topiramate and Seizures

To compare the efficacy and safety of antiseizure medications (ASMs), both as monotherapies and adjunctive therapies, for idiopathic generalized epilepsies (IGEs) and related entities.. Two reviewers independently searched PubMed, Embase, and the Cochrane Library for relevant randomized controlled trials from December 2022 to February 2023. Studies on the efficacy and safety of ASM monotherapies or adjunctive therapies for IGEs and related entities-including juvenile myoclonic epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy, or generalized tonic-clonic seizures alone (GTCA)-were included. Efficacy outcomes were the proportions of patients remaining seizure free for 1, 3, 6, and 12 months; safety outcomes were the proportions of any treatment-emergent adverse event (TEAE) and TEAEs leading to discontinuation. Network meta-analyses were performed in a random-effects model to obtain odds ratios and 95% confidence intervals. Rankings of ASMs were based on the surface under the cumulative ranking curve (SUCRA). This study is registered with PROSPERO (No. CRD42022372358).. Twenty-eight randomized controlled trials containing 4282 patients were included. As monotherapies, all ASMs were more effective than placebo, and valproate and ethosuximide were significantly better than lamotrigine. According to the SUCRA for efficacy, ethosuximide ranked first for CAE, whereas valproate ranked first for other types of IGEs. As adjunctive therapies, topiramate ranked best for GTCA as well as overall for IGEs, while levetiracetam ranked best for myoclonic seizures. For safety, perampanel ranked best (measured by any TEAE).. All of the studied ASMs were more effective than placebo. Valproate monotherapy ranked best overall for IGEs, whereas ethosuximide ranked best for CAE. Adjunctive topiramate and levetiracetam were most effective for GTCA and myoclonic seizures, respectively. Furthermore, perampanel had the best tolerability.

Topics: Anticonvulsants; Child; Epilepsy, Generalized; Ethosuximide; Humans; Levetiracetam; Network Meta-Analysis; Randomized Controlled Trials as Topic; Seizures; Topiramate; Valproic Acid

Epilepsy is one of the most common chronic neurological disorders, affecting more than 50 million people globally. In this review we summarised the evidence from randomised controlled trials of gabapentin used as monotherapy for the treatment of focal epilepsy, both newly diagnosed and drug-resistant, with or without secondary generalisation.. To assess the effects of gabapentin monotherapy for people with epileptic focal seizures with and without secondary generalisation.. We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 24 February 2020) on 25 February 2020. CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, the Cochrane Central Register of Controlled Trials (CENTRA), and the specialised registers of Cochrane Review Groups including the Cochrane Epilepsy Group. We also searched several Russian databases, reference lists of relevant studies, ongoing trials registers, conference proceedings, and we contacted trial authors.. We found five randomised controlled trials (3167 participants) comparing gabapentin to other antiepileptic drugs (AEDs) and differing doses of gabapentin as monotherapy for newly diagnosed focal epilepsy and drug- resistant focal epilepsy with or without secondary generalisation. Two review authors independently applied the inclusion criteria, assessed trial quality, risk of bias, and extracted data. We used the GRADE approach to assess the certainty of evidence and present seven patient-important outcomes in the "Summary of findings" tables. The quality of evidence was very low to moderate due to poor reporting quality, poor trial design, and other risks of bias, such as selective presentation of findings and potential heavy industry input. Better quality research may change our certainty in the effect estimates. None of the included trials reported on the number of people with 50% or greater reduction in seizures and time to withdrawal (retention time) in an extractable way. Gabapentin-treated participants were more likely to withdraw from treatment for any cause (285/539) than those treated with lamotrigine, oxcarbazepine, or topiramate pooled together (695/1317) (RR 1.13, 95% CI 1.02 to 1.25; 3 studies, 1856 participants; moderate-certainty evidence), but not carbamazepine. Fewer people treated with gabapentin withdrew from treatment owing to adverse events (190/525) than those treated with carbamazepine, oxcarbazepine, or topiramate (479/1238), (RR 0.79, 95% CI 0.69 to 0.91; 1763 participants, 3 studies; moderate-certainty evidence), but not lamotrigine.. Gabapentin as monotherapy probably controlled seizures no better and no worse than comparator AEDs (lamotrigine, carbamazepine, oxcarbazepine, and topiramate). Compared to carbamazepine, gabapentin was probably better in retaining people in studies and preventing withdrawals due to adverse events. The most common side effects associated with gabapentin were ataxia (poor co-ordination and unsteady gait), dizziness, fatigue, and drowsiness.

Topics: Anticonvulsants; Carbamazepine; Drug Resistant Epilepsy; Epilepsies, Partial; Epilepsy; Gabapentin; Humans; Lamotrigine; Oxcarbazepine; Seizures; Topiramate

Topiramate (TPM) is widely used as monotherapy or add-on therapy in adults and children (aged 2 to 16 years) with primary generalized tonic-clonic seizures or focal-onset seizures. TPM has also expanded its treatment spectrum to other seizure types and epileptic encephalopathies. Moreover, TPM has beneficial effects in some comorbidities of epilepsy such as migraine/headache and obesity. Interestingly, it also exhibited neuroprotective effects in several preclinical studies. The most common side effects of TPM are generally mild to moderate, including somnolence, dizziness, fatigue, insomnia and weight loss, which may be reduced through starting with a low dose and slowing titration to effective dosages. The mechanisms underlying the antiepileptic effect and adverse reactions of TPM have been extensively studied in the past 14 years since the last comprehensive review of TPM. Multiple mechanisms including but not limited to: (1) blockade of voltage-gated Na

Topics: Adult; Anticonvulsants; Child; Epilepsy; Epilepsy, Generalized; Fructose; Humans; Seizures; Topiramate

The duration and, age of dementia have been linked to a higher risk of seizures. The exact mechanism that drives epileptogenesis in impaired mitophagy and autophagy linked dementia (MAD) is fully defined after reviewing the Scopus, Publon, and Pubmed databases. The epileptogenesis in patients with Alzheimer's disease dementia (ADD) and Parkinson's disease dementia (PDD) is due to involvement of amyloid plaques (Aβ), phosphorylated tau (pTau), Parkin, NF-kB and NLRP3 inflammasome. Microglia, the prime protective and inflammatory cells in the brain exert crosstalk between mitophagy and inflammation. Several researchers believed that the inflammatory brain cells microglia could be a therapeutic target for the treatment of a MAD associated epilepsy. There are conventional antiepileptic drugs such as gabapentin, lamotrigine, phenytoin sodium, carbamazepine, oxcarbazepine, felbamate, lamotrigine, valproate sodium, and topiramate are prescribed by a psychiatrist to suppress seizure frequency. Also, the conventional drugs generate serious adverse effects and synergises dementia characteristics. The adverse effect of carbamazepine is neurotoxic and also, damages haemopoietic system and respiratory tract. The phenytoin treatment causes cerebellar defect and anemia. Dementia and epilepsy have a complicated relationship, thus targeting mitophagy for cure of epileptic dementia makes sense. Complementary and alternative medicine (CAM) is one of the rising strategies by many patients of the world, not only to suppress seizure frequency but also to mitigate dementia characteristics of patients. Therefore our present review focus on the interplay between epilepsy and MAD and their treatment with CAM approaches.

Topics: Anticonvulsants; Carbamazepine; Dementia; Epilepsy; Felbamate; Gabapentin; Humans; Inflammasomes; Lamotrigine; Mitophagy; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Oxcarbazepine; Parkinson Disease; Phenytoin; Seizures; Topiramate; Triazines; Ubiquitin-Protein Ligases; Valproic Acid

Status epilepticus is defined as the situation resulting from the failure of the mechanisms responsible for terminating an epileptic seizure. In 2015, an operational concept was adopted internationally in which two times are identified: a first time, at which treatment must begin (five minutes for convulsive status, 10-15 minutes for focal and non-convulsive status); and a second time, after which there is considered to be a high risk of subsequent sequelae (30 minutes in the case of the convulsive). It occurs in 3-42/100,000 children per year, who are refractory or super-refractory in 10-40% of cases.. This article will review the different therapeutic options for status, from early treatment at home to the different first-line (benzodiazepines), second-line (phenobarbital, valproic acid, phenytoin, levetiracetam and lacosamide) or third-line treatments, which include both pharmacological (anaesthetics, propofol, ketamine, lidocaine, topiramate, brivaracetam or perampanel) and non-pharmacological (ketogenic diet, immunomodulatory treatments or epilepsy surgery) therapies.. Early identification and treatment of a prolonged crisis are essential to prevent progression to status. Although with fewer sequelae than in adults, status epilepticus in children represents a cause of mortality of up to 3-5%, while 25% of them will develop subsequent epilepsy, as well as a considerable percentage of neurological sequelae.. Estado epiléptico pediátrico.. Introducción. El estado epiléptico se define como la situación resultante del fallo de los mecanismos responsables de finalizar una crisis epiléptica. En 2015, se adoptó internacionalmente un concepto operativo en el que se identifican dos tiempos: un primer momento, en el que hay que comenzar un tratamiento (cinco minutos para los estados convulsivos, 10-15 minutos para los estados focales y no convulsivos); y un segundo tiempo, a partir del cual se considera que hay un riesgo elevado de secuelas posteriores (30 minutos en los convulsivos). Ocurre en 3-42/100.000 niños al año, y son refractarios o superrefractarios en el 10-40% de las ocasiones. Desarrollo. En este artículo se revisarán las diferentes opciones terapéuticas del estado, desde el tratamiento precoz domiciliario hasta los diferentes tratamientos de primera línea (benzodiacepinas), segunda línea (fenobarbital, ácido valproico, fenitoína, levetiracetam y lacosamida) o tercera línea, que incluyen tanto terapias farmacológicas (anestésicos, propofol, cetamina, lidocaína, topiramato, brivaracetam o perampanel) como no farmacológicas (dieta cetógena, tratamientos inmunomoduladores o cirugía de epilepsia). Conclusiones. Son fundamentales la identificación y el tratamiento precoz de una crisis prolongada para evitar la evolución a estado. Aunque con menores secuelas que en los adultos, el estado epiléptico en niños representa una causa de mortalidad hasta del 3-5%, al mismo tiempo que un 25% de ellos desarrollará una epilepsia posterior, así como un porcentaje considerable de secuelas neurológicas.

Topics: Adult; Anesthetics; Anticonvulsants; Benzodiazepines; Child; Epilepsy; Humans; Ketamine; Lacosamide; Levetiracetam; Lidocaine; Phenobarbital; Phenytoin; Propofol; Seizures; Status Epilepticus; Topiramate; Valproic Acid

Topiramate is a newer broad-spectrum antiepileptic drug (AED). Some studies have shown the benefits of topiramate in the treatment of juvenile myoclonic epilepsy (JME). However, there are no current systematic reviews to determine the efficacy and tolerability of topiramate in people with JME. This is an update of a Cochrane Review first published in 2015, and last updated in 2019.. To evaluate the efficacy and tolerability of topiramate in the treatment of JME.. For the latest update, we searched the Cochrane Register of Studies (CRS Web) on 26 August 2021, and MEDLINE (Ovid 1946 to 26 August 2021). CRS Web includes randomized or quasi-randomized controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups, including Cochrane Epilepsy.. We included randomized controlled trials (RCTs) investigating topiramate versus placebo or other AED treatment for people with JME, with the outcomes of proportion of responders and proportion of participants experiencing adverse events (AEs).. Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality of the studies.. We included three studies with a total of 83 participants. For efficacy, a greater proportion of participants in the topiramate group had a 50% or greater reduction in primarily generalized tonic-clonic seizures (PGTCS), compared with participants in the placebo group (RR 4.00, 95% CI 1.08 to 14.75; 1 study, 22 participants; very low-certainty evidence). There were no significant differences between topiramate and valproate for participants responding with a 50% or greater reduction in myoclonic seizures (RR 0.88, 95% CI 0.67 to 1.15; one study, 23 participants; very-low certainty evidence) or in PGTCS (RR 1.22, 95% CI 0.68 to 2.21; one study, 16 participants, very-low certainty evidence), or participants becoming seizure-free (RR 1.13, 95% CI 0.61 to 2.11; one study, 27 participants; very-low certainty evidence). Concerning tolerability, we ranked AEs associated with topiramate as moderate to severe, while we ranked 59% of AEs linked to valproate as severe complaints (2 studies, 61 participants; very low-certainty evidence). Moreover, systemic toxicity scores were higher in the valproate group than the topiramate group. Overall we judged all three studies to be at high risk of attrition bias and at unclear risk of reporting bias. We judged the studies to be at low to unclear risk of bias for the remaining domains (selection bias, performance bias, detection bias and other bias). We judged the overall certainty of the evidence for the outcomes as very low using the GRADE approach.. We have found no new studies since the last version of this review was published in 2019. This review does not provide sufficient evidence to support topiramate for the treatment of people with JME. Based on the current limited available data, topiramate seems to be better tolerated than valproate, but has no clear benefits over valproate in terms of efficacy. Well-designed, double-blind RCTs with large samples are required to test the efficacy and tolerability of topiramate in people with JME.

Topics: Anticonvulsants; Humans; Myoclonic Epilepsy, Juvenile; Randomized Controlled Trials as Topic; Seizures; Topiramate; Valproic Acid

Hypoxic ischemic encephalopathy (HIE) is brain injury caused by different reasons and the most common diagnosed is neonatal HIE. Most of the existing treatments have their own shortcomings or there are still some unexplained mechanisms in it. Topiramate (TPM) is a new drug for the treatment for seizures in neonates with HIE, but is currently used off-label. Our protocol aims to access the efficiency and safety of TPM for HIE.. Eight databases will be searched by 2 independent researchers for the article on the topic of using TPM as treatment for HIE, including PubMed, the Cochrane Central Register of Controlled Trials (Cochrane Library), Embase, and Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wang Fang Database and Chinese Science and Technology Periodical database (VIP). The included papers are those published from the established date of the databases to 2019. The therapeutic effects based on the grade of neonatal behavioral neurological assessment will be regarded as the primary outcomes. RevMan V5.3 will be used to compute the data synthesis and carry out meta-analysis. The risk of bias will be appraised by the Cochrane risk of bias tool. Rare ratio for dichotomous outcomes and mean different for continuous data will be expressed with 95% confidence intervals (CI) for analysis. A random effects model or a fixed effects model will be employed, when heterogeneity is found or not. Subgroup analysis and sensitivity analysis will be applied if the heterogeneity is obvious.. This study will provide the recent evidence of TPM for HIE from reducing seizure acticity.. The conclusion of this study will provide proof to evaluate if TPM is effective and safe in the treatment of HIE.PROSPERO registration number: PROSPERO CRD42018117981.

Topics: Anticonvulsants; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Oxidative Stress; Randomized Controlled Trials as Topic; Research Design; Seizures; Severity of Illness Index; Topiramate

Topiramate is a newer broad-spectrum antiepileptic drug (AED). Some studies have shown the benefits of topiramate in the treatment of juvenile myoclonic epilepsy (JME). However, there are no current systematic reviews to determine the efficacy and tolerability of topiramate in people with JME. This is an update of a Cochrane Review first published in 2015, and last updated in 2017.. To evaluate the efficacy and tolerability of topiramate in the treatment of JME.. For the latest update, on 10 July 2018 we searched the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group's Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid 1946- ), and ClinicalTrials.gov. We also searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted study authors and pharmaceutical companies.. We included randomized controlled trials (RCTs) investigating topiramate versus placebo or other AED treatment for people with JME, with the outcomes of proportion of responders and proportion of participants experiencing adverse events (AEs).. Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to the limited available data.. We included three studies with a total of 83 participants. For efficacy, a greater proportion of participants in the topiramate group had a 50% or more reduction in primarily generalized tonic-clonic seizures (PGTCS) compared with participants in the placebo group. There were no significant differences between topiramate and valproate in participants responding with a 50% or more reduction in myoclonic seizures or in PGTCS, or becoming seizure-free. Concerning tolerability, we ranked AEs associated with topiramate as moderate to severe, while we ranked 59% of AEs linked to valproate as severe complaints. Moreover, systemic toxicity scores were higher in the valproate group than the topiramate group.Overall we judged all three studies to be at high risk of attrition bias and at unclear risk of reporting bias. We judged all three studies to be at low to unclear bias for the remaining risk of bias domains (random sequence, allocation, blinding). We judged the quality of the evidence from the studies to be very low.. We have found no new studies since the last version of this review was published in 2017. This review does not provide sufficient evidence to support topiramate for the treatment of people with JME. Based on the current limited available data, topiramate seems to be better tolerated than valproate, but has no clear benefits over valproate in terms of efficacy. Well-designed, double-blind RCTs with large samples are required to test the efficacy and tolerability of topiramate in people with JME.

Topics: Adolescent; Anticonvulsants; Child; Humans; Myoclonic Epilepsy, Juvenile; Randomized Controlled Trials as Topic; Seizures; Topiramate; Treatment Outcome; Valproic Acid; Young Adult

The aim of this study was to describe the treatment pattern of patients with Dravet syndrome (DS) in Germany with routine antiepileptic drugs (AEDs) and emergency medication, and to review the literature of real-world evidence on medicine utilization of patients with DS in Europe.. Patient use of routine AEDs and emergency medications over 3-6 months was analyzed from a 2018 multicenter survey of 93 caregivers of patients with DS throughout Germany. Results were contextualized in a review of real-world evidence on medicine utilization of patients with DS in Europe.. The variety of medications and the most frequent combinations routinely used by patients with DS (AEDs and others) are described. Patients use a large number of pharmaceutical treatments to manage seizures. The five most commonly used AEDs were sodium valproate (66% of the patients; mean daily dose: 660 mg; 24.5 mg per kg bodyweight), bromide (44%; 1462 mg; 51.2 mg per kg), clobazam (41%; 10.4 mg; 0.32 mg per kg), stiripentol (35%; 797 mg; 27.6 mg per kg), and topiramate (24%; 107 mg; 3.5 mg per kg). Ninety percent had reported using emergency medications in the last 3 months;, with the most common medications being Buccolam (40%, an oromucosal form of midazolam) and diazepam (20%, mostly rectal application). No discernable relationships between current medication and age or seizure frequency were observed.. This is the first comprehensive report of routine AEDs and emergency medication use in a large sample of patients with DS in Germany over a period of 3-6 months and shows that despite the most common AED combinations being in line with clinical guidelines/best practice, there is no discernable impact of best treatment on seizure frequency. We find a higher use of bromide in Germany compared with other real-world evidence in Europe.

Topics: Anticonvulsants; Clobazam; Cohort Studies; Drug Prescriptions; Drug Therapy, Combination; Epilepsies, Myoclonic; Female; Germany; Humans; Male; Seizures; Topiramate; Valproic Acid

A generalized tonic-clonic seizure (GTCS) is the most severe form of common epileptic seizure and carries the greatest risk of harm. The aim of this review is to provide an evidence-based guide for the selection of antiepileptic drugs (AEDs) for patients with GTCSs. Eight AEDs are approved in Europe and the USA for the treatment of both primarily GTCSs (PGTCSs) and secondarily GTCSs (SGTCSs) and are considered in this paper.. Each AED is evaluated using five criteria: (1) efficacy, by seizure type (a: PGTCSs and b: SGTCSs); (2) adverse effects; (3) interactions; (4) adherence and dosing; and (5) mechanism of action (MOA). To ensure the inclusions of robust data, only efficacy data accepted by regulatory authorities were considered, and data related to adverse effects, interactions, adherence, and MOA were all extracted from UK Summaries of Product Characteristics (SPCs).. (1a) There is class 1 evidence of the efficacy of only four AEDs in controlling PGTCSs (lamotrigine, levetiracetam, perampanel, and topiramate). (1b) There is no class 1 evidence of the efficacy of any AED in SGTCSs although some evidence from pooled/subgroup analyses or meta-analyses supports the use of the four AEDs (levetiracetam, perampanel, topiramate, and with less robust data for lamotrigine). (2) AEDs are associated with different, but to some extent overlapping, common adverse effect profiles but have differing idiosyncratic adverse effects. (3) Pharmacokinetic interactions are seen with most, but not all, AEDs and are most common with carbamazepine and phenytoin. (4) Good adherence is important for seizure control and is influenced by frequency of dosing, among other factors. (5) Mechanism of action is also a consideration in rationalising AED selection when switching or combining AEDs.. Ultimately, the choice of AED depends on all these factors but particularly on efficacy and adverse effects. Different patients will weigh the various factors differently, and the role of the treating physician is to provide accurate information to allow patients to make informed choices.

Topics: Anticonvulsants; Benzodiazepines; Carbamazepine; Drug and Narcotic Control; Drug-Related Side Effects and Adverse Reactions; Humans; Lamotrigine; Levetiracetam; Nitriles; Phenytoin; Pyridones; Seizures; Topiramate; Treatment Outcome

Topiramate is a newer broad-spectrum antiepileptic drug (AED). Some studies have shown the benefits of topiramate monotherapy in the treatment of juvenile myoclonic epilepsy (JME). However, there are no current systematic reviews to determine the efficacy and tolerability of topiramate monotherapy in people with JME. This is an updated version of the original Cochrane Review published in Issue 12, 2015.. To evaluate the efficacy and tolerability of topiramate monotherapy in the treatment of JME.. For the latest update, on 21 February 2017 we searched Cochrane Epilepsy's Specialized Register, CENTRAL, MEDLINE, and ClinicalTrials.gov. We also searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted study authors and pharmaceutical companies.. We included randomized controlled trials (RCTs) investigating topiramate monotherapy versus placebo or other AED treatment for people with JME, with the outcomes of proportion of responders or experiencing adverse events (AEs).. Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to the limited available data.. We included three studies with 83 participants. For efficacy, a greater proportion of participants in the topiramate group had a 50% or more reduction in primarily generalized tonic-clonic seizures (PGTCS) compared with participants in the placebo group. There were no significant differences between topiramate versus valproate in participants responding with a 50% or more reduction in myoclonic seizures or in PGTCS or seizure-free. Concerning tolerability, we ranked AEDs associated with topiramate as moderate-to-severe, while we ranked 59% of AEDs linked to valproate as severe complaints. Moreover, systemic toxicity scores were higher in the valproate group than the topiramate group. We judged the quality of the evidence from the studies to be very low.. Since the last version of this review we found no new studies. This review does not provide sufficient evidence to support topiramate for the treatment of people with JME. Based on the current limited available data, topiramate seems to be better tolerated than valproate, but there were no more benefits of efficacy in topiramate compared with valproate. In the future, well-designed, double-blind RCTs with large samples are required to test the efficacy and tolerability of topiramate in people with JME.

Topics: Adolescent; Anticonvulsants; Child; Fructose; Humans; Myoclonic Epilepsy, Juvenile; Randomized Controlled Trials as Topic; Seizures; Topiramate; Treatment Outcome; Valproic Acid; Young Adult

Neonatal seizures constitute the most frequent presenting neurologic sign encountered in the neonatal intensive care unit. Despite limited efficacy and safety data, phenobarbital continues to be used near-universally as the first-line anti-seizure drug (ASD) in neonates. The choice of second-line ASDs varies by provider and institution, and is still not supported by sufficient scientific evidence. In this review, we discuss the available evidence supporting the efficacy, mechanism of action, potential adverse effects, key pharmacokinetic characteristics such as interaction with therapeutic hypothermia, logistical issues, and rationale for use of neonatal ASDs. We describe the widely used neonatal ASDs, namely phenobarbital, phenytoin, midazolam, and levetiracetam, in addition to potential ASDs, including lidocaine, topiramate, and bumetanide.

Topics: Anticonvulsants; Fructose; Humans; Hypothermia, Induced; Infant, Newborn; Lidocaine; Midazolam; Phenobarbital; Seizures; Topiramate; Treatment Outcome

The aim of this review was to evaluate current literature for dosing recommendations for the use of antiepileptic medications in patients receiving renal replacement therapy (RRT).. With the assistance of an experienced medical librarian specialized in pharmacy and toxicology, we searched MEDLINE, EMBASE, CINAHL, Web of Science, WorldCat, and Scopus through May 2016.. Four hundred three articles were screened for inclusion, of which 130 were identified as potentially relevant. Micromedex® DRUGDEX as well as package inserts were used to obtain known pharmacokinetic properties and dosage adjustment recommendations in RRT if known.. Data regarding antiepileptic drug use in RRT are limited and mostly consist of case reports limiting our proposed dosing recommendations. Known pharmacokinetic parameters should guide dosing, and recommendations are provided where possible.. Additional studies are necessary before specific dosing recommendations can be made for most antiepileptic drugs in critically ill patients receiving RRT, specifically with newer agents.

Topics: Acetamides; Acute Kidney Injury; Amines; Anticonvulsants; Carbamates; Critical Illness; Cyclohexanecarboxylic Acids; Dibenzazepines; Dose-Response Relationship, Drug; Ethosuximide; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lacosamide; Lamotrigine; Levetiracetam; Phenobarbital; Phenylcarbamates; Phenylenediamines; Phenytoin; Piracetam; Propylene Glycols; Renal Dialysis; Renal Replacement Therapy; Seizures; Topiramate; Triazines; Valproic Acid; Zonisamide

Topiramate is a newer broad-spectrum of antiepileptic drug (AED). Some studies have shown the benefits of topiramate monotherapy in the treatment of juvenile myoclonic epilepsy (JME). However, there are no current systematic reviews to determine the efficacy and tolerability of topiramate monotherapy in people with JME.. To determine the efficacy and tolerability of topiramate monotherapy in the treatment of JME.. We searched the Cochrane Epilepsy Group Specialized Register (2 November 2015), the Cochrane Central Register of Controlled Trials (CENTRAL via the Cochrane Register of Studies CRSO, 2 November 2015), MEDLINE (Ovid, 2 November 2015), EMBASE (1 July 2015) and ClinicalTrials.gov (2 November 2015). In an effort to identify further published, unpublished and ongoing trials, we searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted authors and pharmaceutical companies.. We included randomized controlled trials (RCTs) investigating topiramate monotherapy versus placebo or other AED treatment for people with JME, with the outcomes of proportion of responders or experiencing adverse events (AEs).. Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to the limited available data.. We included three studies with 83 participants. For the efficacy, a greater proportion of participants in the topiramate group had a 50% or more reduction in primarily generalized tonic-clonic seizures (PGTCS) compared with participants in the placebo group. There were no significant differences between topiramate versus valproate in participants responding with a 50% or more reduction in myoclonic seizures or in PGTCS or seizure-free. Concerning tolerability, we ranked AEDs associated with topiramate as moderate-to-severe, while we ranked 59% of AEDs linked to valproate as severe complaints. Moreover, systemic toxicity scores were higher in the valproate group than the topiramate group. We judged the quality of the evidence from the studies to be very low.. This review does not provide sufficient evidence to support topiramate for the treatment of people with JME. Based on the current limited available data, topiramate seems to be better tolerated than valproate, but there were no more benefits of efficacy in topiramate compared with valproate. In the future, well-designed, double-blind RCTs with large samples are required to test the efficacy and tolerability of topiramate in people with JME.

Topics: Adolescent; Anticonvulsants; Child; Fructose; Humans; Myoclonic Epilepsy, Juvenile; Randomized Controlled Trials as Topic; Seizures; Topiramate; Treatment Outcome; Valproic Acid; Young Adult

A case is reported of acute bilateral myopia and angle closure glaucoma in a 7-year-old patient from topiramate toxicity. This is the second known reported case of topiramate induced acute angle closure glaucoma and third known reported case of topiramate induced acute myopia in a pediatric patient.. This case presents a 7-year-old who had recently begun topiramate therapy for seizures and headache. She developed painless blurred vision and acute bilateral myopia, which progressed to acute bilateral angle closure glaucoma. After a routine eye exam where myopia was diagnosed, the patient presented to the emergency room with symptoms of acute onset blurry vision, tearing, red eyes, swollen eyelids, and photophobia. The symptoms, myopia, and angle closure resolved with topical and oral intraocular pressure lowering medications, topical cyclopentolate, and discontinuation of topiramate.. Acute angle closure glaucoma is a well-known side effect of topiramate, but is rarely seen in children. It cautions providers to the potential ophthalmic side effects of commonly used medications in the pediatric population. It highlights the need to keep a broad differential in mind when encountering sudden onset blurry vision in the primary care clinic, the need for careful consideration of side effects when starting topiramate therapy in a child, and the need for parental counseling of side effects.

Topics: Anticonvulsants; Child; Diagnosis, Differential; Female; Fructose; Glaucoma, Angle-Closure; Headache; Humans; Myopia; Seizures; Topiramate

Occurrence of generalized tonic-clonic seizures (GTCS) is one of the most important risk factors of seizure-related complications and comorbidities in patients with epilepsy. Their prevention is therefore an important aspect of therapeutic management both in idiopathic generalized epilepsies and in focal epilepsies.. It has been shown that the efficacy of antiepileptic drugs (AEDs) varies across epilepsy syndromes, with some AEDs efficacious against focal seizures with secondary GTCS (sGTCS) but aggravating primary GTCS (pGTCS). In patients with pGTCS, evidence-based data support the preferential use of valproic acid, lamotrigine, levetiracetam and topiramate. In patients with sGTCS, all AEDs approved in the treatment of focal epilepsies might be used.. Both in pGTCS and sGTCS, additional data are required, specifically to inform about the relative efficacy of AEDs in relation to each other. Although valproic acid might be the most efficacious drug in idiopathic generalized epilepsies, it should be avoided in women of childbearing age due to its safety profile. In patients with sGTCS, AEDs for which the impact on this seizure type has been formally evaluated and which have demonstrated greater efficacy than placebo might preferentially be used, such as lacosamide, perampanel and topiramate.

Topics: Acetamides; Anticonvulsants; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Fructose; Humans; Lacosamide; Lamotrigine; Levetiracetam; Piracetam; Risk Factors; Seizures; Topiramate; Treatment Failure; Triazines; Valproic Acid

Secondary generalized tonic-clonic seizures (SGTCS) are among the most severe forms of seizures, and the main risk factor for sudden unexpected death in epilepsy (SUDEP). Whether some antiepileptic drugs (AEDs) might be more efficacious than others on SGTCS in patients with drug-resistant focal epilepsy thus represents an important clinical issue for which no data are currently available.. We performed a meta-analysis of randomized controlled trials of adjunctive AED in which information on efficacy outcomes (i.e., responder rate and/or frequency per 28 days relative to baseline) were available both for all seizure types and for SGTCS. The primary analysis evaluated the efficacy of AEDs on all types of seizure and on SGTCS by comparing the responder rates for AED and for placebo.. Responder rate was available both for all seizure types and for SGTCS in 13 of the 72 eligible trials, evaluating 7 AEDs. Only three AEDs--lacosamide, perampanel and topiramate--showed greater efficacy than placebo. However, confidence intervals of relative risks overlapped for all AEDs but pregabalin, which demonstrated significantly lower efficacy than lacosamide, perampanel, and topiramate. Moreover, there was a nonsignificant trend toward a lower relative risk of responder rate for SGTCS than for all seizure types, which appeared related to a greater response to placebo for this outcome.. Indirect comparison of AEDs using randomized placebo-controlled add-on trials does not support robust differences between AEDs to prevent SGTCS. Alternative designs for evaluation of therapeutic interventions in patients at risk for SGTCS-related complications are required.

Topics: Acetamides; Anticonvulsants; Chronic Disease; Death, Sudden; Early Medical Intervention; Epilepsies, Partial; Fructose; Humans; Lacosamide; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Seizures; Topiramate; Treatment Outcome

Topics: Administration, Oral; Anticonvulsants; Capsules; Chemistry, Pharmaceutical; Delayed-Action Preparations; Fructose; Humans; Seizures; Topiramate

The treatment of neonatal seizures has not changed significantly over the last 50 years despite advances in antiepileptic drug (AED) development for older children and adults. Recently new drugs have emerged some of which address age-specific challenges or mechanisms and will be discussed in this review. The loop diuretic bumetanide blocks the neuronal NKCC1 co-transporter and is thought specifically to supress seizures in the immature brain. Levetiracetam has been used in children and infants with good efficacy, an excellent safety profile, and near-ideal pharmacokinetic characteristics. Randomised controlled trials are now underway to test the efficacy of some newer AEDs for neonatal seizures. Topiramate has been shown to have neuroprotective properties in addition to its antiepileptic action and trials in babies with hypoxic-ischaemic encephalopathy are now planned. There is an urgent need to develop age-specific AEDs for preterm and term babies. These drugs must be evaluated with multicentre, collaborative trials using innovative methods and high ethical standards to overcome age-specific challenges with the ultimate aim of improving the outcome for neonates with seizures.

Topics: Animals; Anticonvulsants; Brain; Bumetanide; Child Development; Epilepsy; Fructose; Humans; Infant, Newborn; Levetiracetam; Neurogenesis; Neurons; Neuroprotective Agents; Piracetam; Seizures; Sodium Potassium Chloride Symporter Inhibitors; Topiramate

2q23.1 microdeletion syndrome is a recently characterized chromosomal aberration disorder uncovered through array comparative genomic hybridization (array CGH). Although the cardinal feature is intellectual disability (ID), neurodevelopmental features of the syndrome have not been systematically reviewed. We present a 5-year-old boy with severe psychomotor developmental delay/ID, progressive microcephaly with brain atrophy, growth retardation, and several external anomalies. He manifested intractable epilepsy, effectively treated with combined antiepileptic drug therapy including topiramate. Array CGH demonstrated a de novo interstitial deletion of approximately 1 Mb at 2q23.1-q23.2, involving four genes including MBD5. Nineteen patients have been reported to have the syndrome, including present patient. All patients whose data were available had ID, 17 patients (89%) had seizures, and microcephaly was evident in 9 of 18 patients (50%). Deletion sizes ranged from 200 kb to 5.5 Mb, comprising 1-15 genes. MBD5, the only gene deleted in all patients, is considered to be responsible for ID and epilepsy. Furthermore, the deletion junction was sequenced for the first time in a patient with the syndrome; and homology of three nucleotides, identified at the distal and proximal breakpoints, suggested that the deletion might have been mediated by recently-delineated genomic rearrangement mechanism Fork Stalling and Template Switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR).

Topics: Abnormalities, Multiple; Child, Preschool; Chromosomes, Human, Pair 2; Comparative Genomic Hybridization; Developmental Disabilities; DNA-Binding Proteins; Fructose; Humans; Intellectual Disability; Male; Microcephaly; Oligonucleotide Array Sequence Analysis; Seizures; Sequence Deletion; Topiramate

Multiple new anticonvulsants have been introduced recently and they are supplanting the older medications. Whereas the older drugs have well-recognized side effects, both in typical therapeutic doses and in overdosage, the properties of the newer ones are unique and largely unknown to all but sub-specialists.. This article gives a concise overview of the potential complications of these new medications in both therapeutic use and overdose.. Clinically significant side effects of the new anticonvulsants, such as metabolic acidosis from topiramate, autoimmune reactions from lamotrigine, hyponatremia from oxcarbazepine, or psychosis from levitiracetam can cause serious morbidity and mortality if unrecognized. The effects of these medications in overdose are also largely unknown to most emergency physicians.. This article reviews the major potential side effects of the new seizure medications and the treatment of their overdoses for the practicing emergency physician.

Topics: Acidosis; Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Drug Overdose; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Piracetam; Psychoses, Substance-Induced; Seizures; Tiagabine; Topiramate; Triazines

Topiramate is a neuromodulatory compound with stabilizing properties that was initially introduced for the management of partial seizures. Topiramate has been demonstrated to modify several receptor-gated and voltage-sensitive ion channels, including voltage-activated Na+ and Ca2+ channels and non-NMDA receptors. These receptors have been implicated in the pathophysiology of both epilepsy and migraine. The pharmacological mechanisms of action for topiramate that may explain its antiepileptic and migraine preventive activities will be discussed in this review. In addition, the potential relationship between the molecular activities of topiramate and its efficacy in epilepsy and migraine prevention will be emphasized.

Topics: Animals; Anticonvulsants; Fructose; Humans; Ion Channels; Migraine Disorders; Seizures; Topiramate

There has been a growing interest in the use of antiepileptic drugs (AEDs) for neuroprotection, and in the possible role of AEDs in disease modification (i.e., antiepileptogenesis). Increased understanding of the mechanisms underlying brain injury has led to advances in the study of neuroprotection. However, defining the clinical paradigm and selecting appropriate outcomes to detect neuroprotective effects present challenges to clinicians studying the neuroprotective properties of drugs. Established AEDs, such as phenytoin, phenobarbital, and carbamazepine, have shown neuroprotective activity in an ischemic/hypoxic model of neuronal injury. Animal model studies also have suggested that newer AEDs, such as levetiracetam, topiramate, and zonisamide, may have neuroprotective or antiepileptogenic properties. However, the prevention of epileptogenesis by an AED has yet to be demonstrated in clinical trials. The future of neuroprotection may involve established and newer AEDs, as well as other compounds, such as immunophilins, caspase inhibitors, endocannabinoids, and antioxidants.

Topics: Animals; Anticonvulsants; Brain; Epilepsy; Fructose; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Neuroprotective Agents; Piracetam; Seizures; Topiramate; Triazines; Zonisamide

Epilepsy, a functional disturbance of the CNS and induced by abnormal electrical discharges, manifests by recurrent seizures. Although new antiepileptic drugs have been developed during recent years, still more than one third of patients with epilepsy are refractory to treatment. Therefore, the search for new mechanisms that can regulate cellular excitability are of utmost importance. Three currently available drugs are of special interest because they have novel mechanisms of action and are especially effective for partial onset seizures. Vigabatrin is a selective and irreversible GABA-transaminase inhibitor that greatly increases whole-brain levels of GABA. Tiagabine is a potent inhibitor of GABA uptake into neurons and glial cells. Topiramate is considered to produce its antiepileptic effect through several mechanisms, including modification of Na(+)-and/or Ca(2+)-dependent action potentials, enhancement of GABA-mediated Cl- fluxes into neurons, and inhibition of kainate-mediated conductance at glutamate receptors of the AMPA/kainate type. This review will discuss these mechanisms of action at the cellular and molecular levels.

Topics: Anticonvulsants; Fructose; Neuroprotective Agents; Nipecotic Acids; Seizures; Tiagabine; Topiramate; Vigabatrin

Topiramate is an antiepileptic drug (AED) which appears to have a broad range of antiseizure activity in humans. A previous overview focused primarily on results of trials of topiramate in adults with epilepsy, and this review highlights the use of topiramate in children. Clinical trials have shown that topiramate is effective when used adjunctively in children with refractory partial-onset seizures and generalised tonic-clonic seizures. The drug significantly reduced seizure frequency compared with placebo in children with partial-onset epilepsy after 16 weeks of double-blind adjunctive treatment (33.1 vs 10.5%); the frequency of secondarily generalised seizures was also markedly reduced. During a nonblind extension of this trial, the mean dosage was titrated from 4.8 to 9 mg/kg/day and further reductions in the frequency of seizures were observed (71% compared with prestudy levels). In 2 mixed adult/paediatric populations with primary generalised tonic-clonic seizures, topiramate (target dosage 5.2 to 9.3 mg/kg/day) reduced the seizure rate compared with those receiving placebo. This difference was significant in one trial (56.7 vs 9%) but not in another (57.1 vs 33.2%). A subanalysis of the paediatric patients found that the favourable effect of topiramate on seizure rates was not age-related. Topiramate (median average dosage 5.1 mg/kg/day) was also found to be useful as adjunctive therapy in the management of Lennox-Gastaut syndrome and significantly reduced the mean frequency of drop attacks by 14.8% compared with an increase of 5.1% with placebo. Further gains in seizure control were made in a nonblind extension of this trial where the mean topiramate dosage was 10 mg/kg/day. Nine of 11 patients in 1 pilot trial of children with otherwise intractable West syndrome, and 5 of 10 in another, achieved a > or =50% reduction in seizure rate with topiramate (target dosage up to 24 mg/kg/day). In an 18-month extension of the former trial (mean dosage 29 mg/kg/day) a > or =50% reduction in seizures was maintained in 7 of 11 children. Adverse events associated with adjunctive topiramate therapy in children were predominantly neuropsychiatric and generally mild to moderate in severity. Behavioural and cognitive problems do occur and are a limiting factor in some children. Also, weight loss can be problematical in some individuals. Withdrawal rates were low in the controlled trials (4.8%), but appear to be more frequent in noncomparative and post-marketing stu. Well controlled studies have demonstrated that topiramate is an effective agent for the adjunctive therapy of partial and generalised tonic-clonic seizures in children. Treatment-limiting adverse events do occur, but these may be managed by slow titration. Although comparative studies with the other newer AEDs used in adjuntive therapy are required, topiramate is an important extension to the range of drugs that may be used to treat refractory epilepsy in children.

Topics: Animals; Anticonvulsants; Child; Clinical Trials as Topic; Disease Models, Animal; Drug Administration Schedule; Drug Interactions; Drug Tolerance; Epilepsy; Fructose; Humans; Infant; Randomized Controlled Trials as Topic; Seizures; Spasms, Infantile; Tissue Distribution; Topiramate

Topiramate (TPM), a new antiepileptic medication, is efficacious as adjunctive therapy in adults with partial onset seizures. Its efficacy as adjunctive therapy in children was evaluated in two randomized double-blind placebo-controlled trials involving childhood epileptic encephalopathy (the Lennox-Gastaut syndrome) and partial onset seizures. In these studies, topiramate adjunctive therapy resulted in a significant reduction in drop attacks (tonic or atonic seizures) in patients with the Lennox Gastaut syndrome and a significant reduction in partial onset seizures in children with refractory partial epilepsy. In both trials, TPM's efficacy improved as the dose escalated from the double-blind phase to the open-label portion. The minimally effective topiramate dose for adjunctive therapy in children with refractory epilepsy appears to be 6 mg/kg/day. Topiramate was well tolerated with mild or moderate side effects, predominantly related to the central nervous system. Practical tips are provided that may increase the chance that topiramate will be effective and well tolerated. The most important advice is a "start low, go slow" approach. An initial TPM dose of 0.5-1 mg/kg/day followed by weekly increments of 0.5-1 mg/kg is usually well tolerated. Based on these studies, topiramate appears to be an important addition to our pediatric AED armamentarium.

Topics: Adult; Anticonvulsants; Child; Fructose; Humans; Seizures; Topiramate

The objective of this trial was to compare the effectiveness of levetiracetam (LEV) and topiramate (TPM) as adjunctive treatment for patients with focal seizures in Korea.. In this Phase IV, open-label, multicenter trial (NCT01229735), adults were randomized to treatment with LEV (1000-3000 mg/day) or TPM (200-400 mg/day). Only patients achieving LEV ≥1000 mg/day or TPM ≥100 mg/day after a 4-week up-titration entered the 20-week dose-finding and subsequent 28-week maintenance periods. The primary outcome was the 52-week retention rate; others included safety and exploratory efficacy outcomes.. Of 343 randomized patients (LEV 177; TPM 166), 211 (61.5%) completed the trial. In the full analysis set (FAS), retention rate was 59.1% with LEV vs 56.6% with TPM (p = 0.7007), while in the prespecified sensitivity analysis, based on data from patients who received drug doses in the recommended range (LEV 176; TPM 113), it was 59.1% with LEV vs 42.5% with TPM (p = 0.0086). In the FAS, median percent reduction in seizure frequency from baseline was 74.47% with LEV and 67.86% with TPM (p = 0.0665); ≥50% responder rate was 69.0% vs 64.8% (p = 0.4205), and the 6-month seizure-freedom rate was 35.8% vs 22.3% (p = 0.0061). In the sensitivity analysis, differences between groups were greater, favoring LEV. Incidences of treatment-emergent adverse events (TEAEs) were 70.6% with LEV vs 77.1% with TPM; most frequently somnolence (20.3%), dizziness (18.1%), and nasopharyngitis (13.6%) with LEV; and decreased appetite (15.7%), dizziness (14.5%), and headache (14.5%) with TPM. Discontinuations due to TEAEs were 7.9% with LEV and 12.7% with TPM.. In this open-label trial, the 52-week retention rate was not significantly different between LEV and TPM. However, LEV was associated with a substantially higher seizure freedom rate and a more favorable safety profile than TPM in this population of Korean patients with focal seizures.

Topics: Adult; Anticonvulsants; Dizziness; Drug Administration Schedule; Drug Therapy, Combination; Epilepsies, Partial; Female; Headache; Humans; Levetiracetam; Male; Middle Aged; Republic of Korea; Seizures; Sleepiness; Topiramate

The objective was to assess the efficacy and safety of adjunctive brivaracetam (BRV) with concomitant use of lamotrigine (LTG) or topiramate (TPM) in patients with uncontrolled focal seizures.. Data were pooled from three randomized, placebo-controlled Phase III studies (NCT00490035/N01252, NCT00464269/N01253, NCT01261325/N01358) of adults with focal (partial-onset) seizures. Patients taking concomitant levetiracetam were excluded from the efficacy populations, but included in the safety populations. This post-hoc analysis reports data from patients taking BRV in the approved therapeutic range (50-200mg/day) concomitantly with LTG or TPM.. The number of patients in each of the three BRV dosage groups was small, particularly for the TPM subgroup. Mean percent reduction over placebo in baseline-adjusted focal seizure frequency/28days for BRV 50, 100, and 200mg/day was 8.7, 5.3, and 8.9 in the LTG subgroup (n=220), and 8.4, 21.3, and -4.2 in the TPM subgroup (n=122). The ≥50% responder rate with concomitant LTG or TPM with BRV 50, 100, and 200mg/day or placebo was LTG: 28.1%, 36.1%, 34.1%, and 29.1%; and TPM: 14.3%, 44.4%, 25.0%, and 17.5%. There were numerically ≥50%, ≥75%, ≥90%, and 100% responder rates for patients taking BRV ≥50mg/day compared with placebo in both subgroups. In the LTG and TPM safety populations (n=245 versus n=125), treatment-emergent adverse events (TEAEs) were reported with LTG 68.7% versus 68.4%, and TPM 65.6% versus 57.8% (BRV ≥50mg/day versus placebo). Discontinuations due to TEAEs versus placebo were LTG 7.3% versus 6.3% and TPM 8.2% versus 4.7%. The three most frequently reported TEAEs for both subgroups were somnolence, dizziness, and fatigue. Of these, the incidence of fatigue in the LTG population appeared to increase with dose.. In this post-hoc pooled analysis, BRV administered with concomitant LTG or TPM reduced seizure frequency and was generally well tolerated for BRV doses of 50-200mg/day.

Topics: Adult; Anticonvulsants; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Fatigue; Female; Humans; Lamotrigine; Male; Middle Aged; Pyrrolidinones; Seizures; Sleepiness; Topiramate; Treatment Outcome; Young Adult

The aim of this study was to evaluate long-term safety, efficacy, and quality of life (QOL) of ≤400-mg/day USL255, Qudexy® XR (topiramate) extended-release capsules, as adjunctive therapy for partial-onset seizures (POS) in adults.. Patients who completed the 11-week double-blind treatment phase of the phase 3 PREVAIL study were eligible to enroll in this 1-year open-label extension (OLE) study (PREVAIL OLE). The primary objective was to evaluate the safety and tolerability of USL255 (including treatment-emergent adverse events [TEAEs]). The secondary objective was to assess seizure frequency in patients (e.g., median percent reduction from baseline in weekly POS frequency, responder rate [proportion of patients with ≥25%, ≥50%, ≥75%, or 100% reduction from baseline in POS frequency], and seizure-free intervals [proportion of patients who were seizure-free for 4, 12, 24, 36, or 48weeks]). Exploratory clinical-status endpoints included the Global Impression of Change (CGI-C) and Quality of Life in Epilepsy-Problems (QOLIE-31-P) questionnaires. Post hoc analyses evaluated neurocognitive TEAE incidences during the first 11 and entire 55weeks of treatment and efficacy by patient age and drug-resistant status.. Of the 217 patients who completed PREVAIL (USL255, n=103; placebo, n=114), 210 (97%) enrolled in PREVAIL OLE and were included in the ITT population. Across the entire 55-week treatment period, USL255 was generally safe and well tolerated, with low individual neurocognitive TEAE incidences. Seizure reduction was sustained across the year-long study and observed in patient subgroups, including those with highly drug-resistant seizures and those ≥50years of age. Improvements in CGI-C and QOLIE-31-P were also observed.. The results of PREVAIL OLE are consistent with those from PREVAIL and demonstrate that adjunctive treatment with up to 400mg/day of USL255 may be a safe and effective treatment option for a variety of adult patients with refractory POS.

Topics: Adult; Aging; Anticonvulsants; Cognition Disorders; Delayed-Action Preparations; Double-Blind Method; Drug Resistant Epilepsy; Epilepsies, Partial; Female; Fructose; Humans; Male; Quality of Life; Seizures; Surveys and Questionnaires; Topiramate; Treatment Outcome

To develop prognostic models for time to 12-month remission and time to treatment failure after initiating antiepileptic drug monotherapy for generalised and unclassified epilepsy.. We analysed data from the Standard and New Antiepileptic Drug (arm B) study, a randomised trial that compared initiating treatment with lamotrigine, topiramate and valproate in patients diagnosed with generalised or unclassified epilepsy. Multivariable regression modelling was used to investigate how clinical factors affect the probability of achieving 12-month remission and treatment failure.. Significant factors in the multivariable model for time to 12-month remission were having a relative with epilepsy, neurological insult, total number of tonic-clonic seizures before randomisation, seizure type and treatment. Significant factors in the multivariable model for time to treatment failure were treatment history (antiepileptic drug treatment prior to randomisation), EEG result, seizure type and treatment.. The models described within this paper can be used to identify patients most likely to achieve 12-month remission and most likely to have treatment failure, aiding individual patient risk stratification and the design and analysis of future epilepsy trials.

Topics: Adolescent; Adult; Anticonvulsants; Child; Electroencephalography; Epilepsy, Generalized; Female; Fructose; Humans; Lamotrigine; Magnetic Resonance Imaging; Male; Odds Ratio; Predictive Value of Tests; Regression Analysis; Remission Induction; Seizures; Time Factors; Tomography, X-Ray Computed; Topiramate; Treatment Failure; Triazines; Valproic Acid

Results from a previously conducted global phase III study (PREVAIL; NCT01142193) demonstrate the safety and efficacy of once-daily USL255, Qudexy™ XR (topiramate) extended-release capsules, as adjunctive treatment of drug-resistant partial-onset seizures (POSs). In this study, we report a post hoc analysis of PREVAIL data according to patient level of treatment resistance (based upon the number of concomitant antiepileptic drugs [AEDs] and lifetime AEDs) at baseline, with patients defined as either having "highly" drug-resistant seizures (≥ 2 concurrent AEDs and ≥ 4 lifetime AEDs) or having "less" drug-resistant seizures (1 concurrent AED or <4 lifetime AEDs) at baseline. For each subgroup, median percent reduction in POS frequency (primary endpoint), responder rate, Clinical Global Impression of Change (CGI-C), and Quality of Life in Epilepsy--Problems (QOLIE-31-P) survey were assessed. Of 249 PREVAIL patients, 115 were classified as having highly drug-resistant seizures (USL255: n = 52, placebo: n = 63), and 134 were classified as having less drug-resistant seizures (USL255: n = 72, placebo: n = 62) at baseline. For the primary endpoint, USL255 resulted in significantly better seizure outcomes compared with placebo regardless of drug-resistant status (P = .004 and P = .040 for "highly" and "less", respectively). Responder rate was also significantly improved in patients with highly drug-resistant group (P = .023). The CGI-C scores indicated significant improvement in both subgroups (P = .003 and P = .013 for "highly" and "less", respectively). On the QOLIE-31-P, a significant improvement on the seizure worry subscale for the group with less drug-resistant seizures was noted in USL255-treated patients compared with placebo-treated patients (P = .003); the overall score and all other subscales were not significantly different for both subgroups. We conclude that USL255 led to significant improvements across multiple outcomes compared with placebo, including in those classified as having highly drug-resistant seizures to prior treatment, making it a valuable treatment option for patients with epilepsy.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Delayed-Action Preparations; Double-Blind Method; Drug Resistance; Epilepsies, Partial; Female; Fructose; Humans; Male; Middle Aged; Prospective Studies; Quality of Life; Seizures; Topiramate; Treatment Outcome; Young Adult

To evaluate the efficacy and tolerability of topiramate (TPM) as monotherapy for patients with temporal lobe epileptic seizures based on an observational study.. We evaluated 41 patients (20 female, mean age 54+18 years) with temporal lobe epilepsy (TLE) referred to the Epilepsy Unit, University of Catanzaro, Italy. Patients received TPM as monotherapy directly or after having taken other antiepileptic drugs. Seizure frequency changes and adverse events were recorded. Follow-up was conducted for a period of at least two years after treatment.. Patients received TPM, 50-600 mg/day, de novo (n=29) or initially as add-on therapy before the switch (n=12). In total, 28 of 41 patients achieved seizure freedom, whereas 10 showed a ≥ 50% reduction of seizure frequency. Two patients did not respond well and one patient discontinued TPM due to adverse effects.. Our results confirm that TPM as either monotherapy or add-on therapy at doses of 50-600 mg/day effectively reduces seizure frequency in TLE. TPM is particular effective and very well tolerated in patients with mild TLE.

Topics: Adult; Age of Onset; Aged; Anticonvulsants; Drug Resistance; Electroencephalography; Epilepsy, Temporal Lobe; Female; Fever; Follow-Up Studies; Fructose; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Seizures; Topiramate

Data from two global studies (6-week open-label, phase 1 study; 20-day double-blind, phase 3 study) and their 1-year open-label extensions were pooled to assess long-term effects of adjunctive topiramate on adaptive behavior in infants with clinical or video-electroencephalographic evidence of refractory, partial-onset seizures. The primary safety and efficacy results of adjunctive topiramate treatment were reported previously. We report the changes in adaptive behavior of infants, based on Vineland Scales of Adaptive Behavior. Of 284 infants (mean [S.D.] age, 12 [6.3] months) enrolled, 89% (n = 252) manifested partial-onset seizures, and 41% (n = 116) manifested clinically relevant, symptomatic etiologies at pretreatment baseline. Overall, Vineland scores were below average at pretreatment baseline. The most frequently used concomitant antiepileptic drugs included valproic acid (59%), phenobarbital (31%), and carbamazepine (19%). The most common treatment-emergent cognitive and neuropsychiatric adverse events included anorexia (35%) and somnolence (27%). A clinically significant decline (approximately 15 points, or 1 S.D.) occurred in both Vineland Scales composite (mean change, -14.0) and domain standard scores from pretreatment baseline to open-label extension endpoint. However, individual domain raw scores increased, indicating that infants progressed in acquisitions of adaptive skill, but at a slower rate than the normative population.

Topics: Adaptation, Psychological; Anticonvulsants; Child, Preschool; Double-Blind Method; Drug Therapy, Combination; Female; Fructose; Humans; Infant; Infant Behavior; Infant, Newborn; Male; Seizures; Topiramate; Treatment Outcome

To compare the tolerability and efficacy of two titration methods (rapid and slow titration) for TOPINA Tablets with different dosages and periods of escalation, a double-blind comparative study was conducted in patients with localization-related epilepsy. A total of 183 patients were randomized to either rapid titration (initial dosage 100 mg/day increased by 100-200 mg at weekly intervals) or to slow titration (initial dosage 50 mg/day increased in 50 mg/day increments at weekly intervals). TOPINA Tablets were administered for 12 weeks to the maximum dosage of 400 mg/day. The incident of adverse events leading to treatment interruptions or withdrawals was 18.9% in rapid titration and 14.8% in slow titration, with no statistical significance (p = 0.554). The incident of adverse events and adverse reactions of slow titration was slightly lower than that of rapid titration. The common adverse events and adverse reactions reported in the two titration methods were comparable and were well tolerated. On the other hand, the efficacy of slow titration, percent reduction in seizure rate and responder rate, was comparable with that of rapid titration. In conclusion, there were no significant differences of therapeutic response to TOPINA Tablets between the two titration methods.

Topics: Adolescent; Adult; Anticonvulsants; Double-Blind Method; Drug Administration Schedule; Epilepsies, Partial; Female; Fructose; Humans; Male; Middle Aged; Seizures; Tablets; Topiramate; Treatment Outcome; Young Adult

This double-blind, placebo-controlled study investigated the efficacy and tolerability of adjunctive topiramate in 86 elderly Chinese patients with refractory partial epilepsy. Patients who had at least four seizures per 4 weeks during an 8-week baseline period, despite medication with up to three standard antiepileptic drugs (AEDs), were randomly assigned to receive topiramate (n = 46) or placebo (n = 40). Topiramate dosages were titrated (target dose 200 mg/day orally) for 8 weeks and maintained at stable levels for another 12 weeks; concomitant AEDs continued at original dosages. All patients completed the study: 47.8% in the topiramate group and 7.5% on placebo reached ≥ 50% reduction in complex partial seizures. In the topiramate group, the most common adverse events were dizziness, somnolence, fatigue, headache and difficulty with memory; most events were transient and mild or moderate in severity. It was concluded that 200 mg/day topiramate was effective and well-tolerated in elderly patients with refractory partial epilepsy.

Topics: Administration, Oral; Aged; Anticonvulsants; Asian People; China; Epilepsies, Partial; Female; Fructose; Humans; Male; Seizures; Topiramate

Data from 2 studies (phase 1 and phase 3) in infants <2 years old (N = 284; mean [SD] age, 12[6.3] months) with refractory partial-onset seizures were pooled to assess the long-term safety up to 1 year (primary objective) and tolerability of adjunctive topiramate treatment (mean treatment duration = 282 days). Monthly seizure rate summaries were also assessed. During the open-label extensions of these studies, study medication was first titrated to a dose of 25 mg/kg/d with subsequent uptitration to the maximum dosage tolerated, or seizure freedom, or a maximum of 60 mg/kg/d, whichever occurred first. The most common treatment-emergent adverse events (≥30%) were fever (52%), respiratory tract infections (51%), anorexia (35%), and acidosis (31%). Mean (SD) changes from pretreatment baseline to endpoint in Z scores for growth parameters were as follows: -0.82 (1.19) (body weight), -0.45 (1.60) (body length), and -0.36 (1.02) (head circumference).Tolerability in infants was consistent with previous studies.

Topics: Anticonvulsants; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fructose; Humans; Infant; Longitudinal Studies; Male; Seizures; Topiramate; Treatment Outcome

Most patients with epilepsy require long-term medical therapy. Newer antiepileptic drugs (AEDs) appear to be overall similarly effective to older agents but may be better tolerated. However, most of the clinical data available for newer AEDs derive from a number of short-term studies. The objective of this study was to explore long-term outcomes in patients with epilepsy treated with topiramate in routine clinical practice.. This was an open-label, multicentre, optional follow-up monotherapy study that included adolescents and adults with epilepsy who completed two similarly designed 28- or 30-week studies and agreed to participate for an additional 52 weeks. Seizure types and frequency, topiramate dose, vital signs and treatment-emergent adverse events (TEAEs) after 12, 26, 39 and 52 weeks were documented. Post hoc analyses to explore differences between males and females were conducted.. 114 patients (49.0% women, mean ± SD age 43 ± 17.5 years) with a mean ± SD disease duration of 61 ± 118 months (men 54 ± 96 vs women 68 ± 138 months) were followed up for a median of 18.5 months. Seventy-eight percent of patients completed the study. Reasons for premature discontinuation were: loss to follow-up (10.5%), TEAE (5.3%), lack of efficacy (2.6%), non-adherence (0.9%) and other reasons (4.4%). Seizure frequency per 4 weeks decreased from a mean ± SD 5.0 ± 28.3 at baseline to 0.6 ± 2.1 during the whole observation period. Fifty-four patients (52.9%) were seizure free during the whole observation period. In addition, 69 of 95 patients (72.6%) whose topiramate therapy was stable within a range of ±50 mg/day for a period of at least 12 months (maintenance phase) were seizure free while treated with a median topiramate dose of 100 mg/day. The most frequently reported TEAEs were paraesthesias (13.2% of patients), dizziness (7.0%) and seizure-related events (7.0%). No significant differences between males and females were found for treatment response or retention.. Topiramate is an effective and well tolerated long-term treatment option for adolescents and adults with epilepsy.

Topics: Adult; Ambulatory Care Facilities; Anticonvulsants; Disease Progression; Epilepsy; Female; Follow-Up Studies; Fructose; Germany; Humans; Male; Middle Aged; Neurology; Physicians; Prospective Studies; Seizures; Time Factors; Topiramate; Treatment Outcome

To evaluate the efficacy and safety of adjunctive topiramate (sprinkle capsules or oral liquid) in reducing daily rates of partial-onset seizures (POS) in infants with refractory POS.. In this double-blind, placebo-controlled, parallel-group, international study, infants (n = 149) with clinical or EEG evidence of refractory POS were randomly allocated (1:1:1:1) to receive adjunctive topiramate 5, 15, or 25 mg/kg/d or placebo for 20 days. The primary variable was the median percentage reductions in daily POS rate from baseline to final assessment as recorded on a 48-hour video-EEG.. Of the 149 infants (mean age 12 months) included in the intent-to-treat analysis set, 130 completed the study. Median percentage reduction from baseline in daily POS rate was not significantly different (p = 0.97) between topiramate 25 mg/kg (20.4%) and placebo (13.1%). Lower doses were not formally tested, but nominal p values for comparisons with placebo were not significant (15-mg/kg/d dose: p = 0.97; 5-mg/kg/d dose: p = 0.91). Treatment-emergent fever, diarrhea, vomiting, anorexia, weight decrease, somnolence, and viral infection occurred more frequently (> or = 10% difference) with topiramate than with placebo.. In infants aged 1-24 months, topiramate 5, 15, or 25 mg/kg/d was not effective as adjunctive treatment for refractory partial-onset seizures. No new safety concerns associated with topiramate use were noted.. This interventional study provides Class I evidence that topiramate 5, 15, or 25 mg/kg/d compared with placebo does not significantly reduce seizure rates in infants aged 1 month to 2 years with refractory partial-onset seizures.

Topics: Anticonvulsants; Brain; Chemotherapy, Adjuvant; Double-Blind Method; Electroencephalography; Epilepsies, Partial; Female; Fructose; Humans; Infant; Male; Seizures; Topiramate; Treatment Outcome; Video Recording

For a retrospective observational investigation based on real clinical practice of relative efficacy of valpoic acid (VPA), carbamazepine (CBZ) and topiramate (TPM) we have selected 106 patients with age of seizure onset before 17 years with a undoubted diagnosis of symptomatic or cryptogenic occipital lobe epilepsy (OLE), who had received treatment according to ILAE recommendations, and observation time since the last treatment change was from 2 to 10 years. Patients suspicious for idiopathic epilepsies were excluded. The groups of patient receiving CBZ, VPA and TPM did not differ significantly in presenting unfavorable prognostic factors and dose regimes that allowed to conduct direct comparison of efficacy of the investigated drugs. Efficacy of VPA in children with OLE was higher compared with CBZ (69% vs 36%, p < 0.01) and TPM (69% vs 8%, p < 0.001). CBZ and TPM caused seizure aggravation more frequently than VPA (12% and 13% respectively vs 1%, p < 0.001). In case of presence of clinico-electroencephalografic and MRI signs of significant organic brain damage and in patients with seizure onset under 11 years TPM was not effective. In case of focal cortical dysphasia the efficacy of CBZ was lower than VPA (20% vs 63%, p < 0.05). In MRI-negative cases VPA was most effective (79% vs 44% for CBZ, p < 0.001 and 29% for TPM, p < 0.01). Efficacy of CBZ and TPM reduces proportionally the number of previously used antiepileptic drugs (AEDs), this tendency is noted also for VPA but as a second AED it was more effective than CBZ and TPM (56% vs 15%, p < 0.01 and 14%, p < 0.05, respectively); as a first AED VPA was also most effective (82% vs 37%, p < 0.001 for CBZ and 82% vs 33%, p < 0.01 for TPM). Adverse effects were more frequent during treatment with CBZ and TPM, than VPA (21% vs 6%, p < 0.001 and 17% vs 6%, p < 0.05).

Topics: Adolescent; Anticonvulsants; Benzodiazepines; Brain Injuries; Carbamazepine; Child; Epilepsies, Partial; Epilepsy; Fructose; Humans; Retrospective Studies; Seizures; Topiramate; Treatment Outcome; Valproic Acid

This 12-week open label study explored cognitive and seizure outcomes of 53 children treated with topiramate (TPM). The digit symbol test and verbal learning memory test were administered at baseline and study endpoint. Topiramate was started either in monotherapy or add-on therapy. Overall, 57% of children experienced a ≥50% seizure reduction, 36% became seizure free and cognitive testing revealed no significant changes during TPM therapy. Due to the heterogeneity of the study population, post hoc analyses were added to compare patients in initial or conversion to TPM monotherapy as well as patients who continued add-on therapy. Verbal learning memory test parameters showed neither significant differences within any subgroup comparing baseline with endpoint nor significant differences between described subgroups except for one finding. The digit symbol test revealed no differences between each subgroup between baseline and endpoint. Comparing pre-post differences, TPM monotherapy was associated with better cognitive outcomes than treatment in add-on therapy. These results have to be interpreted with caution given the short study duration and the heterogeneity of the study population. Despite these limitations, our overall results suggest that treatment with topiramate is associated with improved seizure control without significant changes in cognitive functions at the low doses tested.

Topics: Adolescent; Anticonvulsants; Body Weight; Child; Cognition Disorders; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Male; Memory Disorders; Neuropsychological Tests; Prospective Studies; Psychiatric Status Rating Scales; Seizures; Severity of Illness Index; Single-Blind Method; Time Factors; Topiramate; Verbal Learning

This 24-week, multicenter, open-label trial was designed to evaluate the dosing, effectiveness, and safety of topiramate monotherapy for epilepsy and to identify patient and clinical characteristics predictive of optimally effective stabilized monotherapy doses. Of 406 randomized patients, 244 comprised the evaluable-for-efficacy population (12 weeks of treatment and stabilized topiramate dose during final 28 days); 213 were on topiramate monotherapy at the end of the trial. The mean stabilized daily dose of topiramate over the last 28 days of treatment (primary endpoint) was significantly lower for patients reporting one to three seizures (low seizure frequency, n=147) than for those reporting more than three seizures (high seizure frequency, n=66) during a 3-month retrospective baseline period (191 mg vs 239 mg, P=0.003). Patients in the low-seizure-frequency group reached a stable topiramate dose after a median of 36 days, compared with 53 days for patients in the high-seizure-frequency group. Linear and stepwise regression analyses showed baseline seizure frequency and lifetime seizure count to be significant (P<0.05) predictors of the stabilized dosage. Most treatment-emergent adverse events (TEAEs) were mild to moderate; those occurring with cumulative incidence rates >10% in either seizure frequency group were paresthesia, fatigue, anorexia, dizziness, somnolence, headache, and hypoesthesia; 18.2% of patients discontinued topiramate because of a TEAE, 5.1% reported serious TEAEs, and no deaths were reported during the study.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Data Interpretation, Statistical; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Outpatients; Seizures; Topiramate; Young Adult

A subsample of 67 adult patients with partial seizures participating in a randomized, double-blind study comparing the cognitive effects of adjunctive lamotrigine (LTG) and adjunctive topiramate (TPM) was administered Performance On-Line (POL) in addition to a battery of neuropsychological tests at baseline, week 8 and week 16 of treatment. The POL is a self-administered computer task that measures scanning, divided-attention, and the effective field of view. Although the POL does not measure driving performance, POL scores are correlated with driving performance. The results show that adjunctive TPM, but not adjunctive LTG, negatively impacted cognition. Both simple target identification and divided-attention performance on POL were compromised in the TPM group but not in the LTG group. The relative POL impairment associated with chronic TPM treatment was similar to that observed with the acute effects of alcohol with a breath level of .045% or a low dose of alprazolam (0.5mg). Thus, driving-related visual and cognitive skills were compromised by adjunctive TPM treatment. Therapeutic doses of adjunctive TPM pose a potential risk of impaired scanning and divided-attention skills.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Cognition; Data Interpretation, Statistical; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Middle Aged; Neuropsychological Tests; Seizures; Topiramate; Triazines; Vision Disorders; Visual Fields; Visual Perception

To explore effectiveness, tolerability and quality of life in elderly patients with epilepsy treated with topiramate.. One year, open-label, flexible-dosing clinical trial.. One hundred and seven patients (mean age 69 years, 53% men) were studied during 273 +/- 141 days. The average final dose in monotherapy was 98 mg/day vs 153 mg/day in adjunctive treatment. Mean monthly cumulative seizure frequency decreased from 3.7 +/- 15 to 1.6 +/- 7.7 (n = 101, P < 0.0001), 78% of patients with seizures at baseline (n = 102) achieved at least 50% reduction in seizure frequency, 44% were seizure-free throughout the trial. Total scores on the quality of life in epilepsy inventory (QOLIE-31) improved from 57 +/- 17 to 68 +/- 18 (n = 64, P < 0.0001). The most frequently reported adverse events included convulsions, dizziness and tiredness.. Elderly patients treated with topiramate showed marked reductions in seizures, good tolerability and significant improvements in several aspects of quality of life.

Topics: Aged; Aged, 80 and over; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Quality of Life; Seizures; Topiramate

Pharmacokinetics of antiepileptic drugs (AEDs) can be altered by age-related changes in physiology, thereby altering clinical effects, especially tolerability, in older adults. We compared two dosages of topiramate (TPM) in a pilot study of patients >or=60 years of age with partial-onset seizures.. In this 24-week, double-blind, randomized, parallel-group study, patients with one or more seizures in previous 6 months were randomized to treatment with 50 or 200 mg/day TPM. TPM was initiated as monotherapy or added to one AED and titrated by 25 mg/day per week to target or maximum tolerated dose as the concomitant AED, if any, was withdrawn.. Thirty-eight patients were randomized to the 50 mg/day TPM (mean age, 68 years) and 39-200 mg/day TPM (69 years). Seizure control was similar with the two dosages when TPM could be used as monotherapy, whereas 200 mg TPM was more effective than 50 mg in patients requiring adjunctive therapy. The overall incidence of adverse events was similar for the two dosages--66% with 50 mg and 62% with 200 mg TPM. Most common adverse events were somnolence (TPM 50, 13%; TPM 200, 8%), dizziness (13% vs. 8%), and headache (13% vs. 5%). Of 10 (13%) patients reporting a cognitive-related adverse event, six patients were assigned to the 50-mg group. A total of 14 patients (18%; seven in each group) discontinued TPM due to adverse events.. This pilot study supports the practice of using low-to-moderate dosages of AEDs in older adults.

Topics: Aged; Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Fructose; Headache; Humans; Male; Middle Aged; Periodicity; Pilot Projects; Recurrence; Seizures; Severity of Illness Index; Topiramate

Few randomized, controlled trials evaluating antiepileptic drug (AED) efficacy and tolerability have focused solely on patients with juvenile myoclonic epilepsy (JME). We conducted a pilot, randomized controlled trial comparing topiramate (N=19) and valproate (N=9) in adolescents/adults with JME to evaluate clinical response when these broad-spectrum agents are titrated to optimal effect. Rating scales were used to systematically assess tolerability. Among patients completing 26 weeks of treatment, 8 of 12 (67%) in the topiramate group and 4 of 7 (57%) in the valproate group were seizure-free during the 12-week maintenance period. Median daily dose was 250mg topiramate or 750mg valproate. Two (11%) topiramate-treated patients and one (11%) valproate-treated patient discontinued due to adverse events. Systemic toxicity scores, but not neurotoxicity scores, differed substantially between the two groups; greater systemic toxicity was associated with valproate. Our preliminary findings that topiramate may be an effective, well-tolerated alternative to valproate warrant validation in a double-blind trial.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Double-Blind Method; Female; Fructose; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Myoclonic Epilepsy, Juvenile; Neurotoxicity Syndromes; Pilot Projects; Seizures; Tomography, X-Ray Computed; Topiramate; Valproic Acid

An open-label, observational prospective study assessed the effectiveness of topiramate (TPM) as add-on therapy. A total of 450 patients aged 12 and above with a diagnosis of epilepsy and at least one epileptic seizure during the 12-week retrospective baseline were to be documented. After baseline evaluation, topiramate was added. Ninety-five percent of patients had at least one baseline AED, most commonly Carbamazepine (53%) or Valproate (34%). In 5% TPM was started in monotherapy. Topiramate dose titration and target dose was determined by clinical response and side effect profile. Patients were intended to be followed for a total of 1 year which included 6 visits during which seizure frequency, adverse events, weight as well as clinical global impression were recorded. During the 12 weeks retrospective baseline, a median of 2.8 seizures per month were recorded which reduced significantly to 0.7 per month during the complete treatment phase (p < 0.0001). Seventy-two percent of patients had a > or =50% seizure reduction. Ten percent of patients were seizure free during the study. The most commonly reported adverse events were difficulties with memory (4.2%), somnolence (3.6%), and dizziness (2.7%). Overall, topiramate was well tolerated, and only 5% of patients discontinued treatment due to an adverse event. Retention in the study was higher than previously reported during randomized, dose controlled studies and is likely due to individualized doses as well as slower titration used.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Body Weight; Child; Drug Resistance; Drug Therapy, Combination; Endpoint Determination; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Prospective Studies; Seizures; Topiramate; Treatment Outcome

Alternating hemiplegia of childhood is a rare syndrome characterized by the onset, before 18 months of age, of frequent attacks of alternating paralysis. Here we report the efficacy of topiramate in four patients with alternating hemiplegia of childhood (AHC) that did not respond to flunarizine, as well as in two newly diagnosed patients. Following treatment with topiramate, the frequency and duration of hemiplegic attacks significantly improved in all patients. Additional symptoms such as seizures, migraine, involuntary movements, autonomic symptoms, and impaired mental development also improved. Topiramate is worth trying when treating patients with AHC as a first trial, or a substitute for flunarizine once the latter agent loses effect.

Topics: Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Fructose; Hemiplegia; Humans; Male; Neuroprotective Agents; Seizures; Time Factors; Topiramate; Treatment Outcome

This randomized, double-blind, placebo-controlled UK trial evaluated the effect of topiramate as add-on therapy on seizure frequency, seizure severity, and quality of life in patients with epilepsy and intellectual disability. There were three phases: 4 weeks baseline, 18 weeks titration to 200-400 mg topiramate/day (adults) or 5-9 mg/kg/day (children), 12 weeks maintenance. Recruitment was low (88/120); analyses were underpowered. Seizure frequency varied enormously (median 17.7, maximum 1706.2). There was no significant difference in reduction in mean total seizure frequency or number of responders between the groups. Topiramate reduced seizure frequency by >30% from baseline (placebo 1%); post hoc analyses showed a trend toward significance (R ratio, P=0.052). There were no significant differences between the groups with respect to mean seizure severity or other outcome measures. Topiramate was generally well tolerated; body weight (P=0.015) and systolic blood pressure (P=0.043) were reduced. The study suggests that topiramate reduces seizure frequency in patients with epilepsy and intellectual disability without the added burden of behavior effects, and was potentially advantageous to physical well-being.

Topics: Adaptation, Psychological; Adult; Anticonvulsants; Body Weight; Double-Blind Method; Epilepsy; Female; Fructose; Humans; Intellectual Disability; Intelligence Tests; Male; Neuropsychological Tests; Quality of Life; Seizures; Sex Characteristics; Topiramate

We performed a prospective study to evaluate the effect of topiramate as an adjunctive therapy in Taiwanese children with intractable partial epilepsy and generalized epilepsy. Thirty children aged from 2 to 16 years (8.5 +/- 3.8 years) were enrolled in this study. Eighteen children (60.0%) had partial epilepsy, and 12 children (40.0%) had generalized epilepsy. These children were experiencing more than one seizure per month even under a stable antiepileptic regimen treatment. Topiramate was begun at 1 mg/kg x day, and the dosage was raised by 1 mg/kg x day each week. Titration continued for 4 weeks or more. The maximal dosage was 10 mg/kg x day. In children with partial epilepsy, six children (33.3%) achieved > or = 50% frequency reduction, while eight children (44.4%) achieved a seizure-free state. In children with generalized epilepsy, including infantile spasms, four children (33.3%) achieved > or = 50% frequency reduction, while five children (41.7%) achieved a seizure-free state. The most common adverse effect was poor appetite (10.0%). No idiosyncratic reactions to topiramate were found. Only one patient discontinued topiramate because of central hyperventilation. Topiramate can be used as an adjunctive antiepileptic drug for intractable epileptic children in Taiwan.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Fructose; Humans; Male; Prospective Studies; Seizures; Topiramate

To compare topiramate (TPM) with investigator's choice of carbamazepine (CBZ) or valproate (VPA) for initial treatment in patients with newly diagnosed epilepsy.. In patients with epilepsy diagnosed within previous 3 months, investigators selected CBZ (600 mg/day) or VPA (1250 mg/day) as preferred therapy based on the patient's clinical presentation. Based on investigators' treatment choice, patients (n=613) were assigned to the CBZ or VPA treatment branch. Within each branch, patients were randomized to double-blind treatment with the traditional antiepileptic drugs (CBZ or VPA), TPM 100 mg/day, or TPM 200 mg/day. Patients continued double-blind treatment until exiting the study or until 6 months after last patient randomized.. No statistically significant differences between fixed doses of TPM and CBZ or VPA were observed in efficacy measures: time to exit, time to first seizure, and the proportion of patients seizure-free during the last 6 months of treatment. TPM 100 mg/day was associated with the fewest discontinuations due to adverse events.. In patients with newly diagnosed epilepsy, an initial target dose of TPM 100 mg/day is at least as effective as therapeutic doses of CBZ and VPA.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anticonvulsants; Carbamazepine; Child; Double-Blind Method; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Seizures; Topiramate; Treatment Outcome; Valproic Acid

To evaluate the relationship between baseline seizure frequency and stabilized topiramate dosage and the effect of individualized treatment on tolerability in adults with partial-onset seizures receiving other antiepileptic drugs (AEDs).. In this 20-week, open-label trial, dosages of medications were adjusted according to clinical response. Dosage and seizure response data were analyzed for 2 groups defined by baseline seizure frequency: <4 and >/=4 seizures per month.. In the outcome evaluable population (n = 471), the mean +/- SEM stable topiramate dosage was 303 +/- 139 mg/d when baseline seizure frequency was <4 seizures/month and 341 +/- 153 mg/d when baseline seizure frequency was >/=4 seizures/month (p = 0.005). The most common adverse events were somnolence (8.5%), fatigue (7.3%), nausea (5.3%), and dizziness (5.0%). Cognitive complaints were reported by <3% of patients. When concomitant AED dosages were reduced, 14% of patients discontinued topiramate due to adverse events compared with 23% if the concomitant AED dosage was unchanged or increased.. When clinicians individualize topiramate dosage according to clinical response, the stabilized topiramate dosage as add-on therapy is influenced by baseline seizure frequency. Topiramate tolerability is improved when dosages of concomitant AEDs are reduced.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Seizures; Topiramate

To establish the concentration response of topiramate in patients with refractory focal epilepsy.. Sixty-five patients with more than eight seizures during an 8-week baseline were randomized to three prespecified plasma levels (low, 6 micromol/L [2 mg/L]; medium, 31 micromol/L [10.5 mg/L]; and high, 56 micromol/L [19 mg/L]). Topiramate treatment was titrated to one of the prespecified plasma levels during an 8-week titration period, followed by a 12-week observation period.. The overall median (25th to 75th percentile) reduction in seizures during the observation compared with baseline was 50% (9.5 to 90%). In the individual groups, the median reduction was as follows: low, 39% (13 to 70%); medium, 85% (41 to 96%); and high, 39% (2.0 to 81%). The primary outcome of the trial was the comparison of seizure reduction (Mann-Whitney U test) between the low and the medium group (p = 0.03). Comparisons between the other groups were as follows: medium vs high (p = 0.05) and low vs high (p = 0.81). Psychiatric adverse events and adverse events related to the CNS were the most frequently encountered. Most adverse events showed concentration response, particularly between low and medium levels.. Patients assigned to the medium plasma level (31 micromol/L [10.5 mg/L]) had the best seizure outcome. Patients in the medium and high groups experienced more adverse events than patients in the low group. Optimal treatment response is thus most likely found at plasma concentrations higher than 6 micromol/L (2 mg/L), but no further increase in efficacy seems to occur at concentrations above 31 micromol/L (10.5 mg/L).

Topics: Adult; Aged; Anticonvulsants; Dose-Response Relationship, Drug; Epilepsies, Partial; Female; Fructose; Humans; Male; Middle Aged; Safety; Seizures; Topiramate; Treatment Outcome; Vertigo

Antiseizure medications (ASMs) remain the mainstay of epilepsy treatment. These ASMs have mainly been tested in trials in adults with epilepsy, which subsequently led to market authorization (MA). For treatment of - especially young - children with epilepsy, several ASMs do not have a MA and guidelines are lacking, subsequently leading to "off-label" use of ASMs. Even though "off-label" ASM prescriptions for children could lead to more adverse events, it can be clinically appropriate and rational if the benefits outweigh the risks. This could be the case if "on-label" ASM, in mono- or polytherapy, fails to achieve adequate seizure control.. The Medical Therapies Task Force of the International League Against Epilepsy (ILAE) Commission for Pediatrics performed a survey to study the current treatment practices in six classic, early life epilepsy scenarios. Our aim was not only to study first- and second-line treatment preferences but also to illustrate the use of "off-label" drugs in childhood epilepsies.. Our results reveal that several ASMs (e.g. topiramate, oxcarbazepine, benzodiazepines) are prescribed "off-label" in distinct scenarios of young children with epilepsy. In addition, recent scientific guidelines were not always adopted by several survey respondents, suggesting a potential knowledge gap.. We report the relatively common use of "off-label" prescriptions that underlines the need for targeted and appropriately designed clinical trials, including younger patients, which will also result in the ability to generate evidence-based guidelines.

Topics: Child; Child, Preschool; Epilepsy; Humans; Infant; Off-Label Use; Oxcarbazepine; Seizures; Topiramate

Topiramate (TPM) is widely used in focal and generalized epilepsies. It is commercially available as tablets and sprinkles capsules for oral treatment. Previous studies comparing intravenous (IV) to oral TPM in healthy adults showed more rapid pharmacodynamic effects in cases of IV administration. Despite promising findings, no clinical application in humans followed. We present a case of a pregnant woman with idiopathic generalized epilepsy who experienced a generalized tonic-clonic seizure in the third trimenon due to low TPM levels attributed to pregnancy followed by repeated prolonged absences. We applied a new meglumine-based solution (1%) of TPM (10 mg/ml) in two IV infusions of 200 mg each under EEG monitoring over a total duration of 1 hour. The infusion was well tolerated and led to a rapid increase in plasma TPM levels. A clinical as well as electroencephalographic improvement was documented within the first hours. To the best available knowledge, this is the first reported case where IV TPM was used therapeutically for seizure treatment in humans. It is also the first time that the new meglumine-based solution was used in a human with epilepsy. The advantages of IV route delivery and the solution's quick preparation, high tolerability, and low toxicity make it ideal for use in many clinical settings and high-care patients. IV TPM seems to be a reasonable adjunctive option for adults with seizures, previously stabilized on oral TPM, who need rapid plasma concentration boosting. Although our experience was successful in using injectable TPM in seizure emergencies, randomized controlled clinical trials are required to make recommendations for the use of IV TPM on patients with epilepsy. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022 in Salzburg, Austria.

Topics: Adult; Anticonvulsants; Emergencies; Epilepsy; Female; Fructose; Humans; Seizures; Topiramate; Treatment Outcome

Epilepsy is a common neurological disorder characterized by seizures that cause neurobiological and behavioral impairment. Caffeine (CAF), which is the most widely consumed stimulant in the world, is reported to influence epileptic seizures and antiepileptic drugs, especially topiramate (TPM). The aim of the study was to optimize the zebrafish larvae pentylenetetrazol-induced seizure model for the study of CAF and TPM interactions, which include the determination of dose space, and the delivery of an analytical method for monitoring CAF, TPM, and CAF metabolite paraxanthine (PAR) in Zebrafish larvae. Methods: The zebrafish larvae, 4 days post-fertilization, were incubated for 18 h with CAF, TPM, or CAF + TPM, with subsequent locomotor activity assessment. Seizures were evoked by adding PTZ solution to obtain a final concentration of 20 mM. Subsequently, the liquid chromatography-mass spectrometry (LC-MS/MS) analytical method was used to simultaneously assess the levels of both CAF and TPM in the larvae. CAF (50 mg/L) and TPM (75 μM) given separately decreased the average larvae locomotor activity compared to the PTZ group but, however, were not able to lower it to the control level. Co-administration of 25 mg/L CAF and 50 μM TPM suppressed the activity to the same level. Adding 25 μM TPM to 50 mg/L CAF decrease the measured CAF level in the larvae. Until proven otherwise, CAF consumption should be regarded as a potential determinant in the modulation of TPM's efficacy in the management of epileptic seizures. The optimized model will contribute to the standardization of studying CAF and TPM interactions and building the understanding of the molecular bases of the interaction.

Topics: Animals; Caffeine; Chromatography, Liquid; Larva; Pentylenetetrazole; Seizures; Tandem Mass Spectrometry; Topiramate; Zebrafish

Status epilepticus in poststroke epilepsy is a challenging condition because of multiple vascular comorbidities and the advanced age of patients. Data on third-generation antiseizure medication (ASM) in this condition are limited. The aim of this study was to evaluate the efficacy of third-generation ASMs in the second- or third-line therapy of benzodiazepine-refractory status epilepticus in poststroke epilepsy following acute ischemic stroke.. Data on the effectiveness of third-generation ASMs in patients with status epilepticus in poststroke epilepsy were gathered from two German Stroke Registries and the Mainz Epilepsy Registry. We included only cases with epilepsy remote to the ischemic event. No patients with acute symptomatic seizures were included. The following third-generation ASMs were included: brivaracetam, lacosamide, eslicarbazepine, perampanel, topiramate, and zonisamide. The assessment of effectiveness was based on seizure freedom within 48 h since the start of therapy with the respective ASM. Seizure freedom was evaluated both clinically (clinical evaluation at least three times per day) and by daily electroencephalogram records.. Of the 138 patients aged 70.8 ± 8.1 years with benzodiazepine-refractory status epilepticus in ischemic poststroke epilepsy, 33 (23.9%) were treated with lacosamide, 24 (17.4%) with brivaracetam, 23 (16.7%) with eslicarbazepine, 21 (15.2%) with perampanel, 20 (14.5%) with topiramate, and 17 (12.3%) with zonisamide. Seizure freedom within 48 h was achieved in 66.7% of patients with lacosamide, 65.2% with eslicarbazepine, 38.1% with perampanel, 37.5% with brivaracetam, 35.0% with topiramate, and 35.3% with zonisamide (p < 0.05 for comparison of lacosamide or eslicarbazepine to other ASMs).. Based on these data, lacosamide and eslicarbazepine might be more favorable in the treatment of refractory status epilepticus in poststroke epilepsy, when administered as second- or third-line ASMs before anesthesia. Because of the fact that these ASMs share the same mechanism of action (slow inactivation of sodium channels), our findings could motivate further research on the role that this pharmaceutical mechanism of action has in the treatment of poststroke epilepsy.. This study was registered at ClinicalTrials.gov (NCT05267405).

Topics: Aged; Anticonvulsants; Benzodiazepines; Epilepsy; Humans; Ischemic Stroke; Lacosamide; Middle Aged; Retrospective Studies; Seizures; Status Epilepticus; Topiramate; Zonisamide

Self-limited infantile epilepsy (SeLIE) is a benign epilepsy. Previous studies have shown that monotherapy with most antiseizure medications can effectively relieve seizures in patients with SeLIE, but the efficacy of levetiracetam has not been investigated.. This study aimed to investigate the efficacy of levetiracetam in the treatment of SeLIE patients with PRRT2 mutations.. The clinical data of 39 SeLIE patients (21 males and 18 females, aged 4.79 ± 1.60 months) with pathogenic variants in PRRT2 or 16p11.2 microdeletion were retrospectively analyzed. Based on the use of initial antiseizure medication (ASM), the patients were classified into two groups: Levetiracetam group (LEG) and Other ASMs group (OAG). The difference of efficacy between the two groups was compared.. Among the 39 SeLIE patients, 16 were LEG (10 males and 6 females, aged 5.25 ± 2.07 months), with whom two obtained a seizure-free status (12.50%) and 14 ineffective or even deteriorated (87.50%). Among the 14 ineffective or deteriorated cases, 13 were seizure-controlled after replacing levetiracetam with other ASMs including topiramate, oxcarbazepine, lamotrigine, and valproate, and the remaining one finally achieved remission at age 3. Of the 39 patients, 23 were OAG (11 males and 12 females; aged 4.48 ± 1.12 months), of whom 22 achieved seizure remission, except for one patient who was ineffective with topiramate initially and relieved by oxcarbazepine instead. Although there were no significant differences in gender and age of onset between the two groups, the effective rate was significantly different (12.50% in LEG vs. 95.65% in OAG) (P < 0.01).. The findings showed that patients with SeLIE caused by the PRRT2 mutations did not benefit from the use of levetiracetam, but could benefit from other ASMs.

Topics: Anticonvulsants; Child, Preschool; Epilepsy; Female; Humans; Infant; Levetiracetam; Male; Membrane Proteins; Nerve Tissue Proteins; Oxcarbazepine; Retrospective Studies; Seizures; Topiramate

STXBP1-related disorders are among the most common genetic epilepsies and neurodevelopmental disorders. However, the longitudinal epilepsy course and developmental end points, have not yet been described in detail, which is a critical prerequisite for clinical trial readiness. Here, we assessed 1281 cumulative patient-years of seizure and developmental histories in 162 individuals with STXBP1-related disorders and established a natural history framework. STXBP1-related disorders are characterized by a dynamic pattern of seizures in the first year of life and high variability in neurodevelopmental trajectories in early childhood. Epilepsy onset differed across seizure types, with 90% cumulative onset for infantile spasms by 6 months and focal-onset seizures by 27 months of life. Epilepsy histories diverged between variant subgroups in the first 2 years of life, when individuals with protein-truncating variants and deletions in STXBP1 (n = 39) were more likely to have infantile spasms between 5 and 6 months followed by seizure remission, while individuals with missense variants (n = 30) had an increased risk for focal seizures and ongoing seizures after the first year. Developmental outcomes were mapped using milestone acquisition data in addition to standardized assessments including the Gross Motor Function Measure-66 Item Set and the Grasping and Visual-Motor Integration subsets of the Peabody Developmental Motor Scales. Quantification of end points revealed high variability during the first 5 years of life, with emerging stratification between clinical subgroups. An earlier epilepsy onset was associated with lower developmental abilities, most prominently when assessing gross motor development and expressive communication. We found that individuals with neonatal seizures or early infantile seizures followed by seizure offset by 12 months of life had more predictable seizure trajectories in early to late childhood compared to individuals with more severe seizure presentations, including individuals with refractory epilepsy throughout the first year. Characterization of anti-seizure medication response revealed age-dependent response over time, with phenobarbital, levetiracetam, topiramate and adrenocorticotropic hormone effective in reducing seizures in the first year of life, while clobazam and the ketogenic diet were effective in long-term seizure management. Virtual clinical trials using seizure frequency as the primary outcome resulted in wide range

Topics: Anticonvulsants; Child; Child, Preschool; Epilepsy; Humans; Infant; Infant, Newborn; Munc18 Proteins; Seizures; Spasms, Infantile; Topiramate

A previously published, single-institution, case series suggested an association between topiramate administration in neonates and subsequent development of necrotizing enterocolitis (NEC). This contradicted our more extensive experiences using topiramate in this population. We therefore studied safety and tolerability of topiramate for treating refractory neonatal seizures, hypothesizing that the risk of developing NEC following topiramate exposure was low and that most infants tolerate topiramate.. This multicenter retrospective cohort study included seventy-five neonates who received topiramate to treat seizures from January 2011 to October 2019 at three geographically diverse level IV neonatal intensive care units affiliated with pediatric tertiary hospitals. Data included demographics, birth history, seizure etiology, treatment response, side effects, and occurrence and details of NEC.. Three of seventy-five infants (4%) developed NEC following topiramate exposure. These infants did not differ in gestational age, birth weight, seizure etiology, postmenstrual age, weight when topiramate was initiated, or dosing of topiramate. Topiramate was well tolerated. Only three infants (4%) discontinued due to side effects. The most common side effect (20%) was weight loss (typically <5%). Topiramate was felt to be efficacious (61%). Most infants (72%) continued topiramate when discharged.. Our multicenter, 75-infant study demonstrated that development of NEC after treatment with topiramate was rare (4%) and refutes prior literature suggesting an association. Topiramate was felt to be efficacious and was well tolerated. Although limited by retrospective design, study data are broadly applicable and support thoughtful use of topiramate as a safe, reasonable option for treating refractory neonatal seizures.

Topics: Child; Cohort Studies; Enterocolitis, Necrotizing; Epilepsy; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Infant, Very Low Birth Weight; Retrospective Studies; Seizures; Topiramate

The prevalence of epilepsy in the world population together with a high percentage of patients resistant to existing antiepileptic drugs (AEDs) stimulates the constant search for new approaches to the treatment of the disease. Previously a significant anticonvulsant potential of cardiac glycoside digoxin has been verified by enhancing a weak activity of AEDs in low doses under screening models of seizures induced by pentylenetetrazole and maximal electroshock. The aim of the present study is to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant activity of valproate, levetiracetam, and topiramate in models of primary generalized seizures with different neurochemical mechanisms. A total of 264 random-bred male albino mice have been used. AEDs were administered 30 min before seizure induction once intragastrically at conditionally effective (ED50) and sub-effective (½ ED50) doses: sodium valproate and topiramate - at doses of 300 and 150 mg/kg; levetiracetam - at doses of 100 and 50 mg/kg. Digoxin was administered once subcutaneously at a dose of 0.8 mg/kg body weight (1/10 LD50) 10-15 min before seizure induction. Picrotoxin (aqueous solution 2.5 mg/kg, subcutaneously), thiosemicarbazide (aqueous solution 25 mg/kg, intraperitoneally), strychnine (aqueous solution 1.2 mg/kg, subcutaneously), camphor (oil solution 1000 mg/kg, intraperitoneally) have been used as convulsive agents for seizure induction. It was found that under the conditions of primary generalized seizures induced by picrotoxin, thiosemicarbazide, strychnine, and camphor, digoxin not only shows its own strong anticonvulsant activity but also significantly enhances the anticonvulsant potential of classical AEDs sodium valproate, levetiracetam, and topiramate. The obtained results substantiate the expediency of further in-depth study of digoxin as an anticonvulsant drug, in particular, the in-depth study of neurochemical mechanisms of its action.

Topics: Animals; Anticonvulsants; Camphor; Cardiotonic Agents; Digoxin; Levetiracetam; Male; Mice; Picrotoxin; Seizures; Strychnine; Topiramate; Valproic Acid

Epilepsy is a widespread neurological disorder frequently associated with a lot of comorbidities. The present study aimed to evaluate the effects of the antiseizure medication topiramate (TPM) on spontaneous motor seizures, the pathogenesis of comorbid mood and cognitive impairments, hippocampal neuronal loss, and oxidative stress and inflammation in a rat model of temporal lobe epilepsy (TLE). Vehicle/TPM treatment (80 mg/kg, p.o.) was administered 3 h after the pilocarpine (pilo)-induced status epilepticus (SE) and continued for up to 12 weeks in Wistar rats. The chronic TPM treatment caused side effects in naïve rats, including memory disturbance, anxiety, and depressive-like responses. However, the anticonvulsant effect of this drug, administered during epileptogenesis, was accompanied by beneficial activity against comorbid behavioral impairments. The drug treatment suppressed the SE-induced neuronal damage in limbic structures, including the dorsal (CA1 and CA2 subfield), the ventral (CA1, CA2 and CA3) hippocampus, the basolateral amygdala, and the piriform cortex, while was ineffective against the surge in the oxidative stress and inflammation. Our results suggest that neuroprotection is an essential mechanism of TPM against spontaneous generalized seizures and concomitant emotional and cognitive impairments.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Epilepsy, Temporal Lobe; Hippocampus; Inflammation; Neuroprotection; Pilocarpine; Rats; Rats, Wistar; Seizures; Status Epilepticus; Topiramate

Approximately 80-90% of patients with Angelman syndrome (AS) develop childhood-onset intractable seizures with major negative impact on the quality of life. Thus adequate management of seizures is the most critical priority to improve health-related quality of life in children with AS.. The primary focus of the review is on pharmacotherapeutic management of seizures. To better comprehend pharmacotherapeutic decision-making, the first section of the paper briefly examines epileptogenesis and polymorphic seizure morphologies related to AS. Next, the review explores individual antiseizure medications (ASMs) and their potential therapeutic utility. Lastly, some future and emerging treatment options are discussed that can transform the management of seizures in patients with AS.. Evidence for treating seizures in AS mainly derives from low-quality studies. Levetiracetam and clobazam are the most commonly used ASMs. Although the potential utility of several other ASMs(valproate, topiramate, lamotrigine, ethosuximide, clonazepam) has been well documented for some time, the treatment landscape may rapidly evolve due to the availability of newer and better tolerated ASMs(cannabidiol oil, brivaracetam, perampanel). In addition, a better understanding of the underlying pathogenesis and the development of molecular therapeutics offer hope for precision therapies for seizures.

Topics: Anticonvulsants; Cannabidiol; Child; Clobazam; Clonazepam; Ethosuximide; Humans; Lamotrigine; Levetiracetam; Quality of Life; Seizures; Topiramate; Valproic Acid

The Norwegian Association for Clinical Pharmacology in their National Guidelines decreased the therapeutic range (TR) of topiramate (TPM) from 5-20 mg/L to 2-10 mg/L. The objective of this study is to ascertain which TR produces better clinical outcomes.. Better seizure control was found in children both in the whole cohort (without seizure 49% vs 37% adults), as well as in monotherapy (56% vs 44%), in children with PL 5-20 mg/L vs <5 mg/L (65% vs 44%) and in children with PL 5-10 mg/L vs <2 mg/L (63 vs 14%). PL in seizure-free patients did not differ from those with seizure. Seizure control was poorer in the period 2003-2005 compared to 2006-2011. ADRs reported in 38 samples (2.8%) were not related to PL.. Change of TR is not recommended.

Topics: Adult; Anticonvulsants; Child; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Fructose; Humans; Seizures; Topiramate

The current study evaluates the anticonvulsant effect low dose whole body gamma irradiation (LDR) alone or combined with topiramate against pentylenetetrazole (PTZ)-induced convulsions. Male Wister rats received either saline or PTZ (75 mg/kg i.p.). The other three groups were pretreated with single low dose radiation (0.5 Gy), topiramate (50 mg/kg, p.o., seven days) and TPM with LDR respectively before PTZ injection. Racine' score, latency, and duration of the convulsions were assessed. Glutamate and GABA were measured. AKT/m-TOR signaling pathway including AKT (protein kinase B), mammalian target of rapamycin (m-TOR), protein S6, and caspase 3 were also assessed. Measurements of markers of oxidative stress including malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) were carried out. Histological examinations of hippocampi were done. PTZ produced behavioral changes (high Racine score, short latency, and long duration). It elevated MDA and NO contents, while reduced GSH content. TPM treatment alone or combined with LDR ameliorated the PTZ-induced convulsions and caused significant improvement in behavioral changes, brain mediators, m-TOR pathway, oxidative stress, and histological pictures in hippocampal regions. Histopathological examinations of the normal group showed normal structure with intact cells, while PTZ-treated rats exhibited necrosis, pyknosis, and atrophy of pyramidal cells. The histological findings corroborated with the amendment of biochemical parameters. The positive effects of LDR could offer a possible contributor in management of convulsions due to modulation of AkT/m-TOR signaling pathway, reduction of oxidative stress and modulation of brain amino acids. LDR improved the oxidative stress side effects of topiramate.

Topics: Animals; Anticonvulsants; Male; Oxidative Stress; Pentylenetetrazole; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Seizures; Topiramate; TOR Serine-Threonine Kinases

We previously reported that P-retigabine (P-RTG), a retigabine (RTG) analogue bearing a propargyl group at the nitrogen atom in the linker of RTG, displayed moderate anticonvulsant efficacy. Recently, our further efforts led to the discovery of

Topics: Animals; Anticonvulsants; Carbamates; Disease Models, Animal; Dogs; Drug Design; Drug Evaluation, Preclinical; Drug Stability; Electroshock; Half-Life; Humans; KCNQ Potassium Channels; Mice; Phenylenediamines; Protein Isoforms; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship

Eating epilepsy was previously known as a kind of focal reflex epilepsy. However, the development of eating-induced multiple generalized seizures and the associated EEG changes were rarely reported. Herein, we present a 13-year-old generalized epilepsy patient with eating-induced generalized seizures since the age of 5.. The 13-year-old male patient had suffered from late-onset eating-induced epileptic spasms during the meal since the age of 5. Meanwhile, he also experienced spontaneous epileptic spasms during the period of sleep. The seizure frequency and type gradually increased from 7 years of age. In addition to epileptic spasms, he started experiencing atypical absence with myoclonic jerks during the meal. Ictal EEG presented as the appearance of an irregular slow-wave mixed with generalized polyspike wave with the intake of food, and gradually evolved to bursts of generalized polyspike wave complexes. At the end of the meal, the EEG returned to normal. Nevertheless, at the age of 13, his seizure frequency increased and appeared new seizure type, and besides epileptic spasm and atypical absence, he began to experience myoclonic seizure during sleep and awaking-generalized tonic-clonic seizure in the morning. In this period he started taking valproic acid, topiramate and clonazepam, and his seizure frequency was reduced.. In conclusion, this case demonstrated the variability of eating induced multiple generalized seizure types, and eight years follow-up also indicates that generalized epilepsy progressed with age. The EEG and clinical changes of our patient contribute to a better understanding of the electro-clinical features of eating-induced multiple generalized seizures and the course of generalized epilepsy with such seizures.

Topics: Adolescent; China; Clonazepam; Eating; Epilepsy, Generalized; Follow-Up Studies; Humans; Male; Myoclonus; Seizures; Sleep; Spasm; Topiramate; Valproic Acid

Status epilepticus (SE) is a neurological disorder characterized by a prolonged epileptic activity followed by subsequent epileptogenic processes. The aim of the present study was to evaluate the early effects of topiramate (TPM) and lacosamide (LCM) treatment on oxidative stress and inflammatory damage in a model of pilocarpine-induced SE.. Male Wistar rats were randomly divided into six groups and the two antiepileptic drugs (AEDs), TPM (40 and 80 mg/kg, i.p.) and LCM (10 and 30 mg/kg, i.p.), were injected three times repeatedly after pilocarpine administration. Rats were sacrificed 24 h post-SE and several parameters of oxidative stress and inflammatory response have been explored in the hippocampus.. The two drugs TPM and LCM, in both doses used, succeeded in attenuating the number of motor seizures compared to the SE-veh group 30 min after administration. Pilocarpine-induced SE decreased the superoxide dismutase (SOD) activity and reduced glutathione (GSH) levels while increasing the catalase (CAT) activity, malondialdehyde (MDA), and IL-1β levels compared to the control group. Groups with SE did not affect the TNF-α levels. The treatment with a higher dose of 30 mg/kg LCM restored to control level the SOD activity in the SE group. The two AEDs, in both doses applied, also normalized the CAT activity and MDA levels to control values. In conclusion, we suggest that the antioxidant effect of TPM and LCM might contribute to their anticonvulsant effect against pilocarpine-induced SE, whereas their weak anti-inflammatory effect in the hippocampus is a consequence of reduced SE severity.

Topics: Animals; Anticonvulsants; Biomarkers; Hippocampus; Inflammation; Interleukin-1beta; Lacosamide; Male; Motor Activity; Oxidative Stress; Pilocarpine; Rats, Wistar; Reactive Oxygen Species; Seizures; Status Epilepticus; Topiramate; Tumor Necrosis Factor-alpha

Combination therapy with two or three antiseizure medications (ASMs) is sometimes a preferred method of treatment in epilepsy patients. (1) Background: To detect the most beneficial combination among three ASMs, a screen test evaluating in vivo interactions with respect to their anticonvulsant properties, was conducted on albino Swiss mice; (2) Methods: Classification of interactions among lacosamide (LCM) and selected second-generation ASMs (lamotrigine (LTG), pregabalin (PGB), oxcarbazepine (OXC), and topiramate (TPM)) was based on the isobolographic analysis in the mouse maximal electroshock-induced seizure (MES) model. Interactions among LCM and second-generation ASMs were visualized using a polygonogram; (3) Results: In the mouse MES model, synergy was observed for the combinations of LCM + TPM + PGB and LCM + OXC + PGB. Additivity was reported for the other combinations tested i.e., LCM + LTG + TPM, LCM + LTG + PGB, LCM + LTG + OXC, and LCM + OXC + TPM in this seizure model. No adverse effects associated with triple ASM combinations, containing LCM and second-generation ASMs were observed in mice; (4) Conclusions: The combination of LCM + TPM + PGB was the most beneficial combination among the tested in this study, offering synergistic suppression of tonic-clonic seizures in mice subjected to the MES model. Both the isobolographic analysis and polygonogram method can be recommended for experimental epileptology when classifying interactions among the ASMs.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Electroshock; Epilepsy; Lacosamide; Lamotrigine; Male; Mice; Oxcarbazepine; Pregabalin; Seizures; Topiramate

Several studies with larvae and adult zebrafish have shown that old and new antiseizure drugs (ASDs) produce discrepant results in seizure tests, locomotor activity or anxiety models. In this study, the pentylenetetrazole seizure test (PTZ) was performed to assess the effectiveness of four new ASDs: lamotrigine (LTG), topiramate (TPM), felbamate (FBM), and levetiracetam (LEV) in the subsequent stages of seizures in adult fish. All ASDs were administered intraperitoneally (i.p.). The time of maximal anticonvulsant effect and the dose-response relationship of the drugs were assessed. The effects of studied ASDs on the locomotor activity and the anxiety-like behavior in the color preference test were also investigated. Furthermore, drug concentrations in zebrafish homogenates were determined. LTG, TPM, and LEV significantly increased the seizure latency at three subsequent stages of seizures (SI-SIII), while FBM was effective only at SI. Locomotor activity decreased after TPM treatment. TPM and FBM exhibited a strong anxiolytic-like effect in the color preference test. LEV at the highest dose tested had a weak anxiolytic-like effect. The HPLC analysis showed average concentrations of the studied ASDs in the fish body during their maximum anticonvulsant activity. The present study shows that FBM cannot inhibit all subsequent PTZ seizure stages in the adult fish. Except for LTG, the studied drugs affected the anxiety-like behavior of treated animals. Furthermore, only TPM significantly changed locomotion parameters. Our findings support the need to accurately characterize the efficacy of new ASDs at different stages of the PTZ-induced seizures in adult zebrafish.

Topics: Age Factors; Animals; Anti-Anxiety Agents; Anticonvulsants; Anxiety; Dose-Response Relationship, Drug; Felbamate; Female; Lamotrigine; Levetiracetam; Locomotion; Male; Pentylenetetrazole; Seizures; Topiramate; Zebrafish

This study was carried out to determine changes over time in use of folic acid, anti-epileptic drugs (AED), seizures during pregnancy and malformation rate over two decades in women with epilepsy enrolled in the Kerala registry of Epilepsy and Pregnancy (KREP).. All completed pregnancies with known outcome between 1998 and 2017 (n = 1962) were analyzed for the use of folic acid and AEDs in the first trimester, seizure count for the entire pregnancy and the presence of major congenital malformation (MCM). The results were presented for three epochs (1998-2004, 2005-2011 and 2012-2017).. There was significant increase (p = .001) in the use of folic acid 5 mg/day or more in pre-pregnancy month (43.9 to 81 %) and first trimester (52.7 to 86.6 %). Occurrence of seizures during pregnancy had declined significantly (57.2 to 32.9 %, p = 0.001) over time. Those who were off AEDs during pregnancy declined from 17.4 to 8.5 % (p = .001). Newer AEDs - lamotrigine, levetiracetam, oxcarbazepine and topiramate) were increasingly preferred in the last seven years instead of older AEDs (phenobarbitone, phenytoin and clonazepam). There was no significant change in the use of carbamazepine or valproate. MCM rates did not show any significant change (7.5 to 7.3 %).. Seizure control and high dose folic acid usage during pregnancy had improved over two decades. Despite the changes in the AED usage over time the MCM rates had remained unchanged probably due to continued use of valproate, increased use of topiramate and clobazam that are associated with higher MCM rates and lack of reduction in polytherapy.

Topics: Adult; Anticonvulsants; Carbamazepine; Female; Folic Acid; Humans; India; Lamotrigine; Levetiracetam; Oxcarbazepine; Phenytoin; Pregnancy; Pregnancy Complications; Registries; Seizures; Topiramate; Valproic Acid

ATP1A3 related disease is a clinically heterogeneous condition currently classified as alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. Recently, it has become apparent that a remarkably large subgroup is suffering from often difficult-to-treat epilepsy. The aim of the present study was to assess the prevalence and efficacy of commonly used anti-epileptic-drugs (AEDs) in patients with ATP1A3 related seizures. Therefore, we performed a retrospective study of patients in combination with a systematic literature-based review. Inclusion criteria were: verified ATP1A3 mutation, seizures and information about AED treatment. The literature review yielded records for 188 epileptic ATP1A3 patients. For 14/188 cases, information about anti-epileptic treatment was available. Combined with seven unpublished records of ATP1A3 patients, a sample size of 21 patients was reached. Most used AED were levetiracetam (n = 9), phenobarbital (n = 8), valproic acid (n = 7), and topiramate (n = 5). Seizure reduction was reported for 57% of patients (n = 12). No individual AEDs used (either alone or combined) had a success rate over 50%. There was no significant difference in the response rate between various AEDs. Ketogenic diet was effective in 2/4 patients. 43% of patients (n = 9) did not show any seizure relief. Even though Epilepsy is a significant clinical issue in ATP1A3 patients, only a minority of publications provide any information about patients' anti-epileptic treatment. The findings of treatment effectiveness in only 57% (or lower) of patients, and the non-existence of a clear first-line AED in ATP1A3 related epilepsy stresses the need for further research.

Topics: Adult; Anticonvulsants; Cerebellar Ataxia; Child; Dystonic Disorders; Epilepsy; Female; Hearing Loss, Sensorineural; Hemiplegia; Humans; Levetiracetam; Male; Mutation; Optic Atrophy; Reflex, Abnormal; Retrospective Studies; Seizures; Sodium-Potassium-Exchanging ATPase; Topiramate; Valproic Acid

Topics: Cold Temperature; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant; Seizures; Topiramate

To assess the possibility that the occurrence of seizures or the use of antiepileptic drug (AED) therapy might have influenced the rate of occurrence of volunteered histories of patient-recognized depression during pregnancy in women with epilepsy.. Analysis of data from 2039 pregnancies in the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy (APR) followed during pregnancy and to the end of the year after its end.. Patient-recognized depression occurrence rates during pregnancy were a little lower rather than higher in seizure-affected than in seizure-free pregnancies (5.67% vs 6.41%), though higher in AED-treated than AED-untreated pregnancies (6.24% vs 5.26%; RR = 1.185, 95% CI 0.612, 2.295). Logistic regression analysis showed that carbamazepine dosage had a statistically significant relationship with a decreasing rate of patient-recognized depression occurring during pregnancy and topiramate dosage with an increasing rate.. Carbamazepine and topiramate both have established potentials for causing teratogenesis, and it is possible that replacement of carbamazepine with a less teratogenic AED, for example levetiracetam, might result in any subsequent depression that occurs in pregnancy being inappropriately attributed to the newly introduced agent.

Topics: Adult; Anticonvulsants; Australia; Carbamazepine; Depression; Epilepsy; Female; Humans; Levetiracetam; Pregnancy; Pregnancy Complications; Seizures; Topiramate

The adequate dosing of topiramate in neonates undergoing therapeutic hypothermia has not been established. The aim of this study was to design a dosing schedule capable of providing topiramate serum concentrations within the accepted therapeutic range.. Neonates (n = 52) with hypoxic ischaemic encephalopathy and subjected to therapeutic hypothermia were dosed with topiramate, 5 mg/kg on day one and 3 mg/kg on days two to five, to decrease seizure events. A total of 451 topiramate serum concentrations obtained in the patients were used to develop a population pharmacokinetic model using a non-linear mixed-effects modelling approach.. A one-compartment model with first-order absorption and two different clearance terms, one for the cooling period and another for the post-warming period, were used to describe the concentration-time topiramate data. The probability of no-seizure events could not be related to topiramate concentrations, which was attributed to excessively low topiramate concentrations. A modified dosage schedule was designed with the aim of obtaining more than 90% of patients with topiramate concentrations within the therapeutic range after the first dose.. The dosage schedule of topiramate in these patients should be modified with the aim of decreasing the frequency of seizure events.

Topics: Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Seizures; Topiramate

Topics: Animals; Anti-Arrhythmia Agents; Anticonvulsants; Disease Models, Animal; Dronedarone; Drug Synergism; Drug Therapy, Combination; Lacosamide; Lamotrigine; Male; Mice; Pregabalin; Seizures; Topiramate

Cannabidiol and cannabidiol-enriched products have recently attracted much attention as an add-on therapy for epilepsy, especially drug-resistant seizures. It should be, however, remembered that concomitant use of cannabidiol and antiepileptic drugs may pose a risk of interactions between them. For this reason, the aim of our study was to assess the effect of cannabidiol on the activity of selected new antiepileptic drugs in the electrically-induced seizure models in mice. We studied the effect of cannabidiol on the anticonvulsant action of topiramate, oxcarbazepine, lamotrigine, and pregabalin in the maximal electroshock-induced seizure test as well as on the activity of levetiracetam, tiagabine, lacosamide, and gabapentin in the 6 Hz seizure test in mice. We showed that cannabidiol increased the activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin. It did not affect the anticonvulsant effect of lamotrigine and lacosamide. Interestingly, cannabidiol attenuated the anticonvulsant activity of levetiracetam. Co-administration of antiepileptic drugs with cannabidiol did not cause adverse effects such as impairment of motor coordination, changes in neuromuscular strength or potentiation of the cannabidiol-induced hypolocomotion. Serum and brain levels of antiepileptic drugs and cannabidiol were determined by using HPLC in order to ascertain any pharmacokinetic contribution to the observed behavioral effects. Only interaction with levetiracetam was purely pharmacodynamic in nature because no changes in serum and brain concentration of either levetiracetam or cannabidiol were observed. Increased anticonvulsant activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin could be, at least in part, related to pharmacokinetic interactions with cannabidiol because there were changes in serum and/or brain concentrations of antiepileptic drugs and/or cannabidiol. Pharmacokinetic interactions cannot be also excluded between lacosamide and cannabidiol because cannabidiol increased brain concentration of lacosamide and lacosamide increased brain concentration of cannabidiol. Further pharmacokinetic studies are required to evaluate the type of interactions between cannabidiol and novel antiepileptic drugs.

Topics: Animals; Anticonvulsants; Brain; Cannabidiol; Chromatography, High Pressure Liquid; Disease Models, Animal; Drug Interactions; Drug Resistant Epilepsy; Electric Stimulation; Gabapentin; Lacosamide; Lamotrigine; Levetiracetam; Male; Mice; Oxcarbazepine; Pregabalin; Seizures; Tiagabine; Topiramate

Seizures are present in over 90% of infants and children with Wolf-Hirschhorn syndrome (WHS). When present, they significantly affect quality of life. The goal of this study was to use caregiver reports to describe the comparative efficacies of commonly used antiepileptic medications in a large population of individuals with WHS. A web-based, confidential caregiver survey was developed to capture seizure semiology and a chronologic record of seizure treatments as well as responses to each treatment. Adverse events for each drug were also cataloged. We received 141 complete survey responses (47% response rate) describing the seizures of individuals ranging in age from 4months to 61years (90 females: 51 males). Using the Early Childhood Epilepsy Severity Scale (E-Chess), WHS-associated seizures are demonstrably severe regardless of deletion size. The best-performing antiepileptic drugs (AEDs) for controlling seizures in this cohort were broad spectrum drugs clobazam, levetiracetam, and lamotrigine; whereas, the three commonly used carboxamide class drugs: carbamazepine, phenytoin, and oxcarbazepine, were reported to have little effect on, or even exacerbate, seizures. The carboxamide class drugs, along with phenobarbital and topiramate, were also associated with the highest rate of intolerance due to cooccurrence of adverse events. Levetiracetam, clobazam, and clonazepam demonstrated higher tolerability and comparatively less severe adverse events (Wilcoxon rank sum comparison between performance of levetiracetam and carboxamide class drugs gives a p<0.0001 after multiple comparison adjustment). This is the largest survey to date assessing WHS seizures. This study design is susceptible to possible bias, as the data are largely drawn from caregiver report and investigators had limited access to medical records. Despite this, our data suggest that the genetic etiology of seizures, together with an accurate electroclinical delineation, are important components of drug selection, even in contiguous gene syndromes which may have complex seizure etiologies.

Topics: Adolescent; Adult; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Clobazam; Female; Humans; Infant; Lamotrigine; Levetiracetam; Male; Middle Aged; Oxcarbazepine; Phenobarbital; Phenytoin; Quality of Life; Seizures; Topiramate; Wolf-Hirschhorn Syndrome; Young Adult

Neonatal seizures represent a significant health burden on the term and preterm neonatal population and are linked to poor long-term neurodevelopmental outcomes. Currently, there are no US Food and Drug Administration-approved antiepileptic drugs for neonates, and authors of the medical literature have yet to reach a consensus on the most adequate approach to neonatal seizures. Topiramate is readily used in the adult and older pediatric population for the management of migraines and partial-onset seizures. Topiramate continues to gain favor among pediatric neurologists who often recommend this medication as a third-line treatment of neonatal seizures. We report our recent experience with 4 preterm neonates, born between 2015 and 2017, who developed radiographic signs of necrotizing enterocolitis after receiving topiramate for seizures. Each was given oral topiramate for the treatment of electrographic and clinical seizures and developed the subsequent diagnosis of necrotizing enterocolitis, with abdominal distention, hemoccult-positive stools, and radiographic signs of intestinal distention and pneumatosis. More research regarding the risk factors of topiramate use in premature infants is needed.

Topics: Anticonvulsants; Enterocolitis, Necrotizing; Female; Humans; Infant, Newborn; Infant, Premature; Male; Seizures; Topiramate

A 22-year-old Japanese male with trisomy 21 was diagnosed with West syndrome at 4 months old. After the suppression of epileptic spasms using adrenocorticotropic hormone therapy, he had complex partial seizures and bilateral frontal epileptic discharges on EEG. Although the introduction of topiramate (TPM) decreased the seizures during wakefulness, frequent episodes of brief eye-opening appeared during sleep while the patient was taking TPM (400 mg/day). EEG showed fast activity at the times of eye-opening. The episodes of eye-opening during sleep and the fast activities disappeared upon TPM discontinuation. This is the first report of TPM-induced microseizures similar to benzodiazepine-induced microseizures.

Topics: Adult; Anticonvulsants; Electroencephalography; Humans; Male; Seizures; Topiramate

We report two series of novel benzenesulfonamide derivatives acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The synthesized compounds were tested against human (h) isoforms hCA I, hCA II, hCA VII, and hCA XII. The first series of compounds, 4-(3-(2-(4-substitued piperazin-1-yl)ethyl)ureido)benzenesulfonamides, showed low nanomolar inhibitory action against hCA II, being less effective against the other isoforms. The second series, 2-(4-substitued piperazin-1-yl)-N-(4-sulfamoylphenyl)acetamide derivatives, showed low nanomolar inhibitory activity against hCA II and hCA VII, isoforms involved in epileptogenesis. Some of these derivatives were evaluated for their anticonvulsant activity and displayed effective seizure protection against MES and scPTZ induced seizures in Swiss Albino mice. These sulfonamides were also found effective upon oral administration to Wistar rats and inhibited MES induced seizure episodes in this animal model of the disease. Some of the new compounds showed a long duration of action in the performed time course anticonvulsant studies, being nontoxic in subacute toxicity studies.

Topics: Animals; Anticonvulsants; Benzenesulfonamides; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Drug Design; Humans; Male; Mice; Protein Isoforms; Rats, Wistar; Seizures; Structure-Activity Relationship; Sulfonamides

Psychiatric comorbidities are common in people with epilepsy. A retrospective study of characteristics associated with withdrawal due to psychiatric side effects was undertaken in patients with treated epilepsy participating in prospective audits with new antiepileptic drugs (AEDs). A total of 1058 treated patients with uncontrolled seizures (942 focal-onset seizures, 116 generalized genetic epilepsies [GGEs]) participated in eight prospective, observational audits from 1996 to 2014. These patients were prescribed adjunctive topiramate (n=170), levetiracetam (n=220), pregabalin (n=135), zonisamide (n=203), lacosamide (n=160), eslicarbazepine acetate (n=52), retigabine (n=64), or perampanel (n=54). Doses were titrated according to efficacy and tolerability to optimize zeizure outcomes and reduce side effects. Psychiatric comorbidities were recorded prior to and after the addition of each AED. At baseline, patients with focal-onset seizures (189 of 942; 20.1%) were statistically more likely to have psychiatric diagnoses compared to patients with GGEs (14 of 116, 12.1%; p=0.039). Following adjunctive AED treatment, neuropsychiatric adverse effects led to AED withdrawal in 1.9-16.7% of patients. Patients with a pre-treatment psychiatric history (22 of 209; 10.5%) were statistically more likely to discontinue their new AED due to psychiatric issues compared to patients with no previous psychiatric diagnosis (50 of 849; 5.9%; p=0.017). Patients receiving sodium channel blocking AEDs (4 of 212, 1.9%) were statistically less likely to develop intolerable psychiatric problems, compared to those on AEDs possessing other mechanisms of action (68 of 846, 8.0%; p=0.012). Depression was the commonest problem, leading to discontinuation of AEDs in 2.8% (n=30) patients. Aggression was statistically more common in men (11 of 527, 2.1%) compared to women (1 of 531, 0.2%; p=0.004). Patients with learning disability (12 of 122, 9.8%; p=0.0015) were statistically less likely to have psychiatric issues prior to adjunctive AED treatment compared to other patients (208 of 936, 22.2%), but there were no statistically significant differences once the new AEDs were added (8 of 122 patients with learning disability, 6.6%; 64 of 936 other patients, 6.8%). Awareness of these issues may assist clinicians in avoiding, identifying and treating psychiatric comorbidities in people with epilepsy.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Dibenzazepines; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Fructose; Humans; Lacosamide; Levetiracetam; Male; Medical Audit; Mental Disorders; Middle Aged; Nitriles; Piracetam; Pregabalin; Prospective Studies; Pyridones; Retrospective Studies; Seizures; Sodium Channel Blockers; Topiramate; Young Adult

The aim was to study the impact of therapeutic drug monitoring (TDM) on patients on lamotrigine (LTG) therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations.. During the period of 2001-2014, 3118 predose samples were taken from 1137 patients >15 years of age as part of their routine TDM. Drug interactions were evaluated using calculation of LTG clearance (CL).. Valproic acid (VPA) decreased LTG CL by 66% in bitherapy, and by 35% and 31% in triple therapy with carbamazepine (CBZ) and phenytoin (PHT), respectively. CBZ and PHT increased LTG CL by 52% and 96% in respective bitherapies but by 88% in triple therapy. Clonazepam, levetiracetam, and topiramate had no effect. The LTG therapeutic range (TR) was exceeded in 1% of cases in monotherapy, and in 4%-5% of cases in combination therapy. Only 54% of results were within the TR during 2001-2005, whereas 60%-62% were within the TR during 2006-2014. Adverse drug reactions (ADRs) were reported in 88 cases and occurred more frequently during TR during 2001-2005. Higher number of supratherapeutic levels in combination therapy led to a 3-fold higher incidence of ADR and poorer seizure control, as seizures occurred more often monthly (2.5%) or a few per year (41%) and fewer patients were seizure free (18%). Seizures occurred more often daily and monthly during the first period and in patients with 3 or 4 drugs in combination.. A significantly higher number of supratherapeutic levels were found in combinations with VPA, despite lower doses of LTG. Hepatic enzyme inducers, such as CBZ and PHT only partially compensated for the inhibitory effect of VPA. Decrease of both the frequency of seizures and the incidence of ADRs after TDM implementation suggests that TDM may have given clinicians the opportunity to achieve more optimal patient treatment.

Topics: Adult; Anticonvulsants; Carbamazepine; Clonazepam; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Fructose; Humans; Lamotrigine; Levetiracetam; Male; Phenytoin; Piracetam; Seizures; Topiramate; Triazines; Valproic Acid

Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment.. Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015.. A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body weight ranged from 8.6 to 105 kg. The median serum concentration of topiramate was 1.7 mcg/mL, and half of the patients received carbamazepine coadministration. Based on a one-compartment model with first order absorption and elimination, the apparent volume of distribution was 105 L/70 kg, and the apparent clearance was allometrically related to the body weight as 2.25 L·h·70 kg without carbamazepine or phenytoin. Combination treatment with carbamazepine or phenytoin increased the apparent clearance to 3.51 L·h·70 kg. Goodness-of-fit plots, prediction-corrected visual predictive check, and external validation using the validation data from 43 patients confirmed an appropriateness of the final model. Simulations based on the final model showed that dosage adjustments allometrically scaling to body weight can equalize the serum concentrations in children of various ages and adults.. The PPK model, using the power scaling of body weight, effectively elucidated the topiramate serum concentration profile ranging from pediatric to adult patients. Dosage adjustments based on body weight and concomitant antiepileptic drug help obtain the dosage of topiramate necessary to reach an effective concentration in each individual.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Asian People; Body Weight; Carbamazepine; Child; Child, Preschool; Drug Monitoring; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Models, Biological; Monitoring, Physiologic; Phenytoin; Seizures; Topiramate; Young Adult

The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyl- and 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl)propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5-38 were prepared in a coupling reaction of the 3-methyl- or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl)propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N,N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED50 MES=74.8mg/kg, ED50scPTZ=51.6mg/kg, ED50 6Hz=16.8mg/kg) which showed TD50=213.3mg/kg in the chimney test that yielded satisfying protective indexes (PI MES=2.85, PI scPTZ=4.13, PI 6Hz=12.70) at time point of 0.5h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice.

Topics: Analgesics; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Injections, Intraperitoneal; Mice; Molecular Structure; Pain; Pain Measurement; Pentylenetetrazole; Piperazines; Pyrrolidinones; Seizures

This study evaluated the effects of different doses of atropine and new antiepileptics, levetiracetam and topiramate, on the development of convulsions triggered by food intake in antimuscarinic-treated fasted animals. Mice deprived of food for 24 h and treated i.p. with atropine at a dose of 2.4 or 24 mg/kg developed convulsions after being allowed to eat ad libitum. No convulsions were observed in fasted animals treated with 0.24 mg/kg atropine. There was no difference in the incidence of convulsions between the two atropine treatments, but latency to convulsions was longer in 24 mg/kg atropine treated animals. The lowest dose of atropine, 0.24 mg/kg, caused stage 1 and stage 2 activity, but did not provide the convulsive endpoint (stage 3, 4, 5 activity). Administration of levetiracetam (50 or 200 mg/kg) or topiramate (50 or 100 mg/kg) to another group of 24-h fasted mice was ineffective in reducing the incidence of convulsions developed in the animals after 2.4 mg/kg atropine treatment and food intake. However, the higher dose of levetiracetam prolonged the onset of convulsions. Present results demonstrated the efficacy of low and high doses of atropine on the development of convulsions in fasted animals and provided additional evidence for the ineffectiveness of antiepileptic treatment in these seizures.

Topics: Animals; Anticonvulsants; Atropine; Eating; Fasting; Fructose; Levetiracetam; Male; Mice, Inbred BALB C; Muscarinic Antagonists; Piracetam; Seizures; Topiramate

The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)pyridine (MPEP - a selective antagonist for the glutamate metabotropic receptor subtype mGluR5) on the protective action of some novel antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) against maximal electroshock-induced seizures in mice. Brain concentrations of antiepileptic drugs were measured to determine whether MPEP altered pharmacokinetics of antiepileptic drugs. Intraperitoneal injection of 1.5 and 2mg/kg of MPEP significantly elevated the threshold for electroconvulsions in mice, whereas MPEP at a dose of 1mg/kg considerably enhanced the anticonvulsant activity of pregabalin and topiramate, but not that of lamotrigine or oxcarbazepine in the maximal electroshock-induced seizures in mice. Pharmacokinetic results revealed that MPEP (1mg/kg) did not alter total brain concentrations of pregabalin and topiramate, and the observed effect in the mouse maximal electroshock seizure model was pharmacodynamic in nature. Collectively, our preclinical data suggest that MPEP may be a safe and beneficial adjunct to the therapeutic effects of antiepileptic drugs in human patients.

Topics: Animals; Anticonvulsants; Brain; Carbamazepine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Therapy, Combination; Electroshock; Excitatory Amino Acid Antagonists; Fructose; Lamotrigine; Male; Mice; Oxcarbazepine; Pregabalin; Pyridines; Random Allocation; Receptor, Metabotropic Glutamate 5; Seizures; Topiramate; Triazines

To characterize the anticonvulsant effects of a combination of 3 antiepileptic drugs (AEDs; i.e. carbamazepine (CBZ), phenobarbital (PB) and topiramate (TPM)) at the fixed-ratio of 1:1:1 in the mouse maximal electroshock (MES)-induced seizure model.. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Type I isobolographic analysis for parallel dose-response relationship curves (DRRCs) was used to analyze the 3-drug combination.. In the mouse MES model, all the studied AEDs (i.e., CBZ, PB and TPM) administered singly had their DRRCs parallel to each other. With type I isobolography for parallel DRRCs, a combination of CBZ, PB and TPM at the fixed-ratio of 1:1:1 exerted supra-additive (synergistic) interaction in the mouse MES model.. Synergistic interaction among CBZ, PB and TPM at the fixed-ratio of 1:1:1 against MES-induced seizures is worthy of consideration in further clinical settings. All detailed calculations required to perform type I isobolographic analysis for the 3-drug combination were presented.

Topics: Animals; Anticonvulsants; Carbamazepine; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Electroshock; Fructose; Male; Mice; Phenobarbital; Seizures; Topiramate

Caffeine may interact with classical antiepileptic drugs (AEDs), reducing their anticonvulsant effects in basic seizure models. The aim of the present study was to ascertain whether intraperitoneal caffeine (acute or chronic for 15 days) could attenuate the anticonvulsant effect of some newer AEDs: gabapentin (GBP) and topiramate (TPM) against electroconvulsions in mice.. Maximal electroshock (MES)-induced mouse seizure model was used for the estimation of the anticonvulsant activity of TPM whilst the protective activity of GBP was evaluated in the threshold test for maximal (tonic) convulsions. Adverse effects were evaluated by measurement of long-term memory (the step-through passive avoidance task) and motor coordination (chimney test). Plasma AED concentrations were also measured to determinate any pharmacokinetic contribution to the observed effects.. Caffeine (both acute and chronic at 23.1 and 46.2mg/kg) significantly reduced the protective effects of TPM against MES. As regards GBP, caffeine (acutely at 46.2mg/kg and chronically at 23.1 or 46.2mg/kg) significantly diminished the GBP-induced increases in the electroconvulsive threshold. In addition, caffeine did not affect the free plasma concentrations of TPM or GBP. Acute and chronic caffeine (23.1 and 46.2mg/kg) enhanced the impairment of motor coordination in mice pretreated with GBP whilst an opposite effect was observed in TPM injected mice and pretreated with chronic caffeine at 46.2mg/kg.. The results indicate that newer AEDs, GBP or TPM behave in the exactly same way as classical antiepileptics in mice challenged with caffeine. This hazardous effect of caffeine is not subject to tolerance.

Topics: Amines; Animals; Anticonvulsants; Caffeine; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Fructose; Gabapentin; gamma-Aminobutyric Acid; Injections, Intraperitoneal; Male; Memory, Long-Term; Mice; Motor Skills; Seizures; Topiramate

The aim of this study was to determine the effects of xanthotoxin (8-methoxypsoralen) on the protective action of 5 various second- and third-generation antiepileptic drugs (i.e., lacosamide, lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock-induced seizure model. Seizure activity was evoked in adult male albino Swiss mice by a current (25mA, 500V, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were determined in the chimney, grip-strength and passive avoidance tests. Total brain antiepileptic drug concentrations were measured to confirm pharmacodynamic nature of observed interactions with xanthotoxin. Results indicate that xanthotoxin (100mg/kg, i.p.) significantly enhanced the anticonvulsant action of lacosamide (P<0.01), oxcarbazepine (P<0.05), pregabalin (P<0.01), and topiramate (P<0.001), but not that of lamotrigine in the maximal electroshock-induced seizure test. Moreover, xanthotoxin (50mg/kg) still significantly potentiated the anticonvulsant action of lacosamide (P<0.05), pregabalin (P<0.05), and topiramate (P<0.001) in this seizure test. Xanthotoxin had no significant impact on total brain concentrations of the studied antiepileptic drugs in mice. Furthermore, combinations of xanthotoxin with oxcarbazepine or topiramate produced no adverse effects. However, xanthotoxin in combination with lacosamide, lamotrigine or pregabalin significantly reduced muscular strength in mice in the grip-strength test. In the chimney test, only the combinations of xanthotoxin with pregabalin significantly impaired motor coordination in mice. In conclusion, the combinations of xanthotoxin with oxcarbazepine and topiramate produce beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced seizure test. A special caution is advised when combining xanthotoxin with pregabalin due to appearance of acute adverse effects.

Topics: Acetamides; Animals; Anticonvulsants; Carbamazepine; Drug Synergism; Electroshock; Fructose; Lacosamide; Lamotrigine; Male; Methoxsalen; Mice; Oxcarbazepine; Pregabalin; Seizures; Topiramate; Triazines

Objective We planned a cross-sectional analysis to determine the frequency and severity of metabolic acidosis in patients taking topiramate while awaiting craniotomy. Methods Eighty patients (18 - 65 years) taking topiramate to control seizures while awaiting elective craniotomy were enrolled. Any signs of metabolic acidosis or topiramate-related side effects were investigated. Blood chemistry levels and arterial blood gases, including lactate, were obtained. The severity of metabolic acidosis was defined according to base excess levels as mild or moderate. Results Blood gas analysis showed that 71% ( n = 57) of patients had metabolic acidosis. The frequency of moderate metabolic acidosis was 56% ( n = 45), while that of mild metabolic acidosis was 15% ( n = 12). A high respiratory rate was reported in only 10% of moderately acidotic patients. Conclusions In patients receiving topiramate, baseline blood gas analysis should be performed preoperatively to determine the presence and severity of metabolic acidosis.

Topics: Acidosis; Adolescent; Adult; Aged; Anticonvulsants; Blood Gas Analysis; Cross-Sectional Studies; Female; Fructose; Humans; Male; Middle Aged; Respiratory Rate; Seizures; Severity of Illness Index; Topiramate

The library of 27 new 1-(4-phenylpiperazin-1-yl)- or 1-(morpholin-4-yl)-(2,5-dioxopyrrolidin-1-yl)propanamides and (2,5-dioxopyrrolidin-1-yl)butanamides as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5, 10, 11, and 24 displayed the broad spectra of activity across the preclinical seizure models, namely, the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-hertz (6 Hz) model of pharmacoresistant limbic seizures. The highest protection was demonstrated by 11 (ED50 MES = 88.4 mg/kg, ED50 scPTZ = 59.9 mg/kg, ED50 6 Hz = 21.0 mg/kg). This molecule did not impair the motor coordination of animals in the chimney test even at high doses (TD50 > 1500 mg/kg), yielding superb protective indexes (PI MES > 16.97, PI PTZ > 25.04, PI 6 Hz > 71.43). As a result, 11 displayed distinctly better safety profile than clinically relevant AEDs ethosuximide, lacosamide, or valproic acid.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Electroshock; HEK293 Cells; Humans; Mice; Models, Molecular; Molecular Structure; Motor Activity; Piperazines; Seizures; Structure-Activity Relationship; Succinimides

There is strong evidence for the use of the ketogenic diet (KD) in Dravet syndrome (DS). The purpose of this study was to evaluate both effectiveness and tolerability in comparison with various antiepileptic drugs (AEDs).. 32 children (19 males) with genetically confirmed DS treated at our center since 1999 were analyzed retrospectively. Data collected from patients' files included type of mutation, age at treatment initiation and treatment lag, overall seizure frequency and frequency of different seizure types, especially prolonged seizures and status epilepticus (SE). Efficacy and safety of the KD were evaluated. In addition, the effect on seizure count was compared with that of various AED regimen and the vagus nerve stimulation (VNS).. Overall response to the KD was 70% at 3 months and 60% at 12 months. No SE occurred while patients were on the diet, and the frequencies of prolonged generalized and myoclonic seizures were reduced. No severe side effects requiring withdrawal of the KD were observed. Although the effect of the KD was independent of age at initiation, it had to be withdrawn due to noncompliance more frequently in solid fed older children compared with infants treated with the liquid ketogenic formula. The KD was not significantly inferior to the current gold standard AED triple combination of Stiripentol+Valproate+Clobazam (89%), Bromides (78%), Valproate alone (48%), Topiramate (35%) and VNS (37%) and significantly more effective than Levetiracetam (30%; p=0.037, Pearson's Chi-square).. These data suggest that the KD ranks among currently used AEDs as an effective treatment for seizures in DS. According to our results (good effect on SE and prolonged seizures, good tolerability, less compliance problems due to formula treatment) the KD should be considered as an early treatment option in infants with DS.

Topics: Adolescent; Anticonvulsants; Benzodiazepines; Bromides; Child; Child, Preschool; Clobazam; Diet, Ketogenic; Dioxolanes; Epilepsies, Myoclonic; Female; Fructose; Humans; Infant; Levetiracetam; Male; Piracetam; Retrospective Studies; Seizures; Topiramate; Treatment Outcome; Vagus Nerve Stimulation; Valproic Acid; Young Adult

Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be time-consuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (d,l)-Allylglycine inhibits glutamic acid decarboxylase (GAD) - the key enzyme in γ-aminobutyric acid (GABA) biosynthesis - leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated cross-species similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.

Topics: Allylglycine; Animals; Anticonvulsants; Diazepam; Disease Models, Animal; Fructose; Levetiracetam; Male; Mice; Phenytoin; Piracetam; Seizures; Topiramate; Treatment Outcome; Valproic Acid; Zebrafish

To evaluate and compare long-term effectiveness of five antiepileptic drugs (AEDs) for monotherapy of adult patients with focal epilepsy in routine clinical practice.. Adult patients with focal epilepsy, who were prescribed with carbamazepine (CBZ), valproate (VPA), lamotrigine (LTG), topiramate (TPM), or oxcarbazepine (OXC) as monotherapy, during the period from January 2004 to June 2012 registered in Wenzhou Epilepsy Follow Up Registry Database (WEFURD), were included in the study. Prospective long-term follow-up was conducted until June 2013. The endpoints were time to treatment failure, time to seizure remission, and time to first seizure.. This study included 654 patients: CBZ (n=125), VPA (n=151), LTG (n=135), TPM (n=76), and OXC (n=167). The retention rates of CBZ, VPA, LTG, TPM, and OXC at the third year were 36.1%, 32.4%, 57.6%, 37.9%, and 41.8%, respectively. For time to treatment failure, LTG was significantly better than CBZ and VPA (LTG vs. CBZ, hazard ratio, [HR] 0.80 [95% confidence interval: 0.67-0.96], LTG vs. VPA, 0.53 [0.37-0.74]); TPM was worse than LTG (TPM vs. LTG, 1.77 [1.15-2.74]), and OXC was better than VPA (0.86 [0.78-0.96]). After initial target doses, the seizure remission rates of CBZ, VPA, LTG, TPM, and OXC were 63.0%, 77.0%, 83.6%, 67.9%, and 75.3%, respectively. LTG was significantly better than CBZ (1.44 [1.15-1.82]) and OXC (LTG vs. OXC, 0.76 [0.63-0.93]); OXC was less effective than LTG in preventing the first seizure (1.20 [1.02-1.40]).. LTG was the best, OXC was better than VPA only, while VPA was the worst. The others were equivalent for comparisons between five AEDs regarding the long-term treatment outcomes of monotherapy for adult patients with focal epilepsy in a clinical practice. For selecting AEDs for these patients among the first-line drugs, LTG is an appropriate first choice; others are reservation in the first-line but VPA is not.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Carbamazepine; Epilepsies, Partial; Female; Fructose; Humans; Lamotrigine; Male; Middle Aged; Oxcarbazepine; Prospective Studies; Seizures; Topiramate; Treatment Failure; Triazines; Valproic Acid; Young Adult

From a theoretical point of view, cholecalciferol (vitamin D3) as a precursor of calcitriol, a representative of secosteroids, may have neuroprotective properties and affect seizure phenomena.. In the present study, interactions between cholecalciferol and three second generation antiepileptic drugs (oxcarbazepine, lamotrigine, and topiramate) were studied in the maximal electroshock test in mice. Effects of drugs on motor coordination, long-term memory and explorative behavior of animals were evaluated in the chimney test, passive-avoidance task and plus-maze test, respectively.. Cholecalciferol applied ip at doses of 37.5-75μg/kg significantly raised the electroconvulsive threshold. Cholecalciferol, administered at the subthreshold dose of 18.75μg, potentiated the anticonvulsant activity of oxcarbazepine and lamotrigine, but did not change their brain concentrations, therefore the revealed interactions seem to be pharmacodynamic. Furthermore, the action of cholecalciferol was not dependent on its conversion to calcitriol. The anticonvulsant effect of topiramate was enhanced by cholecalciferol applied at the higher dose of 37.5μg/kg, at which it also increased the brain level of topiramate. As regards adverse effects, cholecalciferol, antiepileptic drugs, and their combinations did not significantly impair motor coordination or long-term memory in mice. Moreover, cholecalciferol did not show either anxiolytic or anxiogenic properties.. Our findings show that cholecalciferol has not only its own anticonvulsant action but also enhances efficacy of certain antiepileptic drugs, at least in experimental conditions.

Topics: Animals; Anticonvulsants; Anxiety; Avoidance Learning; Cholecalciferol; Dose-Response Relationship, Drug; Electroshock; Exploratory Behavior; Fructose; Male; Maze Learning; Memory, Long-Term; Mice; Neuroprotective Agents; Seizures; Topiramate; Vitamins

The aim of the presented study was to characterize the anticonvulsant effects of levetiracetam in combination with various antiepileptic drugs (carbamazepine, phenytoin, topiramate and vigabatrin) in the mouse 6Hz psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32mA, 6Hz, 3s stimulus duration) delivered via ocular electrodes; type II isobolographic analysis was used to characterize the consequent anticonvulsant interactions between the various drug combinations for fixed-ratios of 1:1, 1:2, 1:5 and 1:10. With type II isobolographic analysis, the combinations of levetiracetam with carbamazepine and phenytoin for the fixed-ratios of 1:5 and 1:10 were supra-additive (synergistic; P<0.01) in terms of seizure suppression, while the combinations for the fixed-ratios of 1:1 and 1:2 were additive. Levetiracetam combined with topiramate and vigabatrin for the fixed-ratio of 1:10 exerted supra-additive interaction (P<0.05), and simultaneously, the two-drug combinations for the fixed-ratios of 1:1, 1:2 and 1:5 produced additive interaction in the mouse 6Hz psychomotor seizure model. The combinations of levetiracetam with carbamazepine and phenytoin for the fixed-ratios of 1:5 and 1:10, as well as the combinations of levetiracetam with topiramate and vigabatrin for the fixed-ratio of 1:10 appear to be particularly favorable combinations exerting supra-additive interaction in the mouse 6Hz psychomotor seizure model. Finally, it may be concluded that because of the synergistic interactions between levetiracetam and carbamazepine, phenytoin, topiramate and vigabatrin, the combinations might be useful in clinical practice.

Topics: Animals; Anticonvulsants; Avoidance Learning; Carbamazepine; Disease Models, Animal; Drug Combinations; Drug Interactions; Fructose; Hand Strength; Levetiracetam; Male; Mice; Phenytoin; Piracetam; Psychomotor Performance; Seizures; Topiramate; Vigabatrin

Additional medications are needed for inflammatory bowel disease (IBD) as existing therapies are incompletely effective and can be costly and toxic. Preclinical studies suggest that topiramate (an anticonvulsant) may have disease-modifying properties in IBD, but its efficacy in humans is unknown.. To evaluate whether topiramate use is associated with clinical benefit in IBD patients.. We conducted a retrospective cohort study using administrative claims data from the MarketScan databases. Persons with IBD were identified between 2000 and 2010. New users of topiramate were compared with users of other anticonvulsant and anti-migraine medications. The primary outcome was a new prescription for an oral steroid (≥14 days). Secondary outcomes included initiation of biologic agents, abdominal surgery, and hospitalization. Cox proportional hazard modeling was used to adjust for potential confounders.. We identified 773 new users of topiramate and 958 users of comparator drugs. After adjusting for potential confounders, topiramate use was not associated with the primary outcome of steroid prescriptions [hazard ratio (HR) 1.14, 95 % confidence interval (CI) 0.74, 1.73]. Results did not differ significantly by IBD subtype. There was no difference between topiramate users and users of comparator drugs with respect to post-exposure initiation of biologic agents (HR 0.93, 95 % CI 0.39, 2.19), abdominal surgery (HR 1.04, 95 % CI 0.17, 6.41), or hospitalization (HR 0.86, 95 % CI 0.62, 1.19).. In this large U.S. administrative claims study, topiramate use was not associated with markers of IBD flares. These results cast doubt on whether topiramate may be an effective adjunct to current IBD therapy.

Topics: Adult; Anticonvulsants; Bipolar Disorder; Child; Child, Preschool; Databases, Factual; Female; Follow-Up Studies; Fructose; Humans; Infant; Infant, Newborn; Inflammatory Bowel Diseases; Male; Middle Aged; Migraine Disorders; Peripheral Nervous System Diseases; Pharmacoepidemiology; Proportional Hazards Models; Retrospective Studies; Seizures; Topiramate; Treatment Outcome; Young Adult

To assess the effectiveness of the newer antiepileptic drugs (AEDs)-in particular lamotrigine, topiramate, and levetiracetam-in controlling epileptic seizures in pregnant women.. Analysis of data in the Australian Register of Antiepileptic Drugs in Pregnancy concerning seizure control in 1,534 pregnancies in women with AED-treated epilepsies.. In AED monotherapy (1,111 pregnancies), use of levetiracetam in pregnancies in the Australian Register was associated with levels of seizure control similar to those that applied for the major older AEDs carbamazepine and valproate, but with levels of seizure control superior to those associated with use of lamotrigine and topiramate.. Levetiracetam shows promise as a satisfactory drug for controlling seizures in pregnancy.

Topics: Anticonvulsants; Female; Fructose; Humans; Lamotrigine; Levetiracetam; Piracetam; Pregnancy; Registries; Seizures; Topiramate; Treatment Outcome; Triazines; Victoria

Almost all experimental studies evaluating interactions between antiepileptic and non-antiepileptic drugs are based on their single administration, whereas epileptic patients require chronic pharmacotherapy. Herein, we attempted to figure out whether single and repeated administration of topiramate leads to the same anticonvulsant and undesired effects.. Experiments were conducted in the model of maximal electroshock in mice. Motor coordination was evaluated in the chimney test. Brain concentrations of topiramate were determined by high-performance liquid chromatography and triple quadrupole mass spectrometry.. The anticonvulsant activity of topiramate administered once or twice a day for 7 days did not significantly differ from the respective effect of topiramate given acutely in a single injection. However, calculating of 50% effective doses for topiramate applied in 14-days protocol (once or two times a day) was impossible. The antiepileptic administered at the dose range of 80-150 mg/kg did not offer protection in more than 50% of mice. This phenomenon cannot be attributed to pharmacokinetic events, because there were no significant differences between plasma and brain concentrations of topiramate after its acute and chronic administration. Topiramate (150 mg/kg) did not affect motor performance in mice.. Maximal electroshock in mice does not seem to be an appropriate seizure model to test anticonvulsant effects of chronic topiramate.

Topics: Animals; Anticonvulsants; Brain; Chromatography, High Pressure Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Electroshock; Fructose; Male; Mass Spectrometry; Mice; Seizures; Tissue Distribution; Topiramate

Lamotrigine (LTG) is a popular modern antiepileptic drug (AED); however, its mechanism of action has yet to be fully understood, as it is known to modulate many members of several ion channel families. In heterologous systems, LTG inhibits Cav 2.3 (R-type) calcium currents, which contribute to kainic-acid (KA)-induced epilepsy in vivo. To gain insight into the role of R-type currents in LTG drug action in vivo, we compared the effects of LTG to two other AEDs in Cav 2.3-deficient mice and controls on KA-induced seizures.. Behavioral seizure rating and quantitative electrocorticography were performed after injection of 20 mg/kg (and 30 mg/kg) KA. One hour before KA injection, mice were pretreated with 30 mg/kg LTG, 50 mg/kg topiramate (TPM), or 30 mg/kg lacosamide (LSM).. Ablation of Cav 2.3 reduced total seizure scores by 28.6% (p = 0.0012), and pretreatment with LTG reduced seizure activity of control mice by 23.2% (p = 0.02). In Cav 2.3-deficient mice, LTG pretreatment increased seizure activity by 22.1% (p = 0.018) and increased the percentage of degenerated CA1 pyramidal neurons (p = 0.02). All three AEDs reduced seizure activity in control mice; however, only the non-calcium channel modulating AED, LSM, had an anticonvulsive effect in Cav 2.3-deficient mice. Furthermore, LTG altered electrocorticographic parameters differently in the two genotypes: decreasing relative power of ictal spikes in control mice but increasing relative power of high frequency fast ripple discharges during seizures in Cav 2.3-deficient mice.. These findings provided the first in vivo evidence for an essential role for Cav 2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Cav 2.3-deficient mice by increasing high frequency components of seizures, resulting in increased neurotoxicity in the CA1. This paradoxical mechanism, possibly reflecting rebound hyperexcitation of pyramidal CA1 neurons after increased inhibition, may be key in understanding LTG-induced seizure aggravation observed in clinical practice.

Topics: Acetamides; Animals; Anticonvulsants; Calcium Channels, R-Type; Cation Transport Proteins; Disease Models, Animal; Electroencephalography; Fructose; Hippocampus; Lacosamide; Lamotrigine; Mice; Seizures; Topiramate; Triazines

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN - a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four second-generation antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), the step-through passive avoidance task (assessing long-term memory) and the grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by high-pressure liquid chromatography to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5mg/kg, i.p.) significantly enhanced the anticonvulsant action of lamotrigine (P<0.05), pregabalin (P<0.001) and topiramate (P<0.05), but not that of oxcarbazepine in the maximal electroshock-induced tonic seizure test in mice. Furthermore, none of the investigated combinations of WIN with antiepileptic drugs were associated with any concurrent adverse effects with regards to motor performance, long-term memory or muscular strength. Pharmacokinetic characterization revealed that WIN had no impact on total brain concentrations of lamotrigine, oxcarbazepine, pregabalin and topiramate in mice. These preclinical data would suggest that WIN in combination with lamotrigine, pregabalin and topiramate is associated with beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced tonic seizure test.

Topics: Animals; Anticonvulsants; Avoidance Learning; Benzoxazines; Brain; Cannabinoid Receptor Agonists; Carbamazepine; Drug Interactions; Drug Therapy, Combination; Electroshock; Fructose; gamma-Aminobutyric Acid; Hand Strength; Lamotrigine; Male; Memory, Long-Term; Mice; Morpholines; Muscle Strength; Naphthalenes; Oxcarbazepine; Pregabalin; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Seizures; Topiramate; Triazines

Epilepsy is a common health problem which carries a huge medical social psychological and economic impact for a developing country. The aim of this hospital-based study was to get an insight into the effectiveness and tolerability of low cost antiepileptic drugs (AEDs) in Bangladeshi people with epilepsy.. This retrospective chart review was done from hospital records in weekly Epilepsy outdoor clinic of Department of Neurology, Dhaka Medical College Hospital (DMCH) from October 1998 to February 2013. A total of 854 epilepsy patients met the eligibility criteria (had a complete record of two years of follow up data) from hospital database. A checklist was used to take demographics (age and gender), epilepsy treatment and adverse event related data. At least two years of follow up data were considered for analysis.. Out of 854 patients selected, majority of the patients attending outdoor clinic were >11-30 years age group (55.2%) with a mean age of 20.3 ± 9 years and with a male (53%) predominance. Focal epilepsy were more common (53%), among whom secondary generalized epilepsy was the most frequent diagnosis (67%) followed by complex partial seizure (21%). Among those with Idiopathic Generalized Epilepsy (46%), generalized tonic clonic seizure was encountered in 74% and absence seizure was observed in 13%. The number of patients on monotherapy and dual AED therapy were 67% and 24% respectively and polytherapy (i.e. >3 AEDs) was used only in 9%. CBZ (67%) was the most frequently prescribed AED, followed by VPA (43%), PHB (17%), and PHT (8%). CBZ was prescribed in 37% patients as monotherapy followed by VPA in 21% and PHB in 8% patients. Newer generation drugs eg lemotrigine and topiramate were used only as add on therapy in combination with CBZ and VPA in only 2% patients. The treatment retention rates over the follow up period for the AEDs in monotherapy varied between 86 and 91% and were highest for CBZ, followed by VPA. Most of the combination regimens had a treatment retention rate of 100%. The effectiveness of AED in terms of reduction of seizure frequency was highest for PHT (100%) and PHB (98%) followed by CBZ (96%) and VPA (95%). PHB and PHT were the cheapest of all AEDs (42 I$ and 56 I$/ year respectively). The costs of VPA and CBZ were two times and LTG and TOP were six to eight times higher. Adverse drug reaction (ADR) were observed among 140 (24.5%) of those with monotherapy. PHT (64%) was the most common drug to cause ADR, CBZ was at the bottom of the list to cause adverse effect (11.6%). VPA and PHB caused weight gain commonly. Adjustment of drug dose or withdrawal due to ADRs was necessary in 39% with PHT and 26% with PHB.. Though PHT and PHB are cheapest and efficacious among all, CBZ and VPA are less costly, effective and well tolerated drug for seizure control in context of Bangladesh.

Topics: Adolescent; Adult; Anticonvulsants; Bangladesh; Carbamazepine; Child; Drug Combinations; Epilepsies, Partial; Epilepsy, Generalized; Female; Follow-Up Studies; Fructose; Hospitals, Teaching; Humans; Male; Middle Aged; Phenobarbital; Phenytoin; Prohibitins; Retrospective Studies; Seizures; Topiramate; Treatment Outcome; Valproic Acid

The effect of anticonvulsant drugs on posttraumatic convulsive reactions and the stability of the brain with respect to complete ischemia and hypoxia upon brain injury has been studied in animals with model contact craniocerebral trauma. It is established that lamotrigine, topiramate, and sodium valproate produce a strong effect on convulsive reactions, while magnesium sulfate and gabapentin produce a moderate action. The antiishemic and antihypoxic action of lamotrigine and sodium valproate is stronger than that of topiramate and gabapentin.

Topics: Amines; Animals; Animals, Outbred Strains; Anticonvulsants; Brain; Brain Injuries; Brain Ischemia; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Electric Stimulation; Fructose; Gabapentin; gamma-Aminobutyric Acid; Lamotrigine; Magnesium Sulfate; Mice; Rats; Seizures; Topiramate; Triazines; Valproic Acid

We report a case of unusually long-lasting remission of type 1 diabetes (T1D). The patient, a Caucasian man, at the age of 43 years developed a ketotic diabetes, classified as type 1 based on clinical presentation and positivity for islet autoantibodies. Shortly after diabetes onset, oral topiramate was added to preexisting valproic acid for generalized seizures and maintained thereafter. Initial intensive insulin treatment was rapidly reduced to low doses (3 Units/day) maintained for a long time and then discontinued at month 55; fasting glucose and glycosylated hemoglobin were basically normalized at 58 months. An oral glucose tolerance test performed at month 53 showed an impaired fasting glucose (6.0 mmol/l) and a value slightly above the threshold for the diagnosis of diabetes at 2 h (11.2 mmol/l). We hypothesize that this unusually prolonged preservation of β-cell function might be ascribed to the concomitant therapy with topiramate, an antiepileptic agent with demonstrated efficacy as antidiabetic in type 2 diabetes (T2D). Topiramate should be further investigated as candidate agent for the preservation of β-cell function also in T1D.

Topics: Adult; Anticonvulsants; Diabetes Mellitus, Type 1; Fructose; Humans; Male; Remission Induction; Seizures; Topiramate

Refractory status epilepticus (RSE) occurs in patients with SE when they fail to respond to traditional medical therapy. Because there are very few case reports of topiramate (TPM) treatment of RSE in adult patients, we examined our experience with TPM with regard to its safety and efficacy in seizure termination in RSE in an adult patient population. We report a retrospective review of 35 adult patients with RSE who were treated with TPM in addition to other antiepileptic drugs (AEDs) between 2003 and 2010. After failure of initial treatments of benzodiazepines and weight-based intravenous loading doses of standard AEDs, TPM tablets were crushed and administered via nasogastric tube. Data were collected on age, gender, history of epilepsy, etiology of RSE, daily dose of TPM, co-therapeutic agents, treatment response, and disposition. Following initiation of TPM use and discontinuation of continuous intravenous anesthetics with no additional AEDs administered, cumulative cessation of RSE in patients was 4/35 (11%) at one day, 10/35 (29%) at two days, and 14/35 (40%) at three days. However, when including all patients and comparing the two patient groups in which RSE was or was not terminated within three days of initiating TPM as the last or not last AED given, there was no significant difference. Time to TPM response was not associated with the type of seizures, etiology of SE, or whether there was a history of epilepsy. There were no documented side effects or complications of therapy with TPM. This study provides support for the use of TPM as an adjunctive agent in the treatment of RSE.

Topics: Adult; Aged; Aged, 80 and over; Anticonvulsants; Female; Fructose; Humans; Male; Middle Aged; Retrospective Studies; Seizures; Status Epilepticus; Time Factors; Topiramate; Young Adult

Psychogenic nonepileptic seizures are clinical events that mimic epileptic seizures but are not associated with electroencephalographic discharges. These seizures are seldom reported in children in the literature and could be misinterpreted as generalized tonicoclonic seizures. We report the case of a child, already treated for epilepsy, who presented at 8 years of age with several psychogenic seizures leading to pseudostatus epilepticus. After several hospitalizations, the diagnosis of pseudostatus was established on the basis of clinical semiology, lack of EEG abnormalities during the seizures, and a positive provocation maneuver, which elicited and blocked the manifestations. The clinical spectrum of psychogenic seizures is wide and it is particularly difficult to differentiate psychogenic seizures from epileptic seizures, especially when occurring in children, some of whom are already treated for epilepsy. Well-described clinical features can suggest the diagnosis of psychogenic seizure. It is important and necessary to make the diagnosis as soon as possible in order to rapidly begin appropriate treatment including psychotherapy. In fact, the long-term prognosis in children is better than in the adult population. Associated risk factors, such as anxiety as reported in the present case, have to be sought. Recognizing psychogenic seizures will thus avoid their fixation in the child's personality and the risk of inappropriate and escalating treatments leading to iatrogenic complications.

Topics: Anticonvulsants; Child; Diagnosis, Differential; Electroencephalography; Fructose; Humans; Male; Psychophysiologic Disorders; Psychotherapy; Seizures; Status Epilepticus; Topiramate; Treatment Outcome

In reflex seizures induced by proprioceptive stimuli, the activated network may be identified as a single anatomo-functional circuit; the sensory-motor network. These seizures may be considered as epileptically-enhanced stretch reflexes. Proprioceptive reflex epilepsies are a good example of the so-called "system epilepsies". We present three cases discussing the clinical features of such epilepsies. [Published with videosequences].

Topics: Age of Onset; Anticonvulsants; Carbamazepine; Child; Electroencephalography; Epilepsy, Reflex; Female; Foot; Fructose; Humans; Lamotrigine; Leg; Magnetic Resonance Imaging; Male; Movement; Nerve Net; Proprioception; Reflex, Stretch; Seizures; Stereotyped Behavior; Topiramate; Triazines; Young Adult

Reported here is the case of a severely disabled young girl who developed Fanconi syndrome secondary to long-term valproic acid administration, ultimately leading to hypophosphatemic rickets. Although nephrocalcinosis is not a common feature in patients with proximal tubulopathy, the patient presented also with this condition, and the concomitant use of another anticonvulsant might have potentiated this condition. The purpose of this report is to increase awareness among healthcare providers of such rare but significant complications associated with anticonvulsants.

Topics: Anticonvulsants; Child; Diagnosis, Differential; Fanconi Syndrome; Female; Fructose; Humans; Nephrocalcinosis; Rickets; Seizures; Topiramate; Valproic Acid

The objective of this study is to describe the usefulness of topiramate in refractory neonatal seizures.. We reported the clinical off-label use of topiramate in three cases of refractory neonatal seizures of unclear origin with no response to conventional antiepileptic drugs. In all cases, the seizures were completely controlled with adding topiramate. All patients became seizure free during hospitalization and were followed by approximately 1 year after hospital discharge, with monotherapy with topiramate.. The clinical off-label use of topiramate in neonatal seizures is still incipient. When searching publications in this matter, only one report was identified. Because of its efficacy for both seizures and neuroprotection, topiramate could be a useful choice in refractory neonatal seizures.

Topics: Anticonvulsants; Drug Administration Schedule; Female; Fructose; Humans; Infant; Male; Off-Label Use; Seizures; Topiramate; Treatment Outcome

Based on the time until treatment failure, we retrospectively analyzed 389 children to compare the long-term effectiveness of first-line antiepileptic drugs (AEDs) in children with generalized onset or unclassified epileptic seizures.. Analyses were based on time until treatment failure and time until remission.. In terms of time until treatment failure, the failure rates of topiramate and carbamazepine were higher than that of sodium valproate (p < 0.05). For time until 1-year remission, sodium valproate was found to be significantly better than either topiramate or carbamazepine (p < 0.05). For the subgroup with generalized onset epilepsy, sodium valproate was much better than either topiramate or carbamazepine (p < 0.05). No significant differences were found between topiramate and carbamazepine (p = 0.319). For unclassified epileptic seizures, no significant differences were found among the three AEDs.. Sodium valproate should be the drug of choice for patients with children with generalized onset, and no significant differences were found among the three AEDs in unclassified epileptic seizures.

Topics: Age of Onset; Anticonvulsants; Asian People; Carbamazepine; Child; Child, Preschool; Epilepsy; Female; Fructose; Humans; Male; Retrospective Studies; Seizures; Topiramate; Treatment Failure; Treatment Outcome; Valproic Acid

Experimental evidence indicates that bupropion hydrochloride, an antidepressant and a first-line smoking cessation aid, exerts dose-dependently anticonvulsant and convulsant effects. In this study, chronic bupropion pretreatment intraperitoneally (i.p.) for 14 days in a dose of 5 mg/kg reduced the ED(50) (i.e. the dose protecting 50% of mice against electroconvulsions) of lamotrigine, topiramate, and felbamate from 4.58, 60.95, and 48.79 (antiepileptic+vehicle) to 3.01, 41.68, and 37.28 mg/kg (antiepileptic+bupropion), respectively, against maximal electroshock-induced seizures in mice. Bupropion significantly increased the plasma and brain concentrations of lamotrigine. Plasma concentration of topiramate was elevated, however, the brain concentration of the drug was not affected. Neither plasma nor brain concentrations of felbamate were elevated by bupropion administration. Bupropion did not exacerbate motor coordination impairment caused by the antiepileptic drugs in the rotarod test. Chronic administration of bupropion significantly potentiates the protective activity of lamotrigine, topiramate, and felbamate against maximal electroshock-induced seizures. A pharmacokinetic interaction is responsible for the effect of bupropion co-administered with lamotrigine.

Topics: Animals; Anticonvulsants; Brain; Bupropion; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Synergism; Electroshock; Felbamate; Fructose; Injections, Intraperitoneal; Lamotrigine; Male; Mice; Motor Activity; Phenylcarbamates; Propylene Glycols; Psychomotor Performance; Rotarod Performance Test; Seizures; Topiramate; Triazines

Cognitive impairment is frequently observed in epileptic patients. It has been seen that not only epilepsy but antiepileptic drugs also impair cognitive functions. The present study was undertaken to assess the effect of three anticonvulsants viz. lamotrigine (5mg/kg, p.o.), oxcarbazepine (15mg/kg, p.o.) and topiramate (10mg/kg, p.o.) on cognitive function and oxidative stress during pentylenetetrazole (PTZ)-kindling in mice. Kindling was induced by the administration of PTZ (25mg/kg, i.p.) on every alternate day till 5 weeks. Cognition was assessed after the development of kindling. Elevated plus maze (EPM) and passive avoidance response (PAR) tests were carried out after 24h and 48h of the last PTZ administration. After completion of behavioural tests malondialdehyde (MDA), glutathione levels, superoxide dismutase and catalase activity were measured as an indicator of oxidative stress. The results of the present study indicate that topiramate (10mg/kg) administration to kindled animals increased transfer latency and decreased step-down latency in EPM and PAR tests, respectively. However, lamotrigine and oxcarbazepine did not alter the two parameters. Topiramate administration to kindled as well as non-kindled animals has shown increase in MDA and decrease in glutathione levels. Lamotrigine and oxcarbazepine did not show significant alteration in oxidative stress parameters. To conclude, long term administration of topiramate impairs cognitive functions during experimental epilepsy while lamotrigine and oxcarbazepine are safer.

Topics: Animals; Anticonvulsants; Carbamazepine; Catalase; Cognition Disorders; Disease Models, Animal; Drug Interactions; Escape Reaction; Fructose; Glutathione; Kindling, Neurologic; Lamotrigine; Male; Malondialdehyde; Maze Learning; Mice; Oxcarbazepine; Oxidative Stress; Pentylenetetrazole; Seizures; Superoxide Dismutase; Topiramate; Triazines

To assess the efficacy of Topiramate as an add-on drug in the treatment of seizures in children of age group 0-12 years.. Fifty children of age 0-12 years with seizures viz. partial seizures with or without secondary generalization, myoclonic jerks, infantile spasms, generalized tonic-clonic seizures, absence or mixed seizures were chosen from the out-patient department. Topiramate was added in small doses to conventional antiepileptics, and increased till the most effective/best-tolerated dose was reached. A Seizure Improvement Scale (SIS) was used. Outcome variables included seizure type, frequency, severity, SIS based on starting dose and the dose at the end of 6th month, EEG pattern, number of concomitant drugs used and adverse effects. Data was collected in monthly follow up visits for next 6 months (0-6 month study period). Details of seizures and medication availed by the study population during the 6 month period prior to the start of study were retrieved from available case records; this was used as control (-6 to 0 month study period). Using each of the outcome variables, efficacy was ascertained by clinical and statistical comparison.. Myoclonic jerks, generalized tonic clonic seizures, partial seizures with secondary generalization and complex partial seizures constituted 75% of seizures. Z-test for proportion showed significant reduction (p < 0.05) in these seizure types. ANOVA test for repeated measures (f = 162.3, p < 0.01) showed a significant fall in seizure frequency in 0 to 6 month period (t = 2.0, df = 49, p < 0.05) in seizure frequency. 50%, 18%, 8% and 10% of children had 100%, >75%, >50% and <50% reduction in seizure frequency, respectively at the end of 6 months. Statistically significant reduction in severity (status epilepticus) was found. An association between starting dose and position in the SIS was noted (Chi-square test); the authors recommend a starting dose of 1-2 mg/kg/day. Similarly, significant association between dose at the end of 6(th) month and position in the SIS was found; the authors recommend an optimum maintenance dose of 2.5-7.5 mg/kg/day. Though not statistically significant, the percentage of subjects using one concomitant antiepileptic drug (monotherapy) increased from 23% to 34%; those using 2 and 3 drugs (polytherapy) decreased from 40% to 34% and 33% to 27%, respectively. EEG pattern reverted back to normal in eight children. Apart from minor adverse effects, none had serious systemic manifestations during the study period.. The authors support the efficacy and safety of Topiramate as an add-on drug in seizures in children.

Topics: Anticonvulsants; Child; Child, Preschool; Drug Therapy, Combination; Female; Fructose; Humans; India; Infant; Infant, Newborn; Male; Seizures; Topiramate

Lennox-Gastaut syndrome (LGS) is a well-defined epileptic encephalopathy highly drug resistant. The first-line treatment option is valproate (VPA), usually in combination with lamotrigine. VPA has been linked to serious hepatotoxicity. We report a 22-year-old liver transplanted patient with LGS successfully treated with VPA in combination with phenobarbital (100 mg/d; blood level: 36 mg/l), lamotrigine (125 mg/d; blood level: 4.81 mg/l) and topiramtate (175 mg/d), as well as immunosuppressive, antiviral, anti-anemic, hypo-phosphoric and alkaline medication. On VPA 1000 mg/d, the seizure frequency decreased significantly. Taking into consideration the patient's good tolerance and the normal liver function, VPA was increased to 1500 mg/d. At this dose the daily drop attacks and generalized tonic-clonic seizures totally ceased. The patient presented only some tonic seizures around awakening. During many years, VPA was avoided in this patient because of its potential hepatotoxicity. However the good functioning of the transplanted liver permitted its introduction. VPA can be used safely in liver transplanted patients under the strict control of the hepatic function.

Topics: Anticonvulsants; Chemical and Drug Induced Liver Injury; Electroencephalography; Female; Fructose; Humans; Immunosuppressive Agents; Intellectual Disability; Lamotrigine; Lennox Gastaut Syndrome; Liver Function Tests; Liver Transplantation; Phenobarbital; Seizures; Spasms, Infantile; Topiramate; Triazines; Valproic Acid; Young Adult

Therapeutic options for treating neonatal seizures, such as phenobarbital and phenytoin, lack efficacy and are potentially harmful to the developing brain. Topiramate appears effective as both an antiseizure and neuroprotective agent in animal models of newborn brain injury. Although topiramate is a common add-on agent in newborns, its use in this population has not yet been reported. We performed a retrospective cohort study of clinical topiramate use in newborns with acute symptomatic seizures that were refractory to standard agents. In four of six newborns, apparent reduction or no further seizures occurred. None of the children experienced side effects resulting in discontinuation of the drug, either during the hospital admission or after discharge. Prospective studies evaluating the safety and efficacy of topiramate for both seizures and neuroprotection will be important in determining whether it deserves widespread use in clinical practice.

Topics: Age Factors; Cohort Studies; Female; Follow-Up Studies; Fructose; Humans; Infant, Newborn; Male; Patient Admission; Patient Discharge; Retrospective Studies; Seizures; Topiramate; Treatment Outcome

Thalidomide was synthesized more than 50 years ago as hypnotic sedative with unique pharmacologic properties. Recently, we have described a notorious anticonvulsant effect of thalidomide on pentylenetetrazole-induced seizures. Here, we report the results of thalidomide administration on amygdaloid kindling. A total of 100 male Wistar rats were implanted with brain electrodes in the basolateral amygdaloid nucleus and the sensory motor cortex. After surgery the animals received a daily electric stimulus through the amygdaline electrode (500 μA intensity, 60 Hz frequency, 1 ms duration) until seizures appeared. The following treatment groups were made: (a) controls; (b) rats treated daily with thalidomide (10 mg/kg) or with topiramate (80 mg/kg); (c) rats treated with different doses of thalidomide. Significant reduction in the after-discharge and retard of behavioral stages were observed in rats treated with thalidomide or with topiramate as compared with controls (p<0.01): Also, a similar anticonvulsant outcome of thalidomide therapy was obtained with doses of either 2.5, 5, 10 or 50 mg/kg; at 100 mg/kg all epileptic activity was suppressed. Anticonvulsant efficacy of thalidomide was superior in most parameters than that obtained with topiramate. In amygdaloid kindling, which simulates human epilepsy characterized by focal seizures secondarily generalized, low doses of thalidomide display strong anticonvulsant properties.

Topics: Amygdala; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Fructose; Humans; Kindling, Neurologic; Male; Rats; Rats, Wistar; Seizures; Thalidomide; Topiramate

Tobacco smoking is a widespread phenomenon, and nicotine is the addictive component of tobacco. Nicotine acts through nicotinic cholinergic receptors and has been associated with different types of psychophysical disorders in human beings. The present study had explored the proconvulsive action of nicotine and its effect on the antiseizure efficacy of topiramate against kainic acid (KA)-induced seizures in mice.. The study had evaluated the dose-response curves for nicotine and KA and for KA in nicotine-pretreated mice and for topiramate against KA-induced seizures. Mecamylamine was used to antagonize the nicotinic receptor-mediated actions of nicotine. CD50 (convulsive dose in 50% of animals) for KA and nicotine and ED50 (effective dose in 50% of animals as anticonvulsant) for topiramate were determined. Brain lipid peroxidation studies were also undertaken in the treated mice.. Nicotine significantly potentiated the convulsive action of KA acid and reduced the CD50 (95% confidence limits [CL]) value for KA from 2.6 mg/kg (2.3-3.1) to 1.4 mg/kg (0.9-2.1), intraperitoneally (i.p.). Topiramate pretreatment significantly inhibited KA-induced seizures and brain lipid peroxidation with ED50 (95% CL) value of 21.90 mg/kg (17.3-28.2), i.p. Nicotine pretreatment caused dose-dependent antagonism to the antiseizure and antilipid peroxidative actions of topiramate. Mecamylamine had antagonized the proconvulsant action of nicotine.. The study highlights the fact that intake of nicotine, through agonism to nAChR, might predispose epileptic patients to lower seizure threshold and induce a state of refractoriness to the protective effects of the antiepileptic drugs, resulting in possible breakthrough seizure attacks.

Topics: Animals; Anticonvulsants; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; Fructose; Humans; Kainic Acid; Lipid Peroxidation; Male; Mecamylamine; Mice; Nicotine; Nicotinic Antagonists; Receptors, Nicotinic; Seizures; Topiramate

Topics: Anticonvulsants; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Cyclohexanols; Dibenzothiazepines; Drug Overdose; Fatal Outcome; Female; Fructose; Humans; Quetiapine Fumarate; Seizures; Time Factors; Topiramate; Venlafaxine Hydrochloride; Young Adult

We established the effects of the antiepileptic drugs (AEDs) carbamazepine (CBZ), topiramate (TPM), and valproic acid (VPA) on the epileptiform activity induced by 4-aminopyridine (4AP) in the rat entorhinal cortex (EC) in an in vitro brain slice preparation.. Brain slices were obtained from Sprague-Dawley rats (200-250 g). Field and intracellular recordings were made from the EC during bath application of 4AP (50 microm). AEDs, and in some experiments, picrotoxin were bath applied concomitantly.. Prolonged (>3 s), ictal-like epileptiform events were abolished by CBZ (50 microm), TPM (50 microm), and VPA (1 mm), whereas shorter (<3 s) interictal-like discharges continued to occur, even at concentrations up to 4-fold as high. gamma-Aminobutyric acid (GABA)(A)-receptor antagonism changed the 4AP-induced activity into recurrent interictal-like events that were not affected by CBZ or TPM, even at the highest concentrations. To establish whether these findings reflected the temporal features of the epileptiform discharges, we tested CBZ and TPM on 4AP-induced epileptiform activity driven by stimuli delivered at 100-, 10-, and 5-s intervals; these AEDs reduced ictal-like responses to stimuli at 100-s intervals at nearly therapeutic concentrations, but did not influence shorter interictal-like events elicited by stimuli delivered every 10 or 5 s.. We conclude that the AED ability to control epileptiform synchronization in vitro depends mainly on activity-dependent characteristics such as discharge duration. Our data are in keeping with clinical evidence indicating that interictal activity is unaffected by AED levels that are effective to stop seizures.

Topics: 4-Aminopyridine; Action Potentials; Animals; Anticonvulsants; Brain; Carbamazepine; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Entorhinal Cortex; Fructose; In Vitro Techniques; Male; Neurons; Patch-Clamp Techniques; Picrotoxin; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Seizures; Topiramate; Valproic Acid

In this study we investigated the effectiveness of two antiepileptic drugs: riluzole and topiramate against pilocarpine-induced seizures, which are considered to be a model of intractable epilepsy commonly used to investigate the antiepileptic effect of drugs and mechanisms of epileptogenesis. Seizures and status epilepticus were induced by pilocarpine in adult male Wistar rats. Riluzole (1-4mg/kg) administered intraperitoneally before pilocarpine dose-dependently protected rats against seizures with the anticonvulsant ED(50) value (50% effective anticonvulsant dose) of 1.8 (1.3-2.6)mg/kg. In contrast, riluzole at 8 and 12mg/kg administered after the onset of pilocarpine-induced seizures affected neither status epilepticus nor mortality of rats. Topiramate significantly enhanced convulsive action of pilocarpine, lowering the convulsant CD(50) value (50% effective convulsant dose) of pilocarpine from 350.8 (329.2-373.8) to 246.4 (218.6-278.2)mg/kg. Riluzole (4mg/kg) lowered plasma and brain concentration of pilocarpine administered at a dose of 400mg/kg from 168.0+/-8.6 to 75.3+/-19.9microg/ml and from 193.7+/-6.6 to 97.0+/-26.1microg/g, respectively. Topiramate (200mg/kg) increased plasma and brain concentration of pilocarpine administered at a dose of 300mg/kg from 78.1+/-2.9 to 106.0+/-6.8microg/ml and from 138.4+/-5.0 to 155.2+/-5.1microg/g, respectively. It seems that both anticonvulsant effect exerted by riluzole and proconvulsant effect exerted by topiramate in pilocarpine model of seizures are due to a pharmacokinetic interaction. Therefore, we postulate that the concentration of pilocarpine should be measured routinely whenever the anticonvulsant effect of drugs is determined in the pilocarpine model of seizures.

Topics: Animals; Anticonvulsants; Brain; Chromatography, High Pressure Liquid; Convulsants; Drug Interactions; Fructose; Male; Pilocarpine; Rats; Rats, Wistar; Riluzole; Seizures; Status Epilepticus; Topiramate

Lamotrigine (LTG) and topiramate (TPM), two of the most commonly used new-generation antiepileptic drugs (AEDs), have been shown to produce no adverse and impaired cognitive effects in patients with epilepsy, respectively. As seizure-induced neurogenesis might contribute to cognitive deficits that are associated with status epilepticus (SE), we examined whether these two drugs produce differential effects on seizure-induced neurogenesis in the hippocampus of adult rats. Lithium pilocarpine model was used to mimic human temporal-lobe epilepsy. Five hours after SE, LTG and TPM were administered intragastrically twice daily throughout the entire length of the experiment with total daily dose of 20 and 80 mg/kg, respectively. The hippocampal neurogenesis was examined using 5-bromodeoxyuridine and doublecortin immunohistochemistry. Both LTG and TPM treatments significantly inhibited seizure-induced proliferation of neural progenitors in the hippocampus, but did not affect the neuronal differentiation of newborn cells. Long-term treatment with both AEDs decreased the number of spontaneous recurrent seizures after SE and alleviated chronic seizure-induced neuronal injury in the dentate hilus. Eventually, TPM significantly increased the number of newborn neurons in the dentate granular cell layer after seizures likely by promoting the survival of newborn neurons. In contrast, LTG treatment significantly reduced the number of ectopic hilar newborn neurons after seizures. Neither of them prevented the formation of hilar basal dendrites of newborn neurons in the epileptic hippocampus. These results indicate that TPM but not LTG promotes aberrant neuron regeneration in the hippocampus after SE, which might be partially related to their differential effects on cognitive function.

Topics: Adult Stem Cells; Animals; Anticonvulsants; Cell Proliferation; Cell Survival; Chronic Disease; Dendrites; Dentate Gyrus; Disease Models, Animal; Doublecortin Protein; Epilepsy, Temporal Lobe; Fructose; Hippocampus; Lamotrigine; Male; Neurogenesis; Neurons; Rats; Rats, Sprague-Dawley; Seizures; Topiramate; Triazines

Topics: Anticonvulsants; Brain; Chemotherapy, Adjuvant; Electroencephalography; Epilepsy; Fructose; Humans; Infant; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Seizures; Topiramate; Treatment Outcome; Video Recording

The aim of this study was to characterize the anticonvulsant effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline (MeTHIQ--an endogenous parkinsonism-preventing substance) in combination with four second-generation antiepileptic drugs (AEDs: lamotrigine [LTG], oxcarbazepine [OXC], pregabalin [PGB], and topiramate [TPM]) in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for parallel and non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of MeTHIQ with LTG, OXC, PGB and TPM at the fixed-ratio of 1:1 from the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain concentrations of MeTHIQ and TPM. In the mouse MES model, MeTHIQ administered singly had its DRRC parallel to those for OXC and TPM, and simultaneously, non-parallel to those for LTG and PGB. With type I isobolography for parallel DRRCs, the combination of MeTHIQ with TPM at three fixed-ratios of 1:3, 1:1 and 3:1 exerted supra-additive (synergistic) interaction, whereas the combination of MeTHIQ with OXC at the fixed-ratios of 1:3, 1:1 and 3:1 produced additive interaction. Similarly, the type I isobolography for non-parallel DRRCs revealed that the combination of MeTHIQ with LTG and PGB at the fixed-ratio of 1:1 produced additive interaction. For all combinations, neither motor coordination, long-term memory nor muscular strength were affected. Total brain concentrations of MeTHIQ and TPM revealed no significant changes in their concentrations when the drugs were combined at the fixed-ratios of 1:3, 1:1 and 3:1. In conclusion, the synergistic interaction of MeTHIQ with TPM at the fixed-ratios of 1:3, 1:1 and 3:1 against MES-induced seizures was pharmacodynamic in nature and thus, it is worthy of consideration in further clinical settings. The combinations of MeTHIQ with LTG, OXC and PGB were neutral in the mouse MES model.

Topics: Animals; Anticonvulsants; Avoidance Learning; Carbamazepine; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Electroshock; Fructose; gamma-Aminobutyric Acid; Lamotrigine; Male; Memory; Mice; Oxcarbazepine; Pregabalin; Seizures; Tetrahydroisoquinolines; Topiramate; Triazines

The aim of this study was to characterize the anticonvulsant effects of pregabalin (PGB-a third-generation antiepileptic drug) in combination with three second-generation antiepileptic drugs (i.e., lamotrigine [LTG], oxcarbazepine [OXC] and topiramate [TPM]) in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Potential adverse-effect profiles of interactions of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured. In the mouse MES model, PGB administered singly had its DRRC non-parallel to that for LTG, OXC and TPM. With type I isobolography for non-parallel DRRCs, the combinations of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 exerted additive interaction. In all combinations, neither motor coordination, long-term memory nor muscular strength were affected. In conclusion, the additive interactions between PGB and LTG, OXC and TPM are worthy of consideration while extrapolating the results from this study to clinical settings.

Topics: Animals; Carbamazepine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Electroshock; Fructose; gamma-Aminobutyric Acid; Lamotrigine; Male; Mice; Oxcarbazepine; Pregabalin; Psychomotor Performance; Seizures; Topiramate; Triazines

In previous studies we identified several 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives displaying potent anticonvulsant effects in different animal models of epilepsy. With the aim to deepen the structure-activity relationships (SAR) for this class of compounds and identify novel anticonvulsant agents we synthesized a series of 1-aryl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamides. The new compounds incorporate the main features of the above-mentioned anticonvulsants and a sulfonamide function capable to inhibit the enzyme carbonic anhydrase (CA, EC 4.2.1.1), which represents an attractive target in epilepsy. Pharmacological effects were evaluated in vivo against audiogenic seizures in DBA/2 mice and in vitro against several CA isoforms. Some of the new molecules showed anticonvulsant properties better than topiramate, but weak inhibitory activity and low selectivity in enzymatic assay.

Topics: Animals; Anticonvulsants; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Isoquinolines; Mice; Mice, Inbred DBA; Seizures; Structure-Activity Relationship

Topics: Administration, Oral; Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Adult; Anticonvulsants; Dexamethasone; Drug Interactions; Female; Fructose; Glucocorticoids; Humans; Seizures; Topiramate

The authors present a 10-year-old girl with tuberous sclerosis complex who has been receiving rapamycin for 10 months for seizure control. She was started at 0.05 mg/kg/d and titrated to an effective dose of 0.15 mg/kg/d. There was a dramatic reduction in seizure frequency with rapamycin therapy. Further studies are needed to objectively investigate the benefits of rapamycin in tuberous sclerosis complex and to clarify its mechanism of seizure control.

Topics: Anticonvulsants; Carbamazepine; Cerebral Cortex; Child; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fructose; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Neurosurgical Procedures; Paresis; Seizures; Sirolimus; Topiramate; Treatment Outcome; Tuberous Sclerosis; Virus Diseases

This noninterventional single-arm study explored effectiveness and behavioral outcomes in intellectually disabled patients treated with topiramate for epilepsy. Data from 21 patients diagnosed with cerebral palsy were available for evaluation. Behavioral changes were assessed using the validated Aberrant Behavior Checklist and Matson Evaluation of Social Skills for Individuals with Severe Retardation (MESSIER) scales. Some improvement in nearly all behavioral aspects was observed under concomitant topiramate therapy; for example, the Aberrant Behavior Checklist total score changed from 33.7+/-25.8 to 25.3+/-19.1 (P=0.047). In addition, seizure frequency decreased from 16.1+/-22.2/4 weeks to 12.2+/-17.0/4 weeks (N=21, P=0.164). Fifty-two percent of the patients experienced at least 50% seizure reduction during the 24-week treatment period. The safety profile is in accordance with the current Summary of Product Characteristics of Topiramate. Two unexpected deaths were attributed to sudden unexpected death in epilepsy.

Topics: Adolescent; Adult; Anticonvulsants; Behavior; Cerebral Palsy; Data Interpretation, Statistical; Drug Resistance; Epilepsy; Female; Fructose; Humans; Intellectual Disability; Male; Middle Aged; Psychiatric Status Rating Scales; Psychotropic Drugs; Seizures; Social Behavior; Topiramate; Treatment Outcome; Young Adult

The mechanism of anticonvulsant action of topiramate includes inhibition of glutamate-activated ion channels. The evidence is most convincing for direct inhibitory action at the ionotropic AMPA (alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and kainate ((2S,3S,4S)-3-(Carboxymethyl)-4-prop-1-en-2-ylpyrrolidine-2-carboxylic acid) glutamate receptor subtypes. Less direct connection has been made to the NMDA (N-Methyl-d-aspartate) subtype. In the present study, we demonstrate that NMDA and AMPA produce concentration-dependent seizure-like activity in planarians, a type of flatworm which possesses mammalian-like neurotransmitters. In contrast, planarians exposed to the inhibitory amino acid, glycine, did not display pSLA. For combination experiments, topiramate significantly reduced planarian seizure-like activity (pSLA) produced by NMDA or AMPA. Additionally, NMDA-induced pSLA was antagonized by either an NMDA receptor antagonist (MK-801) or AMPA receptor antagonist (DNQX), thus suggesting that NMDA-induced pSLA was mediated by NMDA and non-NMDA receptors. The present results provide pharmacologic evidence of a functional inhibitory action of topiramate on glutamate receptor activity in invertebrates and provide a sensitive, quantifiable end-point for studying anti-seizure pharmacology.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Fructose; N-Methylaspartate; Neuroprotective Agents; Planarians; Quinoxalines; Seizures; Topiramate

We investigated the effects of vitamin E and topiramate (TPM) administrations on pentylentetrazol (PTZ)-induced blood and brain toxicity in rats. Forty rats were randomly divided into five equal groups. The first and second groups were used for the control and PTZ groups, respectively. Fifty or 100 mg TPM were administered to rats constituting the third and fourth groups for 7 days, respectively. The TPM and vitamin E combination was given to animals in the fifth group. At the end of 7 days, all groups except the first received a single dose of PTZ. Blood and brain samples were taken at 3 hrs after PTZ administration. Lipid peroxidation levels of plasma, erythrocyte, brain cortex and brain microsomal fraction; nitric oxide levels of serum; and the number of spikes and epileptiform discharges of the EEG were increased by PTZ administration. Plasma and brain vitamin E concentration, erythrocyte glutathione peroxidase (GSH-Px) activity and latency to first spike of the EEG were decreased by PTZ. Plasma lipid peroxidation levels in the third group and plasma and erythrocyte lipid peroxidation levels in the fifth group were decreased compared to the second group, whereas brain vitamin C, vitamin E, erythrocyte GSH-Px and reduced glutathione (GSH) values increased in the fifth group. Brain microsomal GSH levels and EEG records in the third, fourth and fifth groups were restored by the TPM and vitamin E treatment. In conclusion, TPM and vitamin E seems to have protective effects on PTZ-induced blood and brain toxicity by inhibiting free radicals and supporting the antioxidant redox system.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Electroencephalography; Fructose; Glutathione; Lipid Peroxidation; Male; Microsomes; Oxidation-Reduction; Oxidative Stress; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Topiramate; Vitamin E

Most previous studies on the effectiveness of the first antiepileptic drug have dealt with adults. The present retrospective study of 520 patients was designed to investigate the interaction among efficacy, tolerability, and overall effectiveness of the first antiepileptic drug in children with newly diagnosed epilepsy. A total of 344 patients became seizure-free with the first prescribed antiepileptic drug. A lower proportion of patients with symptomatic epilepsy (60.3%) or cryptogenic epilepsy (61.5%) became seizure-free, compared with patients with idiopathic epilepsy (73.8%), and more patients with symptomatic or cryptogenic epilepsy changed their treatments owing to intolerable side effects. Most patients (95.6%) received sodium valproate (n = 234), topiramate (n = 143), or carbamazepine (n = 120). The majority of seizure-free patients required only a moderate daily dose. Patients who took carbamazepine (16.7%) or topiramate (11.9%) had a higher incidence of adverse events, necessitating a change of treatment, compared with patients treated with valproate (4.3%), and fewer of them became seizure-free. Overall, 66.2% of the patients became seizure-free with the first-ever antiepileptic drug, and most of them at a moderate dose. Moreover, tolerability was as important as efficacy in determining overall effectiveness.

Topics: Anticonvulsants; Carbamazepine; Child; Child, Preschool; Epilepsy; Fructose; Humans; Retrospective Studies; Seizures; Topiramate; Treatment Outcome; Valproic Acid

Topics: Anticonvulsants; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Overdose; Female; Fructose; Humans; Myoclonus; Seizures; Topiramate

Recent experimental studies show that ethacrynic acid (ETA), a loop diuretic, exerts the anticonvulsant activity. Therefore, we tested the effect of ETA on the protective action of some second-generation antiepileptic drugs (oxcarbazepine [OXC], lamotrigine [LTG] and topiramate [TPM]) in the mouse maximal electroshock seizure (MES) model. ETA was administered acutely (50 and 100 mg/kg i.p.) or chronically, for 7 days (12.5 mg/kg i.p.). Both ETA acute (up to 100 mg/kg) and chronic (up to 12.5 mg/kg) treatment did not influence the threshold for electroconvulsions. In the MES test, ETA (100 mg/kg) potentiated the protective activity of TPM, decreasing its ED(50) value from 38.1 to 18.7 mg/kg (P<0.01). In contrast, ETA (100 mg/kg) remained without effect on the anticonvulsant action of the other antiepileptics (OXC and LTG) in mice. Chronic administration of ETA (12.5 mg/kg) did not affect the protective action of tested antiepileptics. The observed interaction between acute ETA and TPM was pharmacodynamic in nature because neither plasma nor total brain TPM concentrations were altered after injection of ETA.These results indicate existing interactions between ETA and TPM, which may have some clinical importance for epileptic patients treated with TPM and additionally ETA due to other medical causes.

Topics: Analysis of Variance; Animals; Anticonvulsants; Avoidance Learning; Brain; Brain Chemistry; Carbamazepine; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Electroshock; Ethacrynic Acid; Fructose; Lamotrigine; Male; Mice; Motor Skills; Oxcarbazepine; Seizures; Statistics, Nonparametric; Topiramate; Triazines

A small library of indanesulfonamides was screened for the inhibition of the human carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in neuronal excitation, that is, isoforms VII, XII and XIV. These CA isoforms are becoming interesting target for the design of agents useful for the treatment of epilepsy. The inhibition pattern of these indanesulfonamide compounds towards these three isoforms was excellent, with many nanomolar inhibitors detected (K(I)s in the range of 0.78-10 nM against hCA VII; 0.32-56 nM against hCA XII, and 0.47-1030 nM against hCA XIV, respectively). The maximal electroshock seizure (MES) test performed on mice showed a good anticonvulsant activity for some compounds which protected the mice against convulsions in the 50-62.5% range at a dose of 50 mg/kg. In parallel, the blood-brain barrier passive permeation of these sulfonamides was also estimated by using a computational approach.

Topics: Animals; Anticonvulsants; Blood-Brain Barrier; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Central Nervous System; Computer Simulation; Electroshock; Humans; Isoenzymes; Male; Mice; Mice, Inbred Strains; Models, Animal; Models, Chemical; Molecular Structure; Recombinant Proteins; Reproducibility of Results; Seizures; Stereoisomerism; Structure-Activity Relationship

Clinical studies indicate a decrease in free and total carnitine in children treated with old-generation antiepileptic drugs (especially valproate). Here, we studied the effect of new-generation antiepileptic drugs on serum carnitine levels. Serum carnitine levels were measured in 91 children: 24 treated with vigabatrin, 28 treated with lamotrigine, and 21 treated with topiramate. These drugs were given as monotherapy (54 children) or polytherapy (19 children). Eighteen additional children treated with valproate served as control subjects. Reduced mean serum carnitine level was evident only in children treated with valproate, with mean free and total carnitine level of 26.9 +/- 8.6 micromol/L and 29.1 +/- 10.4 micromol/L, respectively. In contrast, the mean serum carnitine levels of children treated with vigabatrin, lamotrigine, or topiramate were similar and normal. In these children, the free carnitine levels were 38.5 +/- 7.8 micromol/L, 37.2 +/- 7.7 microg/mL, and 40.4 +/- 8.7 micromol/L, respectively, and total carnitine levels were 43.5 +/- 8.8 micromol/L, 44.4 +/- 9.2 micromol/L, and 45.5 +/- 9.8 micromol/L (+/-S.D.), respectively. Only 4 children (treated with valproate) exhibited considerably lower serum carnitine levels. None of these children had significant clinical adverse effects attributable to carnitine deficiency. In conclusion, these new-generation antiepileptic drugs probably do not cause carnitine deficiency. In contrast, valproate may induce carnitine deficiency, but most cases are asymptomatic.

Topics: Adolescent; Anticonvulsants; Carnitine; Child; Child, Preschool; Female; Fructose; Humans; Infant; Lamotrigine; Male; Prospective Studies; Seizures; Topiramate; Triazines; Vigabatrin

The present study was conducted to investigate the possible interaction between low doses of nicotine and pentylenetetrazole (PTZ) in vivo and also to evaluate the influence of nicotine on the antiseizure efficacy of topiramate and sodium valproate in the PTZ-induced seizure model in mice. Graded dose-response study with nicotine showed the CD50 value for nicotine at 6.76 mg/kg. i.p. Subtheshold dose of nicotine (4 mg/kg, i.p.) pretreatment significantly decreased the CD50 value for PTZ from 47.86 mg/kg, i.p. (of PTZ per se) to 31.62 mg/kg, i.p. Sodium valproate but not topiramate, significantly inhibited PTZ-induced seizures in mice with an ED50 value of 177.83 mg/kg, i.p. Nonconvulsive dose of nicotine (1 mg/kg, i.p.) significantly antagonized the protective efficacy of sodium valproate against PTZ-induced seizures and increased the ED50 value to 338.84 mg/kg, i.p. PTZ-induced seizures significantly increased the mouse brain levels of MDA and reduced the level of GSH while sodium valproate reversed such changes. Nicotine pretreatment reversed the anti-lipid peroxidative action of sodium valproate in the PTZ-induced seizure model in mice. The study highlighted the convulsant as well as proconvulsant role of nicotine and established dose discrimination for nicotine as a proconvulsant agent and an anti-antiseizure agent. The study bears significant clinical relevance particularly amongst epileptic smokers who may show failure of efficacy of antiepileptic agents and present with breakthrough seizure attacks on exposure to nicotine.

Topics: Animals; Anticonvulsants; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Fructose; Ganglionic Stimulants; Male; Mice; Nicotine; Pentylenetetrazole; Seizures; Topiramate; Valproic Acid

The protective effect of topiramate (TPM) on seizure-induced neuronal injury is well known; however, its molecular basis has yet to be elucidated. We investigated the effect and signaling mediators of TPM on seizure-induced hippocampal cell death in kainic acid (KA)-treated ICR mice. KA-induced hippocampal cell death was identified by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Immunoreactivity (IR) of p-Erk, p-Jnk, p-P38, and caspase-3, and caspase-3 activity were observed in the hippocampal region 3 h after KA (0.1 microg/5 microL, i.c.v.) administration, and/or TPM (100 mg/kg, i.p.) pretreatment. TPM attenuated seizure-induced neuronal cell death and reduced KA-induced p-Erk IR in the CA3 region of the hippocampus, but did not affect p-Jnk and p-P38. In addition, TPM reduced caspase-3 IR and activation by KA. KA-induced seizures were also suppressed by TPM pretreatment. TPM inhibits seizures, and decreases Erk phosphorylation and caspase-3 activation by KA, thereby contributing to protection from neuronal injury.

Topics: Animals; Apoptosis; Benzoxazines; Blotting, Western; Caspase 3; Cell Death; Cell Survival; Disease Models, Animal; Fructose; Hippocampus; Immunohistochemistry; In Situ Nick-End Labeling; Injections, Intraventricular; Kainic Acid; Male; MAP Kinase Kinase Kinases; Mice; Mice, Inbred ICR; Neurons; Neuroprotective Agents; Oxazines; Seizures; Topiramate

We analyzed the effect of combination therapy on seizure frequency in all adult patients (N=193) with focal epilepsy followed at a single institution in a cross-sectional study. One hundred and thirty-five patients were on two AEDs, of them, 37 (27%) were seizure-free, 50 patients were on three AEDs including 5 (10%) seizure-free patients (p<0.01 for seizure-freedom with two AEDs versus three AEDs). Thirty-five different combinations were used in patients on two AEDs and 40 combinations on patients on three drugs emphasizing the difficulties involved in evaluation of the efficacy and tolerability of specific combinations. The significant proportion of seizure-free cases (27%) on duotherapy is suggesting the usefulness of combination therapy in achieving seizure-freedom in epilepsies refractory to single drug treatment. The material in the study was not from a randomized trial and therefore the comparability of patients on different AEDs is uncertain, but on the other hand the clinical practice followed provides a natural experiment suitable for comparative, non-randomized assessment of treatment outcomes.

Topics: Adult; Anticonvulsants; Brain; Carbamazepine; Drug Therapy, Combination; Female; Frontal Lobe; Fructose; Humans; Lamotrigine; Levetiracetam; Male; Nipecotic Acids; Occipital Lobe; Oxcarbazepine; Parietal Lobe; Piracetam; Seizures; Temporal Lobe; Tiagabine; Topiramate; Treatment Outcome; Triazines; Valproic Acid

Acute "silent" seizures after brain injury are associated with a worsening of patient outcome and are often refractory to anti-epileptic drug (AED) therapy. In the present study we evaluated topiramate (TPM, 1-30 mg/kg, i.v.) in a rodent model of spontaneous non-convulsive seizure (NCS) activity induced by focal cerebral ischemia. For seizure detection, electroencephalographic (EEG) activity was continuously recorded for 24h in male Sprague-Dawley rats subjected to permanent middle cerebral artery occlusion (MCAo). Infarct volume, neurological deficit, and NCS were evaluated by an experimenter blinded to the treatment group. All vehicle treated rats (7/7) exhibited NCS following MCAo. TPM treatment, delivered at 20 min post-occlusion and prior to onset of NCS activity, dose-dependently reduced the incidence of NCS (ED(50)=21.1mg/kg). The highest dose of TPM tested (30 mg/kg) exhibited maximal reductions of 76% in the number of NCS/rat (vehicle=22.1+/-5.3, TPM=4.4+/-3.2, P<0.05), 80% in the total time of NCS (vehicle=1259+/-337 s, TPM=253+/-220 s, P<0.05), 20% in core brain infarction (vehicle=45+/-1%, TPM=36+/-4%, percent of ipsilateral volume corrected for swelling, P<0.05), and 38% in neurological deficit score (vehicle=7.4+/-1.2, TPM=4.6+/-1.5, P<0.05). Despite efficacy as a pre-seizure treatment, TPM was not effective when delivered immediately following onset of the first NCS event (36+/-5 min post-MCAo). In conclusion, TPM exhibited significant efficacy for the prophylactic treatment of brain-injury induced NCS and represents a novel class of AED for treatment of this type of silent brain seizure.

Topics: Animals; Anticonvulsants; Brain Ischemia; Electroencephalography; Fructose; Male; Rats; Rats, Sprague-Dawley; Seizures; Topiramate

This study was aimed to quantitatively evaluate the effects of topiramate (TPM) on seizure susceptibility and hippocampal peripheral-type benzodiazepine receptors (PBRs) in the kainic acid (KA) model of temporal lobe epilepsy. Male rats were randomized into saline control group, KA group, KA/TPM low dose group and KA/TPM high dose group. Three weeks after single injection of KA (10 mg kg(-1), sc), the effects of TPM were tested at two doses (10 and 30 mg kg(-1), sc) once a day for 1 week in KA/TPM low dose group or KA/TPM high dose group, respectively. Rats in KA group received comparable injections of saline. Four weeks after initial KA injection, a subconvulsant dose KA (5 mg kg(-1), sc) was administered in rats in these three groups. Rats in saline control group received equal volume of saline. All animals were decapitated and hippocampus synaptosomes were purified 180 min after behavioral observation. PBRs specific binding sites were assessed by an in vitro binding technique utilizing the highly selective ligand [(3)H]PK11195. Seizure threshold was elevated and specific PBRs binding in hippocampus was decreased by TPM in dose-dependent manner. Specific PBRs binding in hippocampus was significantly related to seizure latency and seizure intensity. These results suggest that TPM can reduce the susceptibility to seizures in KA-kindled rats and its anticonvulsant effect seems resulting from, at least in part, the reduced PBRs binding after treatment. These results also support the hypothesis that PBRs represent a novel target for antiepileptic drug development.

Topics: Animals; Anticonvulsants; Behavior, Animal; Excitatory Amino Acid Agonists; Fructose; Hippocampus; Indicators and Reagents; Isoquinolines; Kainic Acid; Kindling, Neurologic; Male; Peripheral Nervous System; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Seizures; Synaptosomes; Topiramate

This study focused on the evaluation of interactions between MRZ 2/576 (8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridazino(4,5-b)quinoline-5-oxide choline salt), an N-methyl-D-aspartate (NMDA) receptor antagonist acting at the NMDA receptor/glycine(B) site and four newer antiepileptic drugs (felbamate, lamotrigine, oxcarbazepine, and topiramate) in the mouse maximal electroshock seizure model. Results indicate that MRZ 2/576 administered intraperitoneally, 5 min before the test, exerted a clear-cut anticonvulsant effect in the maximal electroshock seizure test in mice and its ED(50) value was 13.71 (11.95-15.73) mg/kg. In the subthreshold method, MRZ 2/576 (administered intraperitoneally, at a subthreshold dose of 5 mg/kg) significantly enhanced the anticonvulsant action of felbamate, oxcarbazepine and topiramate, by reducing their ED(50) values from 73.0 to 53.8 mg/kg (p < 0.05) for felbamate, from 10.77 to 7.48 mg/kg (p < 0.05) for oxcarbazepine, and from 49.3 to 28.7 mg/kg (p < 0.01) for topiramate. In contrast, MRZ 2/576 (5 mg/kg, i.p.) did not significantly affect the antiseizure effects of lamotrigine in the maximal electroshock seizure test in mice. Isobolographic transformation of data revealed that MRZ 2/576 (5 mg/kg, i.p.) exerted barely additive interactions with all investigated antiepileptic drugs in the maximal electroshock seizure test. In conclusion, the isobolographic analysis revealed that MRZ 2/576 additively cooperates with newer antiepileptic drugs in terms of suppression of maximal electroshock-induced seizures in mice.

Topics: Animals; Anticonvulsants; Carbamazepine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Felbamate; Fructose; Injections, Intraperitoneal; Lamotrigine; Male; Mice; Oxcarbazepine; Phenylcarbamates; Phthalazines; Propylene Glycols; Receptors, N-Methyl-D-Aspartate; Seizures; Topiramate; Triazines

The present study examines the effect of rofecoxib in combination with topiramate (a newer antiepileptic) against PTZ (80 mg/kg, i. p.)-induced chemoconvulsions in mice. Pretreatment with rofecoxib (1.0 and 5.0 mg/kg., i. p.) or topiramate (50 and 100 mg/kg., i. p.) dose dependently protected the animals against PTZ-induced convulsions. However, the lower dose of neither rofecoxib (0.5 mg/kg., i. p.) nor topiramate (25 mg/kg., i. p.) modified the latency of any of the phase of PTZ-induced convulsions. When a subeffective doses of rofecoxib (0.5 mg/kg, i. p.) was coadministered with a subprotective dose of topiramate (25 mg/kg, i. p.), there was no increase in onset latency of myoclonic jerks but an increase in the latency for clonus and extensor phase were observed. Rofecoxib may be used as an adjunct therapy with topiramate in the treatment of epilepsy.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Fructose; Lactones; Male; Mice; Pentylenetetrazole; Seizures; Sulfones; Topiramate

To assess the effect of 3 calcium channel antagonists (amlodipine, diltiazem, and verapamil) on the anticonvulsant action of topiramate (a new generation antiepileptic drug) in the mouse maximal electroshock seizure (MES) model. Amlodipine (20 mg/kg) significantly enhanced the anticonvulsant activity of topiramate in the MES test in mice, reducing its ED50 value from 54.83 to 33.10 mg/kg (p < 0.05). Similarly, diltiazem (5 and 10 mg/kg) markedly potentiated the antiseizure action of topiramate against MES, lowering its ED50 value from 54.83 to 32.48 mg/kg (p < 0.05) and 28.68 mg/kg (p < 0.01), respectively. In contrast, lower doses of amlodipine (5 and 10 mg/kg) and diltiazem (2.5 mg/kg) and all doses of verapamil (5, 10, and 20 mg/kg) had no significant impact on the antiseizure action of topiramate. Pharmacokinetic verification of the interaction of topiramate with amlodipine and diltiazem revealed that neither amlodipine nor diltiazem affected total brain topiramate concentration in experimental animals, and thus, the observed interactions were concluded to be pharmacodynamic in nature. The favorable combinations of topiramate with amlodipine or diltiazem deserve more attention from a clinical viewpoint because the enhanced antiseizure action of topiramate was not associated with any pharmacokinetic changes in total brain topiramate concentration.

Topics: Amlodipine; Animals; Anticonvulsants; Behavior, Animal; Brain; Calcium Channel Blockers; Diltiazem; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Electroshock; Fluorescence Polarization Immunoassay; Fructose; Mice; Motor Skills; Seizures; Topiramate; Verapamil

To report a case of hyperventilation caused by topiramate therapy and propose a pathophysiologic mechanism for this disorder.. A 52-year-old woman with refractory seizure disorder was admitted to the burn care unit with burns over 10% of her body. Her seizure medications, unchanged and well tolerated for several months, included carbamazepine 1200 mg, lamotrigine 500 mg, phenobarbital 80 mg, and topiramate 150 mg per day. During hospitalization, despite a relatively normal arterial pH, the woman developed persistent hyperventilation, with respiratory rates up to 50 breaths/min. Alkalinization did not reduce the hyperventilation. Thoracic contrast-enhanced computed tomographic scan ruled out pulmonary embolism and persistent pneumonia. Salicylate and biguanide screening were negative; results of repeated thyroid and liver function tests were normal. Cerebral magnetic resonance imaging excluded a cerebral pathology. After cerebrospinal fluid (CSF) analysis showed acidosis (pH 7.14), topiramate was withdrawn and the patient's general condition rapidly improved. Forty-eight hours later, the CSF pH had increased to 7.26. The woman was discharged from the burn care unit on the 42nd hospital day.. Hyperchloremic normal anion gap metabolic acidosis, which can lead to hyperventilation, has been reported as an adverse effect of topiramate treatment. However, our patient had respiratory alkalosis. Concurrent etiologies of peripheral hyperventilation were excluded, leaving central neurogenic hyperventilation as the remaining etiology. Such central neurogenic hyperventilation associated with topiramate has previously been reported in intensive care. Our case report demonstrates CSF acidosis. Withdrawing topiramate reduced both CSF acidosis and hyperventilation. The mechanism of topiramate-induced CSF acidosis remains unclear. According to the Naranjo probability scale, the relationship of hyperventilation to administration of topiramate in our patient was probable.. Normal doses of topiramate may provoke central neurogenic hyperventilation, as a result of CSF acidosis. The acid-base status of critically ill patients receiving topiramate should be monitored carefully.

Topics: Acidosis; Anticonvulsants; Drug Therapy, Combination; Female; Fructose; Humans; Hyperventilation; Middle Aged; Seizures; Topiramate

Animal models with spontaneous epileptic seizures may be useful in the discovery of new antiepileptic drugs (AEDs). The purpose of the present study was to evaluate the efficacy of carisbamate on spontaneous motor seizures in rats with kainate-induced epilepsy.. Repeated, low-dose (5 mg/kg), intraperitoneal injections of kainate were administered every hour until each male Sprague-Dawley rat had experienced convulsive status epilepticus for at least 3 h. Five 1-month trials (n = 8-10 rats) assessed the effects of 0.3, 1, 3, 10, and 30 mg/kg carisbamate on spontaneous seizures. Each trial involved six AED-versus-vehicle tests comprised of carisbamate or 10% solutol-HS-15 treatments administered as intraperitoneal injections on alternate days with a recovery day between each treatment day.. Carisbamate significantly reduced motor seizure frequency at doses of 10 and 30 mg/kg, and caused complete seizure cessation during the 6-h postdrug epoch in seven of the eight animals at 30 mg/kg. The effects of carisbamate (0.3-30 mg/kg) on spontaneous motor seizures appeared dose dependent.. These data support the hypothesis that a repeated-measures, crossover protocol in animal models with spontaneous seizures is an effective method for testing AEDs. Carisbamate reduced the frequency of spontaneous motor seizures in a dose-dependent manner, and was more effective than topiramate at reducing seizures in rats with kainate-induced epilepsy.

Topics: Analysis of Variance; Animals; Anticonvulsants; Carbamates; Cross-Over Studies; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsy; Fructose; Kainic Acid; Male; Rats; Rats, Sprague-Dawley; Seizures; Time Factors; Topiramate; Video Recording

To examine antiepileptogenic, disease modifying, and anticonvulsant effects of topiramate under conditions of rapid kindling at different stages of development.. Afterdischarge threshold (ADT) and duration (ADD) were examined in 2-, 3-, and 5-week-old Wistar rats before and after administration of topiramate (200 mg/kg). Animals underwent a rapid kindling protocol (sixty 10-s trains, bipolar 20 Hz square wave pulses delivered every 5 min). The progression of behavioral and electrographic seizures, and responses to test stimulations 24 h after the protocol were compared between topiramate and vehicle-treated control rats. In addition, rats that were previously given vehicle only prior to kindling, were then given topiramate to examine the effect on established kindled seizures.. In 2-week-old animals, topiramate affected neither the baseline afterdischarge, nor the progression of kindled seizures. In 3-week-old rats, topiramate did not modify the baseline afterdischarge, but significantly delayed the occurrence of full motor seizures in response to repeated stimulations. Topiramate treatment of 5-week-old rats increased baseline ADT, shortened ADD, and delayed the progression of kindled seizures. Twenty-four h after the last kindling stimulation, animals of all ages exhibited a decreased ADT, an increase ADD, and developed behavioral seizures in response to threshold stimulation. Vehicle-treated kindled rats that were then given topiramate displayed significantly attenuated behavioral seizures induced by the threshold stimulation.. Topiramate exhibited age-dependent disease-modifying effects under conditions of rapid kindling, but failed to block epileptogenesis. Topiramate also inhibited kindled seizures with equal efficacy across the three ages.

Topics: Action Potentials; Age Factors; Animals; Anticonvulsants; Disease Models, Animal; Electric Stimulation; Electroencephalography; Epilepsy; Evoked Potentials, Motor; Fructose; Hippocampus; Kindling, Neurologic; Male; Neural Conduction; Neurons; Pharmaceutical Vehicles; Rats; Rats, Wistar; Seizures; Time Factors; Topiramate

The aim of this study was to determine the influence of acute (single) and chronic (twice daily for 14 consecutive days) treatments with aminophylline (theophylline(2).ethylenediamine) on the anticonvulsant potential of topiramate (a broad-spectrum antiepileptic drug) in the mouse maximal electroshock-induced seizure model. Additionally, the effects of acute and chronic administration of aminophylline on the adverse effect potential of topiramate were assessed in the chimney test (motor performance). To evaluate pharmacokinetic characteristics of interaction between topiramate and aminophylline, total brain concentrations of topiramate and theophylline were estimated with fluorescence polarization immunoassay technique. Results indicate that aminophylline in non-convulsive doses of 50 and 100 mg/kg (i.p.), both in acute and chronic experiments, markedly attenuated the anticonvulsant potential of topiramate by raising its ED(50) value against maximal electroconvulsions. Aminophylline at a lower dose of 25 mg/kg did not affect significantly the ED(50) value of topiramate in the acute experiment, but the drug markedly increased the ED(50) value of topiramate during the chronic treatment in mice. Only, aminophylline at 12.5 mg/kg, in both acute and chronic experiments, did not affect the antielectroshock action of topiramate in mice. Moreover, aminophylline at a dose of 100 mg/kg had no impact on the adverse effect potential of topiramate in the chimney test. Pharmacokinetic evaluation of total brain concentrations of topiramate and theophylline revealed that topiramate significantly increased total brain theophylline concentrations following both acute and chronic applications of aminophylline. Conversely, aminophylline did not alter total brain concentrations of topiramate in mice. Based on this preclinical study, one can conclude that aminophylline attenuated the antiseizure action of topiramate in the mouse maximal electroshock-induced seizure model and the observed interaction between drugs was both pharmacokinetic and pharmacodynamic in nature.

Topics: Aminophylline; Animals; Anticonvulsants; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Fructose; Male; Mice; Motor Activity; Seizures; Topiramate

The objective of this study was to characterize the anticonvulsant and acute adverse-effect potentials of topiramate (TPM) and gabapentin (GBP)-two second-generation antiepileptic drugs administered alone and in combination in the maximal electroshock (MES)-induced seizures and chimney test in mice. The anticonvulsant and acute adverse effects of the combination of TPM with GBP at the fixed ratio of 1:1 were determined using the type I isobolographic analysis for nonparallel dose-response relationship curves (DRRCs). To ascertain any pharmacokinetic contribution to the observed interaction between TPM and GBP, total brain concentrations of both drugs were determined. The isobolographic analysis of interaction for TPM and GBP, whose DRRCs were not parallel in both MES and chimney tests, was accompanied with a presentation of all required calculations allowing the determination of lower and upper lines of additivity. The isobolographic analysis revealed that TPM combined with GBP at the fixed-ratio combination of 1:1 interacted supraadditively (synergistically) in terms of suppression of MES-induced seizures, and simultaneously, the combination produced additive interaction with respect to motor coordination impairment (adverse effects) in the chimney test. The evaluation of pharmacokinetic characteristics of interaction for the combination of TPM with GBP revealed that neither TPM nor GBP affected their total brain concentrations in experimental animals, and thus, the observed interaction in the MES test was pharmacodynamic in nature. In conclusion, the combination of TPM with GBP, because of supraadditivity in the MES test and additivity in terms of motor coordination impairment in the chimney test as well as lack of pharmacokinetic interactions between drugs, fulfilled the criterion of a favorable combination, worthy of recommendation in further clinical practice.

Topics: Amines; Animals; Anticonvulsants; Behavior, Animal; Brain; Brain Chemistry; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Electroshock; Fructose; Gabapentin; gamma-Aminobutyric Acid; Injections, Intraperitoneal; Male; Mice; Models, Biological; Motor Skills Disorders; Neuroprotective Agents; Regression Analysis; Seizures; Time Factors; Topiramate

Topics: Adult; Anticonvulsants; Drug Overdose; Fructose; Humans; Male; Seizures; Suicide, Attempted; Topiramate; Treatment Outcome

To describe the dose-concentration relationship of a continuous intravenous infusion of valproic acid (VPA) in pediatric patients when a dosing protocol is used.. Retrospective and concurrent chart review.. Tertiary care, 473-bed, academic medical center with a 120-bed, dedicated children's hospital.. Twenty-six pediatric patients (< 18 yrs old) who received VPA according to the protocol for continuous intravenous infusions between January 1, 2004, and March 31, 2006, identified by using a pharmacy order-entry system.. Patient demographics, VPA treatment regimens, clinical responses, and safety data were recorded and analyzed. Median patient age was 8.5 years (range 1.4-16 yrs). Approximately two thirds received VPA for seizures, and one third for migraines. Patients were given a mean +/- SD VPA loading dose of 28.5 +/- 5.2 mg/kg followed by a continuous infusion rate of 1 +/- 0.2 mg/kg/hour. Mean +/- SD serum concentration measured 4.5 +/- 1.6 hours after the loading dose was 83.3 +/- 22.8 microg/ml. Steady-state concentration at 23.3 +/- 3.0 hours after the start of the continuous infusion was 80.0 +/- 26.0 microg/ml. Postload and steady-state serum concentrations were within the target concentration of 50-100 microg/ml in 77% and 69% of patients, respectively. On further analysis, when the target range was expanded to 50-125 microg/ml (125 microg/ml was deemed acceptable if no adverse effects were noted), 89% and 92% of patients, respectively, had postload and steady-state VPA serum concentrations within this range. The response rate was excellent, with nearly 85% of patients achieving a complete or partial response to therapy. Adverse effects were generally mild and uncommon.. The continuous-infusion protocol permitted rapid intravenous loading of VPA in pediatric patients while minimizing adverse events and achieving concentrations in the upper region of the therapeutic range.

Topics: Administration, Oral; Adolescent; Anticonvulsants; Child; Child, Preschool; Drug Therapy, Combination; Drug Utilization Review; Female; Fructose; Hallucinations; Humans; Hyperammonemia; Infusions, Intravenous; Male; Medical Records; Metabolic Clearance Rate; Migraine Disorders; Phenobarbital; Phenytoin; Retrospective Studies; Seizures; Topiramate; Treatment Outcome; Valproic Acid

The changes of electromyographic activity (EMG seizure) induced by maximal electroshock were studied in comparison with those of behavioral seizures in mice. In addition, the effects of certain antiepileptics on behavioral seizures and EMG seizure induced by maximal electroshock were also studied. High amplitude with high frequency EMG seizure was observed in parallel with the appearance of tonic extensor (TE) seizure and an intimate relationship was observed between the two parameters. On the other hand, to investigate the intensity of TE seizure, the product of the amplitude and the duration in EMG seizure was calculated, and the effects of antiepileptics on the magnitude of EMG seizure were investigated. As a result, a significant difference was observed at the doses of antiepileptics that showed no significant effects on the durations of TE and EMG seizures; that is, phenytoin, phenobarbital, topiramate, and carbamazepine showed significant effects on the magnitude of EMG seizure at doses of 5, 2, 10, and 5 mg/kg, respectively. From these findings, it may be concluded that this index, that is, the magnitude of EMG seizure induced by maximal electroshock, is a more reliable and highly sensitive method for the assessment of the potential activity of antiepileptics.

Topics: Administration, Oral; Animals; Anticonvulsants; Behavior, Animal; Carbamazepine; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Electromyography; Electroshock; Ethosuximide; Fructose; Male; Mice; Phenobarbital; Phenytoin; Seizures; Time Factors; Topiramate

In this study, a serial day rapid kindling protocol was used to fully kindle rats in a matter of days. Subsequently, the anticonvulsant profile of a relatively new anti-epileptic drug, topiramate, was evaluated in a cross-over design to further validate this rapid kindling model.. Rats were kindled during three consecutive days, according to the serial day rapid kindling protocol. Topiramate was tested at a dose of 100mg/kg, i.p., over the next 2 days using a cross-over design. The stability of the kindled state was evaluated in all rats during two retest paradigms. During the drug-testing procedure, rats received a single i.p. injection of either topiramate or verhicle. Starting 1 h later the rats received additional kindling stimulations during which their response was measured.. Serial day rapid kindling induced a long lasting and stable fully kindled state that allowed for the anti-epileptic drug screening procedure. Topiramate reduced both the afterdischarge duration and ameliorated seizure semiology in the kindled rats.. Serial day rapid kindling provided a tool to rapidly kindle rats in 3 days. Using a cross-over design, clear indications on anti-epileptic activity of a given drug can be determined using few laboratory animals.

Topics: Animals; Anticonvulsants; Electrodes, Implanted; Electroencephalography; Epilepsy; Fructose; Hippocampus; Kindling, Neurologic; Male; Rats; Rats, Sprague-Dawley; Recurrence; Reproducibility of Results; Seizures; Topiramate

In this cross-sectional study, the neuropsychiatric profiles of 42 patients with juvenile myoclonic epilepsy (JME) who were treated with valproate (VPA) or topiramate (TPM) in monotherapy were compared with the aim of verifying the relationship between cognitive dysfunction, psychiatric disorders, and factors related to epilepsy. Patients with JME taking VPA 500-1750 mg/day or TPM 50-175 mg/day were selected. For all patients, psychiatric profiles were evaluated with the Scheduled Clinical Interview, axes I and II (SCID I and SCID II), or the Brazilian version of the Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS-PL). Neuropsychological measures included intellectual functions, attention, memory, executive functions, and language. Patients taking TPM exhibited worse neuropsychological performance on attention, short-term memory, processing speed, and verbal fluency functions related to frontal lobes, which may be dysfunctional in JME. Anxiety disorders were associated with lack of seizure control and having had more than 20 lifetime generalized tonic-clonic seizures.

Topics: Adolescent; Anticonvulsants; Anxiety Disorders; Cross-Sectional Studies; Depressive Disorder; Female; Fructose; Humans; Male; Mental Disorders; Myoclonic Epilepsy, Juvenile; Neuropsychological Tests; Seizures; Topiramate; Valproic Acid

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.. 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.. 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.. 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.

Topics: Animals; Anticonvulsants; Area Under Curve; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsies, Partial; Fructose; Functional Laterality; gamma-Aminobutyric Acid; Glutamates; Hippocampus; Male; Microdialysis; Microinjections; Pilocarpine; Rats; Rats, Wistar; Seizures; Substantia Nigra; Synaptic Transmission; Topiramate

Topics: Anticonvulsants; Dominance, Cerebral; Female; Fructose; Hallucinations; Humans; Illusions; Middle Aged; Occipital Lobe; Seizures; Topiramate; Treatment Outcome

Topics: Anticonvulsants; Clinical Trials as Topic; Epilepsy; Fructose; Humans; Seizures; Topiramate; Valproic Acid

The study investigated the types of interactions between loreclezole (LCZ) and a variety of newly licensed antiepileptic drugs (AEDs) with different mechanisms of actions [felbamate (FBM), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC)] by isobolographic analysis.. Anticonvulsant and adverse-effect profiles of combinations of LCZ with other AEDs at fixed ratios of 1:3, 1:1, and 3:1 were investigated in the maximal electroshock (MES)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combinations could be established.. With isobolography, it was observed that the combination of LCZ and TPM, at the fixed ratios of 1:1 and 3:1, was supraadditive (synergistic; p < 0.05), whereas LCZ with TPM at the fixed ratio of 1:3 and LCZ combined with LTG, FBM, or OXC at the fixed ratios of 1:3, 1:1, and 3:1 were associated with additive interactions. Moreover, the isobolographic analysis in the chimney test revealed that only one combination tested (LCZ and TPM at the fixed ratio of 1:1) was subadditive (antagonistic; p < 0.05), whereas the remaining combinations of LCZ with LTG, FBM, or OXC (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. However, these combinations were associated with significant pharmacokinetic interactions, in that LCZ increased brain TPM (94%), OXC (21%), FBM (46%), and LTG (8%) concentrations. In addition, brain LCZ concentrations were decreased by TPM (26%), OXC (37%), LTG (42%), and FBM (19%). None of the examined combinations between LCZ and TPM, OXC, LTG, and FBM altered long-term memory in the step-through passive-avoidance task.. LCZ plus TPM appears to be a particularly favorable combination, based on the MES test and the chimney test. LCZ and OXC also is a favorable combination. However, these conclusions are confounded by the fact that LCZ is associated with significant pharmacokinetic interactions.

Topics: Animals; Anticonvulsants; Behavior, Animal; Carbamazepine; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Electroshock; Felbamate; Fructose; Kindling, Neurologic; Lamotrigine; Male; Mice; Motor Activity; Oxcarbazepine; Phenylcarbamates; Propylene Glycols; Seizures; Topiramate; Triazines; Triazoles

Topics: Animals; Anticonvulsants; Brain; Clinical Trials as Topic; Drug Resistance; Electroencephalography; Fructose; GABA Modulators; Humans; Infant, Newborn; Ion Channels; Midazolam; Nerve Degeneration; Seizures; Topiramate; Treatment Failure

Topics: Anticonvulsants; Carbamazepine; Drug Eruptions; Female; Fructose; Humans; Middle Aged; Patch Tests; Risk Factors; Seizures; Topiramate

Cholinergic-dependent plateau potentials (PPs) are intrinsically generated conductances that can elicit ictal-type seizure activity. The aim of this study was to investigate the actions of topiramate (TPM) on the generation of PPs.. We used whole-cell patch-clamp recordings from CA1 pyramidal neurons in rat hippocampal slices to examine the effects of TPM on the PPs.. In current-clamp mode, action potentials evoked PPs after cholinergic receptor stimulation. Therapeutically relevant concentrations of TPM (50 microM) depressed the PPs evoked by action potentials. Surprisingly, in voltage-clamp mode, we discovered that the cyclic nucleotide-gated (CNG) current that underlies PP generation (denoted as I(tail)) was not depressed. However, significantly longer depolarizing voltage steps were required to elicit I(tail). This suggested that the calcium entry trigger for evoking PPs was depressed by TPM and not I(tail) itself. TPM had no effect on calcium spikes in control conditions; however, TPM did reduce calcium spikes after cholinergic-receptor stimulation. We recently found that R-type calcium spikes are enhanced by cholinergic-receptor stimulation. Therefore we isolated R-type calcium spikes with a cocktail containing tetrodotoxin, omega-conotoxin MVIIC, omega-conotoxin-GVIA, omega-agatoxin IVA, and nifedipine. R-type calcium spikes were significantly depressed by TPM. We also examined the effects of TPM on recombinant Ca(V)2.3 calcium channels expressed in tsA-201 cells. TPM depressed currents mediated by Ca(V)2.3 subunits by a hyperpolarizing shift in steady-state inactivation.. We have found that TPM reduces ictal-like activity in CA1 hippocampal neurons through a novel inhibitory action of R-type calcium channels.

Topics: Action Potentials; Animals; Anticonvulsants; Calcium Channel Blockers; Calcium Channels, R-Type; Carbachol; Cells, Cultured; Fructose; Hippocampus; Membrane Potentials; Patch-Clamp Techniques; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Seizures; Topiramate; Transfection

Topiramate, an antiepileptic drug with a number of mechanisms of action including blockade of AMPA/KA receptor subtypes, was assessed as a neuroprotective agent following seizures. We administered topiramate or saline chronically during and following a series of 25 neonatal seizures. After completion of the topiramate treatment, animals were tested in the water maze for spatial learning and the open field for activity level. Brains were then examined for cell loss and sprouting of mossy fibers. Rats treated with topiramate performed significantly better in the water maze than rats treated with saline. Topiramate treatment also reduced the amount of seizure-induced sprouting in the supragranular region. There were no differences between topiramate- and saline-treated rats in activity level in the open field, swimming speed, or weight gain. These findings show that long-term treatment with topiramate after neonatal seizures changes the long-term consequences of seizures and improves cognitive function.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Anticonvulsants; Body Weight; Cognition; Drug Interactions; Exploratory Behavior; Flurothyl; Fructose; Hippocampus; Maze Learning; Motor Activity; Rats; Rats, Sprague-Dawley; Reaction Time; Seizures; Topiramate

To report the case of a patient who experienced adverse events in succession to antiepileptic medications being used for both antiepileptic and mood-stabilization benefit.. A 46-year-old white woman developed hyponatremia with carbamazepine, hyperammonemia with divalproex, cognitive impairment with topiramate, and hyponatremia with oxcarbazepine. The patient was stabilized physically and psychiatrically on levetiracetam without any noted adverse events.. The adverse events in this report have been associated with the medications in question. The patient's presentation is unique, as she developed adverse events in succession to antiepileptic drugs being used to treat both a seizure disorder and symptoms of mood instability. The Naranjo rankings for the reported adverse events indicated the associations were probable (carbamazepine, divalproex, oxcarbazepine) and possible (topiramate). After repeated incidences of intolerability to these drugs, levetiracetam was initiated and provided both seizure control and mood-stabilizing benefits, which eventually led to hospital discharge.. Levetiracetam may provide mood-stabilizing qualities through a mechanism that is unique from that of other antiepileptic agents used for their mood-stabilizing properties. There are potential advantages with levetiracetam, as no specific therapeutic drug monitoring parameters need to be followed after its introduction. Additionally, this case emphasizes the importance of therapeutic drug monitoring and frequent assessments to prevent physical and psychiatric adverse reactions.

Topics: Anticonvulsants; Carbamazepine; Drug Therapy, Combination; Female; Fructose; Humans; Levetiracetam; Middle Aged; Mood Disorders; Oxcarbazepine; Piracetam; Seizures; Topiramate; Treatment Outcome; Valproic Acid

To extend our understanding of the properties of topiramate (TPM), we investigated the effect of TPM on GABAergic transmission in the dentate gyrus of gerbil. TPM treatment (> or = 40 mg/kg) dramatically decreased GABA(B)R2, not GABA(B)R1, immunoreactivity in hilar interneurons. In contrast, TPM treatment increased vesicular GABA transporter immunoreactivity and the paired-pulse inhibition in the dentate gyrus of seizure prone gerbils. Furthermore, TPM effectively prevented the reduction of paired-pulse inhibition induced by baclofen treatment. These findings suggest that TPM may enhance GABA release in the dentate gyrus of gerbils by down-regulation of GABA(B) autoreceptor expression. Therefore, these properties of TPM may be another possible antiepileptic effect, which plays an important role in preventing the spread of seizure activity without proconvulsive effects.

Topics: Animals; Baclofen; Blotting, Western; Dentate Gyrus; Excitatory Postsynaptic Potentials; Fructose; GABA Agonists; Gerbillinae; Immunohistochemistry; Neural Inhibition; Neuroprotective Agents; Receptors, GABA-B; Seizures; Topiramate; Vesicular Inhibitory Amino Acid Transport Proteins

Refractory temporal lobe epilepsy (TCE) shows a unique type of hippocampal damage, referred to as hippocampal sclerosis. The mechanisms underlying drug-refractoriness in TCE are poorly understood, which may be connected with pharmacoresistance to antiepileptic drugs (AEDs). Some studies show that expression of the multidrug resistance gene (mdr1a and mdr1b) and p-glycoprotein encoded by mdr1a and mdr1b are high in the brain, especially in the hippocampus, and the expression may lead to reduction of AEDs concentration in the brain. But most of these studies focused on acute epileptic activity shortly after status epilepticus (SE), spontaneous seizures are seldom studied. The authors used a rat model of kainic acid induced spontaneous seizures to investigate expression of mdr1a and mdr1b mRNA, and explore whether topiramate (TPM) affects expression of mdr1a and mdr1b in the hippocampus.. Seizures were induced by intraperitoneal injection of 10 mg/kg kainic acid at postnatal day 28. Control rats were injected with sodium chloride. All rats were divided into 4 groups 1 week after spontaneous seizures developed: status epilepticus complicated with spontaneous seizures (SE, n = 8) group, status epilepticus complicated with spontaneous seizures treated with TPM (SE + TPM, n = 9) group, spontaneous seizures without status epilepticus (N-SE, n = 7) group, spontaneous seizures without status epilepticus treated with TPM (N-SE + TPM, n = 8) group, control (n = 7) group and control treated with TPM (control + TPM, n = 7) group. The treated rats were given therapeutic dose of TPM (25 mg/kg). All the rats were killed on the 42nd day of administration. The mdr1a and mdr1b mRNAs in the hippocampus were measured by RT-PCR.. Expression of mdr1a and mdr1b mRNA in the hippocampus increased significantly in the SE + TPM group, SE group and N-SE + TPM group compared with control group (P < 0.001 or < 0.05). The mRNA in SE + TPM group increased significantly compared with the SE group, too (P < 0.01). The mdr1a and mdr1b mRNA expression in the hippocampus in control + TPM and N-SE groups did not change.. Frequent seizures, especially status epilepticus resulted in overexpression of mdr1a and mdr1b mRNAs in the hippocampus. The drug-refractoriness mechanism in TCE may be related to overexpression of mdr1a and mdr1b mRNAs. TPM could enhance the expression of mdr1a and mdr1b mRNAs in the hippocampus. Seizure activity and TPM are likely to be the main determinant in enhancing mdr1a and mdr1b mRNA expression in epilepsy.

Topics: Animals; Anticonvulsants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Fructose; Hippocampus; Kainic Acid; Rats; RNA, Messenger; Seizures; Status Epilepticus; Topiramate

Topics: Acidosis, Renal Tubular; Adult; Anticonvulsants; Female; Fructose; Humans; Seizures; Topiramate

Topics: Administration, Oral; Adolescent; Anticonvulsants; Benzodiazepines; Capsules; Carbamazepine; Clobazam; Drug Administration Schedule; Drug Hypersensitivity; Drug Therapy, Combination; Epilepsia Partialis Continua; Exanthema; Excipients; Forecasting; Fructose; Hospitalization; Humans; Male; Seizures; Tablets; Time Factors; Topiramate; Valproic Acid

Topiramate, a novel anticonvulsant drug, has CNS depressant activity including enhancement of GABAergic inhibitory synaptic transmission. Drugs of this pharmacological spectrum might have utility in assuaging drug addiction. This study analyzes the ability of TPM to reduce withdrawal signs in the kindling model of ethanol dependence: chronic intermittent ethanol (CIE) rats. After CIE, persistent withdrawal signs are shown by an increased seizure susceptibility to the convulsant drug pentylenetetrazol and increased anxiety measured on the elevated plus-maze. Topiramate increased significantly the PTZ seizure threshold in CIE but not in control rats. On the elevated plus-maze, Topiramate was markedly more effective in CIE rats than in controls. Topiramate may have a therapeutic efficacy in treating alcohol withdrawal symptoms.

Topics: Animals; Ethanol; Fructose; Male; Rats; Rats, Sprague-Dawley; Seizures; Substance Withdrawal Syndrome; Topiramate

Although the mechanism of action of topiramate is not fully understood, its anticonvulsant properties may result, at least in part, from an interaction with AMPA/kainate receptors. We have recently shown that topiramate selectively inhibits postsynaptic responses mediated by GluR5 kainate receptors. To determine if this action of topiramate is relevant to the anticonvulsant effects of the drug in vivo, we determined the protective activity of topiramate against seizures induced by intravenous infusion of various ionotropic glutamate receptor agonists in mice. Topiramate (25-100 mg/kg, i.p.) produced a dose-dependent elevation in the threshold for clonic seizures induced by infusion of ATPA, a selective agonist of GluR5 kainate receptors. Topiramate was less effective in protecting against clonic seizures induced by kainate, a mixed agonist of AMPA and kainate receptors. Topiramate did not affect clonic seizures induced by AMPA or NMDA. In contrast, the thresholds for tonic seizures induced by higher doses of these various glutamate receptor agonists were all elevated by topiramate. Unlike topiramate, carbamazepine elevated the threshold for AMPA- but not ATPA-induced clonic seizures. Our results are consistent with the possibility that the effects of topiramate on clonic seizure activity are due to functional blockade of GluR5 kainate receptors. Protection from tonic seizures may be mediated by other actions of the drug. Together with our in vitro cellular electrophysiological results, the present observations strongly support a unique mechanism of action of topiramate, which involves GluR5 kainate receptors.

Topics: Animals; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Fructose; In Vitro Techniques; Kainic Acid; Male; Mice; N-Methylaspartate; Receptors, Kainic Acid; Seizures; Topiramate

To evaluate the efficacy of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f) quinoxaline-2,3-dione) and topiramate (TPM) given after hypoxia-induced seizures in preventing the delayed effect of hypoxia on subsequent susceptibility to seizures and neuronal injury.. We used "two-hit" rodent seizure model to study the long-term effect of perinatal hypoxia on later kainate (KA) seizure-induced neuronal damage and investigated the therapeutic efficacy of a postseizure treatment protocol in reversing the conditioning effect of early-life seizures.. Hypoxia at P10 induces seizures without cell death but causes an increase in susceptibility to second seizures induced by KA as early as 96 h after hypoxia, and this lowered seizure threshold persists to adulthood. Furthermore, perinatal hypoxia increases KA-induced neuronal injury at postnatal day (P)21 and 28/30. Repeated doses of NBQX (20 mg/kg) or TPM (30 mg/kg) given for 48 h after hypoxia-induced seizures prevent the increase in susceptibility to KA seizure-induced hippocampal neuronal injury at P28/30.. Our results suggest that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor blockade after hypoxia prevents the priming effect of perinatal hypoxia-induced seizures and that this protection occurs independent of its anticonvulsant action.

Topics: Animals; Anticonvulsants; Brain; Cell Death; Disease Models, Animal; DNA Fragmentation; Fructose; Hippocampus; Hypoxia, Brain; In Situ Nick-End Labeling; Kainic Acid; Male; Neurons; Neuroprotective Agents; Quinoxalines; Rats; Rats, Long-Evans; Receptors, AMPA; Seizures; Topiramate

There is emerging evidence to support the efficacy of some antiepileptic drug (AED) combinations in refractory epilepsy. Definitive clinical studies are, however, difficult to perform. Experimental seizure models can be employed to identify potentially useful combinations for subsequent clinical evaluation. We have investigated the anticonvulsant effects of topiramate (TPM) in combination with 13 other AEDs in the pentylenetetrazol (PTZ) and maximal electroshock (MES) seizure models. Single drugs and combinations were administered by intraperitoneal injection and anticonvulsant effects determined at 1-hour post-dosing. TPM was without significant effect in the PTZ test. In contrast, phenobarbital, primidone, ethosuximide, sodium valproate, felbamate and tiagabine all increased the latency to the first generalised seizure. Combinations of TPM and active adjunctive drug were universally effective. Combinations of TPM with clobazam, lamotrigine and levetiracetam were also anticonvulsant, despite the inactivity of the constituent compounds when administered alone. TPM reduced the incidence of MES-induced seizures in a dose-dependent manner, as did phenobarbital, phenytoin, primidone, carbamazepine, sodium valproate, clobazam, lamotrigine, felbamate and tiagabine. All combination treatments were similarly effective. These findings suggest that combinations of TPM with lamotrigine and levetiracetam may demonstrate anticonvulsant synergism and merit further investigation in additional model systems and with recourse to more quantitative mathematical analysis.

Topics: Analysis of Variance; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Electroshock; Fructose; Male; Mice; Mice, Inbred Strains; Pentylenetetrazole; Reaction Time; Seizures; Topiramate

The need for an efficacious treatment of patients with intractable seizures is urgent and pressing, because approximately 30% of epilepsy patients worldwide are still inadequately medicated with current frontline antiepileptic drugs (AEDs). This study sought to determine the interactions among some newer AEDs [topiramate (TPM), felbamate (FBM), oxcarbazepine (OXC), and lamotrigine (LTG)] in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in mice, by using the isobolographic analysis.. Evaluation of the anticonvulsant and acute adverse (neurotoxic) effects in mice produced by the AEDs in combinations at the fixed ratios of 1:3, 1:1, and 3:1 allowed the assessment of their preclinical profile and the determination of benefit indices (BIs) for all individual combinations.. Combinations of TPM+FBM at the fixed ratios of 1:3, 1:1, and 3:1 offered supraadditive (synergistic) interactions against electroconvulsions and subadditivity (antagonism) in terms of acute neurotoxic effects in the chimney test (BIs ranged between 1.90 and 2.59, the best combinations from a preclinical point of view). The examined combinations of TPM+OXC also were advantageous due to synergistic interactions in the MES, and additivity in terms of acute neurotoxic effects produced by the AEDs (BIs ranged between 1.35 and 1.71). In contrast, OXC+FBM exerted subadditive (antagonistic) interactions in the MES test and additive interactions in terms of acute motor impairment of animals (BIs ranged between 0.53 and 0.71). The worst combination was observed for OXC+LTG, at the fixed ratio of 1:1, displaying subadditivity (antagonism) against electroconvulsions and supraadditivity (synergy) with respect to neurotoxicity (BIs, 0.43). The remaining combinations of OXC+LTG tested (i.e., 1:3 and 3:1) exerted additivity in the MES test and supraadditivity in the chimney test (BIs 0.54 and 0.49, respectively). None of the studied AEDs affected the brain concentrations of other AEDs, so the existence of any pharmacokinetic interactions to be responsible for the observed effects is improbable.. Based on the current preclinical data, the pharmacological profile of combinations of TPM+FBM and TPM+OXC evaluated with isobolography was beneficial and might be worth recommendation to further clinical practice. In contrast, utmost caution is required during the use of OXC+FBM or OXC+LTG in clinical practice, because of the high risk of neurotoxic adverse effect appearance.

Topics: Animals; Anticonvulsants; Carbamazepine; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Interactions; Drug Therapy, Combination; Electroshock; Epilepsy; Felbamate; Fructose; Humans; Lamotrigine; Lethal Dose 50; Male; Mice; Neurotoxicity Syndromes; Oxcarbazepine; Phenylcarbamates; Propylene Glycols; Seizures; Topiramate; Triazines

Levetiracetam (LEV) is a new antiepileptic drug with efficacy in partial-onset seizures. We report a case in which generalized-onset absence seizures responded clinically and electrographically to LEV.. We evaluated with continuous video/electroencephalography an adult with generalized-onset seizures given 3 antiepileptic drugs, 1 of which was LEV. Levetiracetam initiation 2 months before admission decreased patient-reported seizures. Interictal electroencephalography revealed generalized 3.5-Hz spike-wave and polyspike-wave discharges. Spike-wave bursts lasting 2 seconds or longer caused a pause in continuous reading aloud, consistent with clinical absence seizures. Levetiracetam was discontinued on admission, lamotrigine was gradually discontinued across 2 days, and topiramate was not changed. One encephalographer counted from video/electroencephalography recordings the number of spike-wave bursts in 1-hour time samples that included wake and sleep time.. Spike-wave bursts increased from 4 to 56 per hour at baseline (4000 mg of LEV per day) to 406 to 914 per hour less than 48 hours after LEV discontinuation. Levetiracetam treatment was restarted, and 3 hours after the first dose of 1000 mg, spike-wave bursts dropped to 135 per hour. Response was sustained during the next 2 days.. This case showed a dramatic, rapid effect of LEV discontinuation and reinstitution on generalized spike-wave burst frequency and clinical absence. The effects were independent of reduction of lamotrigine and without change in topiramate doses and occurred in a time course consistent with LEV pharmacokinetics. Levetiracetam may be effective in generalized-onset epilepsy, and randomized, controlled trials are indicated.

Topics: Adult; Anticonvulsants; Delta Rhythm; Dose-Response Relationship, Drug; Drug Administration Schedule; Electroencephalography; Female; Fructose; Humans; Lamotrigine; Levetiracetam; Piracetam; Retrospective Studies; Seizures; Topiramate; Triazines

Subacute sclerosing panencephalitis can show variations in clinical course, and some ophthalmologic abnormalities can be seen as cortical blindness and optic atrophy. A 4-year-old girl was referred to our hospital with a complaint of diplopia, vomiting, and ataxia. On physical examination, she was found to have stage IV papilledema with retinal hemorrhage. She was diagnosed as having idiopathic intracranial high pressure until magnetic resonance imaging demonstrated T2-weighted hyperintense lesions. After observation of head drop attacks and detection of elevated antimeasles antibodies in cerebrospinal fluid, the diagnosis of subacute sclerosing panencephalitis was established, and isoprinosine and carbamazepine were started for treatment. However, because carbamazepine failed to control the head drop attacks, topiramate was also included, and the attacks were kept under control with topiramate. The case presented in this article is a good example of subacute sclerosing panencephalitis in which, at early stages, some of the signs and symptoms can lead to an erroneous diagnosis. In addition, we have demonstrated that topiramate might be a good choice for treatment for the persistent myoclonus seen in this type of patient.

Topics: Anticonvulsants; Brain; Carbamazepine; Child, Preschool; Diplopia; Female; Fructose; Humans; Intracranial Pressure; Magnetic Resonance Imaging; Papilledema; Seizures; Subacute Sclerosing Panencephalitis; Topiramate; Vomiting

Rett syndrome, a neurodevelopmental disorder, manifests in the first few years of life with developmental arrest, stereotyped behaviors, and respiratory abnormalities. Seizures occur in 70 to 80% of patients. Clinical drug trials have not demonstrated the superiority of any specific antiepilepsy drug. We report our experience with topiramate in eight patients with Rett syndrome. Topiramate was initiated as monotherapy in two patients and as adjunctive therapy in six patients. Seven patients had improved seizure control. Respiratory abnormalities improved by 50 to 75% in two patients and by 20 to 50% in two others. In our cohort, seven of eight patients showed improvement in seizure control and/or respiratory abnormalities on topiramate. Topiramate was well tolerated. The effect of topiramate, a broad-spectrum drug, could be due to its gamma-aminobutyric acid (GABA)ergic and glutaminergic effects, both systems thought to be disordered in Rett syndrome.

Topics: Adolescent; Adult; Anticonvulsants; Child; Child, Preschool; Fructose; Humans; Respiration Disorders; Retrospective Studies; Rett Syndrome; Seizures; Topiramate; Weight Loss

We report two children with localization related epilepsies, who presented with somnolence, seizure exacerbation, behavioral alteration, decline in speech and cognitive abilities, and ataxia while being treated with a combination of valproate and topiramate, but had previously tolerated valproate with other antiepileptic drugs. These children had elevated serum ammonia, normal transaminase levels, and generalized slowing of EEG background activity during encephalopathy, which promptly reverted back to normal along with clinical improvement following withdrawal of valproate. To our knowledge, this is the first documentation of valproate-induced hyperammonemic encephalopathy enhanced by topiramate from India. We intend to alert internists, pediatricians, psychiatrists and neurologists about this underrecognized adverse effect of antiepileptic drug polytherapy.

Topics: Ammonia; Anticonvulsants; Child; Child, Preschool; Drug Therapy, Combination; Female; Fructose; Humans; Hyperammonemia; Male; Neurotoxicity Syndromes; Seizures; Topiramate; Valproic Acid

Topics: Adult; Anticonvulsants; Choroid; Ciliary Body; Female; Fructose; Glaucoma, Angle-Closure; Humans; Middle Aged; Myopia; Seizures; Topiramate; Ultrasonography; Uvea; Uveal Diseases

The objective of this study was to evaluate the interaction of the novel antiepileptic drug (AED), topiramate (TPM), with conventional AEDs against amygdala-kindled seizures in rats and pentylenetetrazol-induced convulsions in mice.. Experiments were performed on mice and fully kindled rats. In pentylenetetrazol test, the chemoconvulsant was used at its CD97 dose of 105 mg/kg, producing clonic seizures in 97% of mice. Adverse effects were evaluated with the chimney test and passive avoidance task. Plasma levels of AEDs were measured with immunofluorescence.. TPM at 20 mg/kg exerted a significant anticonvulsant effect as regards seizure and afterdischarge durations in amygdala-kindled seizures in rats, being ineffective at lower doses. Coadministration of TPM (10 mg/kg) with valproate (VPA; at a subtherapeutic dose of 50 mg/kg) resulted in essential reductions of seizure and afterdischarge durations. TPM (10 mg/kg) combined with carbamazepine (CBZ; at a subtherapeutic dose of 15 mg/kg) significantly increased afterdischarge threshold, simultaneously decreasing the remaining seizure parameters (duration or severity of seizures and afterdischarge duration). TPM (10 mg/kg) given with phenobarbital (PB; 15 mg/kg) markedly shortened seizure severity and seizure and afterdischarge durations. Combinations of TPM with diphenylhydantoin (PHT) were ineffective against kindled seizures in rats. TPM combined with VPA and PB did not alter their plasma levels, but its combination with CBZ resulted in an increased free plasma CBZ concentration. TPM (10 and 20 mg/kg) alone and its combinations with conventional AEDs affected neither motor coordination nor long-term memory, evaluated in the chimney and passive avoidance tests, respectively, in rats. In pentylenetetrazol-evoked convulsions in mice, TPM (175 and 200 mg/kg) showed anticonvulsant effects per se. Moreover, TPM (at its subtherapeutic dose of 150 mg/kg), significantly potentiated the anticonvulsant action of ethosuximide (ESM), but not that of VPA, PB, or clonazepam (CZP) against pentylenetetrazol-induced seizures. Either TPM alone (150 mg/kg) or its combination with ESM did not result in significant undesired effects.. The experimental data indicate that except for PHT, the combinations of TPM with conventional AEDs are beneficial against amygdala-kindled seizures in rats. In the pentylenetetrazol test, this novel AED potentiated only the protection offered by ESM.

Topics: Amygdala; Animals; Anticonvulsants; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Electroencephalography; Epilepsies, Myoclonic; Epilepsy, Complex Partial; Fructose; Kindling, Neurologic; Male; Mice; Pentylenetetrazole; Rats; Seizures; Topiramate

In a prospective open label add-on study on 95 patients (age 1-63 years, mean 17.76 +/- 13.83 years) with seizures refractory to conventional antiepileptic drugs (AEDs) and other new AEDs, the addition of Topiramate (TPM) resulted in seizure worsening in 18 patients (19%) necessitating drug withdrawal over an average follow-up period of 4.94 +/- 1.69 months. Patients who had seizure worsening were older (P = 0.02), were more likely to have had a history of status epilepticus in the past (P = 0.03), were on three conventional AEDs (P = 0.027) or had tried one of the other new AEDs in the past with poor response (P = 0.04). Seven of 18 patients who had seizure worsening with TPM (7.4%) experienced initial seizure worsening, probably representing the subgroup with 'true' seizure worsening whilst 11 (11.6%) had initial improvement followed by 'apparent' seizure worsening. Initial seizure worsening was noted to be significantly more in females when compared with males who worsened after initial improvement (P = 0.05).

Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; India; Infant; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Seizures; Statistics, Nonparametric; Topiramate

A 39-year-old, right-handed woman had seizures for two years which were always triggered by exposure to various types of music: the first occurred while she listened to a tune she particularly liked, Con Te Partiro, by Andrea Boccelli. Other triggering factors were various types of music such as supermarket background music and polyphonic singing or instrumental music played by family members. The seizures had a stereotyped course: she felt anxious, tearful, then occurred slight obtundation, during which she smacked her lips and moved restlessly. There was no complete loss of consciousness, but some degree of amnesia. She never experienced a generalized tonic-clonic seizure, but reported rare spontaneous feelings of déjà-vu that had begun at the same time as the induced seizures. There were no other spontaneous attacks; only one seizure was apparently provoked, not by music but by a loud background noise in her office. She was a music lover and a singer. Interictal EEG showed independent slow waves over the temporal regions. Several seizures with EEG localisation over the right temporal region were elicited after several minutes of exposure to music. Monoauricular stimulation with the same music produced a seizure when applied to the left ear but was ineffective when applied to the right ear. Ictal SPECT demonstrated right temporal hyperperfusion. MRI was normal. On high dose of carbamazepine, seizure frequency decreased. The addition of topiramate resulted in full seizure control. Musicogenic epilepsy is a rare form of reflex epilepsy. Pure cases, when patients do not experience unprovoked seizures, are exceptional. Our report confirms the implication of the right temporal lobe in this epilepsy.

Topics: Adult; Anticonvulsants; Carbamazepine; Drug Resistance; Electroencephalography; Epilepsy, Reflex; Female; Fructose; Humans; Music; Seizures; Temporal Lobe; Tomography, Emission-Computed, Single-Photon; Topiramate

A series of aromatic/heterocyclic sulfonamides incorporating valproyl moieties were prepared to design antiepileptic compounds possessing in their structure two moieties known to induce such a pharmacological activity: valproic acid, one of the most widely used antiepileptic drugs, and the sulfonamide residue included in acetazolamide and topiramate, two carbonic anhydrase inhibitors with antiepileptic properties. Some of these derivatives showed very high inhibitory potency against three carbonic anhydrase (CA) isozymes, such as CA I, CA II, and CA IV, involved in important physiological processes. Topiramate, a recently developed antiepileptic drug possessing a sulfamate moiety, also shares this property, although earlier literature data reported this compound to be a weak-moderate CA I, II, and IV inhibitor. The valproyl derivative of acetazolamide (5-valproylamido-1,3,4-thiadiazole-2-sulfonamide, 6M) was one of the best hCA I and hCA II inhibitor in the series and exhibited very strong anticonvulsant properties in an MES test in mice. In consequence, other 1,3,4-thiadiazolesulfonamide derivatives possessing potent CA inhibitory properties and substituted with different alkyl/arylcarboxamido/sulfonamido/ureido moieties in the 5 position have been investigated for their anticonvulsant effects in the same animal model. It was observed that some lipophilic derivatives, such as 5-benzoylamido-, 5-toluenesulfonylamido-, 5-adamantylcarboxamido-, and 5-pivaloylamido-1,3,4-thiadiazole-2-sulfonamide, show promising in vivo anticonvulsant properties and that these compounds may be considered as interesting leads for developing anticonvulsant or selective cerebrovasodilator drugs.

Topics: Acetazolamide; Animals; Anticonvulsants; Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Carbonic Anhydrase IV; Electroshock; Fructose; Humans; Male; Mice; Models, Molecular; Seizures; Structure-Activity Relationship; Sulfonamides; Topiramate

To characterize weight changes in patients with neurodevelopmental disabilities who received topiramate.. Retrospective, observational study.. State-supported developmental center.. Fifteen patients with neurodevelopmental disabilities who received topiramate therapy. Monthly weights for 1 year after the start of topiramate therapy were recorded. Mean body weight at drug initiation differed significantly compared with the nadir weight during the next 12 months (52.2+/-7.5 vs 49.9+/-7.2 kg, p<0.02). Twelve patients who were receiving ad libitum oral diets demonstrated a significant decrease in body weight (52.1+/-7.5 vs 49.0+/-7.3 kg, p<0.01), whereas the three patients who received enteral nutrition through enterostomy did not experience significant weight loss.. Weight loss is common in patients with neurodevelopmental disabilities who receive topiramate. Since patients who received oral diets lost weight whereas those receiving enteral nutrition did not, decreased nutrient intake is the likely cause of weight loss.

Topics: Adult; Enteral Nutrition; Female; Fructose; Humans; Male; Middle Aged; Nervous System Diseases; Retrospective Studies; Seizures; Statistics, Nonparametric; Topiramate; Weight Loss

The alpha2-adrenergic agonist clonidine is the mainly used drug for the opiate withdrawal. Its efficacy and tolerance in treating withdrawal symptoms is, however, suboptimal. The pharmacological profile of topiramate suggests it could be rather valuable for opiate withdrawal, as there is some evidence that topiramate acts, among others, through inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, which play an important role in the withdrawal-induced activation of the locus coeruleus (LC) by glutamate. Three patients undergoing an inpatient opiate detoxification program were treated with topiramate, which achieved a nearly complete control of withdrawal symptoms.

Topics: Adrenergic alpha-Agonists; Adult; Anticonvulsants; Clonidine; Female; Fructose; Heroin Dependence; Humans; Liver Function Tests; Male; Opioid-Related Disorders; Seizures; Substance Withdrawal Syndrome; Topiramate

Topics: Adolescent; Adult; Anticonvulsants; Child; Child, Preschool; Drug Approval; Fructose; Humans; Seizures; Syndrome; Topiramate; United States; United States Food and Drug Administration

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Epilepsy, Tonic-Clonic; Female; Fructose; Humans; Schizophrenia, Paranoid; Seizures; Topiramate; Treatment Outcome

Neonatal seizures caused by hypoxia can be refractory to conventional anticonvulsants. Currently, there is no effective postnatal intervention for newborn infants with hypoxic encephalopathy to prevent brain injury and long-term neurologic sequelae. We previously developed a rat model of perinatal hypoxia-induced seizures with subsequent long-term increases in seizure susceptibility and showed that these epileptogenic effects are selectively blocked by the alpha-amino-3-hydoxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione. Using this model of perinatal seizures, we evaluated the efficacy of topiramate, a structurally novel anticonvulsant drug recently shown to attenuate AMPA/kainate currents. Topiramate effectively suppressed acute seizures induced by perinatal hypoxia in a dose-related manner with a calculated ED50 of 2.1 mg/kg, i.p. Furthermore, in animals that had seizures suppressed by topiramate during acute hypoxia, there were no long-term increases in susceptibility to kainate-induced seizures and seizure-induced neuronal injury. Our results suggest that topiramate may have clinical potential as a therapeutic agent for refractory seizures in human neonates.

Topics: Animals; Animals, Suckling; Anticonvulsants; Convulsants; Disease Models, Animal; DNA Fragmentation; Dose-Response Relationship, Drug; Fructose; Hippocampus; Hypoxia, Brain; Kainic Acid; Male; Rats; Rats, Long-Evans; Receptors, AMPA; Seizures; Topiramate

We measured the intrinsic optical signals (IOSs) generated by rat hippocampus-entorhinal cortex (EC) slices in response to single shock electrical stimuli delivered in the EC deep layers during application of the convulsant drug 4-aminopyridine (50 microM). With field potential recordings the stimulus-induced responses had duration = 35 +/- 6.3 s mean +/- SEM, n = 7 slices) and characteristics resembling electrographic seizures. IOS changes reflecting an increase in light transmittance occurred in the EC and hippocampus following similar stimuli (n = 45). IOSs increased progressively to reach peak values 20-30 s after the stimulus and returned slowly to prestimulus values within 100 s, thus outlasting the field potential discharge. IOS changes initiated in the medial EC, near to the stimulation site, and spread to the lateral EC, the dentate, and the CA3/CA1 areas. IOS spread from EC to hippocampus was not seen after perforant path cut (n = 5). Moreover, field potential and IOS responses were markedly decreased by excitatory amino acid receptor antagonists (n = 12). The antiepileptic drugs topiramate (10-100 microM, n = 16) or lamotrigine (100-400 microM, n = 12) reduced the IOS changes in the EC and their spread to distant areas. These effects were reversible and dose-dependent (IC50 = 48 microM and 210 microM for topiramate and lamotrigine, respectively). Thus, in 4AP-treated hippocampus-EC slices, IOS changes accompany and outlast the field potential epileptiform responses, depend on glutamatergic transmission and are characterized by temporal and spatial distributions consistent with propagation through established anatomical pathways. We also propose that IOSs may represent a reliable tool for screening the effects of neuroactive compounds such as antiepileptic drugs.

Topics: 4-Aminopyridine; Action Potentials; Animals; Anticonvulsants; Axotomy; Electric Stimulation; Electroencephalography; Electrophysiology; Entorhinal Cortex; Epilepsy, Temporal Lobe; Excitatory Amino Acid Antagonists; Fructose; GABA Antagonists; Hippocampus; Lamotrigine; Neurons; Optics and Photonics; Organ Culture Techniques; Perforant Pathway; Potassium Channel Blockers; Rats; Rats, Wistar; Reaction Time; Seizures; Signal Processing, Computer-Assisted; Synaptic Transmission; Topiramate; Triazines

Mental status changes and metabolic acidosis may occur with topiramate therapy. These adverse events were reported during dosage titration and with high dosages of the drug. A 20-year-old man receiving topiramate, valproic acid, and phenytoin experienced acute-onset mental status changes with hyperchloremic metabolic acidosis. He had been receiving a modest dose of topiramate for 9 months. He was weaned off topiramate over 5 days, and his mental status returned to baseline within 48 hours of discontinuing the agent. This case illustrates the need for close evaluation of patients who experience acute-onset mental status changes during topiramate therapy.

Topics: Acidosis; Acute Disease; Adult; Anticonvulsants; Chlorides; Confusion; Fructose; Humans; Male; Seizures; Topiramate

Topiramate (1-50 mg/kg, intraperitoneally (i.p.)) was able to antagonize audiogenic seizures in DBA/2 mice in a dose-dependent manner. Topiramate at dose of 2.5 mg/kg i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The degree of potentiation induced by topiramate was greatest for diazepam, phenobarbital and valproate, less for lamotrigine and phenytoin and not significant for carbamazepine and felbamate. The increase in anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of the combination of all drugs+topiramate was more favourable than that of antiepileptics+ saline, with the exception of carbamazepine or felbamate+topiramate. Since topiramate did not significantly influence the total and free plasma levels of the anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that topiramate can modify the clearance from the brain of the anticonvulsant drugs studied cannot be excluded. In addition, topiramate did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, topiramate showed an additive effect when administered in combination with some classical anticonvulsants, most notably diazepam, phenobarbital, lamotrigine, phenytoin and valproate.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Body Temperature; Dose-Response Relationship, Drug; Drug Synergism; Female; Fructose; Male; Mice; Mice, Inbred DBA; Motor Activity; Postural Balance; Seizures; Topiramate

These studies further investigate the ability of topiramate (TPM) to enhance gamma-aminobutyric acid (GABA)-mediated inhibition through a benzodiazepine-insensitive pathway.. Topiramate (30 and 100 microM) enhancement of GABA (1 microM)-evoked currents in primary cultures of mouse cortical neurons was studied by using whole-cell electrophysiologic techniques. Results obtained with TPM (30 microM) were compared with those obtained with clonazepam (CZP; 1 microM).. Topiramate enhanced GABA currents in a subset of cortical neurons tested. In addition, TPM enhanced GABA-evoked currents in CZP-insensitive neurons, and CZP was effective in a subset of TPM-insensitive neurons. Related studies in vivo demonstrated that intraperitoneal (i.p.) administration of either TPM (25 mg/kg) or CZP (0.012 mg/kg) increases pentylenetetrazol (PTZ) seizure threshold. This effect of CZP, but not TPM, was reversed by the benzodiazepine (BZD) antagonist flumazenil (FMZ; 40 mg/kg, i.p.).. These results indicate that GABA(A)-receptor sensitivity to TPM is not dependent on the presence of BZD sensitivity. Enhancement of GABA-mediated inhibition through a BZD-insensitive pathway may represent one mechanism through which TPM exerts its anticonvulsant action.

Topics: Action Potentials; Animals; Anticonvulsants; Cells, Cultured; Cerebral Cortex; Clonazepam; Evoked Potentials; Flumazenil; Fructose; GABA Antagonists; GABA Modulators; gamma-Aminobutyric Acid; Mice; Neurons; Patch-Clamp Techniques; Pentylenetetrazole; Receptors, GABA; Seizures; Topiramate

Topiramate is a relatively new antiepileptic drug with several putative anticonvulsant mechanisms. Among them is the ability to inhibit carbonic anhydrase, a property in common with the anticonvulsant acetazolamide. This study examined the effects of topiramate and acetazolamide on the duration of epileptiform activity and on paired-pulse inhibition in the dentate gyrus in urethane anesthetized adult Sprague-Dawley rats. Neither topiramate nor acetazolamide altered excitability in the dentate gyrus, as measured with input-output curves or induction of long-term potentiation. Topiramate increased paired-pulse inhibition, whereas acetazolamide had no effect. Both drugs dose-dependently blocked the lengthening of the duration of epileptiform activity compared to vehicle controls. These results indicate that topiramate has an anticonvulsant-related effect (increase in paired-pulse inhibition), which may contribute to its antiepileptic effect, that is not dependent on its ability to inhibit carbonic anhydrase.

Topics: Acetazolamide; Animals; Anticonvulsants; Dentate Gyrus; Drug Evaluation, Preclinical; Fructose; Long-Term Potentiation; Male; Rats; Rats, Sprague-Dawley; Seizures; Topiramate

The antiepileptic efficacy of topiramate (TPM) has been demonstrated in both whole animal seizure models and clinical trials; however, there is no consensus concerning its mechanism of action. We determined first whether the antiepileptic effect of TPM generalized to in vitro seizure models. Epileptiform discharges, recorded extracellularly, were evoked by repeated tetanic stimulation of Schaffer collaterals and layer III association fibers in entorhinal cortex/hippocampus and piriform cortex slices, respectively. TPM was applied at concentrations of 20 or 100 microM. Whole cell recordings were made from CA1 pyramidal neurons and the effect of TPM was assessed on a variety of intrinsic membrane properties including resting membrane potential, input resistance and postspike potentials. TPM (20 microM) was without effect in entorhinal cortex/hippocampus (N=6); however, 100 microM TPM decreased significantly the Coastline Burst Index from 358.3+/-65.8 to 225. 5+/-77.1 (N=4), the frequency of spontaneous epileptiform discharges to 44.6+/-21.8 (N=5) and the duration of primary afterdischarge (PAD) to 65.9+/-10.1 (N=10) percent of control. In contrast, phenytoin (50 microM, N=7; 100 microM, N=8) reduced PAD to 96.9+/-14. 8 and 86.5+/-17.3 percent of control, respectively. TPM (100 microM) did not reduce significantly the frequency of spontaneous discharges in piriform cortex (85.4+/-12.3 percent of control; N=5). TPM (100 microM) was without significant effect on intrinsic membrane properties in CA1 pyramidal neurons. Likely candidate mechanisms underlying the antiepileptic effect produced by TPM include enhancement of chloride-mediated GABA(A) currents and reduction of kainate and L-type calcium currents.

Topics: Action Potentials; Animals; Anticonvulsants; Cerebral Cortex; Dose-Response Relationship, Drug; Electric Stimulation; Entorhinal Cortex; Fructose; Hippocampus; In Vitro Techniques; Nerve Fibers; Neurons; Olfactory Pathways; Patch-Clamp Techniques; Rats; Rats, Wistar; Seizures; Topiramate

Topics: Adolescent; Ammonia; Anticonvulsants; Drug Therapy, Combination; Electroencephalography; Female; Fructose; Humans; Neurotoxicity Syndromes; Receptors, GABA-A; Seizures; Topiramate; Valproic Acid

We have explored the structure-activity relationship (SAR) surrounding the clinically efficacious antiepileptic drug topiramate (1), a unique sugar sulfamate anticonvulsant that was discovered in our laboratories. Systematic structural modification of the parent compound was directed to identifying potent anticonvulsants with a long duration of action and a favorable neurotoxicity index. In this context, we have probed the pharmacological importance of several molecular features: (1) the sulfamate group (6-8, 22-25, 27, 84), (2) the linker between the sulfamate group and the pyran ring (9, 10, 21a,b), (3) the substituents on the 2,3- (58-60, 85, 86) and 4, 5-fused (30-38, 43, 45-47, 52, 53) 1,3-dioxolane rings, (4) the constitution of the 4,5-fused 1,3-dioxolane ring (2, 54, 55, 63-68, 76, 77, 80, 83a-r, 84-87, 90a, 91a, 93a), (5) the ring oxygen atoms (95, 96, 100-102, 104, 105), and (6) the absolute stereochemistry (106 and 107). We established the C1 configuration as R for the predominant alcohol diastereomer from the highly selective addition of methylmagnesium bromide to aldehyde 15 (16:1 ratio) by single-crystal X-ray analysis of the major diastereomer of sulfamate 21a. Details for the stereoselective syntheses of the hydrindane carbocyclic analogues 95, 96, 100, and 104 are presented. We also report the synthesis of cyclic imidosulfites 90a and 93a, and imidosulfate 91a, which are rare examples in the class of such five-membered-ring sulfur species. Imidosulfite 93a required the preparation and use of the novel sulfur dichloride reagent, BocN=SCl2. Our SAR investigation led to the impressive 4,5-cyclic sulfate analogue 2 (RWJ-37947), which exhibits potent anticonvulsant activity in the maximal electroshock seizure (MES) test (ca. 8 times greater than 1 in mice at 4 h, ED50 = 6.3 mg/kg; ca. 15 times greater than 1 in rats at 8 h, ED50 = 1.0 mg/kg) with a long duration of action (>24 h in mice and rats, po) and very low neurotoxicity (TD50 value of >1000 mg/kg at 2 h, po in mice). Cyclic sulfate 2, like topiramate and phenytoin, did not interfere with seizures induced by pentylenetetrazole, bicucculine, picrotoxin, and strychnine; also, 2 was not active in diverse in vitro receptor binding and uptake assays. However, 2 turned out to be a potent inhibitor of carbonic anhydrase from different rat tissue sources (e. g., IC50 of 84 nM for the blood enzyme and 21 nM for the brain enzyme). An examination of several analogues of 2 (83a-r, 85-87, 90a, 91a, 9

Topics: Animals; Anticonvulsants; Carbonic Anhydrase Inhibitors; Crystallography, X-Ray; Electroshock; Fructose; Mice; Molecular Conformation; Rats; Seizures; Stereoisomerism; Structure-Activity Relationship; Sulfonic Acids; Topiramate

The anticonvulsant topiramate is effective in laboratory animals against maximal electroshock seizures, amygdala kindling, and spike-wave discharges and has demonstrated efficacy in humans for the treatment of complex partial seizures. However, its mechanism of action has yet to be clearly elucidated. When the chloride-sensitive fluorescent probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE) was used as a tool for estimating the effect of anticonvulsant drugs on GABA receptor function, topiramate was observed to enhance GABA-stimulated chloride (Cl-) flux. At a therapeutic concentration, topiramate (10 microM) enhanced GABA-stimulated (10 microM) Cl- influx into cerebellar granule neurons but did not significantly increase Cl- influx alone. Phenytoin (10 microM) and acetazolamide (300 microM) did not enhance GABA-stimulated Cl- influx. In patch-clamp electrophysiological studies, topiramate also enhanced GABA-evoked whole cell Cl- currents in mouse cerebral cortical neurons in culture. In vivo anticonvulsant studies confirmed that topiramate, like phenytoin, is primarily effective against tonic extension seizures induced by maximal electroshock and is ineffective against clonic seizures induced by the subcutaneously administered chemoconvulsants pentylenetetrazol (PTZ), bicuculline (Bic), and picrotoxin (Pic). In contrast to phenytoin, topiramate, at a dose equivalent to the MES median effective dose (ED50), was found to elevate seizure threshold as estimated by the intravenous PTZ seizure threshold test. Taken together these results support the conclusion that enhancement of GABA-mediated Cl- flux may represent one mechanism that contributes to the anticonvulsant activity of topiramate.

Topics: Animals; Anticonvulsants; Brain; Cells, Cultured; Chloride Channels; Convulsants; Drug Synergism; Fluorescent Dyes; Fructose; gamma-Aminobutyric Acid; Infusions, Intravenous; Mice; Neurons; Patch-Clamp Techniques; Pentylenetetrazole; Seizures; Topiramate

The effects of topiramate, a novel antiepileptic drug, on tonic and absence-like seizures in spontaneously epileptic rats (SER; zi/zi, tm/tm) and on sound-induced seizures in DBA/2 mice were investigated. Topiramate (20 and 40 mg/kg i.p.) inhibited both tonic and absence-like seizures in a dose-dependent manner, whereas phenytoin (20 mg/kg i.p.) and zonisamide (40 mg/kg i.p.) inhibited only the tonic seizures. The inhibitory effects of topiramate on absence-like seizures were antagonized by pretreatment with haloperidol (0.5 mg/kg i.p.), but those on the tonic seizures remained unaffected. Topiramate inhibited sound-induced seizures in DBA/2 mice (ED50 = 8.6 mg/kg p.o.). These findings suggest that topiramate may be effective for treatment of both convulsive and absence seizures of human epilepsy. The inhibitory effect of topiramate on absence-like seizures in SER may be mediated through the central dopaminergic system.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Epilepsy, Absence; Epilepsy, Tonic-Clonic; Female; Fructose; Haloperidol; Male; Mice; Mice, Inbred DBA; Rats; Seizures; Topiramate

Novel sugar sulfamate 1 (McN-4853, topiramate) has been found to exhibit potent anticonvulsant activity analogous to that of phenytoin. In the maximal electroshock seizure test, orally at 2 h in mice, 1 had an ED50 of 39 mg/kg. Orally, 1 had a duration of action in excess of 8 h. Other aspects of the pharmacology of 1, as well as neurochemistry and carbonic anhydrase inhibition, are discussed. The conformational behavior of 1 in solution and in the solid state is discussed. A series of analogues of 1 were synthesized and examined for anticonvulsant properties.

Topics: Animals; Carbonic Anhydrase Inhibitors; Chemical Phenomena; Chemistry; Electroshock; Fructose; Kinetics; Lethal Dose 50; Magnetic Resonance Spectroscopy; Male; Mice; Molecular Conformation; Phenytoin; Seizures; Structure-Activity Relationship; Topiramate