[Evaluation of the effectiveness of add-on therapy with tiagabine and evaluation of cognitive functions after application of this therapy in patients with drug-resistant focal epilepsy - an observational study (GABI-EPI)]. / Ocena skutecznosci terapii dodanej tiagabina oraz ocena funkcji poznawczych po zastosowaniu tej terapii u pacjentów z ogniskowa padaczka lekoodporna - badanie obserwacyjne (GABI-EPI).

OBJECTIVE: To assess the efficacy of add-on therapy with tiagabine and cognitive functions in patients with drug-resistant focal epilepsy, when used in everyday clinical practice. MATERIALS AND METHODS: The total number of 437 patients with drug-resistant epilepsy with focal seizures were observed; 436 patients were treated with tiagabine as add-on therapy at a dose of 5-50 mg per day. During the study a number visits were secheduled: Visit V0 - upon enrolment of tiagabine-treated patients into the observational study, visit V1 - four weeks after reaching the initial dose of tiagabine, visit V2 - four weeks after reaching the target dose of tiagabine. The type and number of epileptic seizures, antiepileptic therapy used, concomitant treatment and adverse events were analysed. Analyses were performed using McNemar's, Wilcoxon's, Mann-Whitney's and Fisher's tests. The patients'cognitive functions were assessed using the MM SE scale. RESULTS: The mean observation time was 90 days. Men accounted for 48.3% of the study population and their average age was 41,5±14,0 and women accounted for 51.7% and their average age was 43.4±13.9. About 80% of the patients received valproic acid or carbamazepine before administration of tiagabine. Other most commonly used drugs included acetylsalicylic acid and ramipril. In the group of 185 patients who used drugs inducing liver enzymes before administration of tiagabine, 13% received a dose below 30 mg of tiagabine and 87% above 30 mg. In the group of patients treated with drugs which do not induce liver enzymes, 91.6% received tiagabine in a dose below 30 mg and 8.4% in a dose above 30 mg. The percentage of patients experiencing epileptic seizures was reduced from 72.2% between visits V0-V1 to 58.7% between visits V1-V2 (p<0.001). A decrease in the population of patients who experienced seizures and a reduction of the number of seizures were observed in all age groups. In the youngest age group, the number of seizures since the last visit went down from 5.4 to 3.7 (the average difference amounted to 1.7), in the 40-59 years age group, the number of seizures went down from 4.0 to 3.1 (the average difference amounted to 0.9) and in patients above the age of 60, from 3.0 to 2.1 (the average difference amounted to 0.9) (p<0.001; p=0.001 and p<0.001, respectively). Adverse events occurred in 4 (i.e. 0.9%) patients, dizziness being the most common. The Mini Mental State Examination (MM SE) was performed in 25% of patients. Cognitive functions did not deteriorate. The average MM SE score corresponded to a mild level of cognitive impairment. CONCLUSIONS: Tiagabine is a well tolerated drug providing effective control of focal seizures and in a sub-population of 25% patients whose cognitive functions were evaluated using MM SE, no significant adverse effect of the drug on such functions was observed.

A novel design for a dose finding, safety, and drug interaction study of an antiepileptic drug (retigabine) in early clinical development.

OBJECTIVE: To obtain information on the acceptable doses of the antiepileptic drug (AED) retigabine (RTG), the maximum tolerated dose (MTD), drug interactions, safety and tolerability, and preliminary evidence of efficacy when administered as adjunctive therapy and as monotherapy. MATERIALS: Study 202 was an open-label, add-on study in patients with partial or generalized epilepsy treated with valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), or topiramate (TPM) as monotherapy. Following baseline assessments, patients entered a dose titration phase of 28 – 56 days. The initial daily RTG dose was 100 or 200 mg (2 or 3 × daily). The RTG dose was increased every 1 - 2 weeks by 50 - 200 mg to a maximum of 1,600 mg/day. Once the RTG MTD had been attained, patients entered a 14-day maintenance period. Following this, the patient's background AED dose could be reduced, with the possibility of achieving RTG monotherapy. The final dosing regimen attained was maintained for an additional 14 days. Patients who completed study 202 could choose to continue treatment with RTG (with or without other AEDs) in study 208, the long-term extension of study 202. Safety assessments included adverse event (AE) monitoring, clinical laboratory evaluations, electrocardiograms, and physical and neurologic examinations. Patients' seizure diaries to assess the frequency and type of seizures, the percentage change in seizure rate, and the responder rate (>= 50% reduction in seizure rate from baseline) were evaluated. RESULTS: 60 patients (mean age 37.2, range 16 - 64 years) were enrolled in study 202, and 47 (78%) continued treatment with RTG in the extension study (208). In study 202, the most commonly reported AEs were: dizziness (53%), asthenia (42%), somnolence (33%), nausea (27%), speech disorder (27%), and tremor (27%). In the extension study, AEs were similar and included dizziness, somnolence, diplopia, feeling "drunk", confusion, fatigue, and dysarthria. The median percent reductions in 28-day seizure rate, relative to baseline in Studies 202 and 208, were ~ 20% and 47%, respectively. RTG did not alter the pharmacokinetics of the four monotherapy AEDs investigated. CBZ and PHT increased RTG clearance by 27% and 36%, respectively, whereas TPM and VPA had no effect on RTG clearance. CONCLUSIONS: Studies 202 and 208 provided critical information on RTG safety and tolerability, and reductions in seizure rates towards the design and conduct of subsequent pivotal clinical trials. Likewise, information regarding the appropriate dosage of RTG with VPA, CBZ, PHT, or TPM was obtained, which permitted the subsequent pivotal trials to be performed appropriately. *Currently at Shire Pharmaceuticals, Behavioral Health Business Unit, Wayne, PA, USA **Currently at University of Pennsylvania, Department of Neurology, Philadelphia, PA, USA.

Seizure outcome of surgical treatment of focal epilepsy associated with low-grade tumors in children.

OBJECT: Low-grade tumor (LGT) is an increasingly recognized cause of focal epilepsies, particularly in children and young adults, and is frequently associated with cortical dysplasia. The optimal surgical treatment of epileptogenic LGTs in pediatric patients has not been fully established. METHODS: In the present study, the authors retrospectively reviewed 30 patients (age range 3-18 years) who underwent surgery for histopathologically confirmed LGTs, in which seizures were the only clinical manifestation. The patients were divided into 2 groups according to the type of surgical treatment: patients in Group A (20 cases) underwent only tumor removal (lesionectomy), whereas patients in Group B (11 cases) underwent removal of the tumor and the adjacent epileptogenic zone (tailored surgery). One of the patients, who underwent 2 operations, is included in both groups. Follow-up ranged from 1 to 17 years. RESULTS: Sixteen (80%) of 20 patients in Group A had an Engel Class I outcome. In this group, 3 of 4 patients who were in Engel Classes II and III had temporomesial lesions. All patients in Group B had temporomesial tumors and were seizure free (Engel Class I). In this series, in temporolateral and extratemporal tumor locations, lesionectomy yielded a good seizure outcome. In addition, a young age at seizure onset (in particular < 4 years) was associated with a poor seizure outcome. CONCLUSIONS: Tailored resection in temporomesial LGTs was associated with excellent seizure outcome, indicating that an adequate presurgical evaluation including extensive neurophysiological evaluation (long-term videoelectroencephalography monitoring) to plan appropriate surgical strategy is advised.

Minocycline- and tetracycline-class antibiotics are protective against partial seizures in vivo.

INTRODUCTION: Increasing evidence suggests the role of inflammation in enhancing neuronal excitability and contributing to epileptogenesis. Tetracycline-class antibiotics minocycline, doxycycline and tetracycline have been shown to have anti-apoptotic and anti-inflammatory effects. METHODS: We investigated the anti-seizure effects of tetracycline-class antibiotics minocycline, doxycycline and tetracycline in vivo by using the maximal electric shock (MES), 6-Hz (minimal clonic seizure) test and subcutaneous Metrazol (scMET) models of epilepsy. RESULTS: Minocycline, doxycycline and tetracycline showed anticonvulsant effects in abolishing partial seizures in the mouse 6-Hz seizure test. A dose-dependent effect was found, with ED(50) of 170 mg/kg for minocycline, 157 mg/kg for doxycycline, and 255 mg/kg for tetracycline with peak onset at 0.5h. At high doses, minocycline (250 mg/kg) and doxycycline (150 mg/kg) also had toxic effects, from motor impairments to respiratory failure and death. These drugs had no effects on the MES and scMET tests. CONCLUSIONS: In the three tests of anti-seizure activity, minocycline, doxycycline, and tetracycline were found to be protective in one: the 6-Hz seizure model. Our data suggest that minocycline and other tetracycline-class drugs may offer some degree of anticonvulsant effect in the setting of CNS disease trials.

Is ictal dystonia associated with an inhibitory effect on seizure propagation in focal epilepsies?

PURPOSE: In focal epilepsy, ictal version and ictal dystonia are thought to reflect seizure spread into the frontal eye field and the basal ganglia, respectively. Here we investigated whether the occurrence of dystonia during seizure evolution reflects mechanisms preventing secondary generalization. To this aim, the evolution of seizures in patients with focal epilepsies was compared as to whether concomitant (1) dystonia, (2) dystonia and version, or (3) version occurred. METHODS: Seizure evolutions of 79 patients characterized by either dystonia (n=29; 232 seizures), dystonia and head version in the same seizure evolution (n=9; 83 seizures) or head version (n=41; 330 seizures), were included in the study. RESULTS: The rate of secondary generalization was significant lower in seizures with ictal dystonia (8%, 6 of 72 seizures) compared to seizures with ictal dystonia and version (62%, 13 of 21 seizures, p<0.0001) or compared to seizures with version (95%, 82 of 86 seizures, p<0.0001). CONCLUSION: This study shows that seizures with unilateral ictal dystonia are less likely to generalize as compared to seizures associated with version. This effect is likely to reflect the involvement of inhibitory mechanisms related to the basal ganglia, which exert an inhibiting effect on secondary seizure generalization.

Crisis No Epilépticas Psicógenas: a propósito de un caso / Psychogenic Non-Epileptic Seizures: a case report

Las crisis no epilépticas psicógenas (CNEP) son episodios paroxísticos de alteración conductual, que superficialmente parecen crisis epilépticas verdaderas, pero sin los cambios electroencefalográficos esperables ni la asociación a disfunción del sistema nervioso central. Suponen entre un 17 y un 30% de la población atendida en unidades de epilepsia de hospitales de tercer nivel para evaluación de crisis refractarias al tratamiento farmacológico. Estas crisis comprenden la mayoría de eventos paroxísticos no epilépticos y diversos estudios han encontrado una alta prevalencia a lo largo de la vida de múltiples trastornos psiquiátricos, incluso se ha observado la presencia simultánea de 2 o más diagnósticos psiquiátricos en el 70% de los pacientes. Ante la evidencia de ausencia de crisis epilépticas verdaderas, el primer paso es suprimir lentamente el tratamiento anticomicial. Posteriormente se debe iniciar un adecuado tratamiento psicofarmacológico en relación con las alteraciones psicopatológicas que muestre el paciente. Es preciso identificar las diversas variables emocionales y psicológicas que pueden estar incidiendo en la aparición y perpetuación de las CNEP y abordarlas mediante tratamiento psicológico. El objetivo de presentar este caso clínico es el de plantearlas dificultades que suele entrañar el diagnóstico diferencial entre epilepsia y CNEP, destacando la gran importancia del abordaje conjunto, neurológico y psiquiátrico, en el tratamiento de estos cuadros (AU)

Psychogenic Non-Epileptic Seizures (PNES) are paroxysmal episodes of altered behavior that superficially resemble epileptic seizures but lack both the expected electroencephalographical epileptic changes and the association to dysfunction of central nervous system. They account for 17 to 30% of the population admitted to epilepsy units of tertiary hospitals for evaluation of seizures refractory to the pharmacological treatment. These episodes include most of the paroxysmal non epileptic events and diverse studies have found a high prevalence of multiple psychiatric disorders during the lifetime. The simultaneous presence of 2 or more psychiatric disorders has even been observed in 70% of the patients. When there is evidence on the absence of real epileptic seizures, the first step is to slowly suppress the antiepileptic treatment. After, adequate psychopharmacological treatment should be initiated in relationship with the psychopathological state of the patient. The different emotional and psychological variables that may be affecting the appearance and perpetuation of PNES must be identified and then resolved with psychological treatment. The aim of the present case report is to present the difficulties of differential diagnosis between epilepsy and PNES, emphasizing the great importance of both neurological and psychiatric management in the treatment of these clinical symptoms (AU)

Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy.

PURPOSE: We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy. METHODS: Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation. RESULTS: One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and "most severe" seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events. DISCUSSION: Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.

Similar effects of lamotrigine and phenytoin against cortical epileptic foci in immature rats.

Action of antiepileptic drugs in immature brain may differ from that in adult brain. The aim of our study was to study an anticonvulsant action of lamotrigine and phenytoin, i.e. two drugs active against partial seizures in adult experimental animals as well as human patients, in a model of simple partial seizures in immature rats. Epileptic foci were induced by local application of bicuculline methiodide on sensorimotor cortical area of 12-day-old rat pups. The animals were pretreated with lamotrigine (LTG, 10 or 20 mg/kg i.p.) or phenytoin (PHT, 15, 30 or 60 mg/kg i.p.). Control rats for LTG received saline, controls for PHT solvent composed of propyleneglycol, ethanol and water. Influence of either drug on interictal activity was negligible. High doses of both LTG and PHT suppressed the transition into ictal phases and shortened the duration of persisting seizures. The tricomponent solvent exhibited moderate activity against ictal activity if compared with saline controls. The two drugs exhibited similar action in our model, i.e. the suppression of secondary generalization from epileptic focus. This action is comparable to that described for human patients and adult experimental animals. In favor of lamotrigine speaks the absence of serious side effects.

Emerging concepts in the pathogenesis of epilepsy and epileptogenesis.

Recent studies of the problem of ictogenesis, or the ways that seizures develop in an already hyperexcitable brain, are leading to paradigm-shifting concepts that may lead to exciting new therapies for seizures. Research on the equally important area of epileptogenesis, or the ways that a normal brain becomes epileptic, is also expanding, but comparable research into translation of laboratory findings into successful clinical interventions for those at high risk needs to be developed.

Surgical strategies and seizure control in pediatric patients with dysembryoplastic neuroepithelial tumors: a single-institution experience.

OBJECTIVES: Dysembryoplastic neuroepithelial tumors (DNTs) are commonly associated with medically resistant epilepsy that usually starts in childhood. Presurgical workup and surgical strategies remain controversial. The authors present a study of long-term seizure outcome after noninvasive presurgical investigations and different surgical strategies were used in a series of pediatric patients. METHODS: Twenty-four children who underwent operations at a single center between 1986 and 2006 were eligible for this retrospective study. The authors reviewed medical records including sex, age at seizure onset, age at surgery, seizure type and pharmacoresistance, lesion location, extent and complications of resection, histopathological findings, prescription of seizure and antiepileptic drugs, outcome, and tumor recurrence. RESULTS: At the last follow-up examination (range 1-16 years after initial treatment, mean 6.7 years) 20 children (83.3%) were seizure free. The authors did not find the rundown phenomenon in any of the patients. Complete antiepileptic drug withdrawal was achieved in 12 children (50%). In 4 of 15 children with temporal DNTs, the lesionectomy alone failed to control seizures. These results could be explained by the wider epileptogenic zone. The only significant predictor for favorable seizure outcome was an absence of preoperative generalized seizures. CONCLUSIONS: In children with extratemporal DNTs the results suggest that complete lesionectomy alone without invasive presurgical investigations are effective for long-term seizure control. For children with temporal DNTs not invading the amygdalohippocampal complex, extensive presurgical evaluations seem indicated. The absence of preoperative generalized seizures was associated with a better seizure outcome.

Seizure characteristics and control following resection in 332 patients with low-grade gliomas.

OBJECT: Seizures play an important role in the clinical presentation and postoperative quality of life of patients who undergo surgical resection of low-grade gliomas (LGGs). The aim of this study was to identify factors that influenced perioperative seizure characteristics and postoperative seizure control. METHODS: The authors performed a retrospective chart review of all cases involving adult patients who underwent initial surgery for LGGs at the University of California, San Francisco between 1997 and 2003. RESULTS: Three hundred and thirty-two cases were included for analysis; 269 (81%) of the 332 patients presented with >or=1 seizures (generalized alone, 33%; complex partial alone, 16%; simple partial alone, 22%; and combination, 29%). Cortical location and oligodendroglioma and oligoastrocytoma subtypes were significantly more likely to be associated with seizures compared with deeper midline locations and astrocytoma, respectively (p=0.017 and 0.001, respectively; multivariate analysis). Of the 269 patients with seizures, 132 (49%) had pharmacoresistant seizures before surgery. In these patients, seizures were more likely to be simple partial and to involve the temporal lobe, and the period from seizure onset to surgery was likely to have been longer (p=0.0005, 0.0089, and 0.006, respectively; multivariate analysis). For the cohort of patients that presented with seizures, 12-month outcome after surgery (Engel class) was as follows: seizure free (I), 67%; rare seizures (II), 17%; meaningful seizure improvement (III), 8%; and no improvement or worsening (IV), 9%. Poor seizure control was more common in patients with longer seizure history (p<0.001) and simple partial seizures (p=0.004). With respect to treatment-related variables, seizure control was far more likely to be achieved after gross-total resection than after subtotal resection/biopsy alone (odds ratio 16, 95% confidence interval 2.2-124, p=0.0064). Seizure recurrence after initial postoperative seizure control was associated with tumor progression (p=0.001). CONCLUSIONS: The majority of patients with LGG present with seizures; in approximately half of these patients, the seizures are pharmacoresistant before surgery. Postoperatively, >90% of these patients are seizure free or have meaningful improvement. A shorter history of seizures and gross-total resection appear to be associated with a favorable prognosis for seizure control.

The effect of electrical stimulation and lesioning of the anterior thalamic nucleus on kainic acid-induced focal cortical seizure status in rats.

PURPOSE: The present study aimed to clarify the effect of electrical stimulation and lesioning of the anterior nucleus of the thalamus (ANT) on kainic acid (KA)-induced focal cortical seizures in a rat model. To address the mechanism underlying these anticonvulsant actions, cerebral glucose metabolism after ANT electrical stimulation and lesioning was also examined. METHODS: Wistar rats were divided into five major groups: control (n = 9), unilateral (n = 9), and bilateral (n = 9) ANT electrical stimulation, and unilateral (n = 9) and bilateral (n = 9) ANT lesioning. After KA injection, average clinical-seizure frequencies in each group were measured. Electrical stimulation of ANT was introduced after induction of seizure status epilepticus. Stimulation was on for 30 min and off for 30 min per 60-min cycle. Local cerebral glucose utilization (LCGU) was also measured by using [(14)C] 2-deoxyglucose autoradiography in three groups of rats: control (n = 7), bilateral ANT stimulation (n = 7), and bilateral ANT lesioning (n = 7). RESULTS: Unilateral ANT electrical stimulation and lesioning significantly reduced clinical seizure frequency, compared with control animals. Strikingly, no animals treated with bilateral ANT procedures demonstrated any clinical seizure. LCGU was markedly increased in the sensorimotor cortex, striatum, thalamus, mammillary body, and midbrain tegmentum of control group rats after KA injection, but no increase in LCGU was noted in rats treated with bilateral ANT lesioning or stimulation. CONCLUSIONS: The electrical stimulation and lesioning of ANT suppressed focal cortical clinical seizures induced by KA injection. Additionally, an analysis of cerebral metabolic changes indicated that these procedures might suppress the function as amplifier and synchronizer of seizure activity.

Conventional anticonvulsant drugs in the guinea-pig kindling model of partial seizures: effects of repeated administration.

This study addressed the anticonvulsant effects of repeated administration of phenytoin, carbamazepine, phenobarbital, valproate, and ethosuximide in kindled guinea-pigs in order to further substantiate this novel model of partial seizures for the screening of future anticonvulsant drugs. Behavioral toxic effects were assessed at 30 min following drug administration using scores on a sedation/muscle relaxation rating index. In response to suprathreshold stimulation, the anticonvulsant efficacy of the drugs were evaluated from measurements of afterdischarge duration (ADD) and behavioral seizure severity (SS) during a repeated drug treatment schedule in kindled guinea-pigs. All drugs exerted slight to moderate sedative effects in guinea-pigs on our rating index. We found that phenytoin, carbamazepine, and phenobarbital exhibited effective anticonvulsant properties in kindled guinea-pigs by reducing both ADD and SS. We found that valproate consistently reduced ADD throughout the treatment schedule but failed to significantly reduce SS. Lastly, ethosuximide failed to exhibit effective anticonvulsant properties. Our results indicate that the guinea-pig kindling model correctly predicted the actions of these common anticonvulsant drugs in the treatment of partial seizures. Guinea-pig amygdala kindling appears to serve as a useful and valid model for partial epilepsy.

Influenza A and febrile seizures in childhood.

The aims of the present study are to identify predisposing factors of febrile seizures in influenza A infection and to clarify the special characteristics of febrile seizures in children with influenza A infection. Between January and July 2005, children hospitalized because of febrile seizures and subsequently confirmed influenza A infection were enrolled as subjects. Age-matched control subjects were those admitted as a result of influenza A infection but no febrile seizures (control 1) and children who developed febrile seizures with negative viral studies (control 2). Significant factors for the development of febrile seizures include: history of febrile seizures, family history of seizure disorders, and coexisting gastroenteritis. Independent risk factor for febrile seizures was history of febrile seizures (odds ratio 7.58, 95% confidence interval CI 1.48 to 38.84, P = 0.015). When compared with children who developed febrile seizures with negative virus studies, children who developed febrile seizures in influenza A infection had a significantly higher maximum body temperature, shorter duration of fever before seizure onset, and more frequent occurrence of partial seizures. Current episode represented first seizure in 26.5% of children infected with influenza A as compared with 50% of children whose virus studies were negative (P = 0.04). The findings suggest that effective vaccination may prevent development of febrile seizures, especially in those patients with past history of febrile seizures. Rapid diagnostic testing for influenza infection in the management of complex febrile seizures, especially during influenza season, is cost-effective.

Substantia nigra is an anticonvulsant site of action of topiramate in the focal pilocarpine model of limbic seizures.

PURPOSE: The substantia nigra pars reticulata (SNR) is known to play a role in gating and control of seizures. Prompted by the observation that intrahippocampal topiramate (TPM) administration does not suppress limbic seizures in the focal pilocarpine model, we investigated the role of the SNR in the anticonvulsant mechanism of action of TPM. METHODS: Limbic seizures were evoked in freely moving rats by intrahippocampal administration of pilocarpine via a microdialysis probe. Changes in hippocampal extracellular (EC) glutamate and GABA concentrations were monitored. Effects of intraperitoneal (10-200 mg/kg), intrahippocampal (1-5 mM), and bilateral intranigral (100-300 nmol) TPM administration on pilocarpine-induced seizures and neurochemical changes were evaluated. Effects of TPM administration alone on hippocampal and nigral EC amino acid concentrations were also studied. RESULTS: Systemic and intranigral, but not intrahippocampal TPM administration suppressed pilocarpine-induced seizures and neurochemical changes. Nigral GABA(A) receptor blockade by picrotoxin abolished the anticonvulsant effect of TPM in SNR. Systemic TPM administration increased hippocampal glutamate and decreased GABA. Intranigral TPM administration increased hippocampal glutamate, but not GABA. Intrahippocampal TPM increased hippocampal glutamate and GABA, but only at high concentrations. CONCLUSIONS: In the focal pilocarpine model, TPM does not exert its anticonvulsant effect at the site of seizure initiation. We identified the SNR as a site of action of TPM, and showed that the nigral GABA-ergic system is central to TPM's anticonvulsant effect in SNR. Anticonvulsant effects and neurochemical changes in hippocampus following intranigral TPM administration suggest the existence of a nigro-hippocampal circuit, which may be involved in the control of limbic seizures.

Anticonvulsant effects of transcranial direct-current stimulation (tDCS) in the rat cortical ramp model of focal epilepsy.

PURPOSE: Weak direct currents induce lasting alterations of cortical excitability in animals and humans, which are controlled by polarity, duration of stimulation, and current strength applied. To evaluate its anticonvulsant potential, transcranial direct current stimulation (tDCS) was tested in a modified cortical ramp-stimulation model of focal epilepsy. METHODS: The threshold for localized seizure activity (TLS) was determined in freely moving rats by applying a single train of rising bipolar pulses through a unilateral epicranial electrode. After tDCS, TLS was determined repeatedly for 120 min at intervals of 15 min. The first group of animals received two sessions of cathodal tDCS at 100 microA, one for 30 and one for 60 min. A third session consisted of 60 min of anodal tDCS. A second group received cathodal tDCS at 200 microA for 15 and for 30 min, as well as anodal tDCS for 30 min. RESULTS: Sixty minutes of cathodal tDCS at 100 microA resulted in a TLS increase lasting for >or=2 h. When the intensity was increased to 200 microA, a similar lasting TLS elevation occurred after a stimulation of just 30-min duration. In contrast, anodal tDCS at identical stimulation durations and current strengths had no significant effect on TLS. CONCLUSIONS: The anticonvulsive effect induced by cathodal tDCS depends on stimulation duration and current strength and may be associated with the induction of alterations of cortical excitability that outlast the actual stimulation. The results lead to the reasonable assumption that cathodal tDCS could evolve as a therapeutic tool in drug-refractory partial epilepsy.

A pilot study of a yoga meditation protocol for patients with medically refractory epilepsy.

OBJECTIVE: The objective was to assess the efficacy of a yoga meditation protocol (YMP) as an adjunctive treatment in patients with drug-resistant chronic epilepsy. DESIGN: The design was a prospective, nonrandomized, open-label, add-on trial with a 12-week baseline period, followed by a 12-week supervised YMP administration phase. The frequency of complex partial seizures (CPS) was assessed at 3, 6, and 12 months of the treatment period. SETTING: The setting was a comprehensive epilepsy care center attached to a tertiary referral medical institution situated on the southwest coast of the Indian peninsula. SUBJECTS: The subjects were 20 patients (14 males and 6 females, age range 15 to 47 years, median 27 years) with unequivocally established diagnoses of epilepsy with at least 4 CPS (with or without secondary generalization) during the preceding 3 months. INTERVENTION: Intervention consisted of a YMP 20 minutes twice daily (mornings and evenings) at home, and supervised sessions of a YMP every week for 3 months. Continuation of the YMP beyond 3 months was optional. OUTCOME MEASURE: The outcome measure was the seizure frequency at 3, 6, and 12 months of the treatment period. The subjects with > or = 50% reduction in monthly seizure rate from baseline were classified as responders, and subjects with <50% seizure reduction as nonresponders. RESULTS: At 3 months, a reduction in seizure frequency was noted in all except 1 patient, six of whom had > or = 50% seizure reduction. Of 16 patients who continued the YMP beyond 3 months, 14 patients responded at 6 months; 6 of them were seizure-free for 3 months. All eight patients who continued the YMP beyond 6 months responded; three of them were seizure free for 6 months. CONCLUSIONS: If confirmed through randomized trials involving a larger number of patients, this YMP may become a cost-effective and adverse effect-free adjunctive treatment in patients with drug-resistant epilepsies.