bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactions of Lamotrigine with Topiramate and First‐generation Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis
Authors: Luszczki Jarogniew J. , Czuczwar Mirosław , Kis Jacek , Krysa Jacek , Pasztelan Ireneusz , Swiader Mariusz , Czuczwar Stanislaw J. 
Published: July 2003

Summary:  Purpose: The study investigated the types of interactions between lamotrigine (LTG) and first‐generation antiepileptic drugs (AEDs) or topiramate (TPM) with isobolographic analysis. Methods: Anticonvulsant and adverse‐effect profiles of combinations of LTG with other AEDs, at fixed ratios of 1:3, 1:1, and 3:1, were evaluated in the maximal electroshock (MES)‐induced seizures and the chimney test (motor performance) in mice, which allowed the determination of benefit indices (BIs) for individual combinations. Results: Combinations of LTG with TPM or valproate (VPA), at fixed ratios of 1:1, were significantly supraadditive (synergistic) in the MES test and, simultaneously, subadditive (antagonistic) in the chimney test, showing the best profile for AED combinations. In contrast, combinations between LTG and carbamazepine (CBZ), in terms of antiseizure protection against MES, were subadditive (antagonistic) and additive in the chimney test, resulting in unfavorable AED combinations. Moreover, the combination of LTG with phenobarbital (PB), at a fixed ratio of 1:1, despite synergy in the MES test, also was synergistic in the chimney test, resulting in a modest BI for AED combination. LTG combined with phenytoin was additive in both the MES and chimney tests in mice. The remaining combinations, at fixed ratios not mentioned earlier, also showed an average BI for AED combinations. Furthermore, LTG combined with all studied AEDs did not affect long‐term memory in mice. None of the AEDs influenced the free plasma level of LTG, whereas LTG slightly reduced the free plasma concentration of PB. Conclusions: Interactions between LTG and TPM or LTG and VPA at a fixed ratio of 1:1 might be profitable from a preclinical point of view, displaying the most optimal BI.
Altered Hippocampal Expression of Neuropeptides in Seizure‐prone GALR1 Knockout Mice
Authors: Fetissov Sergueï O. , Jacoby Arie S. , Brumovsky Pablo R. , Shine John , Iismaa Tiina P. , Hökfelt Tomas 
Published: July 2003

Summary:  Purpose: Mice carrying a deletion of the GALR1 galanin receptor have recently showed spontaneous seizure phenotype with 25% penetrance. To better understand the role of neuropeptides, which are known to undergo complex plasticity changes with development of epileptic seizures, we characterized their expression in the hippocampal formation in GALR1‐ knockout (‐KO) mice with or without seizures and in wild‐type (WT) mice. Methods: Immunohistochemistry and in situ hybridization were used to study expression of galanin, neuropeptide Y (NPY), substance P, enkephalin, dynorphin, and cholecystokinin (CCK). Results: In GALR1‐KO mice that had been displaying seizures, a strong upregulation of galanin immunoreactivity (ir) and messenger RNA (mRNA) was found in the polymorph layer of the dentate gyrus; galanin‐ir also appeared in a dense fiber network in the supragranular layer. A strong upregulation of enkephalin was found in the granule cells/mossy fibers, whereas dynorphin mRNA levels were modestly decreased. NPY was strongly expressed in the granule cells/mossy fibers, and an increase of NPY mRNA levels in the polymorph cells was paralleled by an increase of NPY‐ir in the molecular layer. An upregulation of substance P‐ir was confined to the fibers in the granule and molecular layers, whereas substance P mRNA was increased in the cells of the polymorph layer. Both CCK‐ir and mRNA were strongly downregulated in the granule cell/mossy fiber system, but CCK‐ir appeared increased in the supragranular and molecular layers. No changes in neuropeptide‐ir were found in GALR1‐KO mice not displaying seizures. Conclusions: Complex changes in neuropeptide expression in some principal hippocampal neurons and interneurons appear as a characteristic feature of the spontaneous‐seizure phenotype in GALR1‐KO mice. However, to what extent causal relations exist between this “epilepsia peptidergic profile” and development of seizures requires further clarification.
Induction of Prolonged Electrographic Seizures In Vitro Has a Defined Threshold and Is All or None: Implications for Diagnosis of Status Epilepticus
Authors: Rafiq Azhar , Gong Qui‐Zhi , Lyeth Bruce G. , DeLorenzo Robert J. , Coulter Douglas A. 
Published: July 2003

Summary:  Purpose: To study whether induction of prolonged (>30‐min duration) in vitro electrographic seizure discharges resembling status epilepticus (SE) is graded or all‐or‐none, and to determine the critical factors mediating SE induction. Methods: Prolonged electrographic seizure discharges were induced in combined hippocampal–entorhinal cortical (HEC) brain slices by electrical stimulation of the Schaeffer collaterals. Discharges were recorded by using field‐potential electrodes in the dentate gyrus, CA3, CA1, and entorhinal cortex. Slices were prepared from rats that were (a) 21‐ to 30‐day‐old naive, (b) 60‐ to 120‐day old naive, (c) epileptic, and (d) status post a prior traumatic brain injury. Results: Induction of SE discharges was dependent on the duration, but not amplitude of the preceding stimulus train–induced afterdischarge in HEC slices from 21‐ to 30‐day‐old control, brain‐injured, and epileptic animals, but not from 60‐ to 120‐day‐old animals. In slices from 21‐ to 30‐day‐old control animals, once afterdischarges exceeded 4 min in duration, SE was induced in 50% of slices, and after ≥6 min 37 s seizure activity; SE was induced in 95% of slices. A defined SE threshold also was evident in brain‐damaged rats, including rats in which an epileptic condition was induced by pilocarpine injection 4–16 weeks before recording, and rats subjected to a fluid percussive head trauma 1–8 weeks before recording. However, in these brain‐damaged animals, mean SE threshold was considerably lower (24 and 44 s, respectively). HEC slices from 60‐ to 120‐day‐old controls for the brain‐injured and epileptic animals did not develop SE even after 20 stimulations, demonstrating the pronounced effect of brain injury and epilepsy on the development of SE in the HEC slice preparation compared with that in age‐matched controls. Conclusions: In vitro, SE discharges have a defined temporal threshold for initiation. Once a seizure exceeds 6–7 min in duration in control animals, and 30–55 s in brain‐damaged animals, the probability of SE induction is greatly increased. This demonstrates that brain injury lowers the afterdischarge duration required to produce SE and suggests that brains injured from trauma or SE are more susceptible to develop status epilepticus.
Short‐term Nonhormonal and Nonsteroid Treatment in West Syndrome
Authors: Capovilla Giuseppe , Beccaria Francesco , Montagnini Allesandra , Cusmai Raffaella , Franzoni Emilio , Moscano Filomena , Coppola Giangennero , Carotenuto Marco , Gobbi Giuseppe , Seri Stefano , Nabbout Rima , Vigevano Federico 
Published: July 2003

Summary:  Purpose: West syndrome (WS) is considered an age‐dependent epileptic encephalopathy and also a particular type of electrical epileptic status. Short‐term hormonal or steroid treatment of WS with good efficacy is reported in the literature. The aim of this retrospective multiinstitutional study was to evaluate the early discontinuation of nonhormonal and nonsteroid treatment for WS. Methods: Twenty‐two WS cases in which treatment was discontinued after a maximum of 6 months, were collected. Inclusion criteria were the presence of typical EEG hypsarrhythmia (HY) and video‐EEG recorded epileptic spasms. Exclusion criteria were the presence of partial seizures or other seizure types before spasm onset. The patients were treated with vigabatrin (VGB) in 19 cases and nitrazepam (NTZ) in three. The dose range was 70–130 mg/kg/day for VGB and 0.7–1.5 mg/kg/day for NTZ. The drug was discontinued if spasms stopped and HY disappeared after a mean treatment period of 5.1 months (range, 3–6 months). All patients underwent repeated and prolonged awake and sleep video‐EEG, both before and after drug discontinuation. Results: Cryptogenic (15) and symptomatic (seven) WS patients were included. All the symptomatic cases had neonatal hypoxic–ischemic encephalopathy. The mean age at spasm onset was 5.5 months (range, 3–7 months; median, 6). The interval between spasm onset and drug administration ranged from 7 to 90 days (mean, 23 days; median, 20). The interval between drug administration and spasm disappearance ranged from 2 to 11 days (mean, 6 days; median, 6 days). The interval between drug administration and HY disappearance ranged from 3 to 30 days (mean, 9 days; median, 10 days). Drugs were stopped progressively over a 30‐ to 60‐day period. Follow‐up ranged from 13 to 50 months (mean, 26 months; median, 22 months). None of our cases showed spasm recurrence. Conclusions: Our data show that successful nonhormonal and nonsteroid treatment can be shortened to a few months without spasm recurrence in patients with cryptogenic or postanoxic WS.
Identifying Potential Surgical Candidates in Patients with Evidence of Bitemporal Epilepsy
Authors: Holmes Mark D. , Miles Andrew N. , Dodrill Carl B. , Ojemann George A. , Wilensky Alan J. 
Published: July 2003

Summary:  Purpose: To determine which patients with evidence of medically refractory bitemporal epilepsy are potentially good candidates for surgical therapy. Methods: We reviewed 42 adults with intractable seizures who were found to have bitemporal ictal onsets, based on scalp video‐EEG long‐term monitoring (LTM). All underwent invasive LTM before surgery. Surgical outcomes were classified as seizure free, >75% reduction in seizures, or <75% reduction in seizures, ≥1 year after resection. We related the following factors to outcome: (a) >75% preponderance of interictal scalp EEG discharges to one temporal region; (b) magnetic resonance imaging (MRI) findings; (c) lateralizing deficits on verbal or visual reproduction memory testing; and (d) memory failure with injection contralateral to side of surgery on Wada testing. Results: Twenty‐six (62%) of 42 patients had unilateral ictal onsets based on intracranial studies. Seizure freedom (occurring in 64% of this group), or >75% seizure reduction (found in 12% of subjects) occurred only when at least one of the following three factors was concordant with the side of surgery: preponderance of interictal scalp EEG discharges, unilateral temporal lesion on MRI, or lateralizing verbal or visual reproduction memory deficits on neuropsychological tests (p = 0.004). Seven subjects with bilateral ictal onsets based on intracranial studies had resections based on preponderance of seizures to one side, or other lateralizing noninvasive abnormality. Five of these (all of whom had ≥80% of seizures originating from one side) had >75% reduction in seizures. Conclusions: Invasive monitoring to pursue possible surgical therapy for patients with surface EEG evidence of bitemporal epilepsy may be justified only when some lateralizing feature is found in other noninvasive assessments.
Assessment of CNS Effects of Antiepileptic Drugs by Using Quantitative EEG Measures
Authors: Salinsky Martin C. , Oken Barry S. , Storzbach Daniel , Dodrill Carl B. 
Published: July 2003

Summary:  Purpose: Antiepileptic drugs (AEDs) can be associated with adverse neurologic effects including cognitive dysfunction. Objective methods for recognizing AED effects on the brain could be valuable for long‐term management. We compared quantitative EEG measures and cognitive tests in a group of patients beginning or ending AED therapy. Methods: Subjects included 20 patients beginning AED therapy (AEDon), 12 patients stopping AED therapy (AEDoff), 33 patient controls receiving stable AED therapy (AEDco), and 73 healthy controls (Nco). All subjects underwent structured EEG recording and a cognitive test battery before change in AED dose and again 12–16 weeks later, ≥4 weeks after the last dose change. Four occipital EEG measures (peak frequency, median frequency, relative theta and delta power) were analyzed. Cognitive test changes were scored by using test–retest regression equations based on the Nco subjects. Wilcoxon tests were used for two‐group comparisons. Results: AEDons had a significant decrease, and AEDoffs, a significant increase in the peak frequency of the EEG rhythm, as compared with controls. Results for median frequency and theta power were similar. Change in the EEG peak frequency correlated with an aggregate cognitive change measure (r2= 0.71; p < 0.001), individual cognitive measures, and subjective complaints. Of the combined AEDon/AEDoff patients, 58% exceeded the 95% confidence interval for test–retest change in EEG peak frequency. Conclusions: Quantitative measures derived from the occipital EEG are sensitive to AEDs and correlate with AED‐related cognitive effects and subjective complaints. Although this correlation does not indicate a direct relation, quantified EEG may be a practical measure of AED impact on the brain.
Valproate Inhibits the Conversion of Testosterone to Estradiol and Acts as an Apoptotic Agent in Growing Porcine Ovarian Follicular Cells
Authors: Taubøll Erik , Gregoraszczuk Ewa L. , Kołodziej Anna , Kajta Małgorzata , Ropstad Erik 
Published: July 2003

Summary:  Purpose: Long‐term valproate (VPA) treatment has been associated with hyperandrogenism and polycystic ovaries in women with epilepsy. The exact mechanisms of action of the drug on sex steroid hormone function are still unsettled. The aim of the present study was to investigate the action of VPA on basal and gonadotropin‐stimulated steroid secretion in porcine ovarian follicular cells and to measure the conversion of testosterone to estradiol. Second, the action of VPA on proliferation and apoptosis of follicular cells was investigated. Methods: Small and medium follicles were obtained from pig ovaries on days 8–10 and 14–16 of the estrus cycle. Both follicular compartments, theca and granulosa cells, were cultured as a coculture resembling follicles in vivo. VPA in concentrations of 100 and 250 μg/ml was added to the control or gonadotropin‐stimulated cultures. Results: VPA caused a significant increase in basal and luteinizing hormone (LH)‐stimulated testosterone secretion from small follicles, whereas in medium follicles, an increased basal but decreased LH‐stimulated testosterone secretion was found. VPA caused decreased basal and follicle‐stimulating hormone (FSH)‐stimulated estradiol secretion by small follicles, whereas only the higher concentration decreased estradiol secretion in medium follicles. The conversion of testosterone to estradiol by small follicles was decreased under the influence of VPA in testosterone‐alone and in testosterone‐plus‐FSH–stimulated cultures, whereas this was seen at only the higher VPA concentration in medium follicles. VPA had no effect on cell proliferation and viability, whereas in a dose‐dependent manner, VPA increased caspase‐3 activity. Conclusions: VPA affected steroidogenesis in both unstimulated and gonadotropin‐stimulated porcine ovarian follicular cells and inhibited the conversion of testosterone to estradiol. In addition, VPA may act as an apoptotic agent in both small and medium‐sized follicles.
Diazepam Terminates Brief but Not Prolonged Seizures in Young, Naïve Rats
Authors: Goodkin Howard P. , Liu Xianzeng , Holmes Gregory L. 
Published: July 2003

Summary:  Purpose: Ample evidence exists from both clinical and animal studies that the success of benzodiazepine intervention during status epilepticus (SE) in the mature nervous system is inversely related to seizure duration. This relationship has not been well studied in the developing nervous system. Methods: The objective of this study was to investigate the relation of age and success of diazepam (DZP) treatment in the lithium‐pilocarpine model of secondarily generalized seizure in the rat by using naïve rats of three age groups, roughly corresponding to the human ages of infancy (P15), adolescence (P20), and adult (P60). Results: In all age groups, the dosage of DZP that stopped the seizures at 5 min was not effective in terminating seizures at 60 min. This decline in efficacy was present as early as 15 min after seizure onset. Conclusions: These findings demonstrate that the inverse relation between the success of benzodiazepine intervention and seizure duration is observed in young as well as in adult rats and provide further evidence that intervention for SE should commence early.
Entorhinal Cortex MRI Assessment in Temporal, Extratemporal, and Idiopathic Generalized Epilepsy
Authors: Bernasconi Neda , Andermann Frederick , Arnold Douglas L. , Bernasconi Andrea 
Published: July 2003

Summary:  Purpose: We previously showed a reduction in the volume of the entorhinal cortex (EC) ipsilateral to the seizure focus in patients with intractable temporal lobe epilepsy (TLE). The purpose of this study was to examine the specificity of EC atrophy in epilepsy. Methods: We performed volumetric measurement of the EC on high‐resolution magnetic resonance imaging (MRI) in patients with TLE (n = 70), extratemporal lobe epilepsy (ETE; n = 18), and idiopathic generalized epilepsy (IGE; n = 20). EC volumes of epilepsy patients were compared with those of 48 age‐ and sex‐matched normal controls. Within the TLE group, 63 patients were selected prospectively with hippocampal atrophy ipsilateral to the seizure focus. The remaining seven patients were chosen retrospectively based on normal volumetric MRI of the hippocampus and amygdale, as well as normal histopathologic examination of the resected tissue. Results: Compared with normal controls, EC volume was smaller ipsilateral but not contralateral to the seizure focus in patients with TLE (p < 0.001). No difference in the EC volumes ipsilateral and contralateral to the seizure focus was seen in patients with ETE and IGE compared with normal controls. The individual analysis showed that the EC was atrophic in 73% of TLE patients with hippocampal atrophy. Three of the seven TLE patients with normal volumetric MRI of the hippocampus and amygdala and normal histopathologic examination had EC atrophy ipsilateral to the seizure focus. In no patient with ETE or IGE was the EC found to be atrophic. Conclusions: EC atrophy ipsilateral to the seizure focus appears to be specific to mesial temporal lobe structural damage associated with TLE.
Protection Provided by Cyclosporin A against Excitotoxic Neuronal Death Is Genotype Dependent
Authors: Santos Julia Belen , Schauwecker Paula Elyse 
Published: July 2003

Summary:  Purpose: Previous studies have shown that the immunosuppressant cyclosporin A (CsA), a specific blocker of the mitochondrial permeability transition (MPT) pore, can dramatically ameliorate the selective neuronal necrosis resulting from ischemia–reperfusion, traumatic brain injury, and N‐methyl‐d‐aspartate (NMDA)‐evoked neurotoxicity. The purpose of this study was to determine whether two different immunosuppressants, CsA and FK‐506, could ameliorate the neuronal damage observed after kainate‐induced seizures in strains that are differentially susceptible to excitotoxin‐induced cell death. Methods: Excitotoxin‐resistant (C57BL/6) or ‐susceptible (FVB/N) mice were administered kainate alone (30 mg/kg), CsA alone (5, 10, or 20 mg/kg), or one of the immunosuppressants (CsA, 5 mg/kg or 10 mg/kg; FK‐506, 0.5 mg/kg) followed by kainate. After drug administration, mice were monitored continuously for the onset and extent of seizure activity. After a survival of 7 days, animals were assessed for hippocampal damage. Results: Whereas CsA alone induced no epileptogenic effects and both immunosuppressants were without effect on the induction of kainate‐induced seizures, administration of CsA to excitotoxin‐susceptible mice (FVB/N) virtually eliminated neuronal cell death. In contrast, induction of neuronal cell death was evident when CsA was administered to excitotoxin‐resistant mice (C57BL/6). Administration of FK‐506, another commonly used immunosuppressant, which lacks an effect on the MPT, had no effect on modification of susceptibility to kainate‐induced cell death in either strain. Conclusions: As our data show differential protection of hippocampal neurons against excitotoxic cell death by pretreatment with CsA, these results suggest that strain‐dependent differences in mitochondrial integrity and function may exist.
Angelman Syndrome: Difficulties in EEG Pattern Recognition and Possible Misinterpretations
Authors: Valente Kette D. , Andrade Joaquina Q. , Grossmann Rosi M. , Kok Fernando , Fridman Cintia , Koiffmann Célia P. , Marques‐Dias Maria J. 
Published: July 2003

Summary:  Purpose: This study aimed to evaluate the sensitivity of the EEG in Angelman syndrome (AS), to verify the age at onset of suggestive EEGs and to study EEG patterns, analyzing variations and comparing our findings with nomenclature previously used. Methods: Seventy EEG and 15 V‐EEGs of 26 patients were analyzed. Suggestive EEG patterns of AS were classified in delta pattern (DP), theta pattern (TP), and posterior discharges (PDs). Generic terms were used to simplify the analysis. Results: Suggestive EEGs were observed in 25 (96.2%) patients. DP occurred in 22 patients with four variants—hypsarrhythmic‐like: irregular, high‐amplitude, generalized delta activity (DA) with multifocal epileptiform discharges (EDs); slow variant: regular, high‐amplitude, generalized DA with rare EDs; ill‐defined slow spike‐and‐wave: regular, high‐amplitude, generalized DA with superimposed EDs characterizing a slow wave, with notched appearance; triphasic‐like: rhythmic, moderate‐amplitude DA over anterior regions with superimposed EDs. TP was observed in eight patients, as generalized or over the posterior regions. PDs were seen in 19 patients as runs of sharp waves or runs of high‐amplitude slow waves with superimposed EDs. TP was the only age‐related pattern (younger than 8 years) and observed only in patients with deletion. In 15 patients who had an EEG before the clinical diagnosis, 60% had a suggestive tracing. Conclusions: Although some EEG descriptions are not very detailed, and every author describes findings in a slightly different manner, obviously a common denominator must exist. In this context, EEG seems to be a very sensitive method for the diagnosis of AS, offering an opportunity to corroborate this etiologic diagnosis. Conversely, we do not believe that these patterns may be accounted as specific, except for the delta pattern, which seems to be extremely unusual in other syndromes. Other EEG patterns observed in AS, such as theta activity and PDs, occur in a wide variety of disorders. Nonetheless, their importance for the EEG diagnosis of AS is supported by the fact that they are associated with other features and may be helpful in a proper clinical setting.