bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuronal Migration Disorders Increase Susceptibility to Hyperthermia‐Induced Seizures in Developing Rats
Authors: Germano Isabelle M. , Zhang Yang F. , Sperber Ellen F. , Moshé Solomon L.
Published: August 2005

Summary: Purpose: Retrospective studies suggest that adult patients with intractable epilepsy may have a history of febrile seizures in childhood. Risk factors for a febrile seizure may include the rate of increase in the core temperature (T‐core), its peak (Tmax), the duration of the temperature increase, or an underlying brain pathology. Recently, neuronal migration disorders (NMD) have been diagnosed with increasing frequency in patients with epilepsy, but the link between NMD, febrile seizures, and epilepsy is unclear. We studied rat pups rendered hyperthermic to ascertain the incidence of seizures, mortality, and extent of hippocampal cell loss in each group.

Methods: We exposed 14‐day‐old rat pups with experimentally induced NMD (n = 39) and age‐matched controls (n = 30) to hyperthermia (core body temperature >42°C).

Results: The incidence of hyperthermia‐induced behavioral seizures and mortality rate were significantly higher in rats with NMD than in controls (p < 0·05). The longer duration of hyperthermia resulted in a higher incidence of behavioral seizures and higher mortality rate (p < 0·05). In rats with NMD, hyperthermia resulted in hippocampal pyramidal cell loss independent of seizure activity; the extent of neuronal damage correlated positively with the duration of hyperthermia. In control rats, occasional neuronal loss and astrocytosis occurred only after prolonged hyperthermia.

Conclusions: In immature rats, NMD lower the threshold to hyperthermia‐induced behavioral seizures and hyperthermia in the presence of NMD may cause irreversible hippocampal neuronal damage.
Effect of Felbamate on Valproic Acid Disposition in Healthy Volunteers: Inhibition of β‐Oxidation
Authors: Hooper W. D. , Franklin M. E. , Glue P. , Banfield C. R. , Radwanski E. , McLaughlin D. B. , McIntyre M. E. , Dickinson R. G. , Eadie M. J.
Published: August 2005

Summary: We assessed the effects of felbamate (FBM) on the disposition of valproic acid (VPA) in healthy volunteer men. Eighteen subjects received sodium VPA, 400 mg/day for 21 days. Plasma and urine samples were taken on day 7 to document the steady‐state disposition of VPA alone. From day 8 to day 21, subjects received placebo or FBM at the following doses (mg/day): 1,200, 2,400, 3,000, or 3,600 (n = 2–4 per group). Many adverse events (AE) occurred from about day 10; 2 subjects dropped out and 1 continued on a reduced FBM dose. Pharmacokinetic studies were repeated on day 21 for the 16 subjects who completed the study. FBM was measured in plasma and urine by high‐performance liquid chromatography (HPLC). VPA and its 2–en, 4–en, and 3–oxo metabolites in plasma, and VPA (nonconjugated and total), and its 3–oxo and 4–hydroxy metabolites in urine, were measured by gas chromatography/mass spectrometry (GUMS). Mean plasma FBM trough concentrations on day 21 ranged from 26.9 μg/ml (1,200 mg dose) to 76.8 μg/ml (3,600–mg dose). Mean plasma VPA Cmax values were 32–42 μg/ml in the various subgroups when VPA only was administered. Higher plasma VPA levels were observed when FBM was administered concurrently (55.4–63.8 μg/ml). The excretion of 3–oxo–VPA in urine was significantly lower on day 21 than on day 7, whereas VPA‐glucuronide was significantly increased. The effects of FBM on VPA disposition were dose dependent and were maximal at ∼2400 mg/day. FBM had caused significant inhibition of the β‐oxidation pathway for VPA metabolic clearance, and this had been largely compensated by increased VPA glucuronidation.
Lippincott‐Raven Publishers, Philadelphia © International League Against Epilepsy Remacemide Hydrochloride and ARL 15896AR Lack Abuse Potential: Additional Differences from Other Uncompetitive NMDA Antagonists
Authors: Hudzik Thomas J. , Freedman Louis , Palmer Gene C.
Published: August 2005

Summary: This study was designed to determine the possible abuse liability and phencyclidine‐like effects of the low‐affinity uncompetitive N‐methyla‐aspartate (NMDA) antagonists remacemide hydrochloride [(+min)‐2–amino‐N‐(1 ‐methyl‐1,2–diphenylethyl)‐acetamine hydrochloride] and ARL 15896AR [(+)‐a‐phenyl‐2–pyridine‐ethanamine dihydrochloride]. For the abuse‐liability studies, in rats trained to self‐administer cocaine intravenously (0.1 mg/kg/injection), doses of remacemide HCI, ARL 15896AR, phencyclidine, and saline were made available, and the number of injections self‐administered was recorded. In different sets of rats, we assessed the ability of these drugs to induce phencyclidine‐like stereotyped behavior. Doses of the compounds were expressed as multiples of the 50% effective dose (ED,), as determined from the maximal electroshock (MES) test by using either oral or intravenous administration. None of the remacemide hydrochloride or ARL 15896AR doses was self‐administered at a level higher than that of the saline vehicle, unlike cocaine and phencyclidine, which were self‐administered at high and moderate levels, respectively. Unlike that with remacemide hydrochloride and ARL 15896AR, oral administration of the high‐affinity uncompetitive NMDA receptor‐antagonists phencyclidine, ARL 16247 [N‐(3–ethylphenyl)‐N‐methyl‐N'‐naph‐thylguanidine] and MK‐801 engendered phencyclidine‐like stereotypy at doses near their MES ED50, values. These data confirm the unusual safety of remacemide hydrochloride and ARL 15896AR and demonstrate that they do not possess reinforcing properties. As such, they are unlikely to present a drug‐abuse problem in human beings.
Neuron‐Specific Enolase, a Marker of Acute Neuronal Injury, is Increased in Complex Partial Status Epilepticus
Authors: DeGiorgio Christopher M. , Gott Peggy S. , Rabinowicz Adrian L. , Heck Christi N. , Smith Thomas D. , Correale Jorge D.
Published: August 2005

Summary: Purpose: To determine whether complex partial status epilepticus (CPSE) causes brain injury in humans. Serum neuron‐specific enolase (s‐NSE) is an accepted marker of acute brain injury, and increases in s‐NSE have been correlated with the duration and outcome of generalized convulsive status epilepticus. s‐NSE levels in CPSE are unknown. Increase in s‐NSE in CPSE would provide new information about the degree of brain injury in CPSE and would help confirm that CPSE is a medical emergency.

Methods: This was a pilot prospective study of serial levels of s‐NSE and outcome in CPSE. Eight patients with confirmed CPSE and no acute neurologic deficit were identified prospectively. Results were compared with those of normal and epileptic control groups, and outcome was assessed at hospital discharge or at 7 days with the Glasgow Oucome Scale (GOS).

Results: The mean peak s‐NSE was 21.81 ng/ml, which for the 8 patients with CPSE was four times higher than that of normal controls (mean s‐NSE = 5.36 SD = 1.66, p = 0.0003) and epileptic controls (mean s‐NSE = 4.61 SD = 1.74, p. = 0.001).

Conclusion: The increase in s‐NSE provides new evidence that CPSE causes brain injury in humans.
Five‐Year Outcome After Epilepsy Surgery in Nonmonitored and Monitored Surgical Candidates
Authors: Holmes Mark D. , Dodrill Carl B. , Ojemann Linda M. , Ojemann George A.
Published: August 2005

Summary: Purpose: We wished to compare outcome 5 years after temporal lobectomy in 28 patients selected for surgery on the basis of interictal EEG patterns with that in 46 patients who underwent EEG‐video monitoring studies as part of their preoperative evaluation during the same era.

Methods: The 28 nonmonitored patients had interictal EEG patterns that demonstrated a consistent, unilateral, anterior‐midtemporal epileptiform focus, without discordant findings from other studies. Outcomes were assessed for years 4 and 5 after operation.

Results: Twenty‐six of 28 (92.9%) nonmonitored patients were seizure‐free or had at least 75% reduction in seizures. Twenty‐nine of 46 (63.0%) monitored patients were seizure‐free or had at least 75% reduction in seizures. Preoperative interictal EEGs of 29 of these patients showed independently localized bitemporal, ex‐tratemporal, midposterior temporal, or diffuse epileptiform patterns. The remaining 17 monitored patients had preoperative strictly unilateral anterior‐midtemporal interictal discharges, and their outcome was comparable to the nonmonitored group, with 15 (88.8%) seizure‐free or with at least 75% reduction in seizures.

Conclusions: A proportion of candidates for epilepsy surgery can be selected without ictal recordings provided that interictal EEGs demonstrate consistent unilateral anterior‐midtemporal epileptiform discharges and that other data are not discordant.
Treatment with Vigabatrin May Mimic α‐Aminoadipic Aciduria
Authors: Vallat C. , Rivier F. , Bellet H. , de Bornier B. Magnan , Mion H. , Echenne B.
Published: August 2005

Summary: Purpose: We describe a secondary effect of treatment with vigabatrin (VGB). A significant increase in α‐aminoadipic acid (AAA) occurred in plasma and urine of VGB‐treated children, thus mimicking a known rare metabolic disease, α‐aminoadipic aciduria (AAAuria).

Methods: We studied eight children, aged from 3 months to 5 years, who were receiving VGB for drug‐resistant partial epilepsies. Plasma and urine amino acids were assayed with ninhydrin detection on an automated Beckman 6300 analyzer.

Results: In eight out of eight children, there was a significant increase of AAA in plasma and in urine. Plasma values ranged from 7 to 18 μM (control values, < 5) and urinary values from 67 to 274 mmol/mol creatinine (control values, < 25).

Conclusions: The concentrations of AAA in these VGB‐treated children were as high as the concentrations found in the inherited metabolic disease, AAAuria. This could lead to incorrect diagnosis and to inappropriate genetic counseling. Thus whenever a genetic metabolic disease is suspected, amino acid chromatography testing should be performed before initiation of treatment with VGB.
Proton Magnetic Resonance Spectroscopy (MRS) in Epilepsy
Authors: Connelly Alan
Published: August 2005

Summary: For 1H magnetic resonance spectroscopy (MRS) studies in epilepsy in vivo, the main signals of interest have been those from N‐acetyl aspartate (NAA), creatine + phosphocreatine (Cr), choline‐containing compounds (Cho), and lactate (Lac). Several lines of evidence have indicated that NAA is located primarily within neurons. A reduction of the NAA signal is frequently interpreted, therefore, as reflecting loss or dysfunction of neurons. Such a reduction in NAA has been found in practice in many cases where neuronal loss would be expected clinically, and such abnormalities have been shown to be present in patients with intractable focal epilepsy. The acquisition of spectroscopic data in vivo is of limited use unless the spatial origin of the signals obtained is known. It is necessary, therefore, to limit the extent of the volume from which signal is acquired and to relate this volume to the anatomy of the region under investigation. For this reason, a number of common spatial localisation techniques are outlined, and their consequences described. In vivo MRS studies in epilepsy to date have been directed largely at the temporal lobes of patients with intractable epilepsy in whom surgical treatment is under consideration. Results are presented from a number of institutions which demonstrate that 1H MRS can contribute to the lateralization of the epileptic focus and to the identification of bilateral pathology. In providing information both on static metabolic abnormalities, primarily through the NAA signal, and on dynamic changes associated with seizure activity via the lactate signal, MRS offers the possibility of obtaining information on cerebral metabolism that is likely to have significant consequences for the management of patients with epilepsy.
Prefrontal Cortex and Behavior: Encoding of Self‐Movement in Dorsal Prefrontal Neurons
Authors: Niki Hiroaki , Tsutsui Ken‐ichiro
Published: August 2005

Summary: The prefrontal cortex is a heterogeneous structure consisting of several distinct areas, each with its own function. We examined a single unit activity of the dorsal prefrontal cortex during the performance of a delayed conditional discrimination task in which animals were required to discriminate between push‐3 and push‐12 and had to move the stick left or right depending on whether they pushed 3 or 12 times before the delay period. Many neurons in the dorsal prefrontal area showed activity changes related to the encoding of self‐movement information. These findings indicate that the dorsal prefrontal area participates in the processing of self‐movement information.
Nocturnal Sleep and Daytime Somnolence in Untreated Patients with Temporal Lobe Epilepsy: Changes After Treatment with Controlled‐Release Carbamazepine
Authors: Gigli Gian Luigi , Placidi Fabio , Diomedi Marina , Maschio Marta , Silvestri Giulia , Scalise Anna , Marciani Maria Grazia
Published: August 2005

Summary: Purpose: To define sleep disturbances in patients with temporal lobe epilepsy (TLE) and explore the association between carbamazepine (CBZ) therapy, sleep, and daytime somnolence.

Methods: We recorded nocturnal polysomnography and measured subjective and objective daytime somnolence in a group of newly diagnosed TLE patients, who had no evidence of anatomic brain lesion on neuroimaging and had never been treated before. Recordings were performed at baseline, after the initial administration of 400 mg CBZ‐controlled release (CR) and after 1 month of treatment (400 mg twice daily b.i.d.). The findings were compared with those of a group of young healthy volunteers, both at baseline and after the first administration of CBZ. The chronic effect of CBZ‐CR treatment was evaluated only in TLE patients.

Results: At baseline, nocturnal sleep patterns of TLE patients did not show marked alterations when the influence of seizures, cerebral lesions, and drugs had been ruled out. In both the TLE and the control groups, initiation of CBZ therapy provoked a reduction and a fragmentation of rapid eye movement (REM) sleep and an increase in the number of sleep stage shifts. In the TLE group, these effects were almost completely reversed after 1 month of treatment, and no significant difference was noted between baseline condition and long‐term follow‐up. With regard to daytime sleepiness, initial administration of the drug caused an increase in objective sleepiness only in the control group. Subjective sleepiness was higher in the control group than in the TLE group but was not modified by the drug.

Conclusions: We conclude that CBZ‐CR has negative effects on REM sleep during initial administration but chronic treatment does not significantly modify nocturnal sleep or daytime somnolence.
Role of the Claustrum in Convulsive Evolution of Visual Afferent and Partial Nonconvulsive Seizure in Primates
Authors: Wada Juhn A. , Tsuchimochi Hirohito
Published: August 2005

: Purpose: We tested cross‐species validity of the role of the claustrum in the convulsive evolution of the visual afferent and amygdaloid seizure and the specificity of the claustral lesioning effect.

Methods: In 7 Senegalese baboons, we examined the effect of unilateral claustral lesioning on generalized convulsive seizures either kindled from the amygdaloid nucleus (AM) and cingulate cortex (CG) or induced by intermittent photic stimulation (IPS) after systemic administration of D,L‐allylglycine (AG).

Results: A lesioned area common to all animals was the anterior half of the left claustrum. Postoperative restimulation of the kindled left AM or CG evoked only nonconvulsive seizures. When few convulsive seizures emerged in 1 CG‐kindled animal, they were mirror image of the kindled seizure and arose from the nonlesioned right hemisphere. Restimulation of the kindled right AM or CG reactivated kindled seizures. An IPS‐induced generalized convulsive seizure was transformed into a secondarily generalized seizure arising from the nonlesioned right hemisphere.

Conclusions: The primate claustrum regulates the convulsive evolution of partial seizures originating from nonmotor structures such as the AM and CG and also regulates the convulsive development that follows IPS. Our findings suggest that predisposed susceptibility expressed at the claustrum may be involved in the clinical variation with respect to convulsive evolution of nonmotor partial seizures and convulsive susceptibility to IPS in human primates.
Safety of Intrahippocampal Depth Electrodes for Presurgical Evaluation of Patients with Intractable Epilepsy
Authors: Fernández Guillén , Hufnagel Andreas , Van Roost Dirk , Helmstaedter Christoph , Wolf Helmut K. , Zentner Josef , Schramm Johannes , Elger Christian E.
Published: August 2005

: Purpose: Intracerebral depth electrodes are used in preoperative evaluation of selected patients with intractable epilepsies. In spite of their usefulness, safety of depth electrodes is disputed, and the number of insertions is decreasing. This study examined retrospectively possible deleterious effects such as perioperative complications, induction of epileptogenesis, and neuropsychologic deficits.

Methods: Clinical course and neuroradiologic findings of 115 patients with bilaterally inserted longitudinal intrahippocampal depth electrodes (IDEs) were analyzed. Hippocampal resection specimens were examined histopathologically. To detect newly developed epileptogenic areas, EEG recordings, seizure control, and semiology after standardized resection procedures were compared between patients who received IDEs and those who did not. To demonstrate functional deficits caused by IDE insertion into an unaffected hippocampus of the speech‐dominant hemisphere, changes of verbal learning and memory performances before and after right amygdalohippocampectomy were compared between patients evaluated with and without IDEs.

Results: Five significant complications without any permanent neurologic deficit were noted, and only one was specifically linked to IDE insertion. The tissue damage associated with the insertion was minimal and sharply circumscribed. No differences of seizure outcome after standardized resections were identified between patients with and without IDEs. In postoperative EEG recordings, there was no evidence of new epileptogenic areas. No verbal memory deficit caused by IDE implantation into the hippocampus of the speech‐dominant hemisphere was detectable.

Conclusions: Results indicate that it is safe to implant these IDEs in selected patients.
Stereotactic Amygdalohippocampotomy and Mesial Temporal Spikes
Authors: Blume Warren T. , Parrent Andrew G. , Kaibara Masako
Published: August 2005

: Purpose: To investigate the mechanism of mesial temporal spike generation, we sought to determine whether amygdalohippocampotomy by radiofrequency lesions altered spike rates in patients with medically intractable temporal lobe epilepsy.
Successful Treatment by Direct Hemoperfusion of Coma Possibly Resulting From Mitochondria1 Dysfunction in Acute Valproate Intoxication
Authors: Matsumoto Jyunji , Ogawa Hisayuki , Maeyama Ryutaro , Okudaira Ken , Shinka Toshihiro , Kuhara Tomiko , Matsumoto Isamu
Published: August 2005

: Purpose: We evaluated the efficacy of direct hemoperfusion (DHP) for treatment of acute valproate (VPA) intoxication and speculate on the biochemical perturbations that suggest a mechanism of coma induced by VPA overdose.

Patient and Methods: The comatose patient was hospitalized ˜6 h after ingesting 18 g VPA. DHP, with 200 g activated charcoal, was performed for 6 h. The plasma concentrations of VPA and Glasgow coma scale scores after admission were estimated. Before and after DHP, urine samples were tested in serial fashion for VPA metabolites, organic acids, and acyl carnitine esters of fatty acids.

Results: Plasma VPA was efficiently adsorbed on activated charcoal. The patient's plasma concentration of VPA decreased from 471 μml (2,830 μM) to 45 pg/ml (270 μM), at which point the patient became alert. The half‐life (t1/2) of VPA was calculated as 4.4 h before DHP and as 1.8 h during DHP. Before DHP, lactate and VPA‐glucuronide markedly increased in urine samples, but β‐keto‐VPA, a major mitochondria1 metabolite, was not detected. Urinary excretion of carnitine esters of medium chain (C8‐C10) dicarboxylic acids was increased. After DHP, lactate and VPA‐glucuronide decreased, but a significant amount of β‐keto‐VPA was demonstrated. Carnitine esters of medium chain dicarboxylic acids were decreased.

Conclusions: DHP with activated charcoal was effective treatment for the patient with acute VPA intoxication and coma. The onset of coma may have been related to inhibition of β‐oxidation in the mitochondria, which was reversible by elimination of plasma VPA by DHP.
Patients' Experiences of Injury as a Result of Epilepsy
Authors: Buck Deborah , Baker Gus A. , Jacoby Ann , Smith David F. , Chadwick David W.
Published: August 2005

Summary: Purpose: The increased risk of mortality among people with epilepsy is well documented; people with epilepsy are more likely than the general population to die as a result of an accident. Data about incidence of nonfatal accidents and associated factors are not so readily available, even though such accidents are more common than fatal injuries. We report the proportion of people who sustain various injuries during a seizure and the key variables predicting injury.

Methods: Questionnaires were mailed to an unselected, community‐based population of patients with epilepsy. The questionnaire included clinical and demographic details, previously validated scales of psychosocial well‐being, and questions about seizure‐related injuries.

Results: Of patients who had had at least one seizure during the previous year, 24% sustained at least one head injury, 16% sustained a burn or scald, 10% a dental injury, and 6% some other fracture. Seizure type, seizure severity, and seizure frequency were key predictors of having sustained at least one of these four seizure‐related injuries. Key predictors of budscald were seizure severity, seizure frequency and sex; those of head injury were seizure severity and type; that of dental injury was seizure severity; and those of some other fracture were seizure severity, duration of epilepsy, and three or more drug‐related adverse effects.

Conclusions: These data help identify significant risk factors associated with seizure‐related injuries and so facilitate sensible patient counseling about how the risks of such injuries can be minimized.
A Family with Hereditary Spastic Paraparesis and Epilepsy
Authors: Webb Stewart , Flanagan Niamh , Callaghan Noel , Hutchinson Michael
Published: August 2005

Summary: Purpose: We describe a family with hereditary spastic paraparesis (HSP) in which 4 of 6 affected members also have epilepsy.

Methods: All family members were examined by 2 neurologists. Four affected and 3 unaffected family members had EEG recordings. Four affected members were investigated for other causes of spastic paraparesis and epilepsy.

Results: Epileptic symptoms varied among family members: 1 had complex partial seizures, another had focal myoclonic epilepsy, and 2 had simple partial seizures secondarily generalized. All 4 had clinical or EEG evidence to support a focal origin for the epilepsy, and 2 had photoparoxysal responses on EEG. Symptoms were more severe and occurred earlier in the younger generation, suggesting genetic anticipation in this family. The onset of epilepsy developed simultaneously with, or ≤18 years before, onset of gait disturbance. Three unaffected family members had normal EEGs.

Conclusions: The association of HSP and epilepsy should no longer be assumed to be fortuitous.
Population Analysis of the Pharmacokinetics of Tiagabine in Patients with Epilepsy
Authors: Samara E. E. , Gustavson L. E. , El‐Shourbagy T. , Locke C. , Granneman G. R. , Sommerville K. W.
Published: August 2005

Summary: Purpose: In two open‐label long‐term safety studies, we determined tiagabine (TGB) pharmacokinetics in patients with epilepsy.

Methods: In all, 2,147 plasma samples from 511 patients who participated in the studies were available. The total daily dose ranged from 2 mg administered once daily to 80 mg administered in four doses. A one‐compartment model with first‐order absorption and elimination was used to fit the TGB plasma concentration‐time data, with a population pharmacokinetic approach.

Results: The patients’average (±SD) weight and age were 73.8 ± 20.7 kg and 32.1 ± 12.3 years. The most significantly factor affecting TGB pharmacokinetics was concomitant administration of other antiepileptic drugs (AEDs). The central clearance value in patients receiving AEDs known to induce hepatic drug metabolism was 21.4 L/h, a value 67% higher than the central clearance estimate obtained for the patients receiving AEDs not known to affect hepatic drug metabolism (12.8 L/h). There was no evidence of any dose or time effect, indicating that TGB pharmacokinetics are linear. TGB pharmacokinetics were not different in white, black, or Hispanic patients, although our ability to explore racial effects was limited since 90% of the patients were white. No other demographic variables (including age and smoking) or any clinical chemistry measurements (including bilirubin, SGOT, and SGPT) were important in explaining the variability in the clearance estimates.

Conclusions: TGB pharmacokinetics are linear, influenced by enzyme‐inducing AEDs, and largely unaffected by other demographic variables.
Role of Vigabatrin and Lamotrigine in Treatment of Childhood Epileptic Syndromes
Authors: Béanger Stacey , Coulombe Geneviève , Carmant Lionel
Published: August 2005

Summary: Purpose: Vigabatrin (VGB) and lamotrigine (LTG) are two new antiepileptic drugs (AEDs) with different mechanisms of action for treatment of refractory epilepsies. Previous reports have indicated efficacy of both drugs in a number of epileptic syndromes.

Methods: We compared these new AEDs drugs to determine their respective efficacy against different types of epileptic syndrome and to develop a rational approach to their use. We reviewed the charts of 105 children, with partial and generalized epilepsies.

Results: VGB was to be significantly more effective in children with partial epilepsies, and LTG was more effective in those with generalized epilepsies.

Conclusions: VGB and LTG have different therapeutic profiles. Combination treatment with the two drugs may represent rational polytherapy for patients with epilepsy resistant to treatment with either drug alone or as add‐on to other AED treatment.
Proton Magnetic Resonance Spectroscopic Imaging in Patients with Extratemporal Epilepsy
Authors: Stanley Jeff A. , Cendes Fernando , Dubeau François , Andermann Frederick , Arnold Douglas L.
Published: August 2005

Summary: Purpose: Reduced levels of N‐acetylaspartate (NAA) in temporal lobes responsible for temporal lobe epilepsy have been observed consistently in proton magnetic resonance spectroscopy (MRS) studies.

Methods: We investigated the potential of proton MRS to detect low NAA outside of the temporal lobes in patients with non‐lesional partial extratemporal epilepsy. Proton MR spectroscopic imaging (MRSI) data of both frontal lobes and central/postcentral regions were obtained in 20 such patients and 16 normal control subjects. The epileptogenic region was determined by an extensive clinical‐EEG investigation, including the recording of habitual seizures in each patient, and intracranial EEG recordings in 10 patients.

Results: The relative NAA resonance intensities (i.e., NAN/phosphocreatine plus creatine (CRt), NAN/choline‐containing metabolites (Chot) and NAA/Crt+ Chot), were all significantly reduced throughout the spectroscopic image as compared with that of the controls. Furthermore, reduction of the NAA ratios was greater in the epileptogenic region as compared with the nonepileptogenic regions, on EEG investigation.

Conclusions: In vivo proton MRSI of patients with nonlesional partial extratemporal epilepsy detected evidence of widespread neuronal damage or dysfunction that was greatest in the region of seizure focus.
Pharmacokinetic Evaluation of Twice‐Daily Extended‐Release Carbamazepine (CBZ) and Four‐Times‐Daily Immediate‐Release CBZ in Patients with Epilepsy
Authors: Garnett William R. , Levy Benjamin , McLean Angus M. , Zhang Yuxin , Couch Richard A. , Rudnic Edward M. , Pellock John M. , Belendiuk George W.
Published: August 2005

Summary: Purpose: A new capsule dosage form of carbamazepine (CBZ) has been developed, consisting of three different types of beads (immediate‐release, extended‐release, and enteric‐release) that may be taken sprinkled on food or swallowed for easy administration. We compared the pharmacokinetics of the extended‐release dosage form of CBZ (Carbatrol capsules) twice daily with the conventional immediate‐release formulation of CBZ four times daily.

Methods: The randomized, double‐blind, two‐way, cross‐over study was conducted at two sites, with a planned sample size of 24 adult patients with epilepsy. Each treatment was administered for 2 weeks. At the end of the 2‐week period, blood samples were obtained hourly for a 24‐h period.

Results: The 90% confidence intervals (CI) of the ratio of the means of the extended‐release formulation twice daily to the immediate‐release formulation four times daily were within the range of 0.80–1.25 for each of the pharmacokinetic parameters for CBZ and for the summation of CBZ and CBZ‐epoxide (CBZ‐E). There was no difference in the frequency of seizures between treatment (p = 0.103).

Conclusions: Our results demonstrate that extended‐release CBZ twice daily was bioequivalent to immediate‐release CBZ four times daily, with regard to CBZ levels and summation of CBZ and CBZ‐E levels, based on the pharmacokinetic parameters evaluated. Substituting one formulation for the other did not cause patients to have a significant change in seizure frequency.
Comparison of Single‐ and Repeated‐Dose Pharmacokinetics of Diazepam
Authors: Walker M. C. , Tong X. , Brown S. , Shorvon S. D. , Patsalos P. N.
Published: August 2005

Summary: Purpose: To determine whether repeat boluses of diazepam (DZP) lead to significant accumulation in the central nervous system and/or peripheral compartments, as repeat intravenous boluses of diazepam are commonly used in the treatment of status epilepticus (SE).

Methods: In a rat model that permits simultaneous serum and cerebrospinal fluid (CSF) sampling, we characterized the pharmacokinetics of DZP and its metabolite, desmethyldiazepam, in CSF and blood using HPLC. DZP was administered by intraperitoneal injection as either a single dose (20 or 30 mg/kg) or repeat doses (10 or 20 mg/kg × 3, 1 h apart).

Results: After a single intraperitoneal dose, DZP was rapidly absorbed with a time to maximum concentration of 10 min. The serum concentrations then declined biexponentially. DZP rapidly entered the CSF; the CSF to serum ratio reached equilibrium within 10 min, and was equivalent to the ratio of free to total serum concentration. Repeated DZP dosing resulted in a threefold decrease in volume of distribution and clearance (p < 0.001). This was reflected in the CSF concentration data; how‐ever, after the third dose, the ratio of CSF to serum concentration, also increased greatly, representing further persistence of DZP in the CSF compartment.

Conclusions: Repeat dosing of DZP leads to substantial accumulation, and high, persistent serum and CSF concentrations, which may explain the toxic effects of repeat DZP dosing. Repeat dosing of DZP using a tapering protocol, however, may increase the effectiveness of DZP in treating SE by preventing relapses without substantially increasing toxicity.
Astrocytes from Human Hippocampal Epileptogenic Foci Exhibit Action Potential–Like Responses
Authors: O'Connor Edward R. , Sontheimer Harald , Spencer Dennis D. , de Lanerolle Nihal C.
Published: August 2005

Summary: Purpose: We studied Na+ channel expression and the ability to generate action potential (AP)‐like responses in primary cultures of human astrocytes by whole cell patchclamp recording techniques.

Methods: Tissue samples from 22 patients with various classifications of temporal lobe epilepsy (TLE) were plated to form separate astrocyte cultures from three regions; the hippocampus, parahippocampus, and anterolateral temporal neocortex.

Results: The resting membrane potential of seizure focus astiocytes (MTLE, mesial TLE) was significantly depolarized (approximately ‐55 mV) as compared with cortical astrocytes (‐80 mV). Hippocampal astrocytes from other substrates for TLE (MaTLE, mass‐associated TLE; PTLE, paradoxical TLE) in which the hippocampus is not the seizure focus displayed resting membrane potentials similar to those of neocortical astrocytes (approximately ‐75 mV). Astrocytes from the seizure focus (MTLE) displayed much larger tetrodotoxin (TTX)‐ sensitive Na+ currents with ‐66‐fold higher Na+ channel density (113.5 ± 17.41 pA/pf) than that of comparison neocortical astrocytes (1.7 ± 3.7 pA/pf) or than that of the hippocampal and parahippocampal astrocytes of the MaTLE and PTLE groups. As a consequence of this higher channel density, seizure focus astrocytes were capable of generating AP‐like responses. However, at the resting potential, most Na+ channels are inactive and no spontaneous firing was observed. In contrast, astrocytes in the comparison neocortex from all groups and the hippocampus and parahippocampus from the MaTLE and PTLE groups could not fire AP‐like responses even after large current injections.

Conclusions: The function of Na+ channels in these astrocytes is unclear. However, the marked differences in seizure focus astrocytes as compared with cortical and nonseizure focus hippocampal astrocytes suggest a more active role for astrocytes associated with hyperexcitable neurons at a seizures focus.
Functional Plasticity After Left Anterior Temporal Lobectomy: Reconstitution and Compensation of Verbal Memory Functions
Authors: Helmstaedter C. , Elger C. E.
Published: August 2005

Summary:Purpose:This study investigated the functional plasticity of the brain to reconstitute and compensate for verbal memory functions after epilepsy surgery of left temporocortical and temporomesial structures. We hypothesized that memory outcome would be best when surgery is performed within the period of cerebral plasticity, and that the outcome should be worst when fluid intelligence starts to decrease with physiologic aging. We also raised the question of different plasticity and compensation mechanisms for temporomesial and temporocortical memory functions.

Methods: We evaluated preoperative and l‐year‐post‐ operative memory data and other verbal functions in 104 patients with epilepsy, who underwent a standard left anterior temporal lobe. resection. We used memory measures that had been previously shown to be most selective for mesial and lateral functions, respectively. Determinants of postoperative memory outcome were evaluated by multiple regression analysis. Group statistics were calculated on the basis of the periods that are usually assumed to be significant for plasticity and behavioral compensation. Individual postoperative changes in memory functions were evaluated on the basis of test‐retest data obtained in a group of 100 non‐surgical patients with localization‐related epilepsies (mean retest interval >12 months).

Results:Only changes in cortically represented learning and data acquisition were related to age, plasticity, and capacities for behavioral compensation. No patient in the youngest group (younger than 15 years), 33% of patients who had surgery between the ages of 15 and 30 years, and 61% of the patients undergoing surgery older than age 30 years had significant deterioration in verbal learning. In contrast, postoperative changes in temporomesial consolidation/retrieval processes were independent of age at the time of surgery, plasticity, and capacities for behavioral compensation.

Conclusions:Our data indicate different time windows for the reconstitution and compensation of mesial and cortical as‐ pects of memory. Whereas the reconstitution of and compensation for cortical functions appear restricted by decreasing plasticity and physiological aging, mesial functions seem to be reconstituted by contralateral mesial structures over a much longer period. Concerning drug‐resistant localization‐related epilepsies, our results justify early consideration of surgery, especially when cortical structures are affected.
De Novo Psychogenic Nonepileptic Seizures After Epilepsy Surgery
Authors: Parra Jaime , Iriarte Jorge , Kanner Andres M. , Bergen Donna C.
Published: August 2005

Summary: Purpose: The occurrence of de novo nonepileptic seizures (NES) after epilepsy surgery have been reported only twice in the literature (one article and one abstract).

Methods: We report three patients whose de novo NES were documented by video‐EEG telemetry after epilepsy surgery. These patients were drawn from a sample of 166 consecutive patients who underwent epilepsy surgery at our center between 1989 and 1996.

Results: Two patients became seizure free after surgery, and one had significant improvement of her seizures. The interval between the date of surgery and the development of the symptoms was variable (8, 10, and 47 months, respectively). The clinical phenomena of NES differed from those of the epileptic seizures preceding surgery. Their diagnosis had not been suspected in two patients before the diagnostic video‐EEG monitoring study. After the diagnosis of NES, spells stopped in two patients and recurred rarely in one.

Conclusions: We conclude that de novo NES appears to occur rarely after epilepsy surgery. Given that the possibility of NES was suspected in only one patient, its incidence after surgery may be higher than so far reported. Physicians should therefore consider NES in the differential diagnosis of recurrent seizures after a seizure‐free period after epilepsy surgery.
Criteria to Assess In Vivo Performance and Bioequivalence of Generic Controlled‐Release Formulations of Carbamazepine
Authors: Bialer Meir , Yacobi Avi , Moros Daniel , Levitt Barrie , Houle Jean‐Marie , Munsaka Melvin S.
Published: August 2005

Summary: Purpose: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled‐release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (Cmax), and time to reach Cmax (tmax), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time‐concentration curve. They include mean residence time (MRT), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), tapical, and Capical, (the arithmetic mean of the POT times and concentrations within 25% of Cmax respectively). Additional parameters for multiple‐dose studies include the percentage fluctuation and the flatness of the steady state‐concentration curve.

Methods: These proposed parameters were used in two recent (single and multiple dose) two‐way crossover studies of a new CR product of CBZ (Teril 400 CR) in comparison with Tegretol CR Divitab.

Results: Teril 400 CR was found to be bioequivalent to Tegretol CR Divitab, by using both the classic and the additional proposed parameters. Both CBZ CR products have similar rates of absorption and similar flatness of their plasma time‐concentration curves as assessed by visual inspection and the proposed parameters.

Conclusions: The additional parameters examined may supplement the traditional single‐point parameters, Cmax and tmax for assessment of rate of absorption and the flatness of the concentration curve. Their potential benefit and practical utility was confirmed in these two studies. Absorption‐rate assessment is important in light of concentration‐related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.
Cerebellar Changes in Partial Seizures: Clinical Correlations of Quantitative SPECT and MRI Analysis
Authors: Bohnen Nicolaas I. , O'Brien Terence J. , Mullan Brian P. , So Elson L.
Published: August 2005

Summary: Purpose: To determine the frequency and patterns of periictal cerebellar hyperperfusion, whether it is associated with increased cerebellar atrophy, and whether cerebellar hyperperfusion and cerebellar atrophy are associated with predisposing clinical factors or with the outcome of epilepsy surgery.

Methods: Periictal and interictal SPECT scans and volumetric brain magnetic resonance imaging (MRI) were quantitatively analyzed in 54 consecutive patients with medically refractory partial epilepsy. Their histories were reviewed and their postsurgical outcomes assessed.

Results: Significant periictal cerebellar hyperperfusion was found in 26 (48.1%) patients, of whom 18 had CCH, two had homolateral cerebellar hyperperfusion (HCH), and six had symmetrical bilateral hyperperfusion (BCH). No relation found between the site of the SPECT seizure localization and the presence or type of cerebellar hyperperfusion. CCH was more common when the injected seizure involved unilateral clonic motor activity (p < 0.05). A smaller MRI relative cerebellar volume (cerebellar volume/cerebral volume) was correlated with a greater seizure frequency (Rs= ‐0.30; p < 0.05) but not with the duration of epilepsy. There was no difference in the cerebellar volumes between the different patterns of cerebellar perfusion (p > 0.05). However, patients without a focal structural MRI lesion had significantly smaller cerebellar volumes (p < 0.05). In patients who underwent epilepsy surgery (n = 31), there was a trend for those without excellent outcomes to have smaller relative cerebellar volumes than did those with excellent outcome (10.6 vs. 11.8%; p = 0.08).

Conclusions: Periictal changes in cerebellar perfusion, particularly CCH, are common in patients with intractable partial epilepsy. However, periictal hyperperfusion does not appear to be a major contributor to the development of cerebellar atrophy.
Location of the Epileptic Zone and Its Physiopathological Effects on Memory‐Related Activity of the Temporal Lobe Structures: A Study with Intracranial Event‐Related Potentials
Authors: Guillem François , N'Kaoua Bernard , Rougier Alain , Claverie Bernard
Published: August 2005

Summary: Purpose: Neuropsychological research with epileptic patients has suggested that the location of seizure focus may be an important variable determining the nature and severity of memory impairments. According to this assumption, this study was designed to investigate the effects of the location of the epileptic zone on the memory‐related activity recorded directly from different temporal lobe structures.

Methods: Intracranial event‐related potentials (ERPs) were recorded during a continuous recognition memory task, which is known to elicit the modulation of N400 and P600 components (i.e., the ERP old/new effect). The patients were separated into three groups according to the location of their epileptic zone: unilateral temporal (UTE), temporal plus extra‐temporal (TEE), and bitemporal (BTE). Recordings were obtained from three temporal lobe structures: hippocampus, amygdala, and lateral temporal cortex.

Results: The results showed that in the hippocampus, the ERP oldhew effect was abolished in the TEE group only. In the amygdala, although largely unaffected, the ERP modulation appeared to be more impaired in UTE patients. Contrasting with these data is the observation that the magnitude and reliability of the ERP oldnew effect recorded at the neocortical level increases as the epileptic zone extends to the temporal lobes (i.e., BTE>TEE>UTE).

Conclusions: It is concluded that the memory‐related activity modulation of memory ERPs recorded from different temporal lobe structures is affected differently by the presence of an epileptic zone as a function of its location. The possible clinical implications of these findings in surgery planning are also discussed.
Single Photon Emission Computed Tomography (SPECT) in a Patient with Bilateral Temporal Seizures: Correlation Between Ictal EEG and Postictal/Ictal SPECT
Authors: Setoain F. J. , Arroyo S. , Lomeñia F. , Pavía J. , Martinez I. , Fuster D. , Herranz R. , Setoain J.
Published: August 2005

Summary: We report a patient with bilateral independent temporal lobe seizures in whom two [99mTc]HMPAO single photon emission computed tomograph (SPECT) scans were performed during two different seizures. In the first perüctal SPECT, [99mTc]HMPAO was injected in the interval between two closely spaced seizures (one localized in the left temporal lobe and the other in the right temporal lobe). SPECT images showed hypoperfusion in the left lateral temporal lobe, hyper‐perfusion of the left mesial temporal region, and pronounced hyperperfusion in the right anterior temporal lobe. These results suggest both a postictal left temporal SPECT pattern and an ictal right temporal pattern. In the second periictal SPECT, [99mTc]HMPA was injected immediately after a right temporal lobe seizure and showed right lateral temporal lobe hypoperfusion and right mesial hyperperfusion, suggesting a postictal right temporal SPECT pattern. Interpretation of the periictal SPECT should take into account EEG changes at the time or in the minutes immediately after injection of [99mTc] HMPAO.
Acute Management of Hypersensitivity Reactions and Seizures
Authors: Griebel May L.
Published: August 2005

Summary: The most crucial step in the management of an antiepileptic drug (AED) hypersensitivity reaction is the recognition of the clinical syndrome and cessation of the presumed offending agent. The severity of the developing reaction will shape the course of treatment because multiple organ systems may become affected. Management of conjunctival involvement and treatment of skin lesions dominate care, with patients whose skin lesions are extensive benefitting from treatment in a structured burn unit. Neutropenia and sepsis are common and potentially fatal complicating factors. The use of steroids remains controversial, as is the utility of immune modulation with other agents such as cyclophosphamide and i.v. immunoglobulin. Acute treatment of seizures should be addressed with i.v. benzodiazepines, given either intermittently or by continuous infusion. Choice of long‐term maintenance AEDs should take into consideration the crossreactivity among AEDs that share an arene oxide metabolite.