bluuebunny/crossref_metadata_2025 huggingface dataset:
Pregnancies of Women with Epilepsy: A Population‐Based Study in Iceland
Authors: Olafsson Elias , Hallgrimsson Jon Thorgeir , Hauser W. Allen , Ludvigsson Peter , Gudmundsson Gunnar
Published: August 2005

Summary: Purpose: Women with epilepsy who become pregnant are commonly considered to be at high risk for complications during pregnancy or delivery. The offspring are also considered o have increased risk of perinatal mortality, congenital malformations, and maturational delay. Because few of these studies are population based, potential bias exists because of selection.

Methods: We performed a historical population‐based cohort study in Iceland to determine the prevalence of epilepsy among pregnant women, to identify pregnancy and delivery complications in women with epilepsy, and to determine the outcome of their pregnancies as compared with that in the general population of Iceland. We identified all women with active epilepsy who gave birth during a 19‐year period in Iceland.

Results: In this population, 3.3 in 1,000 pregnancies involve mothers with active epilepsy. The frequency of adverse events (AE) during pregnancy in the women with epilepsy is similar to that observed among all live births in the population, but cesarean section was performed twice as frequently as in the general population. Perinatal mortality rate and mean birth weight are not significantly different in the offspring of women with epilepsy as compared with rest of the population. The risk of major congenital malformations (MGM) is increased 2.7‐ fold over that expected when a mother is treated with antiepileptic drugs (AEDs) during a pregnancy.

Conclusions: Our study indicates that the rate of complications of pregnancy in mothers with active epilepsy is low and similar to that of the general population with epilepsy. Use of AEDs by the mother during pregnancy significantly increases the risk of MGM in the offspring.
Sleep‐Wakefulness Alterations in Amygdala‐Kindled Rats
Authors: Raol Y.H. , Meti B.L.
Published: August 2005

Summary: Purpose: Our aim was to study the relation between epilepsy and sleep–wakefulness cycles in the amygdalakindling model of temporal lobe epilepsy.

Methods: Adult male Wistar rats were electrically kindled through bipolar electrodes implanted in the anterior amygdala. Polysomnographic recordings were taken before and after kindled seizures for 6 h. For the studies on the effects of a single, full‐blown seizure, recordings were taken immediately after the seizure and daily thereafter until the recordings returned to baseline values. For studies on the effects of five full‐blown seizures, recordings were taken immediately after the fifth seizure and then on day 1, 2, 3, 5, 7, 14, 21, and 28.

Results: Polysomnographic recordings taken immediately after the first full‐blown seizure revealed an initial increase in the duration of deep slow‐wave sleep (SII), a decrease in the light slow‐wave sleep (SI) stage of non‐rapid eye movement (NREM) sleep, and a decrease in the quiet wakefulness (W,) stage of wakefulness. All these parameters returned to baseline values after 24 h. The duration of rapid eye movement (REM) sleep increased and returned to the baseline value after 48 h. Five consecutive full‐blown seizures caused an increase in the duration of SII from the day the seizures occurred until day 28, whereas the duration of SI decreased for 72 h. The duration of REM sleep, decreased only on the day of the seizures and day 1, while decreases in the number of REM episodes were observed on the day of the seizure, day 2 and day 14.

Conclusions: Our study indicates that even a single, full‐blown seizure can cause alterations in the architecture of sleep–wakefulness cycles for a short duration, and that multiple seizures produce long‐term effects.
Serum Sex Hormones Are Altered in Patients with Chronic Temporal Lobe Epilepsy Receiving Anticonvulsant Medication
Authors: Stoffel‐Wagner B. , Bauer J. , Flügel D. , Brennemann W. , Klingmüller D. , Elger C. E.
Published: August 2005

Summary: Purpose: To evaluate the changes in serum sex hormones of gonadal or adrenal origin, the gonadotropic hormones, and sex hormone‐binding globulin (SHBG) in men and women with chronic temporal lobe epilepsy (TLE), who are undergoing monotherapy with carbamazepine or receiving carbamazepine in combination with other anticonvulsant drugs.

Methods: Gonadal hormones (estradiol, testosterone, free testosterone, and inhibin B), adrenal hormones [cortisol, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and 17a‐hydroxyprogesterone], and gonadotropic hormones (luteinizing hormone [LH] and follicle‐stimulating hormone [FSH]) were measured in 22 women and 26 men with TLE. The study also measured prolactin; human growth hormone and its major mediator, insulin‐like growth factor–I; thyroid hormones (free thyroxine and free triiodothyronine); thyroid–stimulating hormone (TSH); and SHBG. The results were compared with those obtained from 60 healthy women and 106 healthy men.

Results: In the female patients, TSH, DHEAS, follicularphase LH, and luteal‐phase estradiol were significantly lower than in the control groups, with prolactin and SHBG significantly higher. In the male patients, DHEAS, 17α‐hydroxyprogesterone, free testosterone, inhibin B, and the testosterone LH ratio were significantly lower than in the control group, with LH, FSH, and SHBG significantly higher. Increased FSH in 31% of the men indicates an impairment of spermatogenesis; lowered inhibin B in 12% indicates an impaired Sertoli's cell function; and the decreased testosterone LH ratio in 50% indicates an impaired Leydig's cell function.

Conclusions: The case patients had endocrine disorders, mainly concerning the gonadotropic and gonadal functions in both sexes; the adrenal function, with lowered DHEAS levels in both sexes; and lowered 17α‐hydroxyprogesterone levels in the men. SHBG levels were increased in patients taking anticonvulsant medications.
Bilateral Temporal Hypometabolism in Epilepsy
Authors: Blum David E. , Ehsan Tajammul , Dungan David , Karis John P. , Fisher Robert S.
Published: August 2005

Summary: Purpose: Positron emission tomography (PET) has proven useful in epilepsy surgery for its ability to identify unilateral temporal hypometabolism (UTH), which is predictive of good surgical outcome. The significance of bilateral temporal hypometabolism (BTH) is not known.

Methods: We identified all patients who had marked bilateral reduction in temporal lobe metabolism relative to the cerebellar hemispheres and compared their clinical features and treatment outcomes with those of control patients with UTH.

Results: BTH was evident in 10% of PET scans for epilepsy at our institution. We compared these patients with age‐matched controls with UTH. The BTH patients had a higher percentage of generalized seizures; were more likely to have bilateral, diffuse or extratemporal seizure onsets; and had bilateral or diffuse magnetic resonance imaging (MRI) findings. UTH patients were more likely to have unilateral mesial temporal atrophy on MFU. Even when electrical seizure onsets were well localized, surgical outcomes were markedly worse in these patients than in controls. Medical treatment was also less successful. Social and cognitive functioning was worse in the BTH group. The only death occurred in the group with BTH.

Conclusions: Patients with BTH have features distinct from those with UTH and have a worse prognosis for seizure remission after surgery.
Myoclonic Absence‐Like Seizures and Chromosome Abnormality Syndromes
Authors: Elia Maurizio , Guerrini Renzo , Musumeci Sebastiano A. , Bonanni Paolo , Gambardella Antonio , Aguglia Umberto
Published: August 2005

Summary: Purpose: We explored the relationship between myoclonic absence seizures (MAS) and underlying chromosome disorders.

Methods: Among 14 patients with MAS observed in three centers, 5 had typical cryptogenic myoclonic absence epilepsy (MAE), 2 had MAS associated with other seizure types (1 with signs of a neuronal migration abnormality and 1 with signs of a metabolic disorder), and 7 had MAS, with or without other seizure types, complicating a chromosome abnormality syndrome‐2 with trisomy 12p, 4 with Angelman syndrome, and 1 with inv dup (15).

Results: In the 7 patients with chromosomopathy, MAS appeared at a mean age of 2.9 years (range 4 months to 6 years 6 months), had a duration of 4–20 s, and were accompanied by reduced awareness and rhythmic myoclonic jerks involving proximal limb muscles. Ictal EEG showed 2‐ to 3‐Hz generalized spike‐and‐wave discharges.

Conclusions: In these patients, MAS differed slightly from those of typical MAE: age of onset was earlier, absences were of shorter duration, and no clear increase in muscular tone was noted. Abnormal expression of genes codifying for the subfamily of K+ channels and for γ‐aminobutyric acid‐3 subunit receptors (GABRBS), both located in the chromosome segments involved in the chromosomopathies presented by our patients, could be responsible for the same generalized seizure type. Chromosome analysis should be performed in patients with mental retardation and MAS, especially when the ictal pattern does not completely overlap that observed in MAE.
Antiepileptic Drug Hypersensitivity Syndrome
Authors: Schlienger Raymond G. , Shear Neil H.
Published: August 2005

Summary: : The antiepileptic drug hypersensitivity syndrome (AHS) is an adverse drug reaction associated with the aromatic antiepileptic drugs (AEDs) phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), and primidone. The syndrome is defined by the triad of fever, skin rash, and internal organ involvement. It can also be caused by other drugs, such as sulfonamides, dapsone, minocycline, terbinafine, azathioprine, and allopurinol. Diagnosis of AHS may be difficult because of the variety of clinical and laboratory abnormalities and manifestations and because the syndrome may mimic infectious, neoplastic, or collagen vascular disorders. The incidence is approximately 1 in 3,000 exposures. AHS starts with fever, rash, and lymphadenopathy, within the fist 2–8 weeks after initiation of therapy. Internal manifestations include, among others, agranulocytosis, hepatitis, nephritis, and myostitis. AHS is associated with a relative excess of reactive oxidative metabolites of the AED. Insufficient detoxification may lead to cell death or contribute to the formation of antigen that triggers an immune reaction. Crossreactivity among PHT, CBZ, and PB is as high as 70–80%.
Mechanisms of Idiosyncratic Hypersensitivity Reactions to Antiepileptic Drugs
Authors: Leeder J. Steven
Published: August 2005

Summary: Hypersensitivity reactions to the aromatic antiepileptic drugs (AEDs) phenytoin (PHT) and carbamazepine (CBZ) appear to have an immune etiology. Current models of drug hypersensitivity center around the concept of drug bioactivation to reactive metabolites that irreversibly modify cellular proteins. These modified proteins are believed to initiate (or serve as targets of) an autoimmune‐like attack on specific drug‐modified proteins in target organs (e.g., liver, skin) of susceptible individuals. Consistent with this model, antibodies to drug‐modified and native proteins have been identified in the sera of patients experiencing several drug hypersensitivity reactions. New models must incorporate an understanding of the mechanisms by which drug‐modified proteins are processed and presented to the immune system in the appropriate context to culminate in the clinical manifestations of “hypersensitivity.” Idiosyncratic toxicities associated with new AEDs, such as lamotrigine and felbamate, appear mechanistically distinct from PHT and CBZ hypersensitivity but may involve similar processes: bioactivation, detoxification, covalent adduct formation, processing and presentation of antigen to the immune system, and consequent formation of antibody and T‐cell immune effectors. The goal of research is to develop a “susceptibility profile” for identifying individuals at risk for these forms of drug toxicity.
Quantifying the Costs of Serious Adverse Drug Reactions to Antiepileptic Drugs
Authors: Schlienger Raymond G. , Oh Paul I. , Knowles Sandra R. , Shear Neil H.
Published: August 2005

Summary: Purpose: We assessed from an institutional perspective the direct costs of severe adverse cutaneous or hypersensitivity reactions due to antiepileptic drug (AED) therapy that led to hospitalization or prolonged hospital stay. Methods: Patients admitted for or developing severe AED‐induced cutaneous or hypersensitivity reactions while in hospital from January 1990 through June 1996 were identified by ICD‐9 codes E936, E937, E693, E695.1, E995.1, and E995.2. Identified cases were analyzed retrospectively by chart review and were included in the analysis if a causal relationship was determined to be possible, probable, or definite. Clinical outcomes were abstracted and related direct costs of the adverse drug reactions (ADRs) calculated.

Results: A total of 384 cases were identified by ICD‐9 codes, of which 13 cases (mean age ± SD 52.9 ± 21.0 years) were included for further analysis. Eight patients (62%) were admitted because of an ADR (median length of stay 9.5 days; range 4–43), five (38%) experienced an ADR during hospitalization (median duration of ADR episodes 8.5 days; range: 7–21 days). The median direct medical costs of the ADRs were Canadian (CDN) $3,128 (range 1,149–21,293) per patient.

Conclusions: The management of serious cutaneous and hypersensitivity ADRs due to AEDs is associated with considerable direct medical costs. These figures should be considered along with drug acquisition costs and treatment of clinical successes and failures in the overall assessment of the economic impact of pharmacotherapy. Prospective collection of direct costs associated with ADRs in clinical trials would be of value.
Characterization of Seizures in the Flathead Rat: A New Genetic Model of Epilepsy in Early Postnatal Development
Authors: Sarkisian Matthew R. , Rattan Samarjit , D'Mello Santosh R. , LoTurco Joseph J.
Published: August 2005

Summary: Purpose: Disorders in normal central nervous system (CNS) development are often associated with epilepsy. This report characterizes seizures in a novel genetic model of developmental epilepsy, the Flathead (FH) rat.

Methods: Animals (n = 76) ages P0–22 were monitored for clinical and electrographic seizure activity. The effects of various AEDs on seizure frequency and duration also were assessed: phenobarbital (PB; 40 mg/kg), valproate (VPA; 400 mg/kg), or ethosuximide (ESM; 600 mg/kg).

Results: FHs display episodes of behavior characterized by whole‐body tremor, strub tail, alternating forelimb clonus, and complete tonus. EEG recordings from neocortex reveal that FH seizures are bilateral and begin around P7. Seizures occur at a frequency of approximately six per hour from P7 to P18 and the average duration of seizures increases through development. PB, VPA, and ESM failed to prevent seizures; however, PB significantly increased the interval of seizures but had no effects on the duration of seizures, whereas VPA decreased the duration of seizures and not the interval.

Conclusions: Seizures in FH rats occur at a constant and high frequency through a defined period in early postnatal development, and these seizures are not completely blocked by high doses of PB, VPA, or ESM. Because FH is a single‐locus mutant displaying a highly regular pattern of seizure activity, it is an ideal model for examining the process of epileptogenesis in the developing brain, evaluating new AED therapies, and determining the identity of a gene essential to the normal development of cortical excitability.
Hypnotic Recall: A Positive Criterion in the Differential Diagnosis Between Epileptic and Pseudoepileptic Seizures
Authors: Kuyk Jarl , Spinhoven Philip , van Dyck Richard
Published: August 2005

Summary: Purpose: Because the diagnosis of pseudoepileptic seizures (PESs) is mostly made by excluding epilepsy, availability of a positive criterion for PESs is of great importance. This study was aimed at the validation of a diagnostic technique that intends to provide in such a positive criterion.

Methods: In 17 patients with epileptic seizures (ESs) and 20 patients with PESs, a hypnotic procedure was performed by an investigator blind to other data to recover amnesia for the ictus. If recall was obtained, the experimental diagnosis PES was given; if not, ES was diagnosed. The experimental diagnoses were compared with the clinical, EEG‐confirmed diagnoses. Hypnotizability was measured to determine the relation between the outcome of the test and hypnotizability of the patients.

Results: Recall for the ictus was obtained in 17 patients. Each of these had a clinical diagnosis of PES. Seventeen patients with “no recall” had a clinical diagnosis of ES, and three patients had PESs. This result yields a specificity of 100% and a sensitivity of 85% for the recall technique. Hypnotizability was significantly higher in patients with PESs than in patients with ESs. In some “low hypnotizables,” recall was obtained, and in some “high hypnotizables,” no recall was obtained.

Conclusions: A positive recall test indicates PES. A subgroup of patients with PESs is characterized by a high level of hypnotizability. Hypnotizability is not crucial for outcome of the recall test. High hypnotic abilities are especially found in disorders in which it is supposed that “dissociation” is involved. It can be speculated that PES may be one of the dissociative phenomena.
The Early Prognosis of Epilepsy in Childhood: The Prediction of a Poor Outcome. The Dutch Study of Epilepsy in Childhood
Authors: Arts Willem F. M. , Geerts Ada T. , Brouwer Oebele F. , Peters A. C. Boudewyn , Stroink Hans , van Donselaar Cees A.
Published: August 2005

Summary:Purpose:To examine which variables available early in the course of childhood epilepsy are associated with a poor short‐term outcome and to develop models to predict such an outcome.

Methods:We prospectively followed up 466 children with newly diagnosed epilepsy for 2 years. Variables were collected at intake and after 6 months. Outcome was defined as the duration of the terminal remission (TR): poor (<6 months) and not poor (≥6 months).

Results:Of the subjects, 31% had a poor outcome. Multivariate analysis based on the intake variables identified number of seizures, seizure type, and etiology as risk factors for a poor outcome. With the intake and 6‐month variables combined, seizure type, etiology, the number of seizures, and not attaining a 3‐month remission during these 6 months, and the EEG at 6 months were predictive variables. A predictive model based on the multivariate logistic‐regression analysis with the intake variables was correct in 56% of the children in whom it predicted a poor outcome and in 73% of the children in whom it predicted a not‐poor outcome. With the intake and 6‐month variables together, these percentages were 66 and 79%, respectively. The sensitivity of these models was low (29 and 47%, respectively); the specificity was good (90 and 89%).

Conclusions:The 2‐year outcome of childhood epilepsy is closely related to its early course. The prognosis is poor in −30% of patients. By using our data, the prediction of a poor outcome is correct in almost two thirds of the patients; however, the models produce many false‐negative predictions.
Estimation of Topiramate in Subdural Cerebrospinal Fluid, Subcutaneous Extracellular Fluid, and Plasma: A Single Case Microdialysis Study
Authors: Lindberger Martin , Tomson Torbjörn , Öhman Inger , Wallstedt Lars , Ståhle Lars
Published: August 2005

Summary: Purpose: To estimate topiramate (TPM) concentrations in subdural cerebrospinal fluid (CSF), subcutaneous extracellular fluid (ECF), and plasma and to study the correlation of TPM concentrations in these three different compartments.

Methods: In this single case study of a patient with drug‐resistant partial epilepsy undergoing presurgical evaluation with subdural EEG monitoring, we used microdialysis to estimate concentrations of unbound TPM in CSF of the subdural space and ECF of abdominal subcutaneous tissue. Blood samples were drawn for estimation of TPM concentrations in plasma.

Results: The correlation between unbound TPM concentrations in subdural CSF and abdominal subcutaneous ECF was good. The mean ratio of ECF/CSF TPM concentration was 0.93 (SD ± 0.03) and the correlation coefficient was 0.98. The mean ratio of ECF/total plasma TPM was 0.75 (SD ± 0.06), and the correlation coefficient was 0.99. The mean ratio of CSF/total plasma TPM was 0.81 (SD ± 0.06), and the correlation coefficient was 0.97.

Conclusions: Assuming a protein binding of TPM of −13%, it is concluded that, based on nine microdialysis samples from a single subject, TPM levels in the CSF at the cortical surface are approximately the same as the unbound plasma levels. Additional patients should be studied to confirm the results.
Time Course of the GABAergic Effects of Vigabatrin: Is the Time Course‐of Brain GABA Related to Platelet GABA‐Transaminase Inhibition?
Authors: Valdizán Elsa M. , García Agueda P. , Armijo Juan A.
Published: August 2005

Summary: Purpose: To analyze the time course of the effects of vigabatrin (VGB) on brain γ‐aminobutyric acid (GABA), and its relation with 4‐aminobutyrate‐2‐ketoglutarate amino‐transferase (GABA‐T) in brain and platelets.

Methods: Blood and brain samples were collected at 4, 24, 48, and 72 h after a single dose and after 3 and 8 days of treatment with 200 mg/kg of VGB in rats.

Results: Time courses of the GABAergic effects of VGB were different after single and multiple doses: with multiple doses, the inhibition of brain GABA‐T was quicker and longer, the inhibition of platelet GABA‐T was greater and longer, the increase in brain GABA was greater, and recovery began earlier. After pooling the data obtained at 4, 24, 48, and 72 h, we observed a power correlation between the increase in brain GABA in individual rats as percentage of the control and both the inhibition of brain GABA‐T after a single dose of VGB (r=−0.40; p < 0.05), and the inhibition of platelet GABA‐T after 3 days (r=−0.48; p < 0.01) and 8 days of treatment (r=−0.53; p < 0.01). When all data after single and multiple doses were pooled, the increase in brain GABA correlated better with the inhibition of GABA‐T in platelets (r=−0.62; p < 0.001) than in brain (r=−0.38; p < 0.001). Platelet GABA‐T correlated with brain GABA at 4 h (r=−0.64; p < 0.001) and 24 h (r=−0.66; p < 0.001) but not at 48 and 72 h.

Conclusions: Platelet GABA‐T reflects the time course of the increase in brain GABA better than does brain GABA‐T after multiple doses of VGB in rats.
Cognitive Functions After Pilocarpine‐Induced Status Epilepticus: Changes During Silent Period Precede Appearance of Spontaneous Recurrent Seizures
Authors: Hort Jakub , Broźek Gustav , Mareš Pavel , Langmeier Miloš , Komárek Vladimír
Published: August 2005

Summary: Purpose: To study the possible relation between spontaneous recurrent seizures (SRS) and the derangement of cognitive memory.

Methods: Status epilepticus (SE) was induced in adult Long‐Evans rats by pilocarpine (320 mg/kg, i.p.) and interrupted after 2 h by clonazepam (CZPs mg/kg, i.p.). In addition to the animals that were given pilocarpine and CZP (group P), two groups received ketamine (100 mg/kg, i.p.): the first group 15 minutes after SE onset (group K15), and the second immediately after the CZP (group K120). Control groups were formed from animals not treated with pilocarpine as well as animals that received pilocarpine but did not develop motor seizures. Spatial cognitive memory was tested in the Morris water maze.

Results: Testing was impossible for more than 6 days after SE in group P. Ketamine shortened this period for the two groups that received it. During the silent period, deteriorated cognitive memory progressively improved, but the performance of group P started to worsen before the appearance of SRS. Group K120 only expressed a tendency toward declining performance, whereas group K15 never developed SRS, and the behavior of these animals did not differ from that of the controls after the postseizure period was over. Histologically, massive hippocampal cell loss was seen in group P. Ketamine protected hippocampal cells in a time‐dependent manner; group K15 did not exhibit any obvious necrosis in the hippocampus.

Conclusions: There is no close relation between cognitive functions and the appearance of SRS, because ketamine, administered 120 min after the beginning of SE, prevented the derangment of cognitive functions but not the appearance of SRSs.
Mutated Nicotinic Receptors Responsible for Autosomal Dominant Nocturnal Frontal Lobe Epilepsy are More Sensitive to Carbamazepine
Authors: Picard F. , Bertrand S. , Steinlein O. K. , Bertrand D.
Published: August 2005

Summary:Purpose:The recent linkage between a genetically transmissible form of epilepsy (ADNFLE) and mutations within the α4subunit, one component of the major brain neuronal nicotinic acetylcholine receptor (nAChR), raises the question of the role of this receptor in epileptogenesis. Although acting by different mechanisms, the two genetic alterations so far identified both render the nAChR less efficient. In view of the high sensitivity of ADNFLE to carbamazepine (CBZ), we studied the effects of this drug and of valproate (VPA) on the human α4β2nAChR and its mutations.

Methods:The α4β2nAChRs from control and mutant α4subunits were reconstituted inXenopusoocytes and investigated by using a dual‐electrode voltage clamp technique. Acetylcholine (ACh)‐evoked currents recorded in the absence or presence of antiepileptic drugs (AEDs) were studied to analyze the mode of action of these compounds.

Results:ACh‐evoked currents at the human α4β2nAChR were readily and reversibly inhibited by ∼100 μMCBZ. This compound was found to be a noncompetitive inhibitor of the nAChR, which probably acts by entering the channel and causing a blockade by steric hindrance. Dose‐response inhibition curves determined on the control receptor and on ADNFLE‐mutant receptors showed a greater sensitivity of the mutants to CBZ, with median inhibitory concentrations (IC50s) in the range of the antiepileptic plasma levels of CBZ. In contrast, VPA had nearly no effect on control and mutant nAChRs.

Conclusions:CBZ inhibits the neuronal α4β2nAChRs at pharmacologic concentrations, with ADNFLE mutants displaying about threefold higher sensitivity to this compound. The increased sensitivity of these mutant receptors supports the hypothesis that the antiepileptic activity of CBZ can, at least to some extent, be attributed to the nAChR inhibition.
Electrophysiologic Analysis of a Chronic Seizure Model After Unilateral Hippocampal KA Injection
Authors: Bragin Anatol , Engel Jerome , Wilson Charles L. , Vizentin Elizabeth , Mathern Gary W.
Published: August 2005

Summary: Purpose: Unilateral intrahippocampal injections of kainic acid (KA) in rats produce spontaneous recurrent limbic seizures and morphologic changes in hippocampus that resemble hippocampal sclerosis in patients with medically refractory mesial temporal lobe epilepsy (MTLE), that form of temporal lobe epilepsy (TLE) associated with hippocampal sclerosis. Interictal in vivo electrophysiologic studies have revealed high‐frequency (250‐500 Hz) oscillations, termed fast ripples (FRs). These oscillations may uniquely occur in or adjacent to the site of hippocampal KA injection, in areas that generate spontaneous seizures. Similar field potentials also have been demonstrated in the epileptogenic region of patients with TLE. We have now characterized ictal electrographic patterns in this rat model for comparison with those in human TLE and begun to evaluate the role of FRs in the transition to ictus in the KA‐treated rat.

Methods: Rats received unilateral intrahippocampal injections of KA and, after the development of spontaneous seizures, were implanted with multiple fixed and moveable microelectrodes for single unit, field potential, and EEG recording. They were then monitored by using video‐EEG telemetry for several weeks to capture and evaluate electrographic and behavioral seizure types. Results were correlated with Timm's stain demonstration of mossy fiber sprouting.

Results: Low‐voltage fast (LVF) and hypersynchronous electrographic ictal‐onset patterns were seen in the KA‐treated rat that resembled similar ictal‐onset patterns in patients with TLE. Hypersynchronous, but not LVF, ictal discharges were associated with recurrent FRs. As in the human, hypersynchronous ictal onsets originated predominantly in hippocampus, whereas LVF ictal onsets more often involved extrahippocampal structures. LVF ictal onsets occurred during wakefulness or paradoxical sleep and were usually associated with motor behavior, whereas hypersynchronous ictal onsets occurred during slow‐wave sleep or periods of immobility and were not associated with motor behavior unless there was transition to another ictal electrographic pattern. Mossy fiber sprouting did not correlate with the frequency of ictal EEG discharges exhibited by each rat but was greater in those rats that demonstrated frequent behavioral seizures.

Conclusions: The electrographic features of spontaneous seizures in the KA‐treated rat resemble those of patients with medically refractory TLE with respect to EEG pattern and localization. Our data suggest that hypersynchronous ictal onsets represent epileptogenic disturbances in hippocampal circuits, whereas LVF ictal onsets may involve extrahippocampal areas having more direct connections to the motor system. Hypersynchronous seizures may involve the same neuronal mechanisms that generate interictal FRs.
Brain Activation During Intermittent Photic Stimulation: A [15O]‐Water PET Study on Photosensitive Epilepsy
Authors: da Silva Ednéa A. , Müller Ralph‐Axel , Chugani Diane C. , Shah Jagdish , Shah Aashit , Watson Craig , Chugani Harry T.
Published: August 2005

Purpose: Intermittent photic stimulation (IPS) is an activation procedure used during electroencephalogram (EEG) recording to elicit paroxysmal discharges in individuals with photosensitivity. Specific responses on EEG recording may be provoked by IPS at different frequencies of flickering in normal individuals and in patients with photosensitive epilepsy.

Methods: Changes in regional cerebral blood flow (rCBF) were studied during IPS in two groups of subjects by using [15O]‐water positron emission tomography (PET): a control group consisting of eight healthy adults with photic driving response during IPS on EEG recording (mean age, 25 ± 10.5 years) without history of neurologic or psychiatric abnormalities and a patient group consisting of four adults (mean age, 33 ± 7.5 years) with history of photosensitive epilepsy. [15O]‐water PET scanning with concomitant EEG monitoring was performed during baseline and IPS at 4‐, 14‐, and 30‐Hz frequencies.

Results: The control group showed photic driving response at 14‐Hz IPS frequency. The patient group showed photoparoxysmal response at 14 and 30 Hz, but not at 4 Hz. Changes in rCBF were determined by means of statistical parametric mapping. Increases in rCBF in occipital cortex (Brodmann's areas 17, 18, and 19) were observed in both groups. In addition, during photic driving responses, the control group showed rCBF increases in the insula and in the thalamus, on the right side. The patient group showed a significant rCBF increase in the hypothalamic region inferior to the left caudate nucleus during photoparoxysmal response. This activation was not found in the control group. Increased rCBF also was observed in the patient group in the head of the left caudate nucleus, in the left hippocampus, and in left insula during IPS without photoparoxysmal response. No activations in these regions were observed during photoparoxysmal response.

Conclusions: These data may indicate involvement of the hypothalamus in photosensitive epilepsy and may suggest a modulatory function of the caudate nucleus, which might be associated with an inhibition of epileptic discharges during IPS in patients with photosensitive epilepsy.
Low‐Luminance Visual Stimuli Compared with Stroboscopic IPS in Eliciting PPR in Photosensitive Patients
Authors: Takahashi Takeo , Nakasato Nobukazu , Yokoyama Hiroyuki , Tsukahara Yasuo
Published: August 2005

Purpose: Photosensitivity is thought to play the most important role in the genesis of electronic screen games induced seizures (ESGIS). To elicit photoparoxysmal response (PPR) effectively, we performed EEG activation by low‐luminance visual stimuli: 20 cd/m2 deep‐red flicker and flickering 2 c/deg geometric pattern stimuli produced by strobofilters. We investigated efficacy of eliciting PPR by use of Grass PS33‐plus stroboscopic 18‐Hz intermittent photic stimulation (IPS) and low‐luminance 18‐Hz visual stimuli.

Methods: We studied 31 photosensitive patients. We gave stroboscopic IPS (eyes closed and eyes open); after deep‐red flicker stimulation (eyes open), we gave flickering geometric‐pattern stimuli by using dot, vertical grating, and horizontal grating patterns.

Results: Stroboscopic IPS elicited PPR in 14 patients, whereas absence of PPR provocation was found in 17 patients. Low‐luminance visual stimuli elicited PPR in 30 patients, whereas absence of PPR provocation was found in only one patient. These PPR provocation differences in both stimuli were statistically significant (p < 0.001).

Conclusions: The data suggest that low‐luminance visual stimuli as described are useful for EEG diagnosis of ESGIS when seizures are thought to be due to photosensitivity.
Comparative Anticonvulsant and Mechanistic Profile of the Established and Newer Antiepileptic Drugs
Authors: White H. Steve
Published: August 2005

Since 1993, several new antiepileptic drugs (AEDs) have been introduced for management of partial seizures. Like the established AEDs, the new drugs are believed to exert their anticonvulsant action through enhancement of inhibitory‐mediated neurotransmission, or reduction of excitatory‐mediated neurotransmission, or by a combination of both. Among the new drugs, vigabatrin (VGB) and tiagabine (TGB) are unique in that they were derived from mechanistic‐based drug discovery programs designed to identify effective AEDs that inhibit the metabolism and reuptake of the inhibitory neurotransmitter GABA, respectively. For many of the newer AEDs, several molecular mechanisms of action have been identified. For example, felbamate (FBM), lamotrigine (LTG), zonisamide (ZNS), topiramate (TPM), oxcarbazepine (OCBZ), and possibly gabapentin (GBP) share a similar mechanism with that defined for phenytoin (PHT) and carbamazepine (CBZ), i.e., a voltage‐ and use‐dependent block of voltage‐sensitive sodium (Na+) channels. In addition to their effects on Na+ currents, TPM, ZNS, and FBM also appear to act as allosteric modulators of the GABAA receptor, whereas GBP appears to increase brain GABA levels. GBP, ZNS, FBM, LTG, and OCBZ attenuate voltage‐sensitive calcium (Ca2+) channels, albeit through different mechanisms and with different classes of Ca2+ channels. FBM and TPM differ from both the established and newer AEDs in their ability to modulate NMDA‐ and AMPA/kainate‐mediated excitatory neurotransmission, respectively. The multiple mechanisms of action associated with FBM, TPM, ZNS, GBP, and perhaps LTG, and the unique modulation of GABA levels by VGB and TGB, are likely to account for the anticonvulsant efficacy of these newer AEDs in patients with epilepsy. For each of the new drugs, their proposed mechanisms of action are discussed in relationship to their preclinical and clinical anticonvulsant profiles.
Tiagabine
Authors: Schachter Steven C.
Published: August 2005

Tiagabine (TGB) is a recently approved antiepileptic drug (AED) that inhibits γ‐aminobutyric acid (GABA) reuptake into neurons and glia, a mechanism of action that is specific and unique among the AEDs. TGB is potent and has linear and predictable pharmacokinetics. It has no clinically relevant effects on hepatic metabolism or serum concentrations of other AEDs, effects on laboratory values, or interactions with common non‐AEDs. TGB is effective as add‐on therapy for partial seizures in patients with medically refractory epilepsy in doses ranging from 30 to 56 mg daily. Conversion to TGB monotherapy can be achieved in patients with medically refractory epilepsy, although additional controlled studies are needed to confirm the efficacy of TGB as monotherapy and to establish the effective dosage range. In controlled studies, the most common adverse events of TGB are dizziness, asthenia, somnolence, accidental injury, infection, headache, nausea, and nervousness. These are usually mild to moderate in severity and almost always resolve without medical intervention.
Colitis May Be Part of the Antiepileptic Drug Hypersensitivity Syndrome
Authors: Eland Ingo A. , Dofferhoff Anton S. M. , Vink Rob , Zondervan Pieter E. , Stricker Bruno H. Ch.
Published: August 2005

Summary: Purpose: To show that colitis may be part of the antiepileptic hypersensitivity syndrome.

Methods: Description of two case histories.

Results: The first patient was a 47‐year‐old man who developed fever, lymphadenopathy, influenza‐like symptoms, facial edema, skin rash and diarrhea after 3 weeks of carbamazepine (CBZ) treatment. Laparotomy because of severe abdominal pain 2 weeks later showed severe colitis with perforations. The second patient was a 41‐year‐old woman who developed fever, diarrhea, and skin rash 4 weeks after start of CBZ treatment. A colon biopsy confirmed colitis. Stool examinations did not show pathogenic microorganisms, and there was no evidence of Crohn's disease or ulcerative colitis. Both patients had elevated liver enzymes, peripheral eosinophilia, and eosinophils in the infiltrate of the colon.

Conclusions: In view of the close temporal relation between start of CBZ intake and development of colitis, the presence of fever, lymphadenopathy, and rash, and improvement after discontinuation of CBZ, we conclude that the two patients developed an AED hypersensitivity syndrome. Our case histories demonstrate that severe colitis may be part of this syndrome.
No Evidence of a Major Locus for Benign Familial Infantile Convulsions on Chromosome 19q12‐q13.1
Authors: Gennaro Elena , Malacarne Michela , Carbone Ilaria , Riggio Maria Concetta , Bianchi Amedeo , Bonanni Paolo , Boniver Clementina , Bernardina Bernardo Dalla , De Marco Pasquale , Giordano Lucio , Guerrini Renzo , Santorum Enrica , Sebastianelli Rosella , Vecchi Marilena , Veggiotti Pierangelo , Vigevano Federico , Bricarelli Franca Dagna , Zara Federico
Published: August 2005

Summary: Purpose: A locus for benign familial convulsions (BFICs) has been recently mapped on chromosome 19q12–13.1 by studying five families of Italian descent. The main goal of this study was to investigate the role of this locus in a set of seven newly identified families with at least three affected cases.

Methods: Five polymorphic microsatellite markers covering the BFIC locus on chromosome 19q have been typed, and parametric linkage analysis has been performed to analyze the segregation of the BFIC locus within our families.

Results: Cumulative 2‐point lod scores and multipoint analysis showed no evidence of linkage between chromosome 19 markers and the BFIC phenotype. The analysis of family‐specific 2‐point lod scores and haplotypes, however, indicated the presence of linkage to chromosome 19q in a single family, suggesting genetic heterogeneity within our family sample.

Conclusions: Our study demonstrates that the previously reported BFIC locus on chromosome 19q12–13.1 is not a major locus for BFICs. We suggest that genetic heterogeneity may have generated our discordant linkage findings, as it was reported in benign familial neonatal convulsions, a related idiopathic mendelian syndrome.
The Neuropathology of Hyperthermic Seizures in the Rat
Authors: Jiang W. , Duong T. M. , Lanerolle N. C. de
Published: August 2005

Summary: Purpose: Single and repeated hyperthermic seizures were induced in rats beginning at age 22 days to determine the neuroanatomic consequences to the hippocampus and to compare these changes with those in the hippocampi of patients with temporal lobe epilepsy (TLE) experiencing febrile seizures.

Methods: Hyperthermic seizures were induced by placing rats in a bath of water at 45°C for 4 min. Seizures were visually observed, and some animals also were monitored electroen‐cephalographically. Neurodegeneration was examined with a silver stain, whereas granule cell sprouting was detected with the Timm stain.

Results: In a majority of rats, hyperthermia‐induced tonicclonic seizures ranged in duration from 30 s to 6 min; the seizure duration increased with the number of seizures. No neurodegeneration was detectable in these animals, although there was sprouting of granule cell collaterals into the inner molecular layer (IML) of the dentate. In a small number of animals, the short seizures evolved into status epilepticus, and neuronal degeneration was present in the hippocampus and other parts of the temporal lobe, and the mediodorsal thalamus.

Conclusions: This study confirms the relation between hyperthermia and seizure occurrence. It shows in particular that, as in the human, only prolonged seizures such as status epilepticus cause a pattern of neurodegeneration similar to that observed in human TLE.
Muscarinic Receptor Loss and Preservation of Presynaptic Cholinergic Terminals in Hippocampal Sclerosis
Authors: Pennell P. B. , Burdette D. E. , Ross D. A. , Henry T. R. , Albin R. L. , Sackellares J. C. , Frey K. A.
Published: August 2005

Summary: Purpose: Prior single‐photon emission tomography studies showed losses of muscarinic acetylcholine receptor (MAChR) binding in patients with refractory mesial temporal lobe epilepsy. Experimental animal studies demonstrated transient losses of MAChR due to electrically induced seizures originating in the amygdala. However, the relations between cholinergic synaptic markers, seizures, and underlying neuro‐pathology in human temporal lobe epilepsy are unknow. We tested the hypotheses that human brain MAChR changes are attributable to hippocampal sclerosis (HS), and that HS resembles axon‐sparing lesions in experimental animal models.

Methods: We measured MAChR binding‐site density, an intrinsic neuronal marker, within the hippocampal formation (HF) in anterior temporal lobectomy specimens from 10 patients with HS and in 10 autopsy controls. Binding‐site density of the presynaptic vesicular acetylcholine transporter (VAChT) was measured as a marker of extrinsic cholinergic afferent integrity. MAChR and VAChT results were compared with neuronal cell counts to assess their relations to local neuronal losses.

Results: Reduced MAChR binding‐site density was demonstrated throughout the HF in the epilepsy specimens compared with autopsy controls and correlated in severity with reductions in cell counts in several HF regions. In contrast to MAChR, VAChT binding‐site density was unchanged in the epilepsy specimens compared with autopsy controls.

Conclusions: Reduction in MAChR binding in HS is attributable to intrinsic neuronal losses. Sparing of afferent septal cholinergic terminals is consistent with the hypothesis that an excitotoxic mechanism may contribute to the development of HS and refractory partial epilepsy in humans.
The Effect of Menopause and Perimenopause on the Course of Epilepsy
Authors: Harden Cynthia L. , Pulver Melissa C. , Ravdin Lisa , Jacobs Alan R.
Published: August 2005

Summary: Purpose: The purpose of this study was to obtain preliminary information about the effect of menopause and perimenopause on the course of epilepsy, and to determine whether seizure type, use of hormone‐replacement therapy (HRT), or a history of catamenial seizure pattern would influence this course.

Methods: We performed a questionnaire study of women with epilepsy currently in menopause and perimenopause, requesting information regarding the course of their epilepsy and treatment. Statistical analysis was performed by using Pearson X2 with 95% confidence limits.

Results: Forty‐two menopausal women (ages 41–86 years) responded. Twelve subjects reported no change in seizures at menopause, 17 reported a decrease in seizure frequency, and 13 reported an increase. Sixteen (38%) took synthetic HRT. Sixteen (38%) additional subjects (having some overlap with the HRT group) reported having a catamenial seizure pattern before menopause. HRT was significantly associated with an increase in seizures during perimenopause (p = 0.001). A history of catamenial seizure pattern was significantly associated with a decrease in seizures at menopause (p = 0.013). Thirty‐nine perimenopausal women (ages 38–55 years) responded. Nine subjects reported no change in seizures at perimenopause, five reported a decrease in seizure frequency, and 25 reported an increase. Eight (15%) subjects took synthetic HRT, and 28 (72%) reported having a catamenial seizure pattern before menopause. HRT had no significant effect on seizures; however, a history of catamenial seizure pattern was significantly associated with an increase in seizures at perimenopause (p = 0.02).

Conclusions: These pilot data suggest that synthetic HRT may be associated with an increase in seizure frequency in menopausal women with epilepsy. A catamenial seizure pattern may be associated with seizure decrease during menopause but with an increase during perimenopause.
The Long‐Term Use of Gabapentin, Lamotrigine, and Vigabatrin in Patients with Chronic Epilepsy
Authors: Wong I. C. K. , Chadwick D. W. , Fenwick P. B. C. , Mawer G. E. , Sander J. W. A. S.
Published: August 2005

Summary:Purpose:To compare the long‐term retention of gabapentin (GBP), lamotrigine (LTG), and vigabatrin (VGB) by patients with chronic epilepsy and the reasons for treatment discontinuation. To assess the likelihood of seizure freedom, seizure‐related injury/hospital admission and mortality after these drugs were commenced.

Methods:This was a retrospective case‐records survey in five tertiary referral epilepsy centres in the U.K. The retention times on treatment (from initiation to discontinuation) for the different antiepileptic drugs (AEDs) were compared by using Kaplan‐Meier survival analysis and Cox regression. Incidences of seizure freedom and seizure‐related injury/hospital admissions and standardised mortality ratios were calculated.

Results:There were 1,375 patients with chronic epilepsy included; 361 were taking GBP, 1,050 LTG, and 713 VGB. The retention of GBP, LTG, or VGB was >40% at 6 years. Fewer than 4% of patients become seizure free while taking one of the drugs. There was no reduction in mortality or seizure‐related injury/admission.

Conclusions:The impact of these new AEDs on chronic epilepsy can be described only as modest. This view may be revised, however, as more experience is gained with new drugs in previously untreated patients.