bluuebunny/crossref_metadata_2025 huggingface dataset:
A myocyte enhancer factor 2D (MEF2D) kinase activated during neuronal apoptosis is a novel target inhibited by lithium
Authors: Linseman Daniel A. , Cornejo Brandon J. , Le Shoshona S. , Meintzer Mary Kay , Laessig Tracey A. , Bouchard Ron J. , Heidenreich Kim A.
Published: August 2003

Depolarization promotes the survival of cerebellar granule neurons via activation of the transcription factor myocyte enhancer factor 2D (MEF2D). Removal of depolarization induces hyperphosphorylation of MEF2D on serine/threonine residues, resulting in its decreased DNA binding and susceptibility to caspases. The subsequent loss of MEF2‐dependent gene transcription contributes to the apoptosis of granule neurons. The kinase(s) that phosphorylates MEF2D during apoptosis is currently unknown. The serine/threonine kinase, glycogen synthase kinase‐3β (GSK‐3β), plays a pro‐apoptotic role in granule neurons. To investigate a potential role for GSK‐3β in MEF2D phosphorylation, we examined the effects of lithium, a non‐competitive inhibitor of GSK‐3β, on MEF2D activity in cultured cerebellar granule neurons. Lithium inhibited caspase‐3 activation and chromatin condensation in granule neurons induced to undergo apoptosis by removal of depolarizing potassium and serum. Concurrently, lithium suppressed the hyperphosphorylation and caspase‐mediated degradation of MEF2D. Moreover, lithium sustained MEF2 DNA binding and transcriptional activity in the absence of depolarization. Lithium also attenuated MEF2D hyperphosphorylation and apoptosis induced by calcineurin inhibition under depolarizing conditions, a GSK‐3β‐independent model of neuronal death. In contrast to lithium, MEF2D hyperphosphorylation was not inhibited by forskolin, insulin‐like growth factor‐I, or valproate, three mechanistically distinct inhibitors of GSK‐3β. These results demonstrate that the kinase that phosphorylates and inhibits the pro‐survival function of MEF2D in cerebellar granule neurons is a novel lithium target distinct from GSK‐3β.
Effects of Taurine and Glycine on Epileptiform Activity Induced by Removal of Mg2+ in Combined Rat Entorhinal Cortex–Hippocampal Slices
Authors: Kirchner Anne , Breustedt Jorg , Rosche Berit , Heinemann Uwe F. , Schmieden Volker
Published: August 2003

Summary:  Purpose: The imbalance between neuronal inhibition and excitation contributes to epileptogenesis. Inhibition in the central nervous system (CNS) is mediated by γ‐aminobutyric acid (GABA) and glycine. Recent studies indicate the expression of glycine receptor (GlyR) in hippocampus and neocortex. However, the function of GlyR in these regions is not clarified completely. The aim of this study was to investigate whether the GlyR agonists glycine and taurine promote an anticonvulsive effect.

Methods: We induced epileptiform discharges by reducing extracellular Mg2+ concentration in combined rat entorhinal cortex–hippocampal slices (400 μm). Epileptiform discharges were detected by using extracellular recording techniques.

Results: Seizure‐like events were suppressed by taurine, exhibiting a half‐maximal inhibitory effect (IC50) of 0.9 mM. Suppression of late recurrent discharges in the medial entorhinal cortex and recurrent short discharges in the hippocampus was obtained at an IC50 value of 1.6 and 2.1 mM, respectively. Strychnine at concentrations <1 μM abolished these effects. Likewise glycine, after an initial proconvulsant effect, suppressed epileptiform discharges.

Conclusions: These findings show that GlyR agonists, in particular taurine, could serve as potential anticonvulsants and suggest an important role of GlyR in cortical function and dysfunction.
Brain Tumor and Seizures: Pathophysiology and Its Implications for Treatment Revisited
Authors: Schaller Bernhard , Rüegg Stephan J.
Published: August 2003

Summary:  Seizures affect ∼50% of patients with primary and metastatic brain tumors. Partial seizures have the highest incidence, followed by secondarily generalized, depending on histologic subtype, location, and tumor extent. The underlying pathophysiologic mechanisms of tumor‐associated seizures are poorly understood and include theories of altered peritumoral amino acids, regional metabolism, pH, neuronal or glial enzyme and protein expression, as well as immunologic activity. An involvement of changed distribution and function of N‐methyl‐d‐aspartate subclass of glutamate receptors also has been suggested. The often unpredictable responses to seizures after surgical tumor removal add substantial evidence that multiple factors are involved. The therapy of tumor‐related seizures is far from perfect. Several factors contribute to these treatment difficulties, such as tumor growth and drug interactions; however, one of the main reasons for poor seizure control may result from the insufficient or even absent influence of the currently available antiepileptic drugs (AEDs) on most of the pathophysiologic mechanisms of tumor‐related seizures. Studies are needed to elucidate more clearly the pathophysiologic mechanisms of tumor‐related seizures and to identify and develop the optimal AEDs.
Ring Chromosome 14 with Localization‐related Epilepsy: Three Cases
Authors: Morimoto Masafumi , Usuku Tomohiro , Tanaka Masayuki , Otabe Osamu , Nishimura Akira , Ochi Masaharu , Takeuchi Yoshihiro , Yoshioka Hiroshi , Sugimoto Tohru
Published: August 2003

Summary:  Three patients showing epileptic seizures and with mosaicism of ring chromosome 14 and monosomy for chromosome 14 are described. Patients were a 17‐year‐old boy, karyotype 46, XY, r(14)(p12q32.33)/45, XY, −14, a 7‐month‐old boy, karyotype 46, XY, r(14)(p11.2q32.33)/45, XY, −14, and a 10‐month‐old boy, karyotype 46, XY, r(14)(p12q32.31)/45, XY, −14. Microcephaly and alopecia were observed in the first patient. However, few dysmorphic features were found typical of ring 14 chromosome. He had exhibited complex partial seizures with secondary generalization at age 3 months and had mild motor and mental retardation. Both other patients had atonic seizures followed by staring, perioral cyanosis, and respiratory arrest at age 7 or 8 months. Both also showed mild developmental delay and had a few minor anomalies compatible with ring 14 chromosome. Interictal spikes were observed in the second patient in the right occipital region, whereas an interictal encephalogram of the third patient showed sporadic spikes in the left central region. In all three cases, seizures were resistant to common antiepileptic drugs.
Epilepsy in Offspring of Whom Both Parents Have Idiopathic Generalized Epilepsy: Biparental Inheritance
Authors: Marini Carla , Harvey A. Simon , Pelekanos James T. , Berkovic Samuel F.
Published: August 2003

Summary:  Background: Little is known about offspring of parents who both have idiopathic generalized epilepsy (IGE). This is of importance for understanding the complex genetic architecture of IGE

Methods: Families in whom both parents had proven IGE were ascertained through a multiplex families database. Clinical information including EEG recordings and detailed pedigrees was obtained.

Results: In family I, the mother had juvenile myoclonic epilepsy (JME), and the father had IGE. One daughter had Lennox–Gastaut syndrome, and the other had unclassified epilepsy. In family II, the mother had JME, and the father had IGE. Two of three sons had an identical clinical picture of clinical picture of childhood absence epilepsy (CAE), but with fast polyspike–wave discharges on EEG.

Conclusions: The clinical phenotype of affected offspring suggested that their epilepsy could be due to the combination of a putative “double dose” of genes from both sides of the family. In such families, as epilepsy genes could be inherited from both parents, a high risk of epilepsy in the offspring could be expected.
Interictal Patterns of Cerebral Glucose Metabolism, Perfusion, and Magnetic Field in Mesial Temporal Lobe Epilepsy
Authors: Sakamoto Shinichi , Tsuyuguchi Naohiro , Takami Toshihiro , Morino Michiharu , Goto Takeo , Hattori Hideji , Tsutada Tsuyoshi , Haque Moududul , Sunada Ichiro , Shimogawara Masahiro , Hara Mitsuhiro
Published: August 2003

Summary:  Purpose: To characterize the epileptogenic condition of patients with mesial temporal lobe epilepsy, the interictal patterns of glucose metabolism, perfusion, and magnetic field in the temporal lobe were evaluated by using [18F]fluorodeoxyglucose–positron emission tomography, [99mTc]‐ethylcysteinate dimer–single photon emission computed tomography, and magnetoencephalography (MEG).

Methods: Twenty‐one patients with mesial temporal lobe epilepsy related to hippocampal sclerosis were studied. The ictal‐onset area was located by continuous video‐EEG monitoring. Quantitative analysis of glucose metabolism and perfusion in the temporal lobe was performed, and the cerebral magnetic field was evaluated to measure the equivalent current dipole (MEG‐ECD).

Results: Although hypometabolism and hypoperfusion in the temporal lobe were lateralized with the ictal‐onset area in 16 (76.2%) and in 11 (52.4%) respectively, they were localized in diverse ways without any coupling. MEG‐ECD was distributed in diverse ways unrelated to the ictal‐onset area: ipsilateral medial temporal origin in five (23.8%), ipsilateral lateral temporal origin in two (9.5%), ipsilateral mixed (medial and lateral) temporal origin in six (28.6%), bilateral temporal origin in four (19.0%), and contralateral temporal origin in two (9.5%).

Conclusions: MEG‐ECD was distributed in varied ways with the disorder and uncoupling of glucose metabolism and perfusion in the temporal lobe. These results may help resolve the clinical controversy over the possibility that the cortical irritative area generating the interictal epileptic discharge is distinct from the ictal‐onset area, and also may have some functional implications in identifying different brain compartments in the generation of metabolic signals.
Increased Frequency of Rolandic Spikes in ADHD Children
Authors: Holtmann Martin , Becker Katja , Kentner‐Figura Beate , Schmidt Martin H.
Published: August 2003

Summary:  Purpose: Some children with rolandic epilepsy have associated neuropsychiatric deficits resembling symptoms of attention deficit–hyperactivity disorder (ADHD), the most common neurobehavioral disorder of childhood. The clinical overlap between both syndromes has received relatively little attention. The study examines the frequency of rolandic spikes in nonepileptic children with ADHD and compares it with a historic control group of 3,726 normal school‐aged children. ADHD patients with and without discharges are compared regarding age at admission, sex, global functioning, and distribution of ADHD subtypes.

Methods: The EEGs of 483 ADHD outpatients between 2 and 16 years meeting diagnostic criteria for ADHD according to Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV) were evaluated prospectively. If rolandic spikes were present, separate sleep EEGs were performed to exclude a bioelectrical status epilepticus during slow‐wave sleep.

Results: Rolandic spikes were detected in the EEGs of 27 children (5.6%; 22 boys and five girls). Seizure rate during follow‐up tended to be larger in children with rolandic spikes. No significant differences were found between ADHD patients with and without spikes regarding sex and global functioning. ADHD children with rolandic spikes came to our attention significantly earlier than did children without discharges and tended to exhibit more hyperactive–impulsive symptoms, evidenced in a larger proportion of the diagnosis of ADHD combined type than ADHD inattentive type.

Conclusions: The frequency of rolandic spikes in children with ADHD is significantly higher than expected from epidemiologic studies. The question arises how ADHD symptoms are related to rolandic spikes in this ADHD subgroup. Possibly rolandic discharges or underlying, not fully understood mechanisms of epileptogenesis decrease the vulnerability threshold, advance the onset, or aggravate the course of ADHD.
Furosemide Terminates Limbic Status Epilepticus in Freely Moving Rats
Authors: Holtkamp Martin , Matzen Julia , Buchheim Katharina , Walker Matthew C. , Meierkord Hartmut
Published: August 2003

Summary:  Purpose: To evaluate the anticonvulsant properties of furosemide and to determine sedative side effects compared with pentobarbital and diuretic side effects compared with saline‐treated controls in an experimental model of limbic status epilepticus.

Methods: Self‐sustaining status epilepticus was induced in rats by continuous electrical stimulation of the perforant path. Five minutes after the end of the stimulation, animals were given 100 mg/kg furosemide, 30 mg/kg pentobarbital, or an equal amount of saline, intraperitoneally. After administration of the substance, animals were monitored clinically and electrographically for 3 h regarding status epilepticus, level of sedation, and diuresis.

Results: In seven of 10 animals, furosemide terminated status epilepticus after 68 ± 26 min, whereas pentobarbital was successful in all animals after 5 ± 0.8 min. In contrast to pentobarbital, sedation did not occur with furosemide. Weight loss after furosemide was 10.2 ± 1.7% compared with 6.5 ± 1.1% in animals given saline (p < 0.001).

Conclusions: The results suggest that furosemide may serve as an alternative or additional agent for refractory complex partial status epilepticus in patients in whom common anesthetics are not justifiable.
Spatial Stability over Time of Brain Areas Generating Fast Ripples in the Epileptic Rat
Authors: Bragin Anatol , Wilson Charles L. , Engel Jerome
Published: August 2003

Summary:  Purpose: Fast ripples (FRs) are interictal, pathological, high‐frequency oscillations in the 200‐ to 600‐Hz range, which can be recorded from limbic regions capable of generating spontaneous seizures in rodent models of epilepsy and in human mesial temporal lobe epilepsy. To evaluate the spatial stability of FR‐generating brain areas over long periods, we monitored interictal FR oscillations in rats with chronic recurrent spontaneous seizures.

Methods: After unilateral intrahippocampal injection of kainic acid, 22 rats were video monitored until spontaneous behavioral seizures occurred, and then implanted with multiple hippocampal, dentate gyrus, and entorhinal cortex microelectrodes. Electrophysiological monitoring of microelectrode sites was carried out during daily 8‐h recordings for periods ranging from 6 to 98 days.

Results: Interictal FRs were recorded from discretely localized areas, adjacent to non–FR‐generating areas in dentate gyrus and entorhinal cortex. The location of interictal FR oscillations remained fixed, and the electrophysiological pattern of FRs remained the same over the time of our study. For the duration of monitoring, sites initially recording interictal FRs continued to display FR oscillations, and sites that initially did not record FRs never demonstrated FR activity. A direct relation was seen between the total number of electrode contacts recording interictal FRs and the frequency of spontaneous seizure generation (p < 0.0001).

Conclusions: These results suggest that interictal FRs reflect abnormal discharges from a fixed pathologic substrate imbedded within less‐epileptogenic tissue, and that spontaneous seizure frequency is dependent on the extent and distribution of this pathologic substrate.
Overexpression of the Human Major Vault Protein in Gangliogliomas
Authors: Aronica Eleonora , Gorter Jan A. , Van Vliet Erwin A. , Spliet Wim G. M. , Van Veelen Cees W. M. , Van Rijen Peter C. , Leenstra Sieger , Ramkema Marja D. , Scheffer George L. , Scheper Rik J. , Sisodiya Sanjay M. , Troost Dirk
Published: August 2003

Summary:  Purpose: Recent evidence has been obtained that the major vault protein (MVP) may play a role in multidrug resistance (MDR). We investigated the expression and cellular localization of MVP in gangliogliomas (GGs), which are increasingly recognized causes of chronic pharmacoresistant epilepsy.

Methods: Surgical tumor specimens (n = 30), as well as peritumoral and control brain tissues, were examined for the cellular distribution pattern of MVP with immunocytochemistry. Western blot analysis showed a consistent increase in MVP expression in GGs compared with that in control cortex.

Results: In normal brain, MVP expression was below detection in glial and neuronal cells, and only low immunoreactivity (IR) levels were detected in blood vessels. MVP expression was observed in the neuronal component of 30 of 30 GGs and in a population of tumor glial cells. In the majority of the tumors, strong MVP IR was found in lesional vessels. Perilesional regions did not show increased staining in vessels or in neuronal and glial cells compared with normal cortex. However, expression of MVP was detected in the hippocampus in cases with dual pathology.

Conclusions: The increased expression of MVP in GGs is another example of an MDR‐related protein that is upregulated in patients with refractory epilepsy. Further research is necessary to investigate whether it could play role in the mechanisms underlying drug resistance in chronic human epilepsy.
Activation by N‐Acetyl‐l‐Aspartate of Acutely Dissociated Hippocampal Neurons in Rats via Metabotropic Glutamate Receptors
Authors: Yan Hai‐Dun , Ishihara Kumatoshi , Serikawa Tadao , Sasa Masashi
Published: August 2003

Summary:  Purpose: We previously reported that an increase in the N‐acetyl‐l‐aspartate (NAA) level due to the lack of aspartoacylase gene was found in the brain of the tremor rat (tm/tm), which is a mutant with a causative gene named tm that shows epileptic seizures. Therefore, NAA is suggested to be one of the factors involved in the induction of epileptic seizures. Patch‐clamp studies were performed to determine whether NAA produces an excitatory effect on acutely dissociated rat hippocampal neurons.

Methods: Acutely dissociated hippocampal neurons were prepared from normal Wistar rats aged 3–4 weeks. NAA‐induced currents were investigated by using the whole‐cell voltage‐clamp recording technique.

Results: Application of NAA at concentrations of 100 nM to 1 mM through a U‐tube for 2 s produced an inward current in a concentration‐dependent manner at a holding potential of –60 mV. When the current–voltage relation was examined, the reversal potential of the NAA‐induced current was found to be ∼0 mV. The NAA‐induced current was inhibited by bath application of the metabotropic glutamate receptor (mGluR) antagonist (±)‐α‐methyl‐4‐carboxyphenylglycine (MCPG) and by intracellular application of guanosine 5′‐O‐(2‐thiodiphosphate) (GDP‐βS), a nonhydrolyzable GDP analogue. However, the NAA‐induced current remained unaffected by glutamic acid diethyl ester, a non–N‐methyl‐d‐aspartate (NMDA)‐subtype ionotropic glutamate receptor antagonist, or the voltage‐dependent ion channel blockers tetrodotoxin, CdCl2, and tetraethylammonium‐chloride. Conversely, the mGluR agonist, trans‐(1S,3R)‐1‐amino‐1,3‐cyclopentanedicarboxylic acid (ACPD) also induced an inward current, with a reversal potential of 0 mV. The ACPD‐induced current also was inhibited by MCPG.

Conclusions: These results suggest that NAA acts on the G protein‐coupled mGluRs to induce an inward current that results in excitation of the neurons, thereby contributing to the occurrence of epileptic seizures.
Sustained Efficacy and Long‐term Safety of Oxcarbazepine: One‐year Open‐label Extension of a Study in Refractory Partial Epilepsy
Authors: Beydoun Ahmad , Sachdeo Rajesh C. , Kutluay Ekrem , McCague Kevin , D'Souza Joseph
Published: August 2003

Summary:  Purpose: To evaluate the long‐term efficacy, tolerability, and safety of oxcarbazepine (OXC) in medically refractory partial epilepsy.

Methods: This study is the open‐label extension phase that followed a multicenter, randomized, double‐blind, dose‐response clinical study of OXC monotherapy in patients with medically refractory partial epilepsy. We analyzed the efficacy, tolerability, and safety of OXC during the first 48 weeks of open‐label therapy. To evaluate efficacy, we compared the change in seizure frequency throughout the 48 weeks of treatment with OXC with the baseline seizure frequency that preceded the double‐blind phase of the core study by an intent‐to‐treat and completer analysis. Safety and tolerability were evaluated by using an intent‐to‐treat analysis.

Results: Of the 87 patients enrolled in the double‐blind study, 76 patients participated in the open‐label extension phase. Fifty‐five (72%) patients completed 48 weeks of open‐label treatment on a median OXC dose of 2,400 mg/day. Based on an intent‐to‐treat analysis, the median reduction in seizure frequency was 47%(p = 0.0054); the 50 and 75% responder rates were 46.1 and 25.0%, respectively, with 6.6% of patients remaining seizure free. The completer analysis yielded comparable efficacy results. OXC was well tolerated, with 13% of patients exiting because of adverse events. The six most common adverse events, irrespective of their causal relation to OXC, were dizziness, headache, fatigue, diplopia, nausea, and rash. For the most part, these adverse events tended to be transient.

Conclusions: The efficacy of OXC is sustained with good safety and tolerability profiles during long‐term treatment of patients with medically refractory partial epilepsy.
Evidence for Distinct Genetic Influences on Generalized and Localization‐related Epilepsy
Authors: Winawer Melodie Rose , Rabinowitz Daniel , Barker‐Cummings Christie , Scheuer Mark L. , Pedley Timothy A. , Hauser W. Allen , Ottman Ruth
Published: August 2003

Summary:  Purpose: Determining the existence of syndrome‐specific genetic factors in epilepsy is essential for phenotype definition in genetic linkage studies, and informs research on basic mechanisms. Analysis of concordance of epilepsy syndromes in families has been used to assess shared versus distinct genetic influences on generalized epilepsy (GE) and localization‐related epilepsy (LRE). However, it is unclear how the results should be interpreted in relation to specific genetic hypotheses.

Methods: To assess evidence for distinct genetic influences on GE and LRE, we examined concordance of GE and LRE in 63 families containing multiple individuals with idiopathic or cryptogenic epilepsy, drawn from the Epilepsy Family Study of Columbia University. To control for the number of concordant families expected by chance, we used a permutation test to compare the observed number with the number expected from the distribution of individuals with GE and LRE in the study families.

Results: Of the families, 62% were concordant for epilepsy type, and 38% were discordant. In all analyses, the proportion of concordant families was significantly greater than expected.

Conclusions: This suggests that some genetic influences predispose specifically to either GE or LRE. Because of the ascertainment bias resulting from the selection of families containing multiple individuals with epilepsy, we could not test whether there are also shared genetic influences on these two epilepsy subtypes. Population‐based studies will be needed to explore these results further.
Corticothalamic Modulation during Absence Seizures in Rats: A Functional MRI Assessment
Authors: Tenney Jeffrey R. , Duong Timothy Q. , King Jean A. , Ludwig Reinhold , Ferris Craig F.
Published: August 2003

Summary:  Purpose: Functional magnetic resonance imaging (fMRI) was used to identify areas of brain activation during absence seizures in an awake animal model.

Methods: Blood‐oxygenation‐level–dependent (BOLD) fMRI in the brain was measured by using T2*‐weighted echo planar imaging at 4.7 Tesla. BOLD imaging was performed before, during, and after absence seizure induction by using γ‐butyrolactone (GBL; 200 mg/kg, intraperitoneal).

Results: The corticothalamic circuitry, critical for spike–wave discharge (SWD) formation in absence seizure, showed robust BOLD signal changes after GBL administration, consistent with EEG recordings in the same animals. Predominantly positive BOLD changes occurred in the thalamus. Sensory and parietal cortices showed mixed positive and negative BOLD changes, whereas temporal and motor cortices showed only negative BOLD changes.

Conclusions: With the BOLD fMRI technique, we demonstrated signal changes in brain areas that have been shown, with electrophysiology experiments, to be important for generating and maintaining the SWDs that characterize absence seizures. These results corroborate previous findings from lesion and electrophysiological experiments and show the technical feasibility of noninvasively imaging absence seizures in fully conscious rodents.
Electroclinical Patterns and Evolution of Epilepsy in the 4p– Syndrome
Authors: Battaglia Domenica , Zampino Giuseppe , Zollino Marcella , Mariotti Paolo , Acquafondata Celeste , Lettori Donatella , Pane Marika , Vasta Isabella , Neri Giovanni , Dravet Charlotte , Guzzetta Francesco
Published: August 2003

Summary: Background:Wolf–Hirschhorn syndrome (WHS) is a well‐known clinical entity caused by partial deletion of the short arm of one chromosome 4 (4p– syndrome). Seizures occur in almost all the cases, but studies on the electroclinical disorder and its evolution are still scarce. We present a longitudinal study of the electroclinical features in 10 children with WHS.

Methods:Ten patients (five boys and five girls) underwent a detailed clinical assessment and a prolonged EEG study. Six of the 10 also had video‐polygraphy.

Results:Nine of the 10 patients had seizures; they were generalized or unilateral clonic and tonic–clonic, and atypical absences associated with myoclonic jerks. Age at onset of seizures varied from 1 day to 2.5 years. In all the patients, including the only one without seizures, two stereotyped EEG patterns were observed, consisting of (a) bursts of rhythmic (3–5 Hz), high‐voltage slow waves located in the posterior regions and increased by sleep, or bursts of rapid spike–wave complexes in the centroparietal and parietooccipital regions; and (b) repetitive rapid posterior spikes. Sleep organization was constantly absent or very poor. The evolution of epilepsy was frequently good, with four seizure‐free cases at the end of follow‐up, two of them weaned from antiepileptic drugs (AEDs).

Conclusions:Seizure onset in WHS also can occur at neonatal age. At least two electrical stereotyped patterns of the epileptic disorder are associated with a relevant disorganization of the sleep states. Prognosis of epilepsy is generally good both for the seizure control and for its evolution.
Linguistic Processing in Idiopathic Generalized Epilepsy: An Auditory Event‐related Potential Study
Authors: Henkin Yael , Kishon‐Rabin Liat , Pratt Hillel , Kivity Sara , Sadeh Michelle , Gadoth Natan
Published: August 2003

Summary:  Purpose: Auditory processing of increasing acoustic and linguistic complexity was assessed in children with idiopathic generalized epilepsy (IGE) by using auditory event‐related potentials (AERPs) as well as reaction time and performance accuracy.

Methods: Twenty‐four children with IGE [12 with generalized tonic–clonic seizures (GTCSs), and 12 with absence seizures (ASs)] with average intelligence and age‐appropriate scholastic skills, uniformly medicated with valproic acid (VPA), and 20 healthy controls, performed oddball discrimination tasks that consisted of the following stimuli: (a) pure tones; (b) nonmeaningful monosyllables that differed by their phonetic features (i.e., phonetic stimuli); and (c) meaningful monosyllabic words from two semantic categories (i.e., semantic stimuli).

Results: AERPs elicited by nonlinguistic stimuli were similar in healthy and epilepsy children, whereas those elicited by linguistic stimuli (i.e., phonetic and semantic) differed significantly in latency, amplitude, and scalp distribution. In children with GTCSs, phonetic and semantic processing were characterized by slower processing time, manifested by prolonged N2 and P3 latencies during phonetic processing, and prolongation of all AERPs latencies during semantic processing. In children with ASs, phonetic and semantic processing were characterized by increased allocation of attentional resources, manifested by enhanced N2 amplitudes. Semantic processing also was characterized by prolonged P3 latency. In both patient groups, processing of linguistic stimuli resulted in different patterns of brain‐activity lateralization compared with that in healthy controls. Reaction time and performance accuracy did not differ among the study groups.

Conclusions: AERPs exposed linguistic‐processing deficits related to seizure type in children with IGE. Neurologic follow‐up should therefore include evaluation of linguistic functions, and remedial intervention should be provided, accordingly.
Recurrent Postictal Psychosis after Remission of Interictal Psychosis: Further Evidence of Bimodal Psychosis
Authors: Adachi Naoto , Kato Masaaki , Sekimoto Masanori , Ichikawa Ichiro , Akanuma Nozomi , Uesugi Hideji , Matsuda Hiroshi , Ishida Shiro , Onuma Teiichi
Published: August 2003

Summary:  Purpose: To ascertain whether bimodal psychosis (i.e., independent postictal and interictal psychosis) in patients with epilepsy can be characterized by postictal psychosis that develops after interictal psychosis remits.

Methods: We reviewed the records of 14 patients with bimodal psychosis treated at a national center hospital.Clinical and psychopathological characteristics of the patients were examined.

Results: Among the 14 patients with bimodal psychosis, four initially had interictal psychosis, and 10 initially had postictal psychosis. That is, interictal‐antecedent bimodal psychosis characterized four cases, and postictal‐antecedent bimodal psychosis characterized 10 cases. Patients with interictal‐antecedent bimodal psychosis composed 2.2% of the total patients with epilepsy and psychosis (n = 180) and 28.5% of total patients with bimodal psychosis. All four patients with interictal‐antecedent bimodal psychosis had partial epilepsy with complex partial seizures, bilateral EEG abnormalities, and borderline (or decreased) intellectual functioning. Most of these clinical features are common to both types of bimodal psychosis. Among patients with interictal‐antecedent bimodal psychosis, the mean age at the onset of the initial symptoms was 10.8 years (SD, 4.3 years) for epilepsy, 24.4 (6.1) years for interictal psychosis, and 33.8 (4.5) years for postictal psychosis.

Conclusions: In a few patients, postictal psychosis develops after the remission of interictal psychosis. Interictal‐antecedent bimodal psychosis is not likely a discrete entity because of several characteristics common to both types of bimodal psychosis. Patients may have greater vulnerability to psychosis and develop psychotic episodes easily, regardless of the presence of preceding seizures.
Different Electroclinical Manifestations of the Epilepsy Associated with Hamartomas Connecting to the Middle or Posterior Hypothalamus
Authors: Leal Alberto J. R. , Moreira Ana , Robalo Conceição , Ribeiro Constança
Published: August 2003

Summary:  Purpose: The epilepsy associated with hypothalamic hamartomas (HHs) has typical clinical, electrophysiologic, and behavioral manifestations refractory to drug therapy and with unfavorable evolution. It is well known that only sessile lesions produce epilepsy, but no correlation has been established between the different types of sessile hamartomas and the diverse manifestations of the epilepsy. We correlate anatomic details of the hamartoma and the clinical and neurophysiologic manifestations of the associated epilepsy.

Methods: HHs of seven patients with epilepsy (ages 2– 25 years) were classified as to lateralization and connection to the anteroposterior axis of the hypothalamus by using high‐resolution brain magnetic resonance imaging. We correlated the anatomic classification with the clinical and neurophysiologic manifestations of the epilepsy as evaluated in long‐term (24 h) video‐EEG recordings.

Results: HHs ranged in size from 0.4 to 2.6 cc, with complete lateralization in six of seven patients. Ictal manifestations showed good correlation with the lobar involvement of ictal/interictal EEGs. These manifestations suggest the existence of two types of cortical involvement, one associated with the temporal lobe, produced by hamartomas connected to the posterior hypothalamus (mamillary bodies), and the other associated with the frontal lobe, seen in lesions connecting to the middle hypothalamus.

Conclusions: A consistent clinical and neurophysiologic pattern of either temporal or frontal lobe cortical secondary involvement was found in the patients of our series. It depends on whether the hamartoma connects to the mamillary bodies (temporal lobe cases) or whether it connects to the medial hypothalamus (frontal lobe cases).
Antiepileptic Drug Development for “Therapeutic Orphans”
Authors: Trevathan Edwin
Published: August 2003

Summary:  Epilepsy is the most common serious neurological disorder among children. Excluding the elderly, the incidence of epilepsy is highest among children. About half of children with epilepsy have epilepsy syndromes that have unique onset in childhood. Clinical drug trials of antiepileptic drugs (AEDs) among children have been primarily performed using drugs developed for the larger adult partial epilepsy market. The current AED drug development system essentially renders children with epilepsy “therapeutic orphans” who can only benefit from AED development if a drug developed for adult partial epilepsy happens to also be effective for a pediatric epilepsy syndrome. The rapid evolution of different seizure types and childhood epilepsy syndromes, and rapid changes in baseline neurological status, make distinguishing clinical changes due to study drugs in clinical trials and the natural history of the epilepsy syndrome difficult. Unique ethical issues (e.g., informed consent), practical and logistical issues (e.g., serum AED level monitoring with microassay methods), as well as major financial and regulatory disincentives for the pharmaceutical industry are additional barriers to need‐based AED development for children. A government‐funded pediatric epilepsy group or consortium to conduct clinical trials similar to the successful Children's Oncology Group (COG) and regulations plus financial incentives that encourage the pharmaceutical industry to develop AEDs specifically for children are needed.
Preclinical Development of Antiepileptic Drugs: Past, Present, and Future Directions
Authors: White H. Steve
Published: August 2003

Summary:  Since 1993, nine new antiepileptic drugs (AEDs) have been introduced into the U.S. market for the symptomatic treatment of partial epilepsy. Their antiepileptic activity was, for the most part, defined by acute seizure models such as the maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ) seizure tests and the kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage the patient with refractory seizures. In recent years, a number of in vivo and in vitro models have been developed that display varying degrees of pharmacoresistance. As such, they may provide a unique opportunity for identifying the truly novel AED. Through a greater understanding of the pathophysiology of acquired epilepsy at the molecular and genetic level, it may be possible to identify a new therapeutic approach that reaches beyond the symptomatic treatment of epilepsy to modify the progression, or, dare we suggest, prevent the development of epilepsy in the susceptible patient. The realization of such a possibility will necessitate a change in our current AED discovery approach. The present review describes the current approach used in the search for new AEDs and offers some insight into future directions incorporating new and emerging models of therapy resistance and epileptogenesis.
What We Don't Learn from Clinical Trials in Epilepsy
Authors: Gilliam Frank
Published: August 2003

Summary:  The randomized, double‐blind trial design offers the most accurate data regarding the efficacy of antiepileptic treatments. However, translating the results of a trial into clinical care can be complex due to the intrinsic tension between the requirements for scientific methods that minimize systematic and random error, and the need for clinically relevant and generalizable data. The interpretation of the trial results is complicated further by the probable inaccuracy of self‐reported seizure rates and spontaneously reported adverse effects in most trials. Patient preference may be a feasible outcome measure that allows patient‐oriented validation of the results, and also inherently weighs the positive and negative effects of a treatment in a single endpoint.
Evaluating Devices for Treating Epilepsy
Authors: Litt Brian
Published: August 2003

Summary:  Purpose: Research into new implantable devices for treating epilepsy is expanding rapidly. Pilot studies suggest sufficient safety and potential efficacy to justify proceeding with larger scale clinical trials. Understanding the challenges presented by these trials, the testing and approval process for implantable devices, and how these differ from requirements for antiepileptic drugs (AEDs) is vital to evaluating when and where these new technologies will fit into the therapeutic armamentarium.

Methods: Important lessons regarding the limitations of uncontrolled pilot studies, patient registries, and how the Food and Drug Administration (FDA) approval process can influence trials are drawn from the implantable device literature. Some discussion of the role of animal experiments is presented, both as justification for investigational device exemptions and their potential role in establishing safety. Clinical trial experience with the vagal nerve stimulator, the first device approved for the treatment of epilepsy, is also discussed.

Results: New implantable devices hold great promise for medically refractory epilepsy patients who have no other therapeutic alternative. If effective, they may become a viable alternative to epilepsy surgery or multiple AED therapy in appropriate patients.

Conclusions: The proper evaluation, use, and acceptance of antiepileptic devices will ultimately depend on carefully executed clinical trials that take into account unique aspects of these devices, such as the requirement for surgery, electrode placement, and navigation through FDA‐monitored testing and approval.
Assessing the Efficacy of Antiepileptic Treatments: The Ketogenic Diet
Authors: Thiele Elizabeth A.
Published: August 2003

Summary: Purpose:To evaluate the evidence for determining if the ketogenic diet is an effective treatment for epilepsy.

Methods:A literature review of published data over the past 80 years concerning the ketogenic diet was performed, focusing on efficacy, tolerability, age of patient population, as well as study design.

Results:There have been several studies involving prospective and retrospective studies showing the ketogenic diet to be a very efficacious treatment in epilepsy, particularly epilepsy in childhood. However, no Class 1 studies have been published concerning the efficacy of the ketogenic diet.

Conclusions:The ketogenic diet appears to be a very effective treatment for epilepsy, particularly in childhood. It would be beneficial to have Class 1 studies available to help better define the role of the diet both in children and adults.
Clinical Trials for Treatment of Primary Generalized Epilepsies
Authors: Faught Edward
Published: August 2003

Summary:  Purpose: To review the current state of knowledge of the treatment of primary (idiopathic) generalized epilepsy syndromes based on the efficacy results of clinical trials, to highlight obstacles in the design of these trials, and to suggest solutions for future research.

Methods: Published reports of controlled clinical trials, as well as large or significant uncontrolled trials of treatments for these syndromes, were reviewed. Trials were selected for discussion based on their importance or their illustration of design issues.

Results: Only a few randomized, controlled trials of therapy for these syndromes exist. Conclusions based on this Class I data include efficacy in absence epilepsies for ethosuximide, valproate, and lamotrigine, and for eight drugs for primary generalized tonic‐clonic seizures. Many commonly accepted therapeutic strategies are not based on formal data. No controlled data exist for uncommon syndromes.

Conclusions: More clinical trials of therapies for primary generalized epilepsies are needed. To overcome design obstacles, better funding, multicenter cooperation, inclusion of children, study designs requiring fewer patients, equivalent‐control designs, use of EEG and video seizure counting, and better syndrome identification will be required.
Randomized Controlled Trials of Epilepsy Surgery
Authors: Wiebe Samuel
Published: August 2003

Summary:  Purpose: To review the following aspects of surgical randomized controlled trials (RCTs) in epilepsy: rationale, methodological issues, and state of the art.

Methods: An overview of the literature and author's experience with methodological issues in surgical RCTs, contrasting them with those encountered in medical trials; a general comparison of RCTs and non‐RCTs (observational studies); and a literature search for and review of existing surgical RCTs in epilepsy.

Results: Nonrandomized (observational) studies provide useful but potentially biased information about the effect of interventions. Because of their ability to deal with bias, RCTs are the optimum vehicle to obtain a true estimate of the effect of interventions, including surgery. Only seven surgical RCTs, encompassing 535 patients, have been performed in epilepsy, with variable adhesion to standard methodology for conducting RCTs. The major issues facing researchers undertaking surgical RCTs in epilepsy include timing of the study in relation to adoption of the intervention as standard practice, acceptance of randomization to an invasive procedure, timing of randomization in relation to the actual intervention, standardization of the surgical procedure, blinding, and patient recruitment.

Conclusions: RCTs are the gold standard for evaluating surgical treatments. Despite the large number and types of surgical interventions used to treat epilepsy, only a handful has been subjected to the scientific rigour of RCTs. The challenges faced by researchers undertaking surgical RCTs in epilepsy are substantial but not insurmountable. Possible avenues to address these methodological hurdles are suggested.
Three‐Dimensional Catheter Positioning During Radiofrequency Ablation in Patients: First Application of a Real‐Time Position Management System
Authors: DE GROOT NATASJA M.S. , BOOTSMA MARIANNE , VAN DER VELDE ENNO T. , SCHALIJ MARTIN J.
Published: August 2003

Three‐Dimensional Reai‐Time Position Management. Introduction: Precise localization of target sites for radiofrequency catheter ablation (RFCA) of arrhythmias is hampered by the relative inaccuracy of X‐ray localization procedures. This study evaluated the efficacy of a three‐dimensional (3D) real‐time position management system in guiding RFCA procedures in patients.

Methods and Results: Patients (n = 30, age 59 ± 20 years) referred for ablation of either atrial flutter (n = 10), ventricular tachycardia (n = 15), or accessory pathways (n = 5) were studied. The real‐time position management system uses ultrasound ranging techniques to track the position of an ablation catheter relative to two multitransducer reference catheters, positioned in the right atrium or coronary sinus and the right ventricle. Each catheter contains three or four ultrasound transducers. The distance between the transducer(s) is determined hy calculating the time necessary for an ultrasound pulse to reach other transducers, assuming the speed of sound in blood is 1,550 m/sec. The proximal His bundle was marked at the beginning and the end of the procedure as an electrical landmark to verify reproducibility. After identification of target sites, the position of each lesion created with the ablation catheter was marked. Successful ahlation was achieved in 94% of the patients. The distance between the location of the proximal His hundle as marked at the beginning and at the end of the procedure was 2.0 ± 1.2 mm (range 1.5 to 3.5).

Conclusion: The new 3D real‐time position management system facilitated RFCA procedures as it allowed accurate and reproducible 3D tracking of the mapping and ablation catheter.
Diagnosis and Therapy of Atrial Tachyarrhythmias in the Dual Chamber Implantable Cardioverter Defibrillator
Authors: DIJKMAN BARBARA , WELLENS HEIN J.J.
Published: August 2003

Atrial Arrhythmias in ICD Patients. Introduction: Devices capable of monitoring and treating atrial taihyarrhythmias provide information about the natural history of the arrbythmias and potentially can influence their natural course by electrical therapy early after onset.

Methods and results: Types of atrial arrhythmias and efficacy of device therapies were evaluated in 30 patients implanted with the Medtronic model 7250 Jewel AF implantable cardioverter defibrillator (ICD). All patients had structural heart disease and documented sustained ventricular and atrial arrhythmias (27 with atrial fibrillation [AF]) before implant. Twenty patients were taking amiodarone, and three were taking sotalol. During 20 ± 10 months of follow‐up, 600 atrial arrhythmia recurrences were documented in 50% of patients. AF was diagnosed in 19%. fast polymorphic atrial tacbycardia (AT) in 20%, fast monomorpbic AT in 57%. and slow AT in 4% of episodes. The two adaptive pacing therapies, burst and ramp, together with the 50‐Hz burst, were successful in 57% of delected atrial arrhythmias. Burst and ramp were responsible for 49% and 50‐Hz burst for 51% of successfully treated arrbytbmias; 33% of the episodes terminated spontaneously. No ventricular proarrbythmia was observed due to atrial pacing therapies. In 30% of episodes, dual chamber pacing was required due to post termination bradycardia. Atrial arrhythmia recurrences in patients with dilated cardiomyopathy were not amenable to pacing therapies. Several aspects of atrial arrhythmia diagnosis, therapy, and documentation that are specific for functioning of the Jewel AF arc discussed.

Conclusion: Atrial arrhythmias in ICD patients with diseased hearts who are taking Class III antiarrbythmics frequently had longer cycle lengths than AF. Half of these arrhythmias could be terminated with pacing therapies; one third terminated spontaneously.