bluuebunny/crossref_metadata_2025 huggingface dataset:
Occurrence, Outcome, and Prognostic Factors of Infantile Spasms and Lennox‐Gastaut Syndrome
Authors: Rantala Heikki , Putkonen Tuuli
Published: August 2005

Summary: Purpose: To analyze the occurrence, outcome, and prognostic factors of infantile spasms (IS) and the Lennox‐Gastaut syndrome (LGS) in a defined population.

Methods: All children treated because of IS and LGS in the Department of Pediatrics, University of Oulu, from January 1, 1976, until December 31, 1993, who came from the primary catchment area of the hospital were included. Detailed information concerning their individual pre‐, peri‐, and postnatal medical histories and medical and laboratory examinations were compiled.

Results: Thirty‐seven children (18 boys) had IS, and 25 (14 boys) had LGS. The occurrence of IS of 0.41/1,000 live births [95% confidence interval (CI), 0.29–0.57/1,000] did not differ significantly from that of LGS, which was 0.28/1,000 live births (95% CI, 0.18–0.41/1,000). Ten (27%) of the 37 patients with IS evolved to LGS, which was 40% of the LGS cases. All the 10 children with both IS and LGS had symptomatic epilepsy, were mentally retarded, and had active epilepsy at the end of −10 years' follow‐up. Twenty‐six (87%) of the 30 symptomatic IS cases and all the 17 symptomatic LGS cases were due to either congenital or genetic etiologies. The outcome in cryptogenic IS cases was favorable; the risk for a poor neurologic and mental outcome was extremely low; odds ratio, 0.015 (95% CI, 0.001–0.196), as it was for therapy‐resistant epilepsy; odds ratio, 0.013 (95% CI, 0.001–0.166). In LGS patients, cryptogenic etiology did not decrease the risk for a poor outcome.

Conclusions: Cryptogenic etiology is associated with a very low risk for a poor outcome in IS patients, but not in LGS patients. The outcome of IS children and the relation of IS to LGS are determined by the underlying brain disease, not by the epilepsy itself.
Valproate Treatment and Platelet Function: The Role of Arachidonate Metabolites
Authors: Kis Béla , Szupera Zoltán , Mezei Zsófia , Gecse Árpád , Telegdy Gyula , Vécsei László
Published: August 2005

Summary: Purpose: Valproate (VPA) is an extensively used drug in the therapy of epilepsies. One of the most frequently reported side effects of VPA is hemorrhagic diathesis. Some authors emphasized the decreased platelet count as the basis of VPA‐induced hemorrhagic diathesis, but some reports suggested that a significant proportion of patients with normal platelet count may still have an altered platelet function. The mechanism of the VPA‐induced platelet dysfunction has not yet been elucidated. A determining element of platelet functions is the arachidonate cascade. Present ex vivo experiments were designed to determine whether a relation exists between the incidence of hemostasis caused by VPA and the effect of this drug on the arachidonate cascade of platelets.

Methods: Platelets were isolated from patients receiving long‐term VPA treatment (serum level, 36.04 ± 16.12 μg/ml; n = 10) or carbamazepine (CBZ) treatment (serum level, 5.24 ± 2.67 μg/ml; n = 10) and were labeled with [14C]arachidonic acid. (CBZ‐treated patients were chosen as a control group, because CBZ causes blood dyscrasias similar to those elicited by VPA, but there has been no report that CBZ induces a platelet dysfunction.) The 14C‐eicosanoids were separated by means of overpressure thin‐layer chromatography and determined quantitatively by liquid scintillation.

Results: Even when the mean plasma concentration of the drug was low, VPA treatment reduced the activity of the arachidonate cascade in platelets. VPA effectively inhibited the cyclooxygenase pathway and the synthesis of the strong platelet aggregator thromboxane A2.

Conclusions: Inhibition of the platelet arachidonate cascade may contribute to the platelet‐function alterations caused by VPA.
Classification of Childhood Epilepsy Syndromes in Newly Diagnosed Epilepsy: Interrater Agreement and Reasons for Disagreement
Authors: Berg Anne T. , Levy Susan R. , Testa Francine M. , Shinnar Shlomo
Published: August 2005

Summary: Purpose: The International League Against Epilepsy (ILAE) classification of the epilepsies is in increasingly widespread use. The following analysis was done to assess the interrater agreement in classifying epilepsy syndromes in children with newly diagnosed epilepsy.

Methods: In a prospective, community‐based study, 613 children with newly diagnosed epilepsy were recruited. Based on information available at diagnosis or generated as part of the initial diagnostic assessment, three pediatric neurologists independently classified epilepsy syndromes. Interrater agreement was assessed with K.

Results: Interrater agreement was extremely good, with k scores ≥0.80 for almost all comparisons. Relatively limited quality of the EEG and seizure information in some cases, as well as discrepancies between the two, were associated with a tendency for more disagreement.

Conclusions: A high degree of interrater agreement was obtained in this study, indicating that the system for classifying syndromes can be meaningfully used in a community‐based sample. Quality of the information, which is often, by necessity, less than optimal in newly diagnosed epilepsy, is a potential barrier to identification of syndromes. A substantial proportion of children were classified into relatively nonspecific syndromes. Over time, additional information may come to light to allow more precise identification of their forms of epilepsy. In an epidemiologic setting, the ILAE classification of the epilepsies can be successfully used with a high degree of reliability to classify newly diagnosed epilepsy in children.
The Incidence of Epilepsy and Unprovoked Seizures in Multiethnic, Urban Health Maintenance Organizations
Authors: Annegers John F. , Dubinsky Stephanie , Coan Sharon Pasternak , Newmark Michael E. , Roht Lewis
Published: August 2005

Summary: Purpose: Studies of the incidence of epilepsy are limited to a few populations in which new cases can be ascertained. Health maintenance organization (HmO) populations were studied to determine the incidence in a multiethnic, urban United States population.

Methods: Cases of initial unprovoked seizure disorder or epilepsy while enrolled in an HMO between 1988 and 1994 were ascertained. Ethnicity was obtained from the medical records and was part of a nested case‐control study.

Results: There were 197 incidence cases of epilepsy and 275 of initial unprovoked seizure diagnosis. The incidence rate in the age range 0–64 years was 35.5 per 100,000 for epilepsy and 50.9 for initial unprovoked seizure. When compared with population‐based studies, rates were slightly higher in children younger than 15, similar for the 15‐ to 24‐year age group, but lower for ages 25–64 years. The ethnicity‐specific odds ratios for initial unprovoked seizure, by using non‐Hispanic white as the referent, were 1.04 (0.73–1.49) for African‐American, 0.97 (0.64–1.48) for Hispanic, and 0.25 (0.08–0.84) for Asian‐American.

Conclusions: The lower rate in the HMO population is presumably due to a healthy‐worker effect. The ethnicity‐specific incidence rates do not differ in this population.
Ketosis and Epilepsy: 31P Spectroscopic Imaging at 4.1 T
Authors: Pan J. W. , Bebin E. M. , Chu W. J. , Hetherington H. P.
Published: August 2005

Summary: Purpose: To determine whether changes in the high‐energy phosphates occur with use of the ketogenic diet in patients with intractable epilepsy.

Methods:
31P magnetic resonance spectroscopic imaging studies were performed at 4.1 T in seven patients with intractable epilepsy (four Lennox‐Gastaut syndrome, one absence, one primary generalized tonic‐clonic, and one partial complex) before and after institution of the ketogenic diet. Coronal 1H anatomic imaging also was performed to provide correlation to the 31P data.

Results: Taking the patients as a group, the ratio of phosphocreatine (PC)/γ‐adenosine triphosphate (ATP) measured at baseline (regular diet) compared with that measured after the ketogenic diet showed a small but significant increase from 0.61 ± 0.08 to 0.69 ± 0.08 (p < 0.05). Comparing the ratio of PCr inorganic phosphorus (Pi) measured at baseline with the postketogenic diet, there was a significant increase from 2.45 ± 0.27 to 2.99 ± 0.44 (p < 0.05).

Conclusions: As a group, improvement of energy metabolism occurs with use of the ketogenic diet. This is in agreement with the chronic ketosis studies performed earlier in rodents.
Regulation of Limbic Motor Seizures by GABA and Glutamate Transmission in Nucleus Tractus Solitarius
Authors: Walker Benjamin R. , Easton Amy , Gale Karen
Published: August 2005

Summary: Purpose: The nucleus of the solitary tract (NTS) is a primary site at which vagal afferents terminate. Because afferent vagal nerve stimulation has been demonstrated to have anticonvulsant effects, it is likely that changes in synaptic transmission in the NTS can regulate seizure susceptibility. We tested this hypothesis by examining the influence of γ‐amino‐butyric acid (GABA) ergic and glutamatergic transmission in the NTS on seizures evoked by systemic and focal bicuculline and systemic pentylenetetrazol (PTZ) in rats.

Methods: Muscimol (256 pmol), a GABAA‐receptor agonist, bicuculline methiodide (177 pmol), a GABAA‐receptor antagonist, kynurenate (634 pmol), a glutamate‐receptor antagonist, or lidocaine (100 nl; 5%), a local anesthetic, was microinjected into the mediocaudal (m)NTS. Ten minutes later, seizure activity was induced by either a focal microinfusion of bicuculline methiodide (177 pmol) into the rostral piriform cortex, systemic PTZ (50 mg/kg, i.p.), or systemic bicuculline (0.35 mg/kg, i.v.).

Results: Muscimol in mNTS (but not in adjacent regions of NTS) attenuated seizures in all seizure models tested, whereas bicuculline methiodide into mNTS did not alter seizure responses. Kynurenate infusions into mNTS significantly reduced the severity of seizures evoked both systemically and focally. Anticonvulsant effects also were obtained with lidocaine application into the same region of mNTS. Unilateral injections were sufficient to afford seizure protection.

Conclusions: Our results demonstrate that an increase in GABA transmission or a decrease in glutamate transmission in the rat mNTS reduces susceptibility to limbic motor seizures. This suggests that inhibition of mNTS outputs enhances seizure resistance in the forebrain and provides a potential mechanism for the seizure protection obtained with vagal stimulation.
Visual Confrontation Naming Outcome After Standard Left Anterior Temporal Lobectomy with Sparing Versus Resection of the Superior Temporal Gyrus: A Randomized Prospective Clinical Trial
Authors: Hermann Bruce , Davies Keith , Foley Kevin , Bell Brian
Published: August 2005

Summary: Purpose: Intraoperative mapping of eloquent cortex during left (speech dominant) anterior temporal lobectomy has shown a significant proportion of patients to have sites on the anterior superior temporal gyrus at which visual confrontation naming can be disrupted by electrical stimulation. The purpose of this investigation was to conduct a randomized clinical trial to determine whether sparing versus resection of the superior temporal gyrus affected visual confrontation naming outcome after standard left anterior temporal lobectomy. Also examined was the degree to which inherent patient characteristics were associated with language outcome regardless of surgical technique.

Methods: Thirty patients with intractable left temporal lobe epilepsy undergoing standard anterior temporal lobectomy were randomized in regard to whether the superior temporal gyrus was resected or spared. Patients were tested preoperatively and 6–8 months postoperatively by using two conventional tests of visual confrontation naming ability.

Results: No significant differences were found between the groups in either confrontation naming or surgical outcome. Postoperative decline in nominal speech was most closely associated with later age at onset of epilepsy/absence of hippocampal sclerosis.

Conclusions: It appears that specific types of localization‐related temporal lobe epilepsy are more closely associated with the risk of adverse language outcome after anterior temporal lobectomy than with the surgical variations investigated in this study.
Adding Lamotrigine to Valproate: Incidence of Rash and Other Adverse Effects
Authors: Faught Edward , Morris George , Jacobson Mercedes , French Jacqueline , Harden Cynthia , Montouris Georgia , Rosenfeld William ,   Postmarketing Antiepileptic Drug Survey (PADS) Group
Published: August 2005

Summary: Purpose: Valproate (VPA) triples the half‐life of lamotrigine (LTG), and combined use may be difficult. The adverse effect (AE) profile of this combination needs clarification.

Methods: We prospectively recorded our experience in adding LTG to VPA‐containing regimens in 108 patients. Data collected included medications, seizure types and syndromes, and AEs. Patients were followed up to 27 months, until a stable dose was reached, or until LTG was discontinued. Patient management was not altered by this study. There were 60 patients with partial‐onset seizures, 30 with generalized onset, and 12 with the Lennox‐Gastaut syndrome. In 37, LTG was added to VPA monotherapy, and in 71, to VPA and other drugs. The median starting dose of LTG in our adult patients was 20.8 mg/day.

Results: LTG was added successfully in 86 (80%) patients. It was discontinued in 22 (20%): seven because of rash, seven for other AEs, and nine for other reasons. Rash occurred in 14 (13%) but caused discontinuation of LTG in only seven. We found a rash rate of 14.2% and a discontinuation rate because of rash of 8.7% among 310 patients in whom LTG was added to drug regimens not including VPA. Other AEs included fatigue (12%), gastrointestinal (GI) symptoms (9%), dizziness, headache, and insomnia (3% each). Serious AEs were hallucinations (two patients), hepatic enzyme elevations (two patients), irritability (one patient), and low white blood cell count (one patient). Whether LTG was added to VPA monotherapy or polytherapy made no difference in overall AE rate.

Conclusions: LTG can be added to VPA with an acceptable incidence of side effects. LTG‐induced rashes are no more common with VPA than with other drugs when LTG is added at very low initial dosages. Rashes are potentially serious and should be evaluated promptly.
The Efficacy of Valproate‐Lamotrigine Comedication in Refractory Complex Partial Seizures: Evidence for a Pharmacodynamic Interaction
Authors: Pisani F. , Oteri G. , Russo M. F. , Di Perri R. , Perucca E. , Richens A.
Published: August 2005

Summary: Purpose: To assess the comparative therapeutic value of valproate (VPA), lamotrigine (LTG), and their combination in patients with complex partial seizures resistant to other established antiepileptic drugs (AEDs).

Methods: After a 3‐month prospective baseline, 20 adults with refractory complex partial seizures not exposed previously to VPA and LTG were scheduled to receive three consecutive add‐on treatments with VPA, LTG, or their combination, according to an open, response‐conditional, crossover design. Each period consisted of a 6‐ to 12‐week dose optimization followed by 3‐month evaluation at stabilized serum drug levels. Only patients not responding to one phase proceeded to the next.

Results: A >50% reduction in seizure frequency was observed in three of 20 patients given VPA and in four of 17 patients given LTG. Of the remaining 13 patients, four became seizure free, and an additional four experienced seizure reductions of 62–78% when VPA and LTG were given in combination. Mild tremor was observed in three patients receiving VPA and in all patients taking the VPA—LTG combination. In patients responding to combination therapy, optimized dosages and peak serum levels of both VPA and LTG were lower than those during separate administration.

Conclusions: A considerable proportion of patients who failed to respond to VPA and LTG separately improved when the two drugs were combined, although serum levels of both agents were lower during combination therapy. Despite methodologic limitations in the nonrandomized treatment sequence, these findings suggest that VPA and LTG exhibit a favorable pharmacodynamic interaction in patients with refractory partial epilepsy. The dosage of both drugs, however, may need to be reduced to minimize the risk of intolerable side effects.
Two Cases of Nonconvulsive Status Epilepticus in Association with Tiagabine Therapy
Authors: Ettinger Alan B. , Bernal Oscar G. , Andriola Mary R. , Bagchi Sugata , Flores Patricia , Just Cecille , Pitocco Christine , Rooney Terrance , Tuominen John , Devinsky Orrin
Published: August 2005

Summary: We report two patients with intractable partial seizures who developed generalized nonconvulsive status epilepticus (NCSE) after receiving tiagabine (TGB). Neither had a history of absence seizures or generalized epileptic discharges on prior EEG monitoring. Clinicians need to be aware of a possible association between TGB and NCSE.
Effects of Blocking GABA Degradation on Corticotropin‐Releasing Hormone Gene Expression in Selected Brain Regions
Authors: Tran Viet , Hatalski Carolyn G. , Yan Xiao‐Xin , Baram Tallie Z.
Published: August 2005

Summary: Purpose: The γ‐aminobutyric acid (GABA) degradation blocker γ‐vinyl‐GABA (VGB) is used clinically to treat seizures in both adult and immature individuals. The mechanism by which VGB controls developmental seizures is not fully understood. Specifically, whether the anticonvulsant properties of VGB arise only from its elevation of brain GABA levels and the resulting activation of GABA receptors, or also from associated mechanisms, remains unresolved. Corticotropin‐releasing hormone (CRH), a neuropeptide present in many brain regions involved in developmental seizures, is a known convulsant in the immature brain and has been implicated in some developmental seizures. In certain brain regions, it has been suggested that CRH synthesis and release may be regulated by GABA. Therefore we tested the hypothesis that VGB decreases CRH gene expression in the immature rat brain, consistent with the notion that VGB may decrease seizures also by reducing the levels of the convulsant molecule, CRH.

Methods: VGB was administered to immature, 9‐day‐old rats in clinically relevant doses, whereas littermate controls received vehicle.

Results: In situ hybridization histochemistry demonstrated a downregulation of CRH mRNA levels in the hypothalamic paraventricular nucleus but not in other limbic regions of VGB‐treated pups compared with controls. In addition, VGB‐treated pups had increased CRH peptide levels in the anterior hypothalamus, as shown by radioimmunoassay.

Conclusions: These findings are consistent with a reduction of both CRH gene expression and secretion in the hypothalamus, but do not support an indirect anticonvulsant mechanism of VGB via downregulation of CRH levels in limbic structures. However, the data support a region‐specific regulation of CRH gene expression by GABA.
Long‐Term Neuropsychological Consequences of Maternal Epilepsy and Anticonvulsant Treatment During Pregnancy for School‐Age Children and Adolescents
Authors: Koch S. , Titze K. , Zimmermann R. B. , Schröder M. , Lehmkuhl U. , Rauh H.
Published: August 2005

Summary: Purpose: Antiepileptic drugs (AEDs) are potential teratogenic agents. The purpose of this study was to examine the long‐term effects of intrauterine AED exposure on neurologic and psychological functioning.

Methods: Of a prospective study, “Epilepsy, pregnancy, and child development,” children could be retraced at school age and adolescence. Sixty‐seven were born to mothers with epilepsy [no drugs during pregnancy (n = 13), monotherapy (n = 31), polytherapy (n = 23)]; 49 were nonafflicted control children. Assessments included an intelligence test (Wechsler), a neurologic examination (Touwen), and an EEG. Data analyses were performed, controlling for parental social status, type of maternal drug therapy and drug dosage, type of epilepsy, frequency of seizures during pregnancy, the original subgroups, and specific drug effects.

Results: Type of maternal epilepsy and type and kind of AED therapy, but not maternal seizures during pregnancy correlated with an increase in abnormal EEG patterns. Minor neurologic dysfunction was diagnosed, with increased frequency from the control to the risk/no drug or monotherapy to the polytherapy group. The compromised intelligence score of the polytherapy group was primarily due to those children who had been exposed to primidone (PRM). Level of IQ was negatively associated with PRM dosage.

Conclusions: Maternal epilepsy and AED therapy during pregnancy appear to have long‐term effects on the offspring well into adolescence, as evinced in EEG patterns, minor neurologic dysfunction, and intellectual performance. Severity of effects increased from control group to epilepsy/no‐drug group to monotherapy group and was most marked in the polytherapy group. These group differences are assumed to reflect differential neural vulnerability to social and family factors.
Interictal Epileptiform Discharges in Temporal Lobe Epilepsy Due to Hippocampal Sclerosis Versus Medial Temporal Lobe Tumors
Authors: Hamer H. M. , Najm I. , Mohamed A. , Wyllie E.
Published: August 2005

Summary: Purpose: It remains controversial whether a specific pattern of interictal epileptiform activity exists that may help to differentiate temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) from other forms of TLE. In this study, we characterized the distribution of interictal epileptiform discharges in TLE due to HS as compared with those in patients with tumors restricted to the medial temporal lobe structures.

Methods: The study included 21 adult patients with unilateral HS who remained seizure free (>1 year) after anterior temporal lobectomy with amygdalohippocampectomy. Patients with “dual pathology” were excluded. The comparison group consisted of nine patients with tumors restricted to the amygdala and hippocampus. All patients underwent video‐EEG monitoring preoperatively by using 39 scalp electrodes (including the 10–10 system over both temporal regions) and bilateral sphenoidal electrodes.

Results: The HS patient group showed a significantly higher percentage of ipsilateral epileptiform discharges maximal at anterior temporal electrodes (median, 97.0%; sphenoidal electrode alone, 88.1%), as compared with the tumor group (median, 72.1%; p < 0.001; sphenoidal electrode alone, 24.8%; p < 0.001). The HS group had significantly fewer extratemporal spikes/sharp waves (median, 0.0), as compared with the tumor group (10.0%; p < 0.001). At least 90% of the interictal discharges were located in the anterior temporal region in 20 (95.2%) of 21 HS patients, but in none of the tumor patients (p < 0.001). Bilateral temporal discharges were found in nine (42.9%) of 21 patients with HS and in two (22.2%) of nine tumor patients (p = 0.42).

Conclusions: We conclude that ipsilateral interictal epileptiform discharges outside the anterior temporal region are rare (<10%) in adults with intractable TLE due to unilateral HS. Frequent posterior or extratemporal sharp waves may detract from the certainty of this diagnosis in complicated cases. These restricted epileptiform discharges suggest a smaller irritative zone in HS as compared with medial tumors, or a more organized activity associated with intrinsic hippocampal disease. Bilateral epileptiform discharges were not uncommon in both groups.
The Spanish Version of the Quality‐of‐Life in Epilepsy Inventory (QOLIE‐31): Translation, Validity, and Reliability
Authors: Torres Xavier , Arroyo Santiago , Araya Susana , de Pablo Joan
Published: August 2005

Summary: Purpose: Spanish adaptation of the Quality of Life in Epilepsy Inventory (QOLIE‐31).

Methods: Internal consistency and construct validity of the Spanish translation of the QOLIE‐31 were tested in 252 patients with epilepsy. Patients also were administered the General Health Questionnaire (GHQ‐28), and the Nottingham Health Profile (NHP). Two weeks after the first test, a subgroup of randomly selected patients were readministered the QOLIE‐31 along with a new five‐option question about change in health status. Patients reporting no change in health status were included in the study of temporal stability. Sensitivity to clinical change was assessed in 31 additional patients who had successfully undergone epilepsy surgery.

Results: The QOLIE‐31 was highly correlated with the GHQ‐28 (r=−0.63) and the NHP (r=−0.69), demonstrating construct validity. Cronbach's alpha coefficient was 0.92, showing the items of the QOLIE‐31 to be interdependent and homogeneous. For a 2‐week test retest, both Pearson product‐moment correlation and intraclass correlation coefficients were 0.90, indicating temporal stability. Sensitivity to clinical change was suggested by a significant mean difference between the global scores both before and after epilepsy surgery (‐21.87, p < 0.0001; 95% CI, −28.08 to −15.66). The standardized response mean of the global score was 1.67, and the effect size was 1.35, both indicating large clinical change as a result of seizure relief.

Conclusions: The similarity of psychometric properties between the English and the Spanish versions of the QOLIE‐31 supports their conceptual equivalence. The questionnaire's responsiveness to clinical change suggests its utility in outcome assessment of drug trials and epilepsy surgery.
Acute Cellular Alterations in the Hippocampus After Status Epilepticus
Authors: Macdonald Robert L. , Kapur Jaideep
Published: August 2005

The critical, fundamental mechanisms that determine the emergence of status epilepticus from a single seizure and the prolonged duration of status epilepticus are uncertain. However, several general concepts of the pathophysiology of status epilepticus have emerged: (a) the hippocampus is consistently activated during status epilepticus; (b) loss of GABA‐mediated inhibitory synaptic transmission in the hippocampus is critical for emergence of status epilepticus; and, finally (c) glutamatergic excitatory synaptic transmission is important in sustaining status epilepticus. This review focuses on the alteration of GABAergic inhibition in the hippocampus that occurs during the prolonged seizures of status epilepticus. If reduction in GABAergic inhibition leads to development of status epilepticus, enhancement of GABAergic inhibition would be expected to interrupt status epilepticus. Benzodiazepines and barbiturates are both used in the treatment of status epilepticus and both drugs enhance GABAA receptor‐mediated inhibition. However, patients often become refractory to benzodiazepines when seizures are prolonged, and barbiturates are often then used for these refractory cases of status epilepticus. Recent evidence suggests the presence of multiple GABAA receptor isoforms in the hippocampus with different sensitivity to benzodiazepines but similar sensitivity to barbiturates, thus explaining why the two drug classes might have different clinical effects. In addition, rapid functional plasticity of GABAA receptors has been demonstrated to occur during status epilepticus in rats. During status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. The loss of sensitivity of the animals to diazepam during status epilepticus was accompanied by an alteration in the functional properties of hippocampal dentate granule cell GABAA receptors. Dentate granule cell GABAA receptor currents from rats undergoing status epilepticus had reduced sensitivity to diazepam and zinc but normal sensitivity to GABA and pentobarbital. Therefore, the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABAA receptors, possibly explaining why benzodiazepines and barbiturates may not be equally effective during treatment of the prolonged seizures of status epilepticus. A comprehensive understanding of the cellular and molecular events leading to the development, maintenance, and cytotoxicity of status epilepticus should permit development of more effective treatment strategies and reduction in the mortality and morbidity of status epilepticus.
Management Approaches to Prolonged Seizures and Status Epilepticus
Authors: Bleck Thomas P.
Published: August 2005

Status epilepticus (SE) treatment should proceed on four fronts: termination of SE, prevention of recurrence, management of potential precipitating causes, and management of SE complications and underlying conditions. The intensity of the treatment should reflect the risk to the patient from SE, and drugs likely to depress respiration and blood pressure should initially be avoided. The Veterans Administration cooperative trial showed that when treating overt SE, first‐line treatment success rates were: lorazepam 64.9%; phenobarbital 58.2%; diazepam/phenytoin 55.8%; and phenytoin alone 43.6%. The aggregate response rate to second‐line agents for patients who did not respond to first‐line agents was 7.0%, and it was 2.3% for third‐line agents, raising the question of the efficacy of a second and third drug. The recommended treatment for generalized convulsive SE is to begin with lorazepam. As a second‐line agent, phenytoin or fosphenytoin, is still recommended if SE control is not achieved within 5 to 7 min. Fosphenytoin achieves a free phenytoin level of about 2 μ/mL in 15 min, as opposed to 25 min with phenytoin itself. Moreover, fosphenytoin is safer and, despite higher cost, it may be cost‐effective. High‐dose barbiturates, high‐dose benzodiaz‐epines, and propofol are employed for major treatment for refractory SE. Patients at this stage should undergo continuous electroencephalogram monitoring. Once SE is controlled, prevention of seizure recurrence should be individualized to each patient. The major complications of generalized convulsive SE (GCSE), rhabdomyolysis and hyperthermia, should be watched for and treated.
Psychiatric Syndromes Related to Antiepileptic Drugs
Authors: Schmitz Bettina
Published: August 2005

All antiepileptic drugs may provoke positive or negative psychiatric reactions in individual patients. These psy‐chotropic effects are not simply idiosyncratic but depend on the drug's anticonvulsive strength and the person's genetic and biographic psychiatric predisposition. Mechanisms related to psychiatric adverse events are polytherapy and folate deficiency, forced normalization, drug toxicity, and withdrawal. Our knowledge on dose independent, idiosyncratic psycho‐tropic side effects is still limited. With respect to the older antiepileptic drugs there are almost no systematic data, and knowledge is largely empirical and based on anecdotal reports. With respect to the new generation of anticonvulsants there are data on psychiatric side effects from drug trials. However, these data are not always entirely transparent to the interested epileptologist. Moreover, drug trials are designed to test anticonvulsive efficacy and psychiatric adverse events are not systematically reported, thus severity psychopathologic nature of behavioral problems remain obscure. Differences in patients included in trials do not allow comparisons of psychiatric risks of specific drugs, particularly since following the vigabatrin experience, patients with a psychiatric history were often excluded from trials. In this chapter, methodological issues related to data on psychiatric adverse events of AED are discussed followed by an overview on the current knowledge on psychiatric side effect profiles of old and new antiepileptic drugs.
Mental Effort‐Related EEG Modulation During Video‐Game Play: Comparison Between Juvenile Subjects with Epilepsy and Normal Control Subjects
Authors: Pellouchoud Emiliana , Smith Michael E. , McEvoy Linda , Gevins Alan
Published: August 2005

Purpose: This study investigated the effects of mental effort exerted during video‐game play on features of the EEG in juvenile subjects diagnosed with seizure disorders and in age‐matched clinically healthy subjects.

Methods: EEG was recorded from 14 children (9–15 years old) as they played a video game, watched another person playing a video‐game, and sat quietly with their eyes open. Seven of the subjects had been clinically diagnosed with seizure disorders, three of whom had also exhibited photosensitivity.

Results: Three spectral components of the EEG showed cognitive load‐related modulation. The amplitude of a frontal midline theta (6–7 Hz) signal increased with video‐game play relative to the watching and eyes open resting conditions. A posterior alpha band (9–12 Hz) signal was attenuated during the playing and the watching conditions relative to the resting condition. A central mu (10–13 Hz) rhythm was attenuated during the game‐playing condition. No significant differences were found between the patient and control groups for any of these features. Incidence of epileptiform events did not discriminate test conditions in the children with epilepsy.

Conclusions: The results from this small sample suggest that video‐game play tends to produce similar responses from children with epilepsy and in healthy control subjects. These responses in the juvenile population are similar to responses elicited by increased mental load in normal adult populations.
OXCARBAZEPINE
Authors: Tecoma Evelyn S.
Published: August 2005

The success of carbamazepine (CBZ) as a broad‐spectrum antiepileptic drug (AED) has led to its use as first‐line therapy in children and adults for partial and generalized tonic‐clonic seizures. The limitations of CBZ include toxicity in sensitive individuals, autoinduction, which requires dose adjustment when therapy is initiated, and chronic hepatic induction, producing drug interactions when CBZ is used with AEDs and other drugs that undergo hepatic metabolism. One of two main products of CBZ microsomal metabolism, CBZ‐10, 11‐epoxide (formed by oxidation of the double bond between C‐10 and C‐11), appears to provide antiepileptic efficacy but contributes significantly to clinical toxicity. The most common adverse effects of CBZ are central nervous system (CNS) symptoms, followed by gastrointestinal, hepatic, endocrine disturbances, and teratogenic effects. Oxcarbazepine (OXC) was developed to provide a compound chemically similar enough to CBZ to mimic its efficacy and overall safety while improving its side‐effect profile. Biotransformation of OXC does not involve formation of an epoxide metabolite. Compared with the parent compound, hepatic microsomal enzyme induction and auto‐induction are greatly reduced. The clinical efficacy of OXC compares favorably with CBZ in clinical trials. Clinical development of OXC began in Europe. Results of Phase I trials started to appear in the early 1980s. Controlled clinical trials, reported in the mid‐ to late 1980s, led to approval of OXC in many European countries, and now in over 50 nations around the world. United States multicenter clinical trials have recently been completed, and at this writing the drug is awaiting approval by the FDA. This article reviews the pharmacology, animal data, outcomes of published controlled clinical trials, postmarketing data, adverse experiences, and current recommendations for clinical use of OXC.
Felbamate
Authors: Pellock John M.
Published: August 2005

Felbamate (FBM) was the first of the new antiepileptic drugs (AEDs) approved in the United States in 1993 with broad‐spectrum efficacy against partial and generalized seizures of various types, and indicated for use as adjunctive and monotherapy. The identification of idiosyncratic aplastic anemia and hepatotoxicity, however, drastically curtailed its use. To update information concerning FBM and its idiosyncratic effects, case studies and literature reviews were undertaken. Thirty‐four FBM‐associated aplastic anemia patients have been reported, with 13 known fatalities. The overall FBM aplastic anemia risk is estimated at between 27 and 209 per million vs. 2 to 2.5 per million in the general population. Prior AED hypersensitivity, cytopenia, and immune disease significantly increase risk. FBM aplastic anemia has not been reported in children below the age of 13 years. Hepatic failure is much less common, occurring with an overall risk similar to that associated with valproate, but children below the age of 5 years have been affected. The recent identification of a reactive metabolite, atropaldehyde, and HLA studies suggest that high‐risk patients can be identified. The efficacy profile of FBM should encourage further investigations to allow its better use, but at present FBM is not a first‐line AED.
Options After the First Antiepileptic Drug Has Failed
Authors: Elger Christian E. , Fernández Guillén
Published: August 2005

Long‐term antiepileptic drug (AED) treatment is the standard therapy for epilepsies. In about 60% of patients, the first AED tried usually leads to seizure control. After failure of the first AED, it is important to achieve seizure control rapidly and without side effects. Combining the first drug with an add‐on drug appears to be more effective than a second monotherapy. However, no scientifically based data are available that favor any particular drug combination. Along with pharmacokinetic considerations, clinical experience is an important determinant in choosing a second AED for use as an add‐on. The time needed to introduce a particular AED is a further consideration. The simultaneous introduction of two add‐on drugs, one requiring slow titration and one permitting rapid introduction, may be a useful strategy. If the quickly introduced drug is effective as an add‐on, introduction of a slowly titrated second add‐on can be obviated. If the quickly introduced drug reduces seizure frequency, the patient's quality of life is improved during titration of the second add‐on. If the second, slowly titrated drug is more effective than the quickly introduced one, the less‐effective drug can be withdrawn. This strategy also allows a direct comparison between two add‐on drugs at the same time.
Risk Factors for Poor Health‐Related Quality of Life in Adolescents with Epilepsy
Authors: Devinsky Orrin , Westbrook Lauren , Cramer Joyce , Glassman Marc , Perrine Kenneth , Camfield Carol
Published: August 2005

Summary: Purpose: To examine potential risk factors for poor health‐related quality of life (HRQOL) among adolescents with epilepsy by using the newly developed QOLIE‐AD‐48. Risk factors were derived from sociodemographic, social, academic, and epilepsy‐ and health‐related domains.

Methods: The QOLIE‐AD‐48 was administered to 197 English‐speaking adolescents (age 11–17 years from >20 sites in the United States and in Canada). The self‐report instrument yields an overall HRQOL score and eight subscale scores. Other data were obtained from family interviews, physician reports, and health records. Multiple regression analyses were conducted to study risk factors for impairment of HRQOL.

Results: Older adolescents (age 14–17 years), those with more severe epilepsy and more symptoms of neurotoxicity, and those living in households with lower socioeconomic status were more likely to report poor overall HRQOL. Risk factors in the eight HRQOL domains were found as follows: (a) Epilepsy Impact: older age in adolescence, more severe epilepsy and neurotoxicity, more hospitalizations during the past year, and fewer hours of extracurricular activities; (b) Memory and Concentration: longer duration of epilepsy, special education classes, and history of repeating a grade in school; (c) Attitude Toward Illness: older age, female gender, and more severe epilepsy and neurotoxicity; (d) Social Support: younger age, male gender, and fewer hospitalizations in the last year; (e) Stigma: lower socioeconomic status and special‐education classes; and (f) Health Perceptions: older age, female gender, and lower socioeconomic status. None of the factors examined was significantly associated with HRQOL in (g) Physical Functioning or (h) School Behavior subscales.

Conclusions: We identified several risk factors for poor HRQOL outcomes in adolescents with epilepsy. Age, increased seizure severity, and neurotoxicity were most consistently associated with poor HRQOL across domains. Older adolescents, independent of epilepsy severity, reported worse overall HRQOL than did their younger counterparts. Older adolescents also were more likely to perceive a greater negative impact on life and general health, and had more negative attitudes toward epilepsy. Adolescent boys and girls may show different sensitivities to various quality‐of‐life domains.
The Ketogenic Diet for Intractable Epilepsy in Adults: Preliminary Results
Authors: Sirven Joseph , Whedon Barbara , Caplan Deborah , Liporace Joyce , Glosser David , O'Dwyer Joyce , Sperling Michael R.
Published: August 2005

Summary:Purpose:Little is known concerning the efficacy and adverse effects of the ketogenic diet in adults with refractory epilepsy. This review reports preliminary results in 11 adults prospectively treated with the diet who had previously failed to gain seizure control with two or more medications and/or surgery.

Methods:Eleven patients nine women, two men), median age, 32.2 years (range, 19–45 years) were treated with the ketogenic diet with a 4:1 ratio with fluid restriction. Six patients had symptomatic partial epilepsy, and five had symptomatic generalized epilepsy. The diet was administered in addition to antiepileptic medication by a multidisciplinary team geared exclusively to adult patients. Medications were not changed while on the diet. Seizure frequency at 8‐month follow‐up was compared with frequency during a baseline period.

Results:At 8 months of follow‐up, three patients had a 90% seizure decrease, three patients had a 50–89% decrease in seizure frequency, one patient had <50% seizure decrease, and four patients discontinued the diet. Of the four patients who discontinued the diet, two had no appreciable change in their seizures despite high ketone levels. Two patients were unable to maintain persistent ketosis at home, despite having done so in the hospital. All seizure types responded to the diet. Common adverse effects included constipation and menstrual irregularities in women. Most patients reported a subjective improvement in concentration. Serum cholesterol and triglycerides increased while on the diet as well as cholesterol high‐density lipoprotein (HDL) ratios.

Conclusions:The ketogenic diet shows promise in both adult generalized and partial epilepsy. Persistent ketosis was possible in adults, and the diet was tolerable for most patients. Further study assessing the efficacy of the ketogenic diet, and the cognitive and long‐term effects is ongoing.
Postoperative Seizure Control and Antiepileptic Drug Use in Pediatric Epilepsy Surgery Patients: The UCLA Experience, 1986–1997
Authors: Mathern Gary W. , Giza Christopher C. , Yudovin Sue , Vinters Harry V. , Peacock Warwick J. , Shewmon D. Alan , Shields W. Donald
Published: August 2005

Summary: Purpose: Young children with refractory symptomatic epilepsy are at risk for developing neurologic and cognitive disabilities. Stopping the seizures may prevent these disabilities, but it is unclear whether resective surgery is associated with adequate long‐term seizure control.

Methods: This study determined pre‐ and postsurgery seizure frequency and antiepileptic drug (AED) use (6 months to 10 years) in children with symptomatic seizures from unilateral cortical dysplasia (CD; n = 64) and non‐CD etiologies (i.e., ischemia, infection; n = 71), and compared them with older temporal lobe epilepsy (TLE; n = 31) patients with complex partial seizures.

Results: Compared with presurgery, postsurgery seizure frequencies were decreased for CD, non‐CD, and TLE patients (p < 0.002), and there were no differences between the three groups from 6 to 24 months after surgery (p > 0.12). At 5 years after surgery, seizure frequencies were greater in CD compared with TLE cases (p = 0.009). Compared with presurgery, the number of AEDs declined after surgery in all three groups (p < 0.002), and positively correlated with seizure frequencies (p = 0.0001).

Conclusions: This study indicates that seizure relief and AED use after resective surgery for symptomatic CD and non‐CD etiologies was comparable with complex partial TLE cases up to 2 years after surgery. Furthermore, at 5 years after surgery, CD patients had outcomes better than those before surgery, but worse than TLE cases. In young children, these findings support the concept that early removal of symptomatic pathologic substrates is associated with seizure control and reduced AED use, similar to that noted in older TLE cases up to 2 years after surgery. Seizure control may reduce the risk of developing the seizure‐related encephalopathy associated with severe symptomatic early‐onset childhood epilepsy.
Comparison of Antiepileptic Drug Levels in Sudden Unexpected Deaths in Epilepsy with Deaths from Other Causes
Authors: Opeskin Ken , Burke M. P. , Cordner S. M. , Berkovic Samuel F.
Published: August 2005

Summary: Purpose: (a) To compare postmortem antiepileptic drug (AED) levels in patients with sudden unexpected death in epilepsy (SUDEP) with those in a control group of subjects with epilepsy. If SUDEP patients more frequently had undetectable or subtherapeutic AED levels, this would suggest that compliance with AED treatment is poorer in this group and that poor compliance is a risk factor for SUDEP. (b) To determine whether a particular AED was detected more commonly in the SUDEP group, suggesting that this AED is associated with a higher risk of SUDEP.

Methods: A retrospective study of coronial cases was performed. Postmortem AED levels in 44 SUDEP cases and 44 control cases were compared. The control group consisted of epileptics who died of causes other than epilepsy, including natural disease (e.g., ischemic heart disease, accidents, and suicide). The AEDs measured included carbamazepine (CBZ), phenytoin, (PHT), valproate (VPA), phenobarbitone (PB), lamotrigine (LTG), clonazepam (CZP), and clobazam (CLB). The number of SUDEP and control cases in which CBZ only was detected were compared, as were the number in which PHT only was detected.

Results: Compared with the controls, the SUDEP group showed no difference in the number with no detectable AEDs (13 vs. 11), the number with subtherapeutic AEDs (10 vs. 13), and the number with therapeutic levels (21 in both groups). CBZ only was detected in 11 SUDEPs and 11 controls, and PHT only in five SUDEPs and 10 controls.

Conclusions: Our study suggests the SUDEP group were no less compliant with AED treatment than the control group. This study does not support the hypothesis that poor compliance with AED treatment is a risk factor for SUDEP. There was no evidence that PHT or CBZ is associated with a higher risk of SUDEP.
Partial Seizures Manifesting As Apnea Only in an Adult
Authors: Lee Hyang Woon , Hong Seung Bong , Tae Woo Suk , Seo Dae Won , Kim Sang Eun
Published: August 2005

Summary: Purpose: Although several cases of apneic seizures have been reported in neonates, epileptic seizures presenting as apnea only in adults are very rare. We present a case report of a 19‐year‐old man with viral encephalitis and frequent episodes of apneic seizures.

Methods: Prolonged electroencephalograms (EEGs), repiratory monitorings, and imaging including ictal‐interictal subtraction single photon emission computed tomography (SPECT) coregistered with magnetic resonance imaging (MRI) were performed.

Results: Ictal EEGs recorded during apneic episodes showed repetitive sharp waves or rhythmic theta activity arising from the left or right independent bitemporal region. Ictal SPECT was performed during one episode of apnea that showed ictal EEG discharges arising from the left posterior temporal area. Ictal‐interictal subtraction SPECT coregistered with MRI revealed that the seizures originated from the left, posterior, midlateral temporal cortex.

Conclusions: Previous studies with ictal EEG or brain stimulation suggest that apneic seizures might be mediated through the limbic and associated cortical systems. Our study reports on a very rare case of partial seizures with apnea only in an adult patient and is supported by ictal EEG and ictal‐interictal subtraction SPECT coregistered with MRI.