bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinetics of Serum Neuron‐Specific Enolase and Prolactin in Patients After Single Epileptic Seizures
Authors: Tumani Hayrettin , Otto Markus , Gefeller Olaf , Wiltfang Jens , Herrendorf Gregor , Mogge Sebastian , Steinhoff Bernhard J.
Published: August 2005

Summary: Purpose: To investigate and compare the temporal profile of serial levels of neuron‐specific enolase (NSE) and prolactin in serum from patients after single epileptic seizures.

Methods: Measurement of NSE and prolactin by sensitive immunoassays in 21 patients with complex partial seizure (CPSs; n = 11) and secondarily generalized tonic‐clonic seizures (SGTCSs; n = 10) during continuous video‐EEG monitoring at four different time points (1, 3, 6, and 24 h after ictal event). Statistical analysis was performed by using a repeated‐measures analysis of variance (ANOVA) model.

Results: Mean ± SD values for NSE levels (ng/ml) were 12.5 ± 4.4 (1 h), 10.8 ± 3.8 (3 h), 11.1 ± 4.9 (6 h), and 8.2 ± 1.9 (24 h). The corresponding prolactin levels (mU/L) were 1,311 ± 1,034, 232 ± 158, 237 ± 175, and 251 ± 98. There was a significant decrease of NSE and prolactin levels over time (p < 0.001). The pair‐wise comparison of NSE levels showed significant differences between the time points 1 vs. 24 h (p < 0.001), 3 vs. 24 h (p = 0.007), and 6 vs. 24 h (p = 0.009). In contrast, serum prolactin levels showed a significant difference between 1 vs. 3 h (p < 0.001) only. Most of the NSE levels remained normal after CPSs and SGTCSs. At 1 h after the seizure, only 33% of the subjects had increased NSE, whereas abnormal prolactin levels occurred with a sensitivity of 80%.

Conclusions: In contrast to prolactin, serum NSE is not a sensitive marker of individual seizures. Only some individuals showed an increase of NSE beyond the prolactin‐sensitive time frame after a single seizure, and mean NSE levels were not significantly increased compared with those of normal controls.
Depth of EEG Suppression and Outcome in Barbiturate Anesthetic Treatment for Refractory Status Epilepticus
Authors: Krishnamurthy Kaarkuzhali B. , Drislane Frank W.
Published: August 2005

Summary: Purpose: Barbiturate anesthetic treatment of patients with refractory status epilepticus (RSE) is often titrated to a burst‐suppression record on the EEG. We sought to determine whether the depth of EEG suppression correlated with persistent seizure control in such patients.

Methods: We reviewed the EEGs and clinical course of patients treated with pentobarbital (PTB) for RSE. Persistent seizure control or relapse to status epilepticus after the taper of PTB was determined with reference to the depth of EEG suppression during treatment.

Results: Of 35 patients tapering PTB, persistent seizure control was achieved in six of 12 patients reaching a burst‐suppression record at greatest depth of EEG suppression and in 17 of 20 patients reaching a “flat” record; three patients with neither pattern had persistent control. Survival also was somewhat better in the more suppressed group. Isolated epileptiform discharges during the barbiturate infusion did not correlate with outcome. Recurrence of electrographic status after PTB taper predicted clinical relapse.

Conclusions: The EEG is important in managing PTB treatment for patients with RSE. Some period of intense seizure and EEG suppression may help in preventing relapse of status after the PTB taper. It is not necessary to suppress all epileptiform discharges, but persistent clinical and EEG monitoring is necessary to avoid relapses.
Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids
Authors: Thompson Charles D. , Barthen Mary T. , Hopper Darrin W. , Miller Thomas A. , Quigg Mark , Hudspeth Candice , Montouris Georgia , Marsh LaDonna , Perhach James L. , Sofia R. Duane , Macdonald Timothy L.
Published: August 2005

Summary: Purpose: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3‐carbamoyl‐2‐phenylpropionaldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2‐phenyl‐1,3‐propanediol monocarbamate to the major human metabolite 3‐carbamoyl‐2‐phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2‐phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N‐acetyl‐cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde‐derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine.

Methods: We summarize the results of an LC/MS method used to quantify FBM, 3‐carbamoyl‐2‐phenylpropionic acid and two atropaldehyde‐derived mercapturic acids in the patient population.

Results: Analysis was performed on 31 patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured.

Conclusions: This method demonstrated sufficient precision for the identification of patients exhibiting “abnormal” levels of atropaldehyde conjugates and may hold potential for patient monitoring.
Topiramate Pharmacokinetics in Infants
Authors: Glauser Tracy A. , Miles Michael V. , Tang Peter , Clark Peggy , McGee Kathy , Doose Dennis R.
Published: August 2005

Summary: Purpose: This study's goal was to provide preliminary data on the pharmacokinetics of topiramate (TPM) in a cohort of infants (younger than 4 years) participating in an open‐label trial of TPM in refractory infantile spasms.

Methods: The pharmacokinetics of TPM were assessed in infants receiving a stable TPM dose for >7 days during the extension phase of this trial. Blood samples were drawn just before and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after the morning TPM dose. TPM plasma concentrations were determined by fluorescence polarization immunoassay. The noncompartmental analysis module of WinNonlin was used to calculate individual patient pharmacokinetics profiles.

Results: Five infants (ages, 23.5–29.5 months) formed the study cohort. These infants had been given TPM for a median of 9 months (range, 6–11 months) and were currently receiving between 11 and 38.5 mg/kg/day TPM. One was receiving TPM monotherapy, whereas four were taking concomitant antiepileptic medications (AEDs; n = 2, enzyme‐inducing agents; n = 2, non‐enzyme‐inducing drugs). TPM pharmacokinetics in infants appears to be linear. In this cohort, mean TPM plasma clearance (CL/F, 66.6 ± 27.4 ml/h/kg) was slightly higher than that reported for children and adolescents and therefore substantially higher than that reported for adults. TPM CL/F was higher and the calculated half‐life shorter in the infants receiving concomitant enzyme‐inducing AEDs.

Conclusions: Based on this small cohort of patients, it appears that infants may require significantly larger TPM doses, based on weight, than children, adolescents, or adults. Titration to effect and not absolute TPM dose should guide therapy in this age group.
Regional Cerebral Blood Flow During Temporal Lobe Seizures Associated with Ictal Vomiting: An Ictal SPECT Study in Two Patients
Authors: Baumgartner Christoph , Olbrich Achim , Lindinger Gerald , Pataraia Ekaterina , Gröppel Gudrun , Bacher Johanna , Aull Susanne , Serles Wolfgang , Hoffmann Martha , Leutmezer Fritz , Czech Thomas , Prayer Daniela , Pietrzyk Uwe , Asenbaum Susanne , Podreka Ivo
Published: August 2005

Summary: Purpose: Ictal vomiting represents a rare clinical manifestation during seizures originating from the temporal lobes of the nondominant hemisphere. The precise anatomic structures responsible for generation of ictal vomiting remain to be clarified. Ictal single photon emission computed tomography (SPECT), which allows one to visualize the three‐dimensional dynamic changes of regional cerebral blood flow (rCBF) associated with the ongoing epileptic activity, should be useful to study the brain areas activated during ictal vomiting.

Methods: We performed ictal Tc‐HMPAO SPECT scans in two patients with mesial temporal lobe epilepsy (MTLE) whose seizures were characterized by ictal retching and vomiting. MTLE was documented by typical clinical seizure semiology, interictal and ictal EEG findings, hippocampal atrophy on magnetic resonance imaging (MRI) scan, and a seizure‐free outcome after selective amydalohippocampectomy. In both patients, seizures originated in the nondominant temporal lobe. We obtained accurate anatomic reference of rCBF changes visible on SPECT by a special coregistration technique of MRI and SPECT. We used ictal SPECT studies in 10 patients with MTLE who had seizures without ictal vomiting as controls.

Results: In the two patients with ictal vomiting, we found a significant hyperperfusion of the nondominant temporal lobe (inferior, medial, and lateral superior) and of the occipital region on ictal SPECT. In patients without ictal vomiting, on the contrary, these brain regions never were hyperperfused simultaneously.

Conclusions: Ictal SPECT provides further evidence that activation of a complex cortical network, including the medial and lateral superior aspects of the temporal lobe, and maybe the occipital lobes, is responsible for the generation of ictal vomiting.
A Beneficial Effect on Mood in Partial Epilepsy Patients Treated with Gabapentin
Authors: Harden Cynthia L. , Lazar Lorraine M. , Pick Lawrence H. , Nikolov Blagovest , Goldstein Martin A. , Carson Deborah , Ravdin Lisa D. , Kocsis James H. , Labar Douglas R.
Published: August 2005

Summary: Purpose: Antiepileptic drugs (AEDs) are frequently used for their beneficial psychoactive effects on affective disorders. We sought to demonstrate a psychoactive effect of gabapentin (GBP) when used as add‐on AED therapy.

Methods: Forty adult patients with partial epilepsy were studied in a prospective, non‐randomized fashion with interviewer‐rated and self‐rated scales of mood and anxiety: the Cornell Dysthymia Rating Scale (CDRS), Beck Depression Inventory (BDI), and Hamilton Depression (Ham‐D) and Anxiety (Ham‐A) Scales. After completion of baseline mood and anxiety scales (time 1), 20 of the 40 patients were prescribed add‐on GBP (treated group). The remaining 20 patients served as a control group. Both groups were similar in age and sex distribution. Follow‐up mood and anxiety scales were performed in all patients ∼3 months later (time 2). The average GBP dose at time 2 was 1,615 mg/day. All patients were taking stable doses of one to four AEDs at baseline and throughout the study. Seizure frequency was monitored throughout. Statistical significance was assessed by analysis of variance (ANOVA) by using a two‐factor repeated‐measures model.

Results: The GBP‐treated group had a significant decrease in CDRS score over time compared with the control group (p = 0.04). No significant differences between the control and the treated groups were found for any of the remaining mood scales (BDI, p = 0.58; Ham‐D, p = 0.59; Ham‐A, p = 0.93). There was no significant difference or change in seizure frequency between groups.

Conclusions: GBP treatment is associated with mood improvement as measured by the CDRS. This improvement was not accounted for by seizure improvement.
Gabapentin as Add‐On Therapy in Children with Refractory Partial Seizures: A 12‐Week, Multicentre, Double‐Blind, Placebo‐Controlled Study
Authors: Appleton Richard , Fichtner Klaus , LaMoreaux Linda , Alexander Jeannine , Halsall Gwyneth , Murray Guta , Garofalo Elizabeth ,   Gabapentin Paediatric Study Group
Published: August 2005

Summary: Purpose: To evaluate the efficacy and safety of gabapentin (Neurontin; GBP) as add‐on therapy for refractory partial seizures in paediatric patients aged 3–12 years.

Methods: After a 6‐week baseline period, 247 patients (54 centres) entered a 12‐week double‐blind phase and were randomized to receive either GBP (t.i.d., titrated to 23‐35 mg/kg/day) or placebo. Seizure activity and type were recorded daily. Efficacy variables included Response Ratio (RRatio), responder rate, and percentage change in frequency (PCH) for all partial seizures; PCH and RRatio for individual types of partial seizures; and investigator and parent/guardian global assessments of seizure frequency and patient well‐being.

Results: RRatio for all partial seizures was significantly lower (better) for GBP‐treated patients (p = 0.0407). Responder rate favored GBP, but the difference between treatment groups was not statistically significant. Median PCH for all partial seizures for the GBP treatment group (‐17.0%) was better than that for the placebo group (‐6.5%). Median PCH for specific seizure types showed GBP to be most effective in controlling complex partial seizures (‐35%) and secondarily generalized seizures (‐28%) when compared with placebo (‐12%, +13%, respectively). A greater percentage of GBP‐treated patients exhibited improvement according to investigator and parent/guardian global assessments, with a statistically significant difference observed in the parent/guardian global assessment of seizure‐frequency reduction (p = 0.046). Three GBP patients and one placebo patient were seizure free during the double‐blind treatment period. GBP was well tolerated.

Conclusions: GBP was effective and well tolerated as an add‐on therapy for partial seizures in paediatric patients with previously drug‐resistant seizures.
Wallerian Degeneration in the Optic Radiation After Temporal Lobectomy Demonstrated In Vivo with Diffusion Tensor Imaging
Authors: Wieshmann U. C. , Symms M. R. , Clark C. A. , Lemieux L. , Franconi F. , Parker G. J. M. , Barker G. J. , Shorvon S. D.
Published: August 2005

Summary: Purpose: Diffusion tensor imaging allows the quantitative assessment of the microstructural organization of tracts in vivo (MR tractography). We used the new technique of MR tractography to demonstrate the effects of temporal lobectomy on the optic radiation.

Methods: Spatially normalised maps encoding magnitude of the bias (anisotropy) of diffusion of three patients with temporal lobe resections were compared with spatially normalised diffusion maps of 22 control subjects. All three patients were operated on for the treatment of medically intractable temporal lobe epilepsy and had a normal neurologic examination before surgery. One patient had an amygdalocorticectomy. Two patients had standard en bloc resections, one of whom developed a homonymous hemianopia after surgery.

Results: In the patient with hemianopia, a significant reduction of diffusion anisotropy (greater than mean ± 2 SD) consistent with wallerian degeneration was demonstrated in the optic radiation on the side of the temporal lobectomy, extending from the temporal to the occipital lobe. In the other patient with standard en bloc resection but clinically no hemianopia, the optic radiation was only marginally affected. In the third patient (amygdalocorticectomy), the diffusion anisotropy was within the normal range in the expected position of the optic radiation.

Conclusions: Our findings show that MR tractography may be a useful tool to demonstrate wallerian degeneration in the optic radiation after temporal lobectomy in patients with hemianopia. This is the first time that this new method has been applied in postoperative imaging; it enables us to visualise the morphologic correlate of dysfunctional pathways after epilepsy surgery in vivo. The potential for using MR tractography to study other aspects of epilepsy is discussed.
The Depiction of Seizures in Film
Authors: Kerson Jennie F. , Kerson Toba Schwaber , Kerson Lawrence A.
Published: August 2005

Summary: Purpose: The purpose was to describe the depiction of epilepsy in English language film.

Methods: The list of films, developed by consulting several databases, film scholars, and neurologists, includes every film suggested by any source. By using the saturation techniques of grounded theory, names of films were sought until no new names were received. All films were reviewed by an experienced board‐certified neurologist.

Results: Seizures were depicted in 20 films. Generally, seizures are used in film to develop narrative or enrich character. They serve four functions: (a) a principal character has epilepsy; thus the condition is critical to character and narrative; (b) a seizure is used to drive the narrative; (c) a seizure is used to enrich a minor role; and (d) a seizure is feigned to distract attention from another activity.

Conclusions: Conclusions can be drawn in four areas: character, accuracy of depiction, roles and responses of onlookers, and the place of epilepsy in the films: (a) Epilepsy is one dimension linked with other aspects of an individual to enrich character; (b) Seizures are depicted fairly accurately, but their frequent representation as uncontrollable and violent is exaggerated and out of date; (c) In the films, the onlookers' responses range from fear to taking correct measures; and (d) The presence of epilepsy is never arbitrary, but the function varies. Overall, the view of epilepsy conveyed in film continues to be distorted, sensationalized, and presented in the most frightening ways.
Chronic Epileptogenic Cellular Alterations in the Limbic System After Status Epilepticus
Authors: Coulter Douglas A.
Published: August 2005

Status epilepticus (SE) is associated with both acute and permanent pathological sequellae. One common long term consequence of SE is the subsequent development of a chronic epileptic condition, with seizures frequently originating from and involving the limbic system. Following SE, many studies have demonstrated selective loss of neurons within the hilar region of the dentate gyrus, CA1 and CA3 pyramidal neurons. Selective loss of distinct subpopulations of interneurons throughout the hippocampus is also frequently evident, although interneurons as a whole are selectively spared relative to principal cells. Accompanying this loss of neurons are circuit rearrangements, the most widely studied being the sprouting of dentate granule cell (DGC) axons back onto the inner molecular layer of the dentate gyrus, termed mossy fiber sprouting. Less studied are the receptor properties of the surviving neurons within the epileptic hippocampus following SE. DGCs in epileptic animals exhibit marked alterations in the functional and pharmacological properties of γ‐aminobutyric acid (GABA) receptors. DGCs have a significantly elevated density of GABAA receptors in chronically epileptic animals. In addition, the pharmacological properties of GABAA receptors in post‐SE epileptic animals are quite different compared to controls. In particular, GABAA receptors in DGCs from epileptic animals show an enhanced sensitivity to blockade by zinc, and a markedly altered sensitivity to modulation by benzodiazepines. These pharmacological differences may be due to a decreased expression of α1 subunits of the GABAA receptor relative to other α subunits in DGCs of post‐SE epileptic animals. These GABAA receptor alterations precede the onset of spontaneous seizures in post‐SE DGCs, and so are temporally positioned to contribute to the process of epileptogenesis in the limbic system. The presence of zinc sensitive GABA receptors combined with the presence of zinc‐containing “sprouted” mossy fiber terminals innervating the proximal dendrites of DGCs in the post‐SE epileptic hippocampus prompted the development of the hypothesis that repetitive activation of the DG in the epileptic brain could result in the release of zine. This zinc in turn may diffuse to and block “epileptic” zinc‐sensitive GABAA receptors in DGCs, leading to a catastrophic failure of inhibition and concomitant enhanced seizure propensity in the post‐SE epileptic limbic system.
Depression in Epilepsy: Etiology, Phenomenology, and Treatment
Authors: Lambert Michelle V. , Robertson Mary M.
Published: August 2005

A history of depression or depressive symptomatology has been reported in up to two‐thirds of patients with medically intractable epilepsy, whereas community studies have demonstrated affective disorder only in a quarter of these patients. Depression has been reported peri‐ and interictally. However, differentiation may be difficult in patients with frequent seizures. Most authors have found no correlation between depression and epilepsy variables. However, complex partial seizures, especially of temporal lobe origin, appear to be etio‐logic factors, particularly in men with left‐sided foci. Depression is also more common in patients treated with polytherapy especially with barbiturates, phenytoin, and vigabatrin. Depression has also been described de novo after temporal lobectomy. Psychosocial factors also play a part, but underlying risk factors (e.g., genetic, endocrine and metabolic) may explain the increased rates of depression in people with epilepsy compared to those with other neurologic and chronic medical conditions. The depression appears to be endogenous. Patients tend to exhibit fewer neurotic traits and more psychotic symptoms such as paranoia, delusions, and persecutory auditory hallucinations. Treatment approaches include psychotherapy, rationalization of antiepileptic drug medication, antidepressant treatment, and ECT. The tricyclic and related antidepressants appear to be epileptogenic, especially in people at high risk (personal or family history of seizures, abnormal pretreatment EEG, brain damage, alcohol or substance abuse/withdrawal and concurrent use of CNS‐active medication). Seizures tend to occur early in treatment or after dose increments, especially if rapidly titrated. There is little evidence that the newer antidepressants, e.g., selective serotonin reuptake inhibitors, moclobemide, venlafaxine, or nefazodone are more epileptogenic than placebo.
Interactions Between Anticonvulsant and Psychoactive Drugs
Authors: Monaco Francesco , Cicolin Alessandro
Published: August 2005

This review considers the relevance of pharmaco‐kinetic interactions between antiepileptic drugs (AEDs) and psychoactive drugs in the treatment of mood disorders in patients with epilepsy. The determination of plasma levels of some of these drugs (mainly the AEDs) has enabled clinicians to evaluate the kinetic modifications during the course of such combined therapies and to adjusting the dosages in cases of subtherapeutic or toxic levels. In general, phenobarbital, phenytoin, and carbamazepine stimulate the catabolic degradation of tricyclic antidepressants (TCAs), and TCAs have an inhibitory effect on the elimination of AEDs. The newer antidepressants that selectively inhibit the reuptake of serotonin (SSRIs), although in different fashions for the different substances (fluoxetine, fluvoxamine, paroxetine) may cause an increase of plasma AED levels through inhibition of the isoenzyme P450 2D6. Similarly, antipsychotics (APs) are more rapidly metabolized when AEDs are co‐administered, whereas AED metabolism is scarcely influenced by AP. Finally, plasma levels of tranquilizers are lowered by AED co‐therapy. As the concomitant administration of AED and psychoactive drugs becomes increasingly used for treatment of mood disorders in patients with or without epilepsy, therapeutic drug monitoring may be useful in designing correct and rational therapy.
Photosensitive Epilepsy Studied by Functional Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy
Authors: Chiappa Keith H. , Hill Rosamund A. , Huang‐Hellinger Frank , Jenkins Bruce G.
Published: August 2005

Purpose: To study metabolic and hemodynamic correlates of photic stimulation‐triggered discharges.

Methods: Simultaneous EEG, functional MRI (fMRI) and magnetic resonance spectroscopy (MRS) were performed in nine patients with photosensitive epilepsy and in 12 normal subjects.

Results: Prominent visual cortex activation was seen in all normal subjects and patients, and no fMRI‐registered hemodynamic abnormalities were correlated with the brief photoparoxysmal spike‐wave activity evoked in the photosensitive patients. However, irrespective of the presence of a spike‐wave response to the photic stimulation, the photosensitive patients showed four findings not seen in the normal subjects: (a) slightly, but significantly, elevated lactate levels in the occipital cortex in the resting state; (b) an increased area of visual cortical activation with photic stimulation; (c) simultaneous with the occipital cortex stimulus‐induced increased fMRI signal, there were noncontiguous areas of signal attenuation most prominent in perirolandic regions; and (d) a marked decrement (undershoot) of fMRI signal intensity immediately after the photic stimulation in the occipital cortex and in the region of the posterior cingulate gyrus.

Conclusions: These findings suggest abnormal interictal metabolism and increased vascular reactivity in the photosensitive patients.
Mechanisms of Video‐Game Epilepsy
Authors: Fylan F. , Harding G. F. A. , Edson A. S. , Webb R. M.
Published: August 2005

Purpose: We aimed to elucidate the mechanisms underlying video‐game epilepsy by comparing the flicker‐ and spatial‐frequency ranges over which photic and pattern stimulation elicited photoparoxysmal responses in two different populations: (a) 25 patients with a history of seizures experienced while playing video games; and (b) 25 age‐ and medication‐matched controls with a history of photosensitive epilepsy, but no history of video‐game seizures.

Methods: Abnormality ranges were determined by measuring photoparoxysmal EEG abnormalities as a function of the flicker frequency of patterned and diffuse intermittent photic stimulation (IPS) and the spatial frequency of patterns on a raster display.

Results: There was no significant difference between the groups in respect of the abnormality ranges elicited by patterned or diffuse IPS or by spatial patterns. When the groups were compared at one specific IPS frequency (‐50 Hz), however, the flicker frequency of European television displays, the video‐game patients were significantly more likely to be sensitive.

Conclusions: The results suggest that video‐game seizures are a manifestation of photosensitive epilepsy. The increased sensitivity of video‐game patients to IPS at 50 Hz indicates that display flicker may underlie video‐game seizures. The similarity in photic‐ and pattern‐stimulation ranges over which abnormalities are elicited in video‐game patients and controls suggests that all patients with photosensitive epilepsy may be predisposed toward video‐game‐induced seizures. Photosensitivity screening should therefore include assessment by using both IPS at 50 Hz and patterns displayed on a television or monitor with a 50‐Hz frame rate.
Lamotrigine
Authors: Matsuo Fumisuke
Published: August 2005

Clinical use of the antiepileptic drug (AED) lamotrigine (LTG) has dramatically increased since its introduction in Europe in 1991 and in the United States in 1994. This article surveys the English‐language literature of LTG published before 1998. This literature is concerned with the molecular mechanisms of LTG's antiepileptic action, evaluation of its clinical antiepileptic efficacy, adverse experiences associated with its clinical use, and current guidelines for its initiation. LTG's efficacy has been extensively confirmed in multiple postmarketing studies, and its applications are broad. The most serious adverse experiences have involved skin rash. Valproic acid affects LTG metabolism, and a specific set of guidelines for the concurrent use of valproic acid and LTG has been developed. Unique issues are also associated with its pediatric use. LTG has a significant place in clinical management of a wide range of epilepsy syndromes, and the scope of its use is expanding. Accumulating clinical data enable the clinician to maximize its efficacy and minimize adverse experiences. Guidelines for its pediatric use must be followed diligently.
Monotherapy Trials with Gabapentin for Partial Epilepsy
Authors: Beydoun Ahmad
Published: August 2005

The efficacy and safety of gabapentin as monotherapy for treatment of partial onset seizures were evaluated in three large multicenter, double‐blind, parallel‐group, dose‐controlled trials. In the first trial, 275 outpatients with refractory partial epilepsy maintained on stable doses of one or two antiepileptic drugs (AEDs) were switched to gabapentin (GBP) monotherapy at 600 mg, 1200 mg, or 2400 mg daily. Patients were required to exit the 26‐week double‐blind phase of the study if they experienced worsening of seizure frequency. With respect to time to exit, there was no statistically significant difference among the three groups; only 3% of patients withdrew from the trial because of adverse events. In the second study, 82 hospitalized patients with medically refractory epilepsy were tapered off baseline AEDs and randomly assigned to GBP monotherapy at 300 mg/day or 3600 mg/day. Patients remained in the trial for a maximum of 8 days but had to exit the trial if they experienced one or more exit events. Time to exit was significantly longer in patients in the 3600‐mg group (151 h) compared with those in the 300‐mg group (85 h) (p= 0.0001). None of the patients withdrew from the trial because of side effects. In the third study, 292 patients with newly diagnosed partial seizures were randomized to GBP 300, 900, or 1800 mg/day or to carbamazepine (CBZ) 600 mg/day. Patients remained in the trial for up to 6 months or until they experienced an exit event. Mean time to exit was significantly longer for patients who received GBP 900 mg/day (p= 0.02) or 1800 mg/day (p= 0.04) compared with those who received 300 mg/day. The completion rate for the CBZ group (37%) was similar to that of the GBP 900‐mg (39%) and 1800‐mg (38%) groups. Patients receiving CBZ had a higher withdrawal rate because of adverse events compared with the GBP 900‐mg and 1800‐mg groups. The results of these trials provide good evidence of the efficacy and safety of GBP as monotherapy for the treatment of partial‐onset seizures.
Dosing to Efficacy with Neurontin: The STEPS Trial
Authors: Morrell Martha J.
Published: August 2005

The STEPS (Study of Titration to Effect Profile of Safety) trial, a 16‐week, open‐label, postmarketing multicenter study, assessed the efficacy of gabapentin as adjunctive therapy in patients with inadequately controlled partial seizures. Inclusion criteria were less restrictive than for Phase III studies, to include a population more representative of the patient population treated in clinical practice. Gabapentin was titrated up to a maximal dosage of 3600 mg/day to achieve seizure control or to tolerability. The efficacy analysis included compliant patients who had completed ∼16 weeks of therapy (n= 1055); 573 received ≤1800 mg/day and 482 received ≥1800 mg/day. The average decrease in seizure frequency was 61%, the percentage of seizure‐free patients was 46.35%, and the percentage of patients with a ≥50% decrease in seizure frequency was 76.05%. The cumulative percentage of responders and of patients who were seizure free increased with each dosage increase. The results confirm that titration to efficacy is appropriate for adjunctive therapy with gabapentin in patients with partial epilepsy treated in clinical practice.
Use of New Antiepileptic Drugs in the Treatment of Childhood Epilepsy
Authors: Pellock John M. , Appleton Richard
Published: August 2005

The management of epilepsy in children requires careful evaluation, classification, and pharmacologic treatment. With classic antiepileptic drugs (AEDs), at least 25% of children remain refractory to appropriate therapy. The past decade has allowed the introduction of a number of newer AEDs for treatment of both adults and children with epilepsy. These include felbamate, gabapentin, lamotrigine, topiramate, tiagabine, and vigabatrin. Emerging information regarding the efficacy of these AEDs in treating childhood epilepsy syndromes suggests advantages for many patients. Limited data are available that define the optimal use of new AEDs in pediatric patients. Further research must be completed to validate the positive effects described in existing clinical trials of the new AEDs in the treatment of childhood epilepsy.
Gabapentin in the Management of Convulsive Disorders
Authors: McLean Michael J.
Published: August 2005

Gabapentin, in clinical use since 1993, is indicated as an adjunctive antiepileptic drug (AED) for treatment of complex partial seizures, with or without secondary generalization, in patients over 12 years of age. Although several cellular actions have been described in the literature, the molecular mechanism(s) of action responsible for the anticonvulsant effect of gabapentin has not been conclusively determined. It is likely that gabapentin has multiple concentration‐dependent actions that combine in a unique manner to produce antiepileptic efficacy. The pharmacokinetic properties of this water‐soluble, amino‐acid AED are generally favorable. Absorption appears to be dependent on transport by the L‐system amino acid transporter. Elimination of unmetabolized drug occurs by the renal route. Although its therapeutic range is not well characterized, gabapentin has a broad therapeutic index. This implies that a wide range of doses can be used, based on individual patient needs, without significant limitation due to dose‐dependent side effects. Gabapentin has few drug‐drug interactions, none of which is clinically limiting. Several studies have demonstrated the long‐term efficacy of gabapentin with no systematic evidence of tachyphylaxis. In addition, there is increasing evidence to support the use of gabapentin as monotherapy. Gabapentin is safe and is generally well tolerated. To date, nearly 3 million patients have been treated in studies and in open use without causal relationship to a specific life‐threatening organ toxicity. Seizure control superior to that observed in well‐controlled trials has been reported at higher doses used in clinical practice and in studies. Therefore, gabapentin dosing must be optimized on an individual basis to achieve an adequate trial of the drug and obtain the best seizure control.
Postherpetic Neuralgia: Role of Gabapentin and Other Treatment Modalities
Authors: Beydoun Ahmad
Published: August 2005

Postherpetic neuralgia (PHN) is a chronic and painful condition that may occur after a herpes zoster infection. The frequency of PHN after untreated zoster varies widely. Age is the most important risk factor for development of PHN. The condition occurs in an estimated 50% of patients older than 50 years. The pain of PHN can be severe and debilitating and is frequently associated with allodynia. Although in most patients pain remits within the first year, it may persist for a lifetime. Tricyclic antidepressants (TCAs), topical agents, opioids, and gabapentin, a structural γ‐amino butyric acid (GABA) analogue, are the only agents that have demonstrated efficacy in randomized clinical trials for treatment of both the shooting and the burning form of pain associated with PHN. TCAs are among the most commonly used classes of agents for treating PHN and are effective in a significant proportion of patients. However, various adverse events can limit treatment. These side effects tend to be more acute in the elderly, the population most likely to suffer from PHN. Topical agents have led to mild to moderate improvement in patients with PHN but are usually ineffective as monotherapy for this condition. Until recently, carbamazepine was the only antiepileptic drug evaluated for the treatment of PHN. Over the past few years, however, gabapentin has received increasing attention as a useful treatment for neuropathic pain. Gabapentin lacks significant drug‐drug interactions and has a favorable safety profile, which makes it particularly useful for treatment of PHN.
Gabapentin Monotherapy for the Symptomatic Treatment of Painful Neuropathy: A Multicenter, Double‐blind, Placebo‐controlled Trial in Patients With Diabetes Mellitus1
Authors: Backonja Misha‐Miroslav
Published: August 2005

Pain is the most disturbing symptom of diabetic neuropathy. Traditionally this type of pain was treated with tricyclic antidepressants which frequently have many side effects. In the study reported here, gabapentin was administered in escalating doses up to 3600 mg per day to eligible patients with moderate to severe diabetic neuropathy pain in a double blind placebo controlled fashion. Gabapentin provided superior and significant pain relief over placebo. In addition, patients taking gabapentin had improvement of sleep scores and a number of items on mood and quality of life questionnaires. Gabapentin was tolerated well with mild and tolerable side effects.
NMDA‐Receptors 1 and 2A/B Coassembly Increased in Human Epileptic Focal Cortical Dysplasia
Authors: Mikuni Nobuhiro , Babb Thomas L. , Ying Zhong , Najm Imad , Nishiyama Kazutoshi , Wylie Christi , Yacubova Karina , Okamoto Takashi , Bingaman William
Published: August 2005

Summary: Purpose: This study was designed to quantify the relation between expressions of NMDA receptor (NMDAR) subunits (1 and 2A/B) and the epileptogenicity in human focal cortical dysplasia.

Methods: Immunoblotting and immunoprecipitation were used to quantify these receptor subunits in tissue resected from EEG‐verified epileptic and distal nonepileptic frontal cortical areas in each of three patients as determined by chronic subdural electrode recordings. In each patient, adjacent sections were immunostained to verify that the numbers of dysplastic neurons were greater in epileptic than in nonepileptic cortex.

Results: In all patients, NMDAR2A/B expressions and their coassemblies with NMDAR1 were increased in epileptic dysplastic cortex compared with the relatively normal appearing nonepileptic cortex. For all three patients, there were no significant differences in NMDAR1 protein expressions between the two EEG groups.

Conclusions: These results suggest that increased NMDAR1‐NMDAR2A/B coassembly contributes to hyperexcitability in dysplastic cortical neurons and focal seizure onsets.
Prognostic Factors in Anterior Temporal Lobe Resections for Mesial Temporal Lobe Epilepsy: Multivariate Analysis
Authors: Jeong Sang‐Wuk , Lee Sang Kun , Kim Kwang‐Ki , Kim Ho , Kim Joo‐Yong , Chung Chun‐Ki
Published: August 2005

Summary: Purpose: Even though there have been several studies on the prognostic factors of temporal lobe epilepsy (TLE) after lobectomy, no studies have been performed for homogeneous mesial TLE. Furthermore, most studies on the predictors of outcome of epileptic surgery were based on univariate analyses and did not consider modern epileptic surgery investigation modalities such as brain magnetic resonance imaging (MRI) and positron emission tomography (PET). We attempted to identify the prognostic factors in anterior temporal lobectomy (ATL) for mesial TLE with multivariate analysis.

Methods: Ninety‐three patients with mesial TLE (54 men and 39 women, mean age at surgery, 28.3 ± 8.2 years) were included in the study. The primary outcome variable was the status of patients in the second postoperative year, classified as either seizure free (except aura), or not seizure free. Clinical, electroencephalographic, MRI, PET, Wada test, and pathological data were considered.

Results: Seventy‐eight (84.0%) patients had remission of seizures. With univariate analysis, age at surgery (p < 0.001), epilepsy duration before surgery (p = 0.04), and ipsilateral hippocampal sclerosis on MRI (p = 0.02) were found to be significant. By using multivariate analysis, age at surgery (p = 0.001) and ipsilateral hippocampal sclerosis on MRI (p = 0.03) were found to be the most significant prognostic factors.

Conclusions: Age at surgery and hippocampal sclerosis are independent prognostic factors for ATL in mesial TLE. These findings suggest that mesial TLE may be a progressive disorder, and surgical outcome is better when early ATL is performed.
Long‐Term Treatment of Children with Epilepsy with Valproate or Carbamazepine May Cause Subclinical Hypothyroidism
Authors: Eirís‐Puñal J. , Río‐Garma M. Del , Del Río‐Garma M. C. , Lojo‐Rocamonde S. , Novo‐Rodríguez I. , Castro‐Gago M.
Published: August 2005

Summary: Purpose: The aim of the study was to evaluate serum thyroid hormone balance in children receiving long‐term therapy with carbamazepine (CBZ), valproate (VPA), and phenobarbital (PB).

Methods: We determined serum levels of triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), thyroxine‐binding globulin (TBG), and thyroid‐stimulating hormone (TSH) in 148 healthy children and 141 children with epilepsy who had been receiving CBZ (61 patients), VPA (51 patients), or PB (29 patients) for 12–161 months. In view of TSH values, three categories of subclinical hypothyroidism were considered: I, TSH greater than the control‐group mean + 2 SD (4.37 mIU/L in our study) and <6 mIU/L; II, TSH between 6 and 12 mIU/L; and III, TSH >12 mIU/L.

Results: In all treated groups, mean T4 and FT4 levels were lower than in the control group, whereas the CBZ‐ and VPA‐treated children additionally showed reduced mean T3 and TBG levels and increased mean TSH levels. In the group receiving CBZ, 8.2% had TSH values higher than the normal‐range maximum, by comparison with only 3.6% of healthy children. The increase in TSH levels was particularly marked in VPA‐treated children, accounting for 26% of patients with subclinical hypothyroidism.

Conclusions: Our results, in contrast to previous reports, suggest that CBZ and particularly VPA may induce subclinical hypothyroidism. This suggests a need for careful monitoring of TSH levels in children receiving CBZ or VPA.
Topiramate in Medically Intractable Partial Epilepsies: Double‐Blind Placebo‐Controlled Randomized Parallel Group Trial
Authors:   Korean Topiramate Study Group
Published: August 2005

Summary: Purpose: To evaluate the efficacy and safety of topiramate (TPM) as add‐on therapy in medically intractable partial epilepsies.

Methods: We used a multicenter double‐blind placebo‐controlled randomized parallel‐group trial consisting of 12 weeks of baseline phase, 10 weeks of titration phase, and 8 weeks of stabilization phase. The primary efficacy variable was the median seizure frequency reduction rate (MSFRR), and the other efficacy variables included responder rate, seizure‐free rate, and global evaluations by the patient and the physician. The patient should have partial epilepsies refractory to the maximally tolerable doses of one to two antiepileptic drugs (AEDs) and should have two or more episodes of clinical seizures every 4 weeks during the baseline phase. The target dose of study drugs was 600 mg/day. The study drugs were started at the initial dose of 50 mg/day and gradually increased to the target dose over a 10‐week period.

Results: A total of 177 patients was randomized into the TPM group (n = 91) and the placebo (PLC) group (n = 86). Baseline median seizure frequencies were 5.6 episodes/4 weeks in the TPM and the PLC groups. Among those who were randomized, 174 patients (TPM, 89 patients; PLC, 85 patients) were available for the efficacy measurement by intention‐to‐treat analysis. The MSFRR was 51.3% for TPM and 9.1% for PLC, which was highly in favor of TPM (p = 0.0001). The responder rate was 50.6% for TPM and 12.9% for PLC (p = 0.001). Seven (7.9%) of 89 patients taking TPM became seizure free compared with one (1.2%) of 85 patients taking PLC (p = 0.004). The global evaluation greatly favored TPM (p = 0.001). The incidence of adverse events (AEs) was higher in the TPM (81.3%) than in the PLC (48.9%) group, with central nervous system (CNS)‐related AEs being the most frequent. Among individual AEs, anorexia (20.9%) and abdominal pain or discomfort (20.9%) were the most common AEs in the TPM group. AEs precipitated early drop‐out in seven (7.6%) patients taking TPM and three (3.5%) patients taking PLC. No serious systemic AEs were observed.

Conclusions: TPM was highly effective and safe as add‐on therapy in medically intractable partial epilepsies. Slower titration of TPM might be responsible for the lesser drop‐out rate than previous trials, but the incidence of AEs was still high. The AE profile of TPM in Koreans was different from that in whites.
Seizure‐Refractory Period After a Single Stimulation and Inhibition of Seizures After Repetitive Stimulation in the Gerbil: Effects on Blood Cortisol Levels
Authors: Revilla Victoria , Robles María Sagrario , Bermejo Juan Carlos , Paniagua Miguel Angel , Fernádez‐López Arsenio
Published: August 2005

Summary: Purpose: To determine the epileptic response of gerbils to external shock stimulus, assessing blood cortisol levels as a parameter to determine stress conditions.

Methods: Five sets of two‐month‐old Mongolian gerbils were stimulated to elicit seizures by the clapping of a sheaf of papers. Stimulation was done once a week over a 10‐week period to obtain a stable situation and a similar response in all the animals. Four of the sets were killed to collect blood samples: those not manipulated; those stimulated twice a day for 5 days; those stimulated once to obtain samples immediately after seizure recovery; and those stimulated once to obtain samples 30 min after seizure recovery. Blood samples from the fifth set of animals were taken in vivo from the retro‐orbital plexus.

Results: Eliciting seizures with this stimulus, twice a day in a repetitive way, prevented further induced seizures from the second day of stimulation on. Changes in the gerbils’behavior—from exploratory to escape mode—were also observed. The blood cortisol levels found in the sets of animals killed without induced seizures were similar to the others, regardless of whether the animals had been subjected to repetitive stimulation. Additionally, significant decreases in blood cortisol levels were detected in the animals killed immediately and 30 min after recovering from an induced epileptic episode.

Conclusions: The normal refractory period in gerbils can be estimated at 1 h. The lack of correlation between cortisol levels and the inhibition of seizure‐elicitation through repetitive stimulation supports the environmental and exploratory hypothesis of seizure generation rather than a stress hypothesis.
Muscarinic Receptors Mediate Carbachol‐Induced Inhibition of Maximal Electroshock Seizures in the Nucleus Reticularis Pontis Oralis
Authors: Peterson Steven L. , Armstrong Juli J.
Published: August 2005

Summary: Purpose: Previous reports from this laboratory indicated a role for N‐methyl‐D‐aspartic acid (NMDA) and γ‐aminobutyric acid (GABA) receptors among the neuronal mechanisms of the nucleus reticularis pontis oralis (RPO) that regulate the tonic hindlimb extension (THE) component of maximal electroshock seizures (MESs) in rats. This study was intended to determine the role of cholinergic mechanisms in the RPO regulation of THE.

Methods: Rats were surgically prepared with microinjection guide cannulas for the focal administration of drug solutions directly into the RPO. MES was induced with corneal electrodes.

Results: RPO microinjection of carbachol significantly inhibited the incidence of THE. RPO microinjection of atropine by itself had no effect on the seizure response but significantly antagonized the anticonvulsant effect induced by RPO microinjection of carbachol. The selective nicotinic agonist dimeth‐ylpiperizinium (DMPP) by itself had no effect on THE. RPO microinjection of 10 ng pertussis toxin by itself had no effect on THE but significantly antagonized the anticonvulsant effect induced by RPO microinjection of carbachol.

Conclusions: RPO microinjection of carbachol inhibited the THE component of MESs in rats. The carbachol effect appeared to be mediated by muscarinic receptors as the anticonvulsant activity was antagonized by atropine, and the selective nicotinic agonist DMPP induced no anticonvulsant activity. Because pertussis toxin acts to inhibit muscarinic receptor‐linked G proteins, the pertussis toxin antagonism of carbachol also supports a muscarinic mechanism of action.