter case, very fast oscillations became continuous when chemical synapses were blocked. Simulations replicate these data, when axonal gap junctions are included.

Conclusions: Electrical coupling between principal neurons, perhaps via axonal gap junctions, could underlie very fast population oscillations, in seizure‐prone brain, but possibly also in normal brain. The anticonvulsant potential of gap‐junction blockers such as carbenoxolone, now in clinical use for treatment of ulcer disease, should be considered.
Cerebrospinal Fluid and Serum Neuron‐Specific Enolase Levels After Febrile Seizures
Authors: Tanabe Takuya , Suzuki Shuhei , Hara Keita , Shimakawa Shuiti , Wakamiya Eiji , Tamai Hiroshi
Published: March 2003

Summary:  Purpose: Neuron‐specific enolase (NSE) has been established as a reliable marker of neuronal damage in various neurologic disorders. The aim of this study was to evaluate whether febrile seizures (FS) cause brain damage, based on the serum and cerebrospinal fluid (CSF) levels of NSE.

Methods: Fifty‐three patients aged from 6 months to 7 years were enrolled. Among them, 36 patients had generalized seizures, and 17 had partial seizures. The maximal seizure duration was 90 min. Blood and CSF samples for measurement of NSE were obtained immediately after the seizure. NSE was measured using an enzyme immunoassay (EIA).

Results: Serum and CSF levels of NSE ranged up to 10 ng/mL, but very high levels were not observed. In patients with partial seizures, the NSE level in the CSF and the ratio of the CSF to serum NSE levels showed a strong correlation with seizure duration. Conversely, there were no correlations between NSE levels and seizure duration in the patients with generalized seizures.

Conclusions: These results indicate that FS seldom cause severe neurologic damage, but prolonged partial seizures may cause slight neuronal injury.
Patients' Aims for Epilepsy Surgery: Desires Beyond Seizure Freedom
Authors: Taylor David C. , McMackin Deirdre , Staunton Hugh , Delanty Norman , Phillips Jack
Published: March 2003

Summary:  Purpose: To evaluate prospectively patient's aims for epilepsy surgery as previously outlined theoretically by Taylor et al. (Epilepsia 1997;3:625–30).

Methods: Ninety‐three consecutive patients were interviewed by a psychiatrist as part of their evaluation for epilepsy surgery. Open‐ended questions about the patient were asked, and carers' aims or ambitions for change as a result of putative relief of seizures were elicited. The interviewer aimed to obtain a maximum of five aims for later follow‐up purposes. These questions were part of an extensive psychiatric interview that is described.

Results: The aims of 69 patients or carers were analyzed. The 204 statements of aims were grouped into 59 categories initially. The five most frequently cited constituted 50% of all the aims listed. These aims were desire for work, driving of motor vehicles, independence, socializing, and freedom from drugs. The patients rarely identified a desire for improvement in cognitive functioning as an aim for epilepsy surgery. A final analysis into six categories showed that changes in social process predominated, even over changes in personal behavior.

Conclusions: The social and personal aims to accompany relief of epilepsy identified by patients are consistent with the literature on psychosocial adjustment to epilepsy.
Interaction of the Novel Anticonvulsant, BIA 2‐093, with Voltage‐Gated Sodium Channels: Comparison with Carbamazepine
Authors: Bonifácio M. J. , Sheridan R. D. , Parada A. , Cunha R. A. , Patmore L. , Soares‐da‐Silva P.
Published: March 2003

Summary:  Purpose: BIA 2‐093 [(S)‐(‐)‐10‐acetoxy‐10,11‐dihydro‐5H‐dibenz/b,f/azepine‐5‐carboxamide] is endowed with an anticonvulsant potency similar to that of carbamazepine (CBZ), but produces less cognitive and motor impairment. This study evaluated whether voltage‐gated sodium channels (VGSCs) are a primary locus for the action of BIA 2‐093.

Methods: We used the whole‐cell voltage‐clamp technique in the mouse neuroblastoma cell line N1E‐115 to investigate the effects of BIA 2‐093 and CBZ on VGSCs, displacement of [3H]‐batrachotoxinin A 20‐α‐benzoate ([3H]‐BTX), and [3H]‐saxitoxin to define their relative potency to bind to rat brain sodium channels, and inhibition of uptake of 22Na by rat brain cortical synaptosomes stimulated by veratridine as a measure of sodium entry.

Results: The inhibitory potencies of BIA 2‐093 and CBZ increased as the holding potential was made less negative (−100, −90, −80, and −70 mV) with median inhibitory concentration (IC50) values (in μM) of, respectively, 4,337, 618, 238, and 139 for BIA 2‐093, and 1,506, 594, 194, and 101 for CBZ. BIA 2‐093 displayed a similar potency in displacing [3H]‐BTX (IC50 values, 222 vs. 361 μM; p > 0.05) and inhibiting the uptake of 22Na (IC50 values, 36 vs. 138 μM; p > 0.05). Both drugs failed to displace [3H]‐saxitoxin in concentrations up to 300 μM.

Conclusions: BIA 2‐093, like CBZ, inhibits sodium currents in a voltage‐dependent way by an interaction predominantly with the inactivated state of the channel and interacts with neurotoxin receptor site 2, but not with receptor site 1. BIA 2‐093 displayed a potency blocking VGSCs similar to that of CBZ.
Concomitant Treatment with Topiramate and Ketogenic Diet in Pediatric Epilepsy
Authors: Takeoka Masanori , Riviello James J. , Pfeifer Heidi , Thiele Elizabeth A.
Published: March 2003

Summary:  Purpose: Topiramate (TPM) is widely used as add‐on therapy for epilepsy. TPM inhibits carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate. The ketogenic diet (KGD) predisposes patients to metabolic acidosis, especially during induction. In children with refractory epilepsy, cotreatment with TPM and KGD may be considered, but special attention should be paid to the combined risks for metabolic acidosis and nephrolithiasis. We report our experience in 14 children cotreated with TPM and the KGD.

Methods: Medical records of 14 children cotreated with the KGD and TPM for medically refractory epilepsy were reviewed retrospectively. Bicarbonate levels were analyzed and correlated with clinical profiles, including duration of cotreatment, TPM dose, KGD ratio, and seizure control.

Results: Nine children had a <20% decrease in bicarbonate levels, from 5.3 to 12.3 mEq/L (mean, 7.6 mEq/L). Cotreatment was continued in all patients for duration of 33 to 544 days (seven had remained on cotreatment at the end of the study period), although two children required bicarbonate supplements to continue the KGD. No patient had nephrolithiasis.

Conclusions: Although a large decrease in bicarbonate level occurred in the majority of children, the decrease appeared mostly at the time of KGD induction when added to prior TPM therapy. Bicarbonate levels should be monitored carefully with TPM and KGD cotreatment, and bicarbonate supplements given when symptomatic.
Topiramate Selectively Decreases Intracortical Excitability in Human Motor Cortex
Authors: Reis Janine , Tergau Frithjof , Hamer Hajo M. , Müller Hans‐Helge , Knake Susanne , Fritsch Brita , Oertel Wolfgang H. , Rosenow Felix
Published: March 2003

Summary:  Purpose: Topiramate (TPM) is a novel drug with broad antiepileptic effect in children and adults. In vitro studies suggest activity as sodium‐channel blocker, as γ‐aminobutyric acid type A (GABAA)‐receptor agonist and as non–N‐methyl‐D‐aspartate (NMDA)‐glutamate receptor antagonist.

Methods: With transcranial magnetic stimulation (TMS), we evaluated which of the mechanisms of action of TPM detected in vitro are relevant for the modulation of human motor cortex excitability. In a double‐blind, placebo‐controlled, crossover study design, we investigated the effect of single oral doses of 50 mg and 200 mg TPM on motor thresholds, cortical silent period (CSP), and on intracortical inhibition (ICI) and intracortical facilitation (ICF) in 20 healthy subjects.

Results: A significant dose‐dependent increase of ICI was noticed after 200 mg TPM as compared with placebo at short interstimulus intervals of 2 to 4 ms. TPM had no effect on motor thresholds or the CSP.

Conclusions: We conclude that a single dose of TPM selectively increases ICI by GABAAergic and/or glutamatergic mechanisms without a relevant influence on measures, depending on ion‐channel blockade or GABAB‐receptor activity. The decrease of intracortical excitability (as measured by ICI and ICF) caused by TPM may correlate with its lack of proconvulsive potential in idiopathic generalized epilepsy, because drugs without this action or with less pronounced action may exacerbate seizures in this condition.
Selective Middle Cerebral Artery Wada Tests as a Part of Presurgical Evaluation in Patients with Drug‐resistant Epilepsies
Authors: Urbach Horst , Von Oertzen Joachim , Klemm Edzard , Koenig Roy , Linke Detlef B. , Kurthen Martin , Schramm Johannes , Elger Christian E.
Published: March 2003

Summary:  Purpose: To analyze the role of selective middle cerebral artery (MCA) Wada tests in the presurgical workup of patients with drug‐resistant focal epilepsies.

Methods: Twenty MCA Wada test procedures were performed to identify eloquent cortex (a) in nine patients with hemispheric lesions involving the motor cortex (connatal MCA infarct, n = 5; unilateral cortical dysplasia, n = 3; Rasmussen encephalitis, n = 1), (b) five patients with circumscribed neoplastic or nonneoplastic lesions adjacent to the motor cortex or classic language areas, and (c) for purely electrophysiologic reasons, in two patients with electrical status epilepticus in sleep (ESES). Sodium amobarbital and [99mTc]‐HMPAO were simultaneously injected via a microcatheter into the distal M1 segment (n = 7), the inferior MCA trunk (n = 3), or into MCA branches (n = 10).

Results: Co‐registered single‐photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI;n = 18) showed that sodium amobarbital did not reach the target area in three procedures. Temporary neurologic deficits occurred in 12 procedures. Eleven patients were operated on with the following surgical approaches: functional hemispherectomy, n = 3; partial or extended lesionectomy, n = 4; anterior temporal lobectomy, n = 1; and multiple subpial transsections, n = 3. Seizure freedom (Engel class I) was achieved in five patients.

Conclusions: Selective MCA Wada tests can contribute to risk assessment concerning postsurgical motor deficits before functional hemispherectomy. Other indications are less clear: The identification of language areas is targeted primarily by electrical‐stimulation mapping after subdural grid implantations, and selective MCA Wada tests in ESES patients yet have to be validated in larger patient groups.
FDG‐PET Images Quantified by Probabilistic Atlas of Brain and Surgical Prognosis of Temporal Lobe Epilepsy
Authors: Lee Sang Kun , Lee Dong Soo , Yeo Jeong Seok , Lee Jae Sung , Kim Yu Kyeong , Jang Myoung Jin , Kim Kwang‐Ki , Kim Seok‐Ki , Oh Jong‐Bai , Chung Chun‐Kee
Published: March 2003

Summary:  Purpose: This study evaluated the relation between hypometabolism, diagnosed by fluorodeoxyglucose positron emission tomography (FDG‐PET), and the surgical outcome of a large and homogeneous series of cases of mesial temporal lobe epilepsy (mTLE), by using a probabilistic atlas of the human brain (statistical probabilistic anatomical maps: SPAM).

Methods: Ninety‐five surgically proven intractable mTLE patients and 22 age‐matched controls were spatially normalized to the average brain PET template of international consortium of brain mapping (ICBM). The diagnosis of mTLE was confirmed by the presence of hippocampal sclerosis on magnetic resonance imaging (MRI) and video‐EEG monitoring. Counts from normalized PET images were multiplied by the probability from 98 volumes of interest (VOIs) of SPAM. Asymmetric indexes (AIs) reflecting the severity of hypometabolism were calculated by counts of selected 12 VOIs from SPAM images in both temporal lobes. Extent of hypometabolism was determined by the number of voxels showing decreased metabolism in each VOI segmented by SPAM.

Results: Of the 95 patients studied, 76 (80%) were seizure free, and 19 (20%) had postoperative seizures for the ≥2‐year follow‐up period. No significant association between the severity of hypometabolism in each VOI of the temporal lobe and surgical outcome was identified (p > 0.05). The number of voxels showing decreased hypometabolism was not significantly different between the good‐ and poor‐outcome groups (p > 0.05).

Conclusions: Our results demonstrated that focal severity and extent of hypometabolism quantified by a probabilistic atlas of brain were not related to the surgical outcome in mTLE patients who had hippocampal sclerosis on MRI. We should develop a more localized and specified anatomic map for mTLE for further results.
Agranulocytosis Associated with Lamotrigine in a Patient with Low‐grade Glioma
Authors: Fadul Camilo E. , Meyer Louise P. , Jobst Barbara C. , Cornell Cornelius J. , Lewis Lionel D.
Published: March 2003

Summary:  Purpose: To report agranulocytosis associated with lamotrigine (LTG) in a patient with a brain tumor.

Methods: A 59‐year‐old woman with a low‐grade glioma and difficult‐to‐control partial seizures developed agranulocytosis between 9 and 14 weeks after starting LTG. The patient underwent chemotherapy 2 years previously.

Results: After stopping LTG, the agranulocytosis persisted for 9 days despite 7 days of granulocyte–colony‐stimulating factor (G‐CSF), and ultimately resolved.

Conclusions: In this case, the use of LTG was associated with the development of agranulocytosis, and it is likely that this association was causative.
Increased Expression of the Neuronal Glutamate Transporter (EAAT3/EAAC1) in Hippocampal and Neocortical Epilepsy
Authors: Crino Peter B. , Jin Hong , Shumate Melissa D. , Robinson Michael B. , Coulter Douglas A. , Brooks‐Kayal Amy R.
Published: March 2003

Summary: Purpose:To define the changes in gene and protein expression of the neuronal glutamate transporter (EAAT3/EAAC1) in a rat model of temporal lobe epilepsy as well as in human hippocampal and neocortical epilepsy.

Methods:The expression of EAAT3/EAAC1 mRNA was measured by reverse Northern blotting in single dissociated hippocampal dentate granule cells from rats with pilocarpine‐induced temporal lobe epilepsy (TLE) and age‐matched controls, in dentate granule cells from hippocampal surgical specimens from patients with TLE, and in dysplastic neurons microdissected from human focal cortical dysplasia specimens. Immunolabeling of rat and human hippocampi and cortical dysplasia tissue with EAAT3/EAAC1 antibodies served to corroborate the mRNA expression analysis.

Results:The expression of EAAT3/EAAC1 mRNA was increased by nearly threefold in dentate granule cells from rats with spontaneous seizures compared with dentate granule cells from control rats. EAAT3/EAAC1 mRNA levels also were high in human dentate granule cells from patients with TLE and were significantly elevated in dysplastic neurons in cortical dysplasia compared with nondysplastic neurons from postmortem control tissue. No difference in expression of another glutamate transporter, EAAT2/GLT‐1, was observed. Immunolabeling demonstrated that EAAT3/EAAC1 protein expression was enhanced in dentate granule cells from both rats and humans with TLE as well as in dysplastic neurons from human cortical dysplasia tissue.

Conclusions:Elevations of EAAT3/EAAC1 mRNA and protein levels are present in neurons from hippocampus and neocortex in both rats and humans with epilepsy. Upregulation of EAAT3/EAAC1 in hippocampal and neocortical epilepsy may be an important modulator of extracellular glutamate concentrations and may occur as a response to recurrent seizures in these cell types.
Clinical and Genetic Analysis of a New Multigenerational Pedigree with GEFS+ (Generalized Epilepsy with Febrile Seizures Plus)
Authors: Gérard Frédérique , Pereira Sandrine , Robaglia‐Schlupp Andrée , Genton Pierre , Szepetowski Pierre
Published: March 2003

Summary: Febrile seizures affect 2–5% of all children younger than 6 years. A small proportion of children with febrile seizures later develop epilepsy. The syndrome of generalized epilepsy with febrile seizures plus (GEFS+) is a heterogeneous disorder characterized by febrile seizures that may persist beyond age 6 years and nonfebrile seizures. Several genes have been localized for FS by linkage analysis, and three GEFS+ genes (SCN1A, SCN1B, GABRG2) have been identified. We identified a large multigenerational family with GEFS+ in France. All affected members had FSs. Among them, seven had other types of epileptic seizures including FSs after age 6 years, nonfebrile generalized seizures, or partial seizures later in life. Genetic linkage study excluded the candidate genes and loci for FS and GEFS+, thus proving the existence of a new GEFS+ genetic locus underlying the phenotype observed in this family.